POLYPEPTIDE HAVING MMP2-INHIBITORY EFFECT

Abstract

The present invention provides a substituted polypeptide having the effect of inhibiting MMP2 and represented by formula [I], or a pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A substituted polypeptide represented by formula [I]: ##STR00240## or a pharmaceutically acceptable salt thereof, wherein AA.sup.1 represents: Asp, ?-Asp, ?-(d)-Asp, ?-Glu, or ?-(d)-Glu; AA.sup.2 represents one group selected from the group consisting of: Ala, a group represented by any of formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12], and [IV-13]: ##STR00241## a group represented by formula [IV-27]: ##STR00242## Pro, and a group represented by any of formulas [II-1] and [II-2]: ##STR00243## wherein R.sup.AA2 represents hydroxy or amino; AA.sup.1 and AA.sup.2 may be taken together to form a structure represented by formula [IV-32]: ##STR00244## AA.sup.3 represents one group selected from the group consisting of: Val, Leu, Ile, a group represented by formula [IV-2]: ##STR00245## Phe, Trp, Tyr, Lys, a group represented by any of formulas [IV-3], [IV-4], and [IV-5]: ##STR00246## and a group represented by formula [IV-9]: ##STR00247## AA.sup.4 represents one group selected from the group consisting of: a single bond, Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, Pro, (d)-Pro, (N-Me)Phe, (d)-Phe, (N-Me)Tyr, (d)-Tyr, (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu, (N-Me)Asn, (N-Me)Arg, (d)-Arg, a group represented by any of formulas [IV-7], [IV-9], and [IV-13]: ##STR00248## Lys, and (N-Me)Lys, wherein if AA.sup.4 represents Lys, then the amino in the side chain of the Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy; AA.sup.5 represents one group selected from the group consisting of: a single bond, Ala, a group represented by formula [IV-1]: ##STR00249## a group represented by any of formulas [IV-27], [IV-28], and [IV-29]: ##STR00250## Pro, (d)-Pro, ?-homoPro, homoPro, a group represented by formula [II-1]: ##STR00251## Phe, His, Thr, Arg, (d)-Arg, a group represented by any of formulas [IV-7], [IV-9], and [IV-13]: ##STR00252## Lys, (d)-Lys, ?-Ala, (N-Me)-?-Ala, GABA, Ape, Acp, a group represented by any of formulas [III-6] to [III-13]: ##STR00253## and a group represented by any of formula [IV-25] and [IV-26]: ##STR00254## W.sup.1 represents -L.sup.1- or -L.sup.1-L.sup.1-; wherein L.sup.1 represents a single bond; and L.sup.1 represents one group selected from the group consisting of: a single bond, ?-Ala, GABA, (N-Me)GABA, Ape, Acp, a group represented by any of formulas [III-6] to [III-13] ##STR00255## and a group represented by any of formulas [IV-23] and [IV-24]: ##STR00256## and L.sup.1 represents one group selected from the group consisting of: a single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, a group represented by formula [IV-27]: ##STR00257## Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, a group represented by any of formulas [IV-7], [IV-9], [IV-10], and [IV-13]: ##STR00258## Lys, (N-Me)Lys, (d)-Lys, a group represented by formula [IV-14]: ##STR00259## ?-Ala, ?-Asp, ?-(d)-Asp, and a group represented by any of formulas [III-6] and [III-7]: ##STR00260## wherein if L.sup.1 represents Lys or (d)-Lys, then the amino in the side chain of the Lys or (d)-Lys is optionally substituted with a group represented by formula [VII-1]:
FA.sup.N-AA.sup.N5-AA.sup.N4-AA.sup.N3-AA.sup.N2-AA.sup.N1-[VII-1] wherein FA.sup.N represents C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy; AA.sup.N5 represents: a single bond, Arg, (d)-Arg, Lys, (d)-Lys, ?-Glu, or a group represented by formula [IV-24]: ##STR00261## AA.sup.N4 represents: a single bond, Arg, (d)-Arg, Lys, (d)-Lys, or a group represented by formula [IV-24]: ##STR00262## AA.sup.N3 represents: a single bond, Arg, (d)-Arg, Lys, (d)-Lys, ?-Glu, or a group represented by formula [IV-24]: ##STR00263## AA.sup.N2 represents: a single bond, or (d)-Lys; and AA.sup.N1 represents: a single bond, or (d)-Lys; wherein if L.sup.1 represents by Glu and AA.sup.3 represents Lys, then the compound represented by formula [I] may be taken together with L.sup.3 attached to each of functional groups in the side chains of the two amino acids to form a cyclic structure, as represented by formula [I-?]: ##STR00264## wherein the L.sup.3 represents Gly, ?-Ala, or GABA; L.sup.N1 represents the formula C(?O) or the formula S(?O).sub.2; L.sup.N2 represents: a single bond, C.sub.1-3 alkanediyl, C.sub.2-3 alkenediyl, ethynediyl, the formula O, the formula C(?O), the formula C(?O)NH, or triazolediyl; L.sup.2 represents a single bond; ring A represents an aromatic ring or a heteroaromatic ring; R.sup.A1 and R.sup.A2 each independently represent: a hydrogen atom, a halogen atom, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; ring B represents: aryl or heteroaryl; R.sup.B1, R.sup.B2, and R.sup.B3 each independently represent: a hydrogen atom, carbamoyl, cyano, a halogen atom, C.sub.1-6 alkyl optionally substituted with one hydroxy, halo C.sub.1-6 alkyl, C.sub.1-6 alkoxy optionally substituted with one hydroxy, halo C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarbonylamino, mono C.sub.1-6 alkylaminocarbonyl, di C.sub.1-6 alkylaminocarbonyl, wherein the alkyl in each of the mono C.sub.1-6 alkylaminocarbonyl and the di C.sub.1-6 alkylaminocarbonyl is optionally substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino, C.sub.1-6 alkylsulfonyl, or aryl; W.sup.C is a single bond or a linker consisting of one to three amino acids, wherein the one to three amino acids forming the linker are same or different and each selected from the group consisting of: Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, and Ape, wherein if Lys or (d)-Lys is included in the group represented by W.sup.C, then the amino in the side chain of the Lys or (d)-Lys is optionally substituted with: C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, Lys, wherein the amino in the side chain of the Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, or (d)-Lys, wherein the amino in the side chain of the (d)-Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy; and R.sup.C is: the formula OH, the formula NH.sub.2, C.sub.1-6 alkylamino, wherein the C.sub.1-6 alkyl of the C.sub.1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, C.sub.1-6 alkoxy, and four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom, or four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom; wherein the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom is optionally substituted with one group selected from the group consisting of hydroxy, amino, and C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one carbamoyl; and two carbon atoms in the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom are optionally crosslinked with C.sub.1-4 alkanediyl.

2. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein W.sup.C is: a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, ?-Ala-(d)-Lys, ?-Ala-(d)-Lys-(d)-Arg, ?-Ala-(d)-Arg-(d)-Lys, or ?-Ala-(d)-Arg-(d)-Arg, wherein if Lys is contained in the group represented by W.sup.C, then the amino in the side chain of the Lys is optionally substituted with: C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, or (d)-Lys, wherein the amino in the side chain of the (d)-Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy.

3. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a benzene ring, a thiophene ring, or a pyridine ring; R.sup.A1 and R.sup.A2 are each independently: a hydrogen atom, or a halogen atom; ring B is: phenyl, oxazolyl, thiadiazolyl, pyridyl, or benzofuranyl; R.sup.B1, R.sup.B2, and R.sup.B3 are each independently: a hydrogen atom, carbamoyl, cyano, a halogen atom, C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one hydroxy, halo C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkoxy is optionally substituted with one hydroxy, halo C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbonyl, mono C.sub.1-6 alkylaminocarbonyl, di C.sub.1-6 alkylaminocarbonyl, wherein the alkyl in each of the mono C.sub.1-6 alkylaminocarbonyl and the di C.sub.1-6 alkylaminocarbonyl is optionally substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino, or C.sub.1-6 alkylsulfonyl; and R.sup.C is: the formula OH, the formula NH.sub.2, C.sub.1-6 alkylamino, wherein the C.sub.1-6 alkyl of the C.sub.1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, C.sub.1-6 alkoxy, and morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, wherein the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl is optionally substituted with one group selected from the group consisting of hydroxy, amino, and C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one carbamoyl, wherein two carbon atoms in the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl are optionally crosslinked with C.sub.1-4 alkanediyl.

4. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein in the substituted polypeptide represented by formula [I], ring A is a benzene ring; ring B is phenyl; L.sup.1 is one group selected from the group consisting of: a single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, a group represented by formula [IV-27]: ##STR00265## Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, a group represented by any of formulas [IV-7], [IV-9], [IV-10], and [IV-13]: ##STR00266## Lys, (N-Me)Lys, (d)-Lys, a group represented by formula [IV-14]: ##STR00267## ?-Ala, ?-Asp, ?-(d)-Asp, and a group represented by any of formulas [III-6] and [III-7]: ##STR00268## W.sup.C is: a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, ?-Ala-(d)-Lys, ?-Ala-(d)-Lys-(d)-Arg, ?-Ala-(d)-Arg-(d)-Lys, or ?-Ala-(d)-Arg-(d)-Arg.

5. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein in the substituted polypeptide represented by formula [I], AA.sup.2 is one group selected from the group consisting of: a group represented by formula [II-1]: ##STR00269## and a group represented by any of formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]: ##STR00270## wherein R.sup.AA2 is amino; AA.sup.3 is Val, Leu, Ile, Phe, or Trp; AA.sup.4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA.sup.5 is ?-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or ?-homoPro; W.sup.C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; and R.sup.C is the formula OH or the formula NH.sub.2.

6. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein in the substituted polypeptide represented by formula [I], W.sup.1 is -L.sup.1-L.sup.1-; L.sup.2 is a single bond; AA.sup.1 is Asp; L.sup.1 is one group selected from the group consisting of ?-Ala, GABA, Ape, Acp, and a group represented by any of formulas [IV-23] and [IV-24]: ##STR00271## L.sup.1 is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu; L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2; L.sup.N2 is the formula O or the formula C(?O)NH; R.sup.A1 and R.sup.A2 are each a hydrogen atom; and R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy.

7. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein in the substituted polypeptide represented by formula [I], W.sup.1 is -L.sup.1-, wherein L.sup.1 is a single bond; L.sup.2 is a single bond; AA.sup.1 is ?-Asp, ?-(d)-Asp, ?-Glu, or ?-(d)-Glu; AA.sup.2 is one group selected from the group consisting of: a group represented by formula [II-1]: ##STR00272## and a group represented by any of formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]: ##STR00273## wherein R.sup.AA2 is amino; AA.sup.3 is Val, Leu, Ile, Phe, or Trp; AA.sup.4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA.sup.5 is ?-Ala, GABA, Ape, Acp, or ?-homoPro; L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2; L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH; R.sup.A1 and R.sup.A2 are each a hydrogen atom; and R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy.

8. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted polypeptide represented by formula [I] is a substituted polypeptide represented by formula [I]: ##STR00274## wherein AA.sup.1 is ?-Asp, ?-Glu, or ?-(d)-Glu; AA.sup.2 is a group represented by formula [II-1] or formula [II-2]: ##STR00275## wherein R.sup.AA2 is hydroxy or amino; AA.sup.3 is Val, Leu, Ile, Phe, or Trp; AA.sup.4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu; AA.sup.5 is a single bond, Pro, (d)-Pro, ?-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, Ape, or Acp; L.sup.1 is a single bond; L.sup.2 is a single bond; L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2; L.sup.N2 is a single bond, C.sub.1-3 alkanediyl, the formula O, or the formula C(?O)NH; R.sup.A is a hydrogen atom, a halogen atom, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; R.sup.B is a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; L.sup.C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys; and R.sup.C is the formula OH or the formula NH.sub.2.

9. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein in the substituted polypeptide represented by formula [I], AA.sup.1 is Asp, ?-(d)-Asp, or ?-(d)-Glu; AA.sup.2 is one group selected from the group consisting of: a group represented by formula [II-1]: ##STR00276## and a group represented by any of formulas [IV-7] and [IV-9]: ##STR00277## wherein R.sup.AA2 is amino; AA.sup.3 is Val, Leu, or Ile; AA.sup.4 is (N-Me)Ile or (N-Me)Glu; AA.sup.5 is Ape or ?-homoPro; W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, wherein L.sup.1 is a single bond, L.sup.1 is GABA or Ape, and L.sup.1 is Asn, (d)-Ser, (d)-Thr, or Glu; L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2; L.sup.N2 is the formula O or the formula C(?O)NH; R.sup.A1 and R.sup.A2 are each a hydrogen atom; R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy; W.sup.C is a single bond or (d)-Lys; and R.sup.C is the formula NH.sub.2.

10. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted polypeptide is selected from compounds shown in the following: ##STR00278## ##STR00279## ##STR00280##

11. A pharmaceutical comprising the substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

12. An MMP2 inhibitor comprising the substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

13. A drug for preventing or treating cancerous disease or organ fibrosis, or a symptom associated with cancerous disease or organ fibrosis, comprising the substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

14. A method for inhibiting MMP2 in a subject in need thereof, comprising administering to the subject an effective amount of the substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1.

15. A method for preventing or treating cancerous disease or organ fibrosis, or a symptom associated with cancerous disease or organ fibrosis in a subject in need thereof, comprising administering to the subject an effective amount of the substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1.

Description

DESCRIPTION OF EMBODIMENTS

[0343] The present invention provides a substituted polypeptide represented by formula [I], or a pharmaceutically acceptable salt thereof, having an effect to inhibit MMP2.

[0344] The compounds of the present invention will be described in more detail in the following; however, the present invention is not limited to exemplified ones.

[0345] Herein, amino acid is, in a broad sense, an organic compound having two functional groups: amino and carboxy. In a narrow sense (in particular, in the field of biochemistry), amino acid refers to ?-amino acid (the ?-amino acid is an amino acid in which amino is bonding to the carbon atom to which carboxy is bonding (a carbon)) that serves as a constituent unit of biogenic proteins.

[0346] Examples of amino acids in the present specification include natural proteogenic L-amino acids; natural nonproteogenic amino acids; and nonnatural amino acids. Examples of nonnatural amino acids include the D-forms of natural proteogenic L-amino acids; chemically modified amino acids such as amino acid variants and derivatives; and chemically synthesized compounds having properties that are characteristic to amino acids and known in the art.

[0347] Herein, when amino acid is shown as its name without abbreviating, for example, as a three-letter code or a one-letter code, the name indicates the amino acid in the L-form, D-form, or both.

[0348] Herein, when amino acid is shown as an abbreviation, for example, in a three-letter code or a one-letter code, the abbreviation indicates the amino acid in the L-form. L or l is occasionally added immediately before amino acid to explicitly show that the amino acid is in the L-form.

[0349] Herein, D or d added immediately before amino acid indicates that the amino acid is in the D-form.

[0350] Herein, natural proteogenic L-amino acid is a naturally occurring amino acid in L-form that constitutes proteins, and examples thereof include Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, and Arg.

[0351] Herein, D-form of natural proteogenic L-amino acid refers to an enantiomer of the natural proteogenic L-amino acid. Natural proteogenic L-amino acids except glycine each have at least one asymmetric carbon, thus being optically active. The structures of these amino acids are classified into L-forms and D-forms on the basis of the structures of the L-form and D-form of glyceraldehyde.

[0352] Amino acids other than natural proteogenic L-amino acids can also have D-forms.

[0353] Herein, natural nonproteogenic amino acid is a naturally occurring amino acid that does not constitute proteins, and examples thereof include L-norleucine (hereinafter, also designated as Nle; hereinafter, code following in parentheses shows an abbreviation), ?-alanine (?-Ala), and L-ornithine (Orn).

[0354] If a natural nonproteogenic amino acid has an asymmetric carbon, there exist an L-form and a D-form for the amino acid. There can be L-forms and D-forms also for amino acids other than natural nonproteogenic amino acids.

[0355] Herein, nonnatural amino acid refers to an amino acid that does not constitute proteins and is primarily artificially produced, being an amino acid not included in the above-described natural proteogenic L-amino acid and natural nonproteogenic amino acid. Examples of nonnatural amino acids include the D-forms of natural proteogenic L-amino acids (such as D-Cys, D-Ser); ?-methylamino acids (such as 2-aminoisobutyric acid (Aib)); amino acids with excessive methylene in the side chain (homo amino acids such as L-?-homoproline (?-Hep or ?-homoPro), L-homoserine (Hes or homoSer), L-homocysteine (Hec or homoCys), L-homoproline (homoPro), L-homoglutamic acid (homoGlu)); amino acids in which the side chain of an amino acid with a carboxylic acid functional group is substituted with a sulfonic acid group (such as L-cysteic acid); chemically modified amino acids such as amino acid variants and derivatives (such as hydroxyproline, L-2,3-diaminopropionic acid (Dap), L-2,4-diaminobutyric acid (Dab), N-methylglycine); and chemically synthesized compounds having properties that are characteristic to amino acids and known in the art (such as 4-aminobenzoic acid).

[0356] If a nonnatural amino acid has an asymmetric carbon, there exist an L-form and a D-form for the amino acid.

[0357] Specific examples of nonnatural amino acid in the present specification include the followings: [0358] (d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys [0359] ?-homoPro [0360] ?-Ala, GABA, Ape, Acp [0361] (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, (N-Me)Glu [0362] a group represented by formula [II-1] or formula [II-2]:

##STR00043##

wherein R.sup.AA2 is hydroxy or amino; and [0363] amino acids listed later in Table 1 and Table 2

[0364] The nitrogen atom involved in peptide bonding in any amino acid in the present specification may be alkylated. In this case, the amino acid is also called N-alkyl amino acid. Examples of the alkyl include methyl and ethyl.

[0365] Herein, the expression ?-Asp means aspartic acid involved in amide bonding of the main chain via carboxy in the side chain, as illustrated in the structure represented by formula [III-1]. Likewise, the expressions ?-(d)-Asp, ?-Glu, and ?-(d)-Glu mean the structures represented by formula [III-2] to formula [III-4].

##STR00044##

[0366] The expression (N-Me)Glu(OtBu) means the N-methyl form of the amino acid (Glu(OtBu)), as illustrated in the structure represented by formula [III-5].

##STR00045##

[0367] The expression (2S,4S)-(4-amino)Pro on the structure corresponding to AA.sup.2 means the structure represented by formula [II-3]. Likewise, the expressions (2S,4R)-(4-amino)Pro, (2S,4S)-(4-hydroxy)Pro, and (2S,4R)-(4-hydroxy)Pro mean the structures represented by formula [II-4] to formula [II-6]. Further, the expression (S)-piperazine means the structure represented by formula [II-2].

##STR00046##

[0368] Herein, n indicates normal, i indicates iso, s indicates secondary, t and tert each indicate tertiary, c indicates cyclo, o indicates ortho, m indicates meta, and p indicates para.

[0369] Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0370] C.sub.1-6 alkyl refers to linear or branched alkyl having one to six carbon atoms. Examples of C.sub.1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0371] Halo C.sub.1-6 alkyl refers to linear or branched alkyl having one to six carbon atoms and substituted with a halogen atom. A preferred number of halogen atoms as substituents is one to five, and a preferred halogen atom is a fluorine atom. Examples of halo C.sub.1-6 alkyl include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 1-fluoropentyl, 1-fluorohexyl, and 2,2,2-trifluoro-1-methylethyl.

[0372] Aryl refers to a monocyclic aromatic hydrocarbon group or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of aryl include phenyl, naphthyl, and anthryl.

[0373] Aromatic ring refers to a monocyclic aromatic hydrocarbon group or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of aromatic ring include a benzene ring, a naphthalene ring, and an anthracene ring.

[0374] Partially saturated aryl is also included in the scope of aryl. The same is applied to aromatic rings. Partially saturated aryl and the corresponding aromatic ring, partially saturated aromatic ring, refer to a group wherein a monocyclic aromatic hydrocarbon group or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms is partially saturated, and a ring having such a structure. Examples thereof include dihydroindenyl and a dihydroindene ring.

[0375] Heteroaryl refers to a five- to seven-membered monocyclic aromatic heterocyclic group consisting of one to six carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, or a fused polycyclic aromatic heterocyclic group composed of 9 to 14 atoms, specifically, consisting of 1 to 13 carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of heteroaryl include imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, and quinoxalyl.

[0376] Heteroaromatic ring refers to a five- to seven-membered monocyclic aromatic heterocycle consisting of one to six carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, or a fused polycyclic aromatic heterocycle composed of 9 to 14 atoms, specifically, consisting of 1 to 13 carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of heteroaromatic ring include an imidazole ring, a pyrazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, a thiadiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a pyrrole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, an indole ring, a benzopyrazole ring, a benzotriazole ring, a benzofuran ring, a benzothiophene ring, a quinoline ring, an isoquinoline ring, and a quinoxaline ring.

[0377] Partially saturated heteroaryl is also included in the scope of heteroaryl. The same is applied to heteroaromatic rings. Partially saturated heteroaryl, and the corresponding heteroaromatic ring, partially saturated heteroaromatic ring, refer to a five- to seven-membered partially saturated monocyclic heterocyclic group consisting of one to six carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, or a partially saturated fused polycyclic heterocyclic group composed of 9 to 14 atoms, specifically, consisting of 1 to 13 carbon atoms and one or more atoms that are same or different and selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and a ring having such a structure. Examples thereof include oxazolidinyl, thiazolinyl, dihydropyridinyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridinyl, dihydrofuropyridinyl, tetrahydroquinolyl, dihydrobenzodioxinyl, tetrahydrotriazoloazepinyl, an oxazolidine ring, a thiazoline ring, a dihydropyridine ring, a dihydrobenzofuran ring, a chroman ring, a dihydropyranopyridine ring, a dihydrofuropyridine ring, a tetrahydroquinoline ring, a tetrahydroquinoline ring, a dihydrobenzodioxine ring, and a tetrahydrotriazoloazepine ring.

[0378] Four- to seven-membered saturated heterocyclyl containing nitrogen atom refers to a four- to seven-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and three to six carbon atoms, and may further contain, in addition to the nitrogen atom, one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of four- to seven-membered saturated heterocyclyl containing nitrogen atom include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0379] Four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom refers to a four- to seven-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and three to six carbon atoms, and may further contain, in addition to the nitrogen atom, one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0380] Examples of four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom, and optionally crosslinked with C.sub.1-4 alkanediyl include 8-oxa-3-azabicyclo[3.2.1]octan-3-yl (the group represented by formula [VI-16]) and 3,8-diazabicyclo[3.2.1]octan-3-yl (the group represented by formula [VI-18]):

##STR00047##

[0381] C.sub.1-6 alkoxy refers to linear or branched alkoxy having one to six carbon atoms. Examples C.sub.1-6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0382] Halo C.sub.1-6 alkoxy refers to linear or branched alkoxy having one to six carbon atoms and substituted with a halogen atom. A preferred number of halogen atoms as substituents is one to five, and a preferred halogen atom is a fluorine atom. Examples of halo C.sub.1-6 alkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropan-2-yloxy, 1,1-difluoro-2-methylpropan-2-yloxy, and 4,4,4-trifluorobutoxy.

[0383] C.sub.1-6 alkylcarbonyl refers to a group in which C.sub.1-6 alkyl described above and carbonyl are bonding together. Examples of C.sub.1-6 alkylcarbonyl include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

[0384] C.sub.1-6 alkylcarbonylamino refers to a group in which C.sub.1-6 alkylcarbonyl described above and an amino group are bonding together. Examples of C.sub.1-6 alkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino, and n-hexylcarbonylamino.

[0385] C.sub.1-6 alkylamino refers to amino having one or two C.sub.1-6 alkyl described above, as substituents, that are same or different. Examples of C.sub.1-6 alkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0386] Mono C.sub.1-6 alkylamino refers to amino having one C.sub.1-6 alkyl described above as a substituent. Examples of mono C.sub.1-6 alkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, and n-hexylamino.

[0387] Di C.sub.1-6 alkylamino refers to amino having two C.sub.1-6 alkyl described above, as substituents, that are same or different. Examples of di C.sub.1-6 alkylamino include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0388] Mono C.sub.1-6 alkylaminocarbonyl refers to a group in which mono C.sub.1-6 alkylamino described above and carbonyl are bonding together. Examples of mono C.sub.1-6 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, n-pentylaminocarbonyl, and n-hexylaminocarbonyl.

[0389] Di C.sub.1-6 alkylaminocarbonyl refers to a group in which di C.sub.1-6 alkylamino described above and carbonyl are bonding together. Examples of di C.sub.1-6 alkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, and methyl(n-propyl)aminocarbonyl.

[0390] C.sub.1-6 alkylcarbonyl refers to a group in which C.sub.1-6 alkyl described above and carbonyl are bonding together. Examples of C.sub.1-6 alkylcarbonyl include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

[0391] C.sub.2-16 alkylcarbonyl refers to a group in which linear or branched alkyl having 2 to 16 carbon atoms and carbonyl are bonding together. Examples of C.sub.2-16 alkylcarbonyl include ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-decylcarbonyl(undecanoyl), n-dodecylcarbonyl(tridecanoyl), and n-tetradecylcarbonyl(pentadecanoyl).

[0392] C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy refers to a group in which a terminus of C.sub.2-16 alkyl in C.sub.2-16 alkylcarbonyl described above is substituted with carboxy. Examples of C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy include 11-carboxyundecanoyl, 13-carboxytridecanoyl, and 15-carboxypentadecanoyl.

[0393] C.sub.1-6 alkylsulfonyl refers to a group in which C.sub.1-6 alkyl described above and sulfonyl are bonding together. Examples of C.sub.1-6 alkylsulfonyl include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, and n-hexylsulfonyl.

[0394] C.sub.1-3 alkanediyl refers to a divalent hydrocarbon formed by removing one hydrogen atom from alkyl having one to three carbon atoms. Examples of C.sub.1-3 alkanediyl include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, and propane-2,2-diyl.

[0395] C.sub.1-4 alkanediyl refers to a divalent hydrocarbon formed by removing one hydrogen atom from alkyl having one to four carbon atoms. Examples of C.sub.1-4 alkanediyl include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, and butane-1,4-diyl.

[0396] C.sub.2-3 alkenediyl refers to a divalent unsaturated hydrocarbon formed by removing one hydrogen atom from alkenyl having two or three carbon atoms. Examples of C.sub.2-3 alkenediyl include ethene-1,1-diyl, ethene-1,2-diyl, prop-1-ene-1,1-diyl, prop-2-ene-1,1-diyl, prop-1-ene-1,3-diyl, prop-2-ene-1,3-diyl, and prop-1-ene-2,2-diyl.

[0397] Triazolediyl refers to divalent triazole formed by removing two hydrogen atoms from a triazole ring. Examples of triazolediyl include structures represented by formulas [VIII-1] to [VIII-5]:

##STR00048##

[0398] Abbreviations used herein indicate structures listed in Table 1 to Table 4.

TABLE-US-00001 TABLE 1-1 # Formula number Abbreviation Structure 1 [III-6] ?-Dap [00049] 2 [III-7] ?-(d)-Dap [00050] 3 [III-8] ?-Dab [00051] 4 [III-9] ?-(d)-Dab [00052] 5 [III-10] ?-Orn [00053] 6 [III-11] ?-(d)-Orn [00054] 7 [III-12] ?-Lys [00055] 8 [III-13] ?-(d)-Lys [00056]

TABLE-US-00002 TABLE 2-1 # Formula number Abbreviation Structure 1 [IV-1] Aib [00057] 2 [IV-2] Nle [00058] 3 [IV-3] Ala(cPropyl) [00059] 4 [IV-4] Ala(2-Pyr) [00060] 5 [IV-5] Ala(4-Thz) [00061] 6 [IV-6] homoSer [00062] 7 [IV-7] Dap [00063] 8 [IV-8] Dap(Me) [00064] 9 [IV-9] Dab [00065] 10 [IV-10] (d)-Dab [00066] 11 [IV-11] Dab(Me) [00067] 12 [IV-12] Dab(Me).sub.2 [00068] 13 [IV-13] Orn [00069] 14 [IV-14] Lys(Ac) [00070] 15 [IV-15] Cit [00071] 16 [IV-16] (d)-Cit [00072] 17 [IV-17] ?-Ala [00073] 18 [IV-18] (NMe)-?-Ala [00074] 19 [IV-19] GABA [00075] 20 [IV-20] (NMe)GABA [00076] 21 [IV-21] Ape [00077] 22 [IV-22] Acp [00078] 23 [IV-23] NH(CH.sub.2).sub.2OCH.sub.2CO [00079] 24 [IV-24] Adox [00080] 25 [IV-25] cis-NH(3)cPen [00081] 26 [IV-26] (4)Abz [00082] 27 [IV-27] Aze(2) [00083] 28 [IV-28] (d)-Aze(2) [00084] 29 [IV-29] Aze(3) [00085] 30 [IV-30] ?-homoPro [00086] 31 [IV-31] homoPro [00087] 32 [IV-32] aspartimide- Dab [00088] 33 [IV-33] homoGlu [00089]

TABLE-US-00003 TABLE 3-1 Formula # number Abbreviation Structure 1 [V-1] Lys(CO(CH.sub.2).sub.10CO.sub.2H) [00090] 2 [V-2] Lys(CO(CH.sub.2).sub.12CO.sub.2H) [00091] 3 [V-3] Lys(CO(CH.sub.2).sub.14CO.sub.2H) [00092]

TABLE-US-00004 TABLE 4-1 # Formula number Abbreviation Structure 1 [VI-1] NHMe [00093] 2 [VI-2] NHEt [00094] 3 [VI-3] NH(CH.sub.2).sub.2OH [00095] 4 [VI-4] NH(CH.sub.2).sub.2NH.sub.2 [00096] 5 [VI-5] NH(CH.sub.2).sub.3NH.sub.2 [00097] 6 [VI-6] NH(CH.sub.2).sub.4NH.sub.2 [00098] 7 [VI-7] NH(CH.sub.2).sub.5NH.sub.2 [00099] 8 [VI-8] the formula [VI-8] [00100] 9 [VI-9] azetidin-1-yl [00101] 10 [VI-10] pyrrolidin-1-yl [00102] 11 [VI-11] piperidin-1-yl [00103] 12 [VI-12] (3-OH)azetidin-1-yl [00104] 13 [VI-13] (4-OH)piperidin-1-yl [00105] 14 [VI-14] the formula [VI-14] [00106] 15 [VI-15] morpholin-4-yl [00107] 16 [VI-16] the formula [VI-16] [00108] 17 [VI-17] (4-Me)piperazin-1-yl [00109] 18 [VI-18] the formula [VI-18] [00110]

[0399] Preferable embodiments of the substituted polypeptide represented by formula [I], or pharmaceutically acceptable salt thereof according to the present invention are as follows.

[0400] Preferable AA.sup.1 is Asp, ?-Asp, ?-(d)-Asp, ?-Glu, or ?-(d)-Glu, [0401] one more preferable AA.sup.1 is ?-Asp, ?-Glu, or ?-(d)-Glu, [0402] wherein further preferable AA.sup.1 is ?-(d)-Glu, [0403] another more preferable AA.sup.1 is ?-(d)-Asp or ?-(d)-Glu, [0404] wherein further preferable AA.sup.1 is ?-(d)-Asp, and [0405] another more preferable AA.sup.1 is Asp.

[0406] Preferable AA.sup.2 is a group represented by formula [II-1] or formula [II-2]:

##STR00111## [0407] a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]:

##STR00112## [0408] Ala, [0409] a group represented by formula [IV-27]:

##STR00113## [0410] or [0411] Pro, [0412] wherein preferable R.sup.AA2 is hydroxy or amino, [0413] more preferable AA.sup.2 is a group represented by formula [II-1]:

##STR00114## [0414] or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]:

##STR00115## [0415] wherein preferable R.sup.AA2 is amino, [0416] further preferable AA.sup.2 is [0417] a group represented by formula [IV-7] or [IV-9]:

##STR00116## [0418] or a group represented by formula [II-1]:

##STR00117## [0419] wherein preferable R.sup.AA2 is amino, [0420] one particularly preferable AA.sup.2 is [0421] a group represented by formula [II-1]:

##STR00118## [0422] wherein preferable R.sup.AA2 is amino, and [0423] another particularly preferable AA.sup.2 is [0424] a group represented by formula [IV-7] or [IV-9]:

##STR00119## [0425] Preferable AA.sup.3 is Val, Leu, Ile, a group represented by formula [IV-2]:

##STR00120## [0426] Phe, a group represented by formula [IV-3], [IV-4], or [IV-5]:

##STR00121## [0427] or Trp, [0428] more preferable AA.sup.3 is Val, Leu, Ile, Phe, or Trp, [0429] further preferable AA.sup.3 is Val, Leu, or Ile, [0430] one particularly preferable AA.sup.3 is Val, [0431] another particularly preferable AA.sup.3 is Leu, and [0432] another particularly preferable AA.sup.3 is Ile.

[0433] Preferable AA.sup.4 is a single bond, Pro, Gly, homoSer, Met, Glu, (N-Me)Ala, [0434] (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Met, [0435] (N-Me)Asp, (N-Me)Glu, (d)-Pro, (d)-Ala, (d)-Phe, (d)-Tyr, (d)-Ser, (d)-Thr, or [0436] (d)-(N-Me)Glu, [0437] more preferable AA.sup.4 is (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, [0438] (N-Me)Tyr, (N-Me)Ser, (N-Me)Met, (N-Me)Asp, (N-Me)Glu, (d)-Pro, (d)-Ala, (d)-Phe, [0439] (d)-Tyr, (d)-Ser, (d)-Thr, or (d)-(N-Me)Glu, [0440] one further preferable AA.sup.4 is (N-Me)Glu or (N-Me)Asp, [0441] wherein particularly preferable AA.sup.4 is (N-Me)Glu, and [0442] another further preferable AA.sup.4 is (N-Me)Ile, (N-Me)Val, or (N-Me)Leu, [0443] wherein particularly preferable AA.sup.4 is (N-Me)Ile.

[0444] Preferable AA.sup.5 is ?-Ala, GABA, Ape, Acp, Pro, (d)-Pro, -homoPro, a single bond, Arg, (d)-Arg, [0445] a group represented by [IV-7], [IV-9], or [IV-13]:

##STR00122## [0446] Lys, (d)-Lys, [0447] Ala, a group represented by formula [IV-1]:

##STR00123## [0448] a group represented by formula [IV-27], [IV-28], or [IV-29]:

##STR00124## [0449] Phe, His, Thr, or [0450] a group represented by any of formulas [III-6] to [III-13]:

##STR00125## [0451] more preferable AA.sup.5 is ?-Ala, GABA, Ape, Acp, Pro, (d)-Pro, ?-homoPro, a single bond, [0452] Arg, (d)-Arg, [0453] a group represented by formula [IV-7], [IV-9], or [IV-13]:

##STR00126## [0454] Lys, or (d)-Lys, [0455] further preferable AA.sup.5 is ?-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or ?-homoPro, and [0456] particularly preferable AA.sup.5 is ?-Ala, GABA, Ape, Acp, or ?-homoPro.

[0457] Preferable W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, [0458] wherein L.sup.1 is a single bond, [0459] L.sup.1 is selected from the group consisting of ?-Ala, GABA, Ape, Acp, [0460] a group represented by any of formulas [III-6] to [III-13]:

##STR00127## [0461] and a group represented by any of formulas [IV-23] and [IV-24]:

##STR00128## [0462] and L.sup.1 is a single bond, Asn, (d)-Ser, (d)-Thr, Lys, Arg, or Glu, [0463] one more preferable W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, [0464] wherein L.sup.1 is a single bond, [0465] L.sup.1 is ?-Ala, GABA, Ape, Acp, or [0466] a group represented by any of formulas [III-6] to [III-13]:

##STR00129## [0467] and L.sup.1 is Asn, (d)-Ser, (d)-Thr, or Glu, [0468] wherein further preferable W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, [0469] wherein L.sup.1 is a single bond, [0470] L.sup.1 is ?-Ala, GABA, Ape, or Acp, and [0471] L.sup.1 is Asn, (d)-Ser, (d)-Thr, or Glu, [0472] wherein particularly preferable W.sup.1 is -L.sup.1-, [0473] wherein L.sup.1 is a single bond, and [0474] another more preferable W.sup.1 is -L.sup.1-L.sup.1-, [0475] wherein L.sup.1 is a group represented by formula [IV-23] or [IV-24]:

##STR00130## [0476] and L.sup.1 is a single bond.

[0477] Preferable L.sup.2 is a single bond.

[0478] Preferable L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0479] one more preferable L.sup.N1 is the formula C(?O), and [0480] another more preferable L.sup.N1 is the formula S(?O).sub.2.

[0481] Preferable L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH, [0482] more preferable L.sup.N2 is the formula O or the formula C(?O)NH, [0483] one further preferable L.sup.N2 is the formula O, and [0484] another further preferable L.sup.N2 is the formula C(?O)NH.

[0485] Preferable ring A is a benzene ring or a pyridine ring, [0486] more preferable ring A is a benzene ring, [0487] preferable R.sup.A1 and R.sup.A2 are each independently a hydrogen atom or a halogen atom, and [0488] more preferable R.sup.A1 and R.sup.A2 are each a hydrogen atom.

[0489] Preferable ring B is phenyl or pyridyl, [0490] more preferable ring B is phenyl, [0491] preferable R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy, and [0492] more preferable R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy.

[0493] Preferable W.sup.C is a single bond or a linker consisting of one to three amino acids, [0494] wherein [0495] the one to three amino acids forming the linker are not limited, but preferably same or [0496] different and each selected from the group consisting of: Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, [0497] ?-Ala, GABA, and Ape, wherein [0498] if Lys or (d)-Lys is included in the group represented by W.sup.C, [0499] then the amino in the side chain of the Lys or (d)-Lys is optionally substituted with: [0500] C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, [0501] Lys, wherein the amino in the side chain of the Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, or [0502] (d)-Lys, wherein the amino in the side chain of the (d)-Lys is optionally substituted with C.sub.2-16 alkylcarbonyl terminally-substituted with carboxy, [0503] more preferable W.sup.C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, [0504] further preferable W.sup.C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys, [0505] one particularly preferable W.sup.C is a single bond, and [0506] another particularly preferable W.sup.C is (d)-Lys.

[0507] Preferable R.sup.C is: [0508] the formula OH, the formula NH.sub.2, [0509] C.sub.1-6 alkylamino, wherein the C.sub.1-6 alkyl of the C.sub.1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, and a four- to seven-membered saturated heterocyclyl containing one nitrogen atom, or [0510] four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom, wherein the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom is optionally substituted with one group selected from the group consisting of hydroxy, and C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one carbamoyl; and two carbon atoms in the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom are optionally crosslinked with C.sub.1-4 alkanediyl,
more preferable R.sup.C is the formula OH or the formula NH.sub.2, and
further preferable R.sup.C is the formula NH.sub.2.

[0511] Another preferable embodiment of the compounds of the present invention is a substituted polypeptide represented by formula [I], or a pharmaceutically acceptable salt thereof, wherein [0512] AA.sup.1 is ?-Asp, ?-Glu, or ?-(d)-Glu, [0513] AA.sup.2 is a group represented by formula [II-1] or formula [II-2]:

##STR00131## [0514] wherein R.sup.AA2 is hydroxy or amino, [0515] AA.sup.3 is Val, Leu, Ile, Phe, or Trp, [0516] AA.sup.4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, [0517] (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu, [0518] AA.sup.5 is a single bond, Pro, (d)-Pro, ?-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, [0519] Ape, or Acp, [0520] W.sup.1 is L.sup.1, and L.sup.1 is a single bond, [0521] L.sup.2 is a single bond, [0522] L.sup.N1 is the formula S(?O).sub.2, [0523] L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH, [0524] ring A is a benzene ring, [0525] R.sup.A1 and R.sup.A2 are each a hydrogen atom, [0526] ring B is phenyl, [0527] R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, or [0528] C.sub.1-6 alkoxy, [0529] W.sup.C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, and [0530] R.sup.C is the formula NH.sub.2.

[0531] Another preferable embodiment of the present invention is a substituted polypeptide represented by formula [I], or a pharmaceutically acceptable salt thereof, wherein [0532] AA.sup.1 is ?-Asp, ?-Glu, or ?-(d)-Glu, [0533] wherein further preferable AA.sup.1 is ?-(d)-Glu, [0534] AA.sup.2 is a group represented by formula [II-1]:

##STR00132## [0535] wherein R.sup.AA2 is amino, [0536] AA.sup.3 is Val, Leu, or Ile, [0537] wherein one further preferable AA.sup.3 is Val, [0538] another further preferable AA.sup.3 is Leu, and [0539] another further preferable AA.sup.3 is Ile, [0540] AA.sup.4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu, [0541] wherein one further preferable AA.sup.4 is (N-Me)Val, (N-Me)Leu, or (N-Me)Ile, [0542] wherein particularly preferable AA.sup.4 is (N-Me)Ile, [0543] another further preferable AA.sup.4 is (N-Me)Asp or (N-Me)Glu, [0544] wherein particularly preferable AA.sup.4 is (N-Me)Glu, [0545] AA.sup.5 is Pro, (d)-Pro, ?-homoPro, ?-Ala, GABA, Ape, or Acp, [0546] wherein one further preferable AA.sup.5 is Pro, (d)-Pro, or ?-homoPro, [0547] wherein particularly preferable AA.sup.5 is ?-homoPro, [0548] another further preferable AA.sup.5 is ?-Ala, GABA, Ape, or Acp, [0549] wherein particularly preferable AA.sup.5 is ?-Ala, GABA, or Ape, [0550] W.sup.1 is L.sup.1, [0551] L.sup.1 is a single bond, [0552] L.sup.2 is a single bond, [0553] L.sup.N1 is the formula S(?O).sub.2, [0554] L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH, [0555] wherein one further preferable L.sup.N1 is the formula C(?O), and [0556] another further preferable L.sup.N1 is the formula S(?O).sub.2, [0557] ring A is a benzene ring, [0558] R.sup.A1 and R.sup.A2 are each a hydrogen atom, [0559] ring B is phenyl, [0560] R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, or [0561] C.sub.1-6 alkoxy, [0562] W.sup.C is a single bond or (d)-Lys, [0563] wherein one further preferable W.sup.C is a single bond, and [0564] another further preferable W.sup.C is (d)-Lys, and [0565] R.sup.C is the formula NH.sub.2.

[0566] Another preferable embodiment of the compounds of the present invention is the substituted polypeptide or a pharmaceutically acceptable salt thereof, wherein [0567] W.sup.1 is -L.sup.1-L.sup.1-, [0568] L.sup.2 is a single bond, and [0569] the polypeptide is represented by formula [I-A]:

##STR00133## [0570] wherein preferable embodiments of AA.sup.2, AA.sup.3, AA.sup.4, AA.sup.5, L.sup.1, L.sup.1, L.sup.N1, L.sup.N2, R.sup.B1, R.sup.B2, R.sup.B3, W.sup.C, and R.sup.C are as described above.

[0571] In a more preferable embodiment of the polypeptide represented by formula [I-A] or [0572] a pharmaceutically acceptable salt thereof, [0573] AA.sup.2 is a group represented by formula [II-1]:

##STR00134## [0574] or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]:

##STR00135## [0575] wherein R.sup.AA2 is amino, [0576] AA.sup.3 is Val, Leu, Ile, Phe, or Trp, [0577] AA.sup.4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu, [0578] AA.sup.5 is ?-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or ?-homoPro, [0579] L.sup.1 is ?-Ala, GABA, Ape, Acp, or a group represented by formula [IV-23] or [IV-24]:

##STR00136## [0580] L.sup.1 is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu, [0581] L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0582] L.sup.N2 is the formula O or the formula C(?O)NH, [0583] R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, [0584] C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy, [0585] W.sup.C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys, and [0586] R.sup.C is the formula OH or the formula NH.sub.2.

[0587] In a further preferable embodiment of the polypeptide represented by formula [I-A] [0588] or a pharmaceutically acceptable salt thereof, [0589] AA.sup.2 is a group represented by formula [IV-7] or [IV-9]:

##STR00137## [0590] AA.sup.3 is Val, Leu, or Ile, [0591] AA.sup.4 is (N-Me)Ile or (N-Me)Glu, [0592] AA.sup.5 is ?-Ala, GABA, Ape, Acp, or ?-homoPro, [0593] L.sup.1 is GABA or Ape, [0594] L.sup.1 is Asn, Glu, (d)-Ser, or (d)-Thr, [0595] L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0596] L.sup.N2 is the formula O or the formula C(?O)NH, [0597] R.sup.B1 is carbamoyl or fluorine atom, [0598] R.sup.B2 is a hydrogen atom, [0599] R.sup.B3 is a hydrogen atom, [0600] W.sup.C is a single bond, and [0601] R.sup.C is the formula NH.sub.2.

[0602] One particularly preferable mode of the present embodiment is as follows.

[0603] In the polypeptide represented by formula [I-A] or a pharmaceutically acceptable salt thereof, [0604] AA.sup.2 is a group represented by formula [IV-7] or [IV-9]:

##STR00138## [0605] AA.sup.3 is Val, [0606] AA.sup.3 may be Leu, [0607] AA.sup.3 may be Ile, [0608] AA.sup.4 is (N-Me)Ile, [0609] AA.sup.4 may be (N-Me)Glu, [0610] AA.sup.5 is ?-Ala, GABA, Ape, or Acp, [0611] AA.sup.5 may be ?-homoPro, [0612] L.sup.1 is GABA or Ape, [0613] L.sup.1 is Asn, Glu, (d)-Ser, or (d)-Thr, [0614] the combination of L.sup.1 and L.sup.1 is preferably GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or [0615] Ape-(d)-Thr, [0616] L.sup.N1 is the formula C(?O), [0617] L.sup.N1 may be the formula S(?O).sub.2, [0618] L.sup.N2 is the formula O, and L.sup.N2 may be the formula C(?O)NH, [0619] R.sup.B1 is carbamoyl or fluorine atom, [0620] R.sup.B2 is a hydrogen atom, [0621] R.sup.B3 is a hydrogen atom, [0622] W.sup.C is a single bond, and [0623] R.sup.C is the formula NH.sub.2.

[0624] In another particularly preferable mode of the present embodiment, [0625] the substituted polypeptide represented by formula [I-A] is any of the followings:

##STR00139##

[0626] Another preferable embodiment of the compounds of the present invention is the substituted polypeptide or a pharmaceutically acceptable salt thereof, [0627] wherein W.sup.1 is -L.sup.1-, wherein L.sup.1 is a single bond, [0628] L.sup.2 is a single bond, and [0629] the substituted polypeptide is represented by formula [I-B]:

##STR00140## [0630] wherein preferable embodiments of AA.sup.1, AA.sup.2, AA.sup.3, AA.sup.4, AA.sup.5, L.sup.N1, L.sup.N2, R.sup.B1, R.sup.B2, R.sup.B3, W.sup.C, and R.sup.C are as described above.

[0631] In a more preferable embodiment of the polypeptide represented by formula [I-B] or [0632] a pharmaceutically acceptable salt thereof, [0633] AA.sup.1 is ?-Asp, ?-(d)-Asp, ?-Glu, or ?-(d)-Glu, [0634] AA.sup.2 is a group represented by formula [II-1]:

##STR00141## [0635] or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]:

##STR00142## [0636] wherein R.sup.AA2 is amino, [0637] AA.sup.3 is Val, Leu, Ile, Phe, or Trp, [0638] AA.sup.4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu, [0639] AA.sup.5 is ?-Ala, GABA, Ape, Acp, or ?-homoPro, [0640] L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0641] L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH, [0642] R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, [0643] C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy, [0644] W.sup.C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys, and [0645] R.sup.C is the formula OH or the formula NH.sub.2.

[0646] In a further preferable embodiment of the polypeptide represented by formula [I-B] [0647] or a pharmaceutically acceptable salt thereof, [0648] AA.sup.1 is ?-(d)-Asp or ?-(d)-Glu, [0649] AA.sup.2 is a group represented by formula [II-1]:

##STR00143## [0650] or a group represented by formula [IV-7] or [IV-9]:

##STR00144## [0651] wherein R.sup.AA2 is amino, [0652] AA.sup.3 is Val, Leu, or Ile, [0653] AA.sup.4 is (N-Me)Ile or (N-Me)Glu, [0654] AA.sup.5 is ?-Ala, GABA, Ape, Acp, or ?-homoPro, [0655] L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0656] L.sup.N2 is the formula O or the formula C(?O)NH, [0657] R.sup.B1 is carbamoyl, a chlorine atom, a bromine atom, methoxy, or trifluoromethoxy, [0658] R.sup.B2 is a hydrogen atom, [0659] R.sup.B3 is a hydrogen atom, [0660] W.sup.C is a single bond or (d)-Lys, and [0661] R.sup.C is the formula NH.sub.2.

[0662] One particularly preferable mode of the present embodiment is as follows.

[0663] In the polypeptide represented by formula [I-B] or a pharmaceutically acceptable [0664] salt thereof, [0665] AA.sup.1 is ?-(d)-Asp, [0666] AA.sup.1 may be ?-(d)-Glu, [0667] AA.sup.2 is a group represented by formula [II-1]:

##STR00145## [0668] wherein R.sup.AA2 is amino, [0669] AA.sup.2 may be a group represented by formula [IV-7] or [IV-9]:

##STR00146## [0670] AA.sup.3 is Val, [0671] AA.sup.3 may be Leu, [0672] AA.sup.3 may be Ile, [0673] AA.sup.4 is (N-Me)Ile, [0674] AA.sup.4 may be (N-Me)Glu, [0675] AA.sup.5 is ?-Ala, GABA, Ape, or Acp, [0676] AA.sup.5 may be ?-homoPro, [0677] L.sup.N1 is the formula C(?O), [0678] L.sup.N1 may be the formula S(?O).sub.2, [0679] L.sup.N2 is the formula O, [0680] L.sup.N2 may be the formula C(?O)NH, [0681] R.sup.B1 is carbamoyl, a chlorine atom, a bromine atom, methoxy, or trifluoromethoxy, [0682] R.sup.B2 is a hydrogen atom, [0683] R.sup.B3 is a hydrogen atom, [0684] W.sup.C is a single bond, [0685] W.sup.C may be (d)-Lys, and [0686] R.sup.C is the formula NH.sub.2.

[0687] In another particularly preferable mode of the present embodiment, [0688] the substituted polypeptide represented by formula [I-B] is any of the followings:

##STR00147## ##STR00148##

[0689] Another preferable embodiment of the compounds of the present invention is the substituted polypeptide or a pharmaceutically acceptable salt thereof, [0690] wherein L.sup.2 is a single bond, and [0691] the substituted polypeptid is represented by formula [I-C]:

##STR00149## [0692] wherein [0693] preferable embodiments of AA.sup.1, AA.sup.2, AA.sup.3, AA.sup.4, AA.sup.5, W.sup.1, L.sup.N1 L.sup.N2, R.sup.B1, R.sup.B2, R.sup.B3, W.sup.C, and [0694] R.sup.C are as described above.

[0695] In a more preferable embodiment of the polypeptide represented by formula [I-C] or [0696] a pharmaceutically acceptable salt thereof, [0697] AA.sup.1 is Asp, ?-(d)-Asp, or ?-(d)-Glu, [0698] AA.sup.2 is a group represented by formula [IV-7] or [IV-9]:

##STR00150## [0699] or a group represented by formula [II-1]:

##STR00151## [0700] wherein R.sup.AA2 is amino, [0701] AA.sup.3 is Val, Leu, or Ile, [0702] AA.sup.4 is (N-Me)Ile or (N-Me)Glu, [0703] AA.sup.5 is Ape or ?-homoPro, [0704] W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, [0705] wherein L.sup.1 is a single bond, [0706] L.sup.1 is GABA or Ape, and [0707] L.sup.1 is Asn, (d)-Ser, (d)-Thr, or Glu, [0708] L.sup.N1 is the formula C(?O) or the formula S(?O).sub.2, [0709] L.sup.N2 is the formula O or the formula C(?O)NH, [0710] R.sup.B1, R.sup.B2, and R.sup.B3 are each independently a hydrogen atom, carbamoyl, a halogen atom, [0711] C.sub.1-6 alkoxy, or halo C.sub.1-6 alkoxy, [0712] W.sup.C is a single bond or (d)-Lys, and [0713] R.sup.C is the formula NH.sub.2.

[0714] In a further preferable embodiment of the polypeptide represented by formula [I-C] or a pharmaceutically acceptable salt thereof, [0715] AA.sup.1 is Asp, [0716] AA.sup.1 may be ?-(d)-Asp, [0717] AA.sup.1 may be ?-(d)-Glu, [0718] AA.sup.2 is a group represented by formula [IV-7] or [IV-9]:

##STR00152## [0719] AA.sup.2 may be a group represented by formula [II-1]:

##STR00153## [0720] wherein R.sup.AA2 is amino, [0721] AA.sup.3 is Val, [0722] AA.sup.3 may be Leu, [0723] AA.sup.3 may be Ile, [0724] AA.sup.4 is (N-Me)Ile, [0725] AA.sup.4 may be (N-Me)Glu, [0726] AA.sup.5 is Ape, [0727] AA.sup.5 may be ?-homoPro, [0728] W.sup.1 is -L.sup.1- or -L.sup.1-L.sup.1-, [0729] L.sup.1 is a single bond, [0730] the combination of L.sup.1 and L.sup.1 (-L.sup.1-L.sup.1- is GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or [0731] Ape-(d)-Thr, [0732] L.sup.N1 is the formula C(?O), [0733] L.sup.N1 may be the formula S(?O).sub.2, [0734] L.sup.N2 is the formula O, [0735] L.sup.N2 may be the formula C(?O)NH, [0736] R.sup.B1 is carbamoyl, a chlorine atom, a bromine atom, methoxy, or trifluoromethoxy, [0737] R.sup.B2 is a hydrogen atom, [0738] R.sup.B3 is a hydrogen atom, [0739] W.sup.C is a single bond, [0740] W.sup.C may be (d)-Lys, and [0741] R.sup.C is the formula NH.sub.2.

[0742] In one particularly preferable mode of the present embodiment, [0743] the substituted polypeptide represented by formula [I-C] is any of the followings:

##STR00154## ##STR00155## ##STR00156##

[0744] In another particularly preferable mode of the present embodiment, [0745] the substituted polypeptide represented by formula [I-C] is the following:

##STR00157##

[0746] In another particularly preferable mode of the present embodiment, [0747] the substituted polypeptide represented by formula [I-C] is the following:

##STR00158##

[0748] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00159##

[0749] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00160##

[0750] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00161##

[0751] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00162##

[0752] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00163##

[0753] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00164##

[0754] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00165##

[0755] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00166##

[0756] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00167##

[0757] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00168##

[0758] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00169##

[0759] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00170##

[0760] In another particularly preferable mode of the present embodiment, the substituted polypeptide represented by formula [I-C] is the following:

##STR00171##

[0761] Another preferable embodiment of the compounds of the present invention is a substituted polypeptide represented by formula [I-C], or a pharmaceutically acceptable salt thereof, wherein [0762] AA.sup.1 is ?-Asp, ?-Glu, or ?-(d)-Glu, [0763] AA.sup.2 is a group represented by formula [II-1] or formula [II-2]:

##STR00172## [0764] wherein R.sup.A2 is hydroxy or amino, [0765] AA.sup.3 is Val, Leu, Ile, Phe, or Trp, [0766] AA.sup.4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, [0767] (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu, [0768] AA.sup.5 is a single bond, Pro, (d)-Pro, ?-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, ?-Ala, GABA, [0769] Ape, or Acp, [0770] L.sup.1 is a single bond, [0771] L.sup.2 is a single bond, [0772] L.sup.N1 is the formula S(?O).sub.2, [0773] L.sup.N2 is a single bond, the formula O, or the formula C(?O)NH, [0774] R.sup.A is a hydrogen atom, [0775] R.sup.B is a hydrogen atom, carbamoyl, a halogen atom, or C.sub.1-6 alkoxy, [0776] L.sup.C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, and [0777] R.sup.C is the formula NH.sub.2.

[0778] The compounds of the present invention are each a compound having a basic backbone of polypeptide consisting of three to seven amino acids and further having substituted benzoyl or substituted phenylsulfonyl, and may be in the form of a pharmaceutically acceptable salt thereof.

[0779] Examples of the pharmaceutically acceptable salt include: mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, and nitrates; acid addition salts such as sulfonates including methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and trifluoromethanesulfonates, and organic acid salts including oxalates, tartrates, citrates, maleates, succinates, acetates, trifluoroacetates, benzoates, mandelates, ascorbates, lactates, gluconates, and malates; amino acid salts such as glycinates, lysinates, argininates, ornithinates, glutamates, and aspartates; inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts; and salts with organic base such as ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts. Salts include hydrate salts.

[0780] Each of the compounds of the present invention may have an asymmetric center, and in this case various optical isomers exist therefor. Thus, each of the compounds of the present invention may exist as an individual optically active substance in any of the (R)-form and the (S)-form, or as a racemate or an (RS) mixture. For a compound having two or more asymmetric centers, diastereomers due to the optical isomerism of them further exist. The scope of the compounds of the present invention also includes mixtures containing all the forms at any ratio. For example, diastereomers can be separated with a method well known to those skilled in the art such as a fractional crystallization method, and optically active substances can be obtained with a technique of organic chemistry well known to those skilled in the art for that purpose. In addition, geometric isomers such as a cis form and a trans form may exist for each of the compounds of the present invention. Moreover, the compounds of the present invention each exhibit tautomerism, and there exist various tautomers therefor. The scope of the compounds of the present invention also includes those isomers and mixtures containing them at any ratio.

[0781] Further, if any of the compounds of the present invention or a salt thereof forms a hydrate or solvate, the hydrate or solvate is also included in the scope of the compounds of the present invention or a salt thereof.

[0782] Matrix metalloprotease 2 (MMP2) is one of endopeptidases having an active center of zinc.

[0783] As described above, MMP2 degrades the extracellular matrix including collagen and gelatin, and hence is involved in cell infiltration and migration, metastasis, and so on, thus being involved in pathological condition of cancerous disease, organ fibrosis, and so on.

[0784] Therefore, cancerous disease and organ fibrosis, and symptoms relating to cancerous disease and organ fibrosis can be prevented or treated by inhibiting MMP2.

[0785] The compounds of the present invention have an effect to inhibit MMP2. Accordingly, the compounds of the present invention can be used as an MMP2 inhibitor, or an active ingredient of a drug for preventing or treating cancerous disease and organ fibrosis.

[0786] In addition, the compounds of the present invention can be used as an active ingredient of a drug for preventing or treating symptoms relating to cancerous disease and organ fibrosis.

[0787] Examples of cancerous disease include breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumor, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, and glioma. Examples of symptoms relating to cancerous disease include pain associated with neoplastic cell multiplication or tumor growth, loss of body weight, and paraneoplastic syndrome.

[0788] Examples of organ fibrosis include chronic kidney disease, interstitial pneumonia, and idiopathic pulmonary fibrosis. Examples of symptoms relating to organ fibrosis include proteinuria, kidney dysfunction, and so on in chronic kidney disease, and exertional dyspnea, dry cough, and so on in interstitial pneumonia and idiopathic pulmonary fibrosis.

[0789] Evaluation of the effect of any of the compounds of the present invention to inhibit MMP2 can be carried out with a known procedure such as a method described later in Test Examples in the present specification.

[0790] For the pharmaceutical according to the present invention, a compound having an effect to inhibit MMP2, being any of the compounds of the present invention contained in the pharmaceutical, or a pharmaceutically acceptable salt thereof may be administered singly, or together with a pharmaceutically acceptable additive.

[0791] A common excipient or diluent, and, as necessary, a binder, a disintegrant, a lubricating agent, a coating agent, a sugar-coating agent, a pH adjuster, and a solubilizer or aqueous or nonaqueous solvent which is commonly used can be used as the additive.

[0792] Specific examples of the additives may include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, cornstarch, gum, gelatin, arginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl para-hydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low-viscosity hydroxypropylcellulose (HPC-L), microcrystalline cellulose, carboxymethylcellulose (CMC), carboxymethylcellulose sodium (CMC-Na), and other common additives.

[0793] The pharmaceutical according to the present invention may be in any form of solid compositions, liquid compositions, and other compositions, and an optimum form is selected according to necessity.

[0794] The pharmaceutical according to the present invention can be prepared, for example, as a tablet, a pill, a capsule, a granule, a powdered agent, a powder, a solution, an emulsion, a suspension, or an injection through a common formulation technique with addition of the aforementioned additive to any of the compounds of the present invention.

[0795] The pharmaceutical according to the present invention can be formulated by forming a clathrate compound with any of the compounds of the present invention and ?-, ?-, or ?-cyclodextrin or methylated cyclodextrin.

[0796] With respect to compounds that can be used in combination with any of the compounds of the present invention, the pharmaceutical according to the present invention can be prepared as a single formulation (combination drug) or two or more formulations (concomitant drugs) obtained by separately formulating.

[0797] If those compounds are separately formulated into two or more formulations, the individual formulations can be administered simultaneously, or separately at specific time intervals. In the latter case, any formulation may be first administered. The two or more formulations may be administered in different numbers of doses per day. The two or more formulations may be administered through different routes.

[0798] If those compounds are separately formulated into two or more formulations, they may be administered simultaneously, or separately at very short intervals, and it is preferable to instruct to use them in combination by means of a document such as an accompanying document or sales brochure of a commercially available pharmaceutical.

[0799] It is also preferable to separately formulate those active ingredients into the form of a kit consisting of two formulations.

[0800] The form of administration when any of the compounds of the present invention is used as an MMP2 inhibitor or the like is not limited, and any of the compounds of the present invention can be directly administered orally or parenterally. Alternatively, an agent containing any of the compounds of the present invention as an active ingredient may be orally or parenterally administered.

[0801] Also in the case that any of the compounds of the present invention is used as an agent for preventing or treating cancerous disease and organ fibrosis, and symptoms relating to cancerous disease and organ fibrosis, any of the compounds of the present invention can be directly administered orally or parenterally. Alternatively, an agent containing any of the compounds of the present invention as an active ingredient may be orally or parenterally administered.

[0802] In the parenteral administration, it is preferable to perform intravenous administration, subcutaneous administration, or transdermal administration.

[0803] Examples of the dosage form for parenteral administration include an injection, an infusion drip, an implant drug, a transdermal drug, a transmucosal drug, and a patch, and the dosage form may be a microsphere formulation.

[0804] The dose of any of the compounds of the present invention differs among subjects, routes of administration, target diseases, symptoms, and so on, and it is typically desirable in oral administration or parenteral administration to an adult patient to administer a single dose of 0.1 mg to 1000 mg, preferably of 1 mg to 200 mg, once to three times per day, or once every 2 to 3 days.

[0805] Production Examples for formulations of the compounds of the present invention will be shown in the following.

Production Example 1

[0806] A granule containing the following components is produced.

[0807] Components: compound represented by general formula [I], lactose, and cornstarch, HPC-L.

[0808] The compound represented by general formula [I] and lactose are sieved. Cornstarch is sieved. These are mixed by using a mixer. HPC-L aqueous solution is added to the mixed powder, and the resultant is kneaded, granulated (extrusion granulation), and then dried. The resulting dry granule is sieved through a vibrating screen to obtain a granule.

Production Example 2

[0809] A powder for encapsulation containing the following components is produced.

[0810] Components: compound represented by general formula [I], lactose, and cornstarch, magnesium stearate.

[0811] The compound represented by general formula [I] and lactose are sieved. Cornstarch is sieved. These together with magnesium stearate are mixed by using a mixer to obtain a powder. The powder obtained can be encapsulated.

Production Example 3

[0812] A granule for encapsulation containing the following components is produced.

[0813] Components: compound represented by general formula [I], lactose, and cornstarch, HPC-L.

[0814] The compound represented by general formula [I] and lactose are sieved. Cornstarch is sieved. These are mixed by using a mixer. HPC-L aqueous solution is added to the mixed powder, and the resultant is kneaded, granulated, and then dried. The resulting dry granule is sieved through a vibrating screen to regulate the particle seize, and a granule is obtained. The granule obtained can be encapsulated.

Production Example 4

[0815] Tablets containing the following components are produced.

[0816] Components: compound represented by general formula [I], lactose, microcrystalline cellulose, magnesium stearate, and CMC-Na.

[0817] The compound represented by general formula [I], lactose, microcrystalline cellulose, and CMC-Na are sieved, and mixed together. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation. This mixed powder is subjected to direct compression to obtain tablets.

Production Example 5

[0818] An injection containing the following compositions is produced.

[0819] Components: compound represented by general formula [I], purified egg yolk lecithin, oleic acid, purified soybean oil, glycerin, and water for injection.

[0820] The compound represented by general formula [I], purified egg yolk lecithin, and oleic acid are added to purified soybean oil to dissolve therein; water for injection, mixed with glycerin, is then added; and the resultant is emulsified by using an emulsifying machine. Thereto, water for injection is added, and the resultant is aliquoted into ampules, which are sealed and sterilized to form an injection.

[0821] Production methods for compound [I] according to the present invention will be described in detail in the following, but the production is not limited to the exemplified production methods. Solvent to be used for the production may be any solvent that does not inhibit individual reactions, and is not limited by the following description.

[0822] In the production of compound [I], the order of steps in the production can be appropriately changed.

[0823] In the production, each raw material compound may be used as a salt thereof, and examples of such salts include pharmaceutically acceptable salt presented above.

[0824] Compound [I] can be produced through solid-phase synthesis, liquid-phase synthesis, or a combination of them. Production examples with solid-phase synthesis will be shown in the following production methods.

[0825] Compound [I] can be produced through methods shown in any of Schemes 1 to 9 or any combination of them.

[0826] The side chain of each amino acid to form the polypeptide moiety of compound [I] may have a functional group, and the functional group may be protected with a protecting group. Examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for phenolic hydroxy, tBu for thiol (sulfanyl), Boc for amino, Trt for imidazolyl, Boc for indolyl, and Pbf for guanidino. These protecting groups can be each subjected to deprotection by treating with an acid.

[0827] Each of the amino acids can be used for the production even if the functional group in the side chain is not protected.

Method A: A Method for Producing Compound [1-f], a Compound in which the amino of the N-Terminal amino acid of the polypeptide moiety is sulfonylated and the carboxy of the C-Terminal amino acid is amidated (CONH.sub.2)

[0828] Compound [1-f] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 1).

##STR00173## [0829] wherein [0830] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N2, ring A, and ring B have the same definitions as those described [0831] above, [0832] HZ.sup.xOH represents an amino acid, [0833] x represents an integer of 1 to m, [0834] m represents an integer of 2 to 15, [0835] wherein Z.sup.x corresponds to AA.sup.x, L.sup.2, W.sup.1, or W.sup.C in the compound represented by formula [I], [0836] and may represent a single bond, and [0837] PG.sup.x represents a liposoluble protecting group protecting the amino of the amino acid [0838] (HZ.sup.xOH).

(1) [Step 1-1]

[0839] A resin having amino protected with Fmoc (compound [1-a]) is subjected to deFmoc by using a base.

(2) [Step 1-2]

[0840] The resin obtained in (1) is reacted with an amino acid whose amino has been protected with a liposoluble protecting group (PG.sup.x) (compound [1-b]) for amidation reaction between the free amino in the resin and the carboxy in compound [1-b].

(3) [Step 1-3]

[0841] The liposoluble protecting group of the amino of the N-terminal amino acid of the polypeptide moiety in the compound obtained in (2) is subjected to deprotection.

(4) By repeating steps (2) and (3) twice or more times, compound [1-c] can be produced in which the carboxy of the C-terminal amino acid of the polypeptide moiety is bonding to the resin and the amino of the N-terminal amino acid is free.

(5) [Step 1-4]

[0842] Compound [1-e] can be produced by reacting compound [1-c] obtained in (4) with compound [1-d] to sulfonylate the free amino in compound [1-c].

(6) [Step 1-5]

[0843] Compound [1-f], one of the present inventive compounds, can be produced by using an acid on compound [1-e] obtained in (5) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0844] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0845] Compound [1-f] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0846] In the method described in Scheme 1, resin [1-a], compound [1-b], and compound [1-d] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them.

Method B: A Method for Producing Compound [2-c], a Compound in which the amino of the N-Terminal amino acid of the polypeptide moiety is acylated and the carboxy of the C-Terminal amino acid is amidated (CONH.sub.2)

[0847] Compound [2-c] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 2) with use of compound [1-c] as a starting material.

##STR00174## [0848] wherein [0849] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3 L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, and Z.sup.x have the same definitions as those described above, and [0850] Y.sup.1 represents hydroxy or a chlorine atom.

(1) [Step 2-1]

[0851] Compound [2-b] can be produced by allowing compound [2-a] to act on compound [1-c] for amidation reaction.

(2) [Step 2-2]

[0852] Compound [2-c], one of the present inventive compounds, can be produced by using an acid on compound [2-b] obtained in (1) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0853] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0854] Compound [2-c] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0855] In the method described in Scheme 2, compound [2-a] to be used as a raw material compound can be obtained by producing with a method known per se, or purchasing a commercially available product of it. Compound [1-c] can be produced with the method described in Scheme 1.

Method C-1: A Method for Producing Compound [3-h], a Compound in which the amino of the N-Terminal amino acid of the polypeptide moiety is sulfonylated or acylated and the carboxy of the C-Terminal amino acid is Secondary- or Tertiary-amidated

[0856] Compound [3-h] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 3).

[0857] Examples of the resin (resin [3-a]) applicable in the present production method may include chlorotrityl chloride resin and Wang resin.

##STR00175## [0858] wherein [0859] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3 L.sup.N1 L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, Z.sup.x, PG.sup.x, and Y.sup.1 have the same definitions as those described above, [0860] R.sup.r represents hydroxy or a chlorine atom, [0861] R.sup.c and R.sup.c are same or different and each represent a hydrogen atom or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted with one group selected from the group consisting of hydroxy, amino, and C.sub.1-6 alkoxy, [0862] R.sup.c and R.sup.c may be taken together with the neighboring nitrogen atom to form a four- to seven-membered saturated heterocycle containing a nitrogen atom, wherein [0863] the four- to seven-membered saturated heterocycle containing a nitrogen atom, formed by R.sup.c and R.sup.c taken together with the neighboring nitrogen atom, is optionally substituted with one group selected from the group consisting of hydroxy, amino, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, and [0864] two carbon atoms in the four- to seven-membered saturated heterocycle containing a nitrogen atom, formed by R.sup.c and R.sup.c taken together with the neighboring nitrogen atom, are optionally crosslinked with C.sub.1-4 alkanediyl.

(1) [Step 3-1]

[0865] Compound [3-c] can be produced by reacting the resin (compound [3-a]) with an amino acid whose amino has been protected with a liposoluble protecting group (PG.sup.1) (compound [3-b]).

(2) [Step 3-2]

[0866] The liposoluble protecting group (PG.sup.1) in compound [3-c] obtained in (1) is subjected to deprotection.

(3) [Step 3-3]

[0867] The compound obtained in (2) is reacted with an amino acid whose amino has been protected with a liposoluble protecting group (PG.sup.x) (compound [1-b]) for amidation reaction between the free amino in the compound obtained in (1) and the carboxy in compound [1-b].

(4) [Step 3-4]

[0868] The liposoluble protecting group of the amino of the N-terminal amino acid of the polypeptide moiety in the compound obtained in (3) is subjected to deprotection.

(5)

[0869] By repeating steps (3) and (4) twice or more times, compound [3-d] can be produced in which the carboxy of the C-terminal amino acid of the polypeptide moiety is bonding to the resin and the amino of the N-terminal amino acid is free.

(6) [Step 3-5]

[0870] Compound [3-e] can be produced by reacting compound [3-d] obtained in (5) with compound [1-d] or compound [2-a] to sulfonylate or acylate the free amino in compound [3-d].

(7) [Step 3-6]

[0871] Compound [3-f], in which the carboxy of the C-terminal amino acid of the polypeptide moiety is free, can be produced by using an acid on compound [3-e] obtained in (6) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0872] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

(8) [Step 3-7]

[0873] Compound [3-h], one of the present inventive compounds, can be produced by allowing compound [3-g] to act on compound [3-f] obtained in (7) for amidation reaction.

[0874] Compound [3-h] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0875] In the method described in Scheme 3, compound [3-a], compound [3-b], compound [1-b], compound [1-d], compound [2-a], and [3-g] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them.

Method C-2: A Method for Producing Compound [4-e], a Compound in which the amino of the N-Terminal amino acid of the polypeptide moiety is sulfonylated or acylated and the carboxy of the C-Terminal amino acid is Secondary- or Tertiary-amidated

[0876] Alternatively, compound [4-e] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 4).

[0877] In Scheme 4, a method for producing a compound wherein a functional group is present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety in compound [4-e] is presented as an example.

[0878] Examples of the resin applicable in the present production method may include, as in Scheme 3, chlorotrityl chloride resin and Wang resin.

##STR00176## [0879] wherein [0880] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N1, L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, Z.sup.x, R.sup.c, and R.sup.c have the same definitions as those described above, [0881] m represents an integer of 1 to 15, provided that the relationship m?m is satisfied, [0882] L.sup.sc represents C.sub.1-4 alkanediyl, [0883] FG.sup.sc represents the aforementioned functional group present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety, wherein examples of the functional group may include the formula O (the formula OH), the formula S (the formula SH), the formula NH (the formula NH.sub.2), the formula C(?O)O (the formula C(?O)OH), the formula C(?O)NH (the formula C(?O)NH.sub.2), and the formula NHC(?NH)NH (NHC(?NH)NH.sub.2), and [0884] PG.sup.sc represents a protecting group for the functional group, [0885] wherein examples of the functional group may include, as described above, tBu, Trt, Boc, and Pbf.

(1) [Step 4-1]

[0886] Compound [4-b], in which the carboxy of the C-terminal amino acid of the polypeptide moiety is free, can be produced by using an acid on compound [4-a] to cleave the bond to the resin.

[0887] At that time, the deprotection for the protecting group (PG.sup.sc) present in the side chain of the mth amino acid counted from the C-terminal amino acid can be prevented by using a weak acid as the acid. Examples of the weak acid may include HFIP, acetic acid, and diluted TFA.

(2) [Step 4-2]

[0888] Compound [4-d] can be produced by allowing compound 4-c to act on compound [4-b] obtained in (1) for amidation reaction between the free carboxy in compound [4-b] and the amino in compound [4-c].

(3) [Step 4-3]

[0889] Compound [4-e], one of the present inventive compounds, can be produced by using an acid for deprotection for the aforementioned protecting group (PG.sup.sc) present in the side chain of the mth amino acid counted from the C-terminal amino acid. Examples of the acid applicable in the present step may include TFA.

[0890] Compound [4-e] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0891] In the method described in Scheme 4, compound [4-c] to be used as a raw material compound can be obtained by producing with a method known per se, or purchasing a commercially available product of it. Compound [4-a] can be produced with the method described in Scheme 3.

Method D: A Method for Producing Compound [5-f], in which a Functional Group is Present in the Side Chain of an amino acid Forming the polypeptide moiety, the Functional Group is Substituted with a polypeptide Linker and the amino of the N-Terminal amino acid of the polypeptide Linker is Substituted with C.sub.1-20 alkylcarbonyl Substituted with carboxy

[0892] Compound [5-f] can be produced through solid-phase synthesis the summary of which is described in the following (Scheme 5).

[0893] Here, the polypeptide linker consists of one to five amino acids.

[0894] In Scheme 5, a method for producing a compound wherein a functional group is present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety in compound [5-f], the functional group is substituted with a polypeptide linker, and the amino of the N-terminal amino acid of the polypeptide linker is substituted with C.sub.1-20 alkylcarbonyl substituted with carboxy is presented as an example.

##STR00177## [0895] wherein [0896] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N1, L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, m, Z.sup.x, and L.sup.sc have the same definitions as those described above, [0897] PG.sup.s represents a protecting group for the aforementioned functional group (FG.sup.sc) present in the side chain of an amino acid, wherein examples of the protecting group include Dde, ivDde, Alloc, and Mtt for amino, [0898] HZ.sup.sc yOH represents an amino acid forming the polypeptide linker attached to the functional group (FG.sup.sc), [0899] y represents an integer of 1 to p, [0900] p represents an integer of 0 to 5, PG.sup.sc y represents a liposoluble protecting group protecting the amino of the amino acid (HZ.sup.sc yOH), [0901] FG.sup.sc represents a functional group present in the side chain of an amino acid; examples of the functional group may include the formula NH (the formula NH.sub.2) and the formula COO (the formula COOH); Scheme 5 shows the case that FG.sup.sc is the formula NH (the formula NH.sub.2), and [0902] n represents an integer of 1 to 20.

(1) [Step 5-1]

[0903] The protecting group (PG.sup.S) for the functional group present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety in compound [5-a] is subjected to selective deprotection.

(2) [Step 5-2]

[0904] The compound obtained in (1) is reacted with an amino acid whose amino has been protected with a liposoluble protecting group (PG.sup.sc y) (compound [5-b]) for amidation reaction between the free functional group (FG.sup.sc) in the compound obtained in (1) and the carboxy in compound [5-b].

(3) [Step 5-3]

[0905] The liposoluble protecting group (PG.sup.sc y) is subjected to deprotection.

(4)

[0906] By repeating steps (2) and (3) once or more times, compound [5-c], in which the carboxy of the C-terminal amino acid of the polypeptide moiety is bonding to the resin, the functional group present in the side chain of the mth amino acid counted from the C-terminal amino acid is substituted with a polypeptide linker, and the amino of the N-terminal amino acid of the polypeptide linker is free, can be produced.

(5) [Step 5-4]

[0907] Compound [5-e] can be produced by reacting compound [5-c] obtained in (4) with compound [5-d], which is an alkanedicarboxylic acid, for amidation reaction of the free amino in compound [5-c] with one carboxy in compound [5-d].

(6) [Step 5-5]

[0908] Compound [5-f], one of the present inventive compounds, can be produced by using an acid on compound [5-e] obtained in (5) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0909] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0910] Compound [5-f] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0911] In the method described in Scheme 5, compound [5-b] and compound [5-d] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them. Compound [5-a] can be produced with the method described in Scheme 1 or Scheme 2, or a method similar to any of these.

Method E: A Method for Producing Compound [6-c], in which a Functional Group is Present in the Side Chain of Each of Two amino acids Among the amino acids Forming the polypeptide moiety, and the Functional Groups are Substituted with the Same polypeptide Linker (Z.sup.sc 1Z.sup.sc 2 . . . Z.sup.sc y) to Form a Ring

[0912] Compound [6-c] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 6).

[0913] Here, the polypeptide linker consists of one to four amino acids.

[0914] In Scheme 6, a method for producing a compound wherein a functional group is present in the side chain of each of the mth and mth amino acids counted from the C-terminal amino acid of the polypeptide moiety, and the functional groups are substituted with the same polypeptide linker to form a ring is presented as an example.

##STR00178## [0915] wherein [0916] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N1, L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, m, Z.sup.x, and L.sup.sc have the same definitions as those described above, [0917] m represents an integer of 2 to 15, provided that the relationship m<m?m is satisfied, the polypeptide linker (Z.sup.sc 1Z.sup.sc 2 . . . Z.sup.sc y) in compound [6-c] corresponds to L.sup.3 in the compound represented by formula [I], wherein L.sup.3 represents Gly, ?-Ala, or GABA, [0918] y represents an integer of 1 to p, [0919] p represents an integer of 1 to 4, [0920] L.sup.sc and L.sup.sc each represent C.sub.1-4 alkanediyl, [0921] FG.sup.sc and FG.sup.sc each represent a functional group present in the side chain of an amino acid, wherein the functional group represents the formula O (the formula OH), the formula S (the formula SH), the formula NH (the formula NH.sub.2), the formula C(?O)O (the formula C(?O)OH), or the formula C(?O)NH (the formula C(?O)NH.sub.2), and [0922] PG.sup.sc and PG.sup.sc each represent a protecting group for a functional group present in the side chain of an amino acid, wherein the functional group is, for example, Dde, ivDde, Alloc, or allyl.

(1) [Step 6-1]

[0923] The protecting group (PG.sup.sc) for the functional group present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety in compound [6-a] is subjected to selective deprotection.

(2) [Step 6-2]

[0924] The compound obtained in (1) is reacted with an amino acid whose amino has been protected with a liposoluble protecting group (PG.sup.sc y) (compound [6-d]) for amidation reaction between the free functional group (FG.sup.sc) in the compound obtained in (1) and the carboxy in compound [6-d], the amino of which has been protected with the liposoluble protecting group.

(3) [Step 6-3]

[0925] The liposoluble protecting group is subjected to deprotection.

(4) By repeating steps (2) and (3) once or more times, compound [6-b], in which the functional group present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety is substituted with a polypeptide linker, the amino of the N-terminal amino acid of the polypeptide linker is free, and the functional group (FG.sup.sc) present in the side chain of the mth amino acid counted from the C-terminal amino acid is protected with a protecting group (PG.sup.sc), can be produced.

(5) [Step 6-4]

[0926] The protecting group (PG.sup.sc) present in the side chain of the mth amino acid counted from the C-terminal amino acid of the polypeptide moiety in compound [6-b] is subjected to selective deprotection.

(6) [Step 6-5]

[0927] Free functional group (FG.sup.sc) and free amino in Z.sup.scp in the compound obtained in (5) are reacted for intramolecular cyclization reaction.

(7) [Step 6-6]

[0928] Compound [6-c], one of the present inventive compounds, can be produced by using an acid on the compound obtained in (6) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0929] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0930] Compound [6-c] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0931] In the method described in Scheme 6, compound [6-d] to be used as a raw material compound can be obtained by producing with a method known per se, or purchasing a commercially available product of it. Compound [6-a] can be produced with the method described in Scheme 1 or Scheme 2, or a method similar to any of these.

[0932] Method F: a method for producing compound [7-f], which has a substituent, alkylaminocarbonyl substituted with functional group, on ring B Compound [7-f] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 7).

##STR00179## [0933] wherein [0934] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, L.sup.N1, L.sup.N2, ring A, ring B, HZ.sup.xOH, x, m, Z.sup.x, and Y.sup.1 have the same definitions as those described above, [0935] L.sup.R represents C.sub.1-4 alkanediyl, [0936] FG.sup.R represents a functional group attached to alkyl (L.sup.R) of alkylaminocarbonyl (L.sup.R-NHC(?O)), a substituent present on ring B, and examples thereof may include the formula O (the formula OH), the formula S (the formula SH), the formula NH (the formula NH.sub.2), the formula C(?O)O (the formula C(?O)OH), and the formula C(?O)NH (the formula C(?O)NH.sub.2), [0937] PG.sup.R represents a protecting group for the functional group (FG.sup.R), wherein examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for thiol (sulfanyl), and Boc for amino, and these protecting groups can be each deprotected by treating with an acid.

(1) [Step 7-1]

[0938] Compound [7-c], which has carboxy on ring B, can be produced by reacting compound [1-c] with compound [7-a] or compound [7-b] to sulfonylate or acylate the free amino of the N-terminal amino acid of the polypeptide moiety in compound [1-c].

(2) [Step 7-2]

[0939] Compound [7-e] can be produced by reacting compound [7-c] with compound [7-d] for amidation reaction between the carboxy in compound [7-c] and the amino in compound [7-d].

(3) [Step 7-3]

[0940] Compound [7-f], one of the present inventive compounds, can be produced by using an acid on compound [7-e] obtained in (2) to cleave the bond to the resin and simultaneously deprotect the protecting group (PG.sup.R) of the functional group of alkylaminocarbonyl substituted with functional group (FG.sup.R) present on ring B. Examples of the acid applicable in the present step may include TFA. At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0941] Compound [7-f] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0942] In the method described in Scheme 7, compound [7-a], compound [7-b], and compound [7-d] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them. Compound [1-c] can be produced with the method described in Scheme 1, or a method similar to it.

Method G: A Method for Producing Compound [8-f], in which Ring A is Directly Substituted with Ring B

[0943] Compound [8-f] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 8).

##STR00180## [0944] wherein [0945] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N1, ring A, ring B, HZ.sup.xOH, x, m, Z.sup.x, and Y.sup.1 have the same definitions as those described above, [0946] LG.sup.A represents a leaving group, wherein examples of the leaving group may include a chlorine atom, a bromine atom, an iodine atom, and halo C.sub.1-6 alkylsulfonyloxy, and [0947] M.sup.B represents boronic acid, boronic acid ester, alkyltin, alkylsilane, or alkoxysilane.

(1) [Step 8-1]

[0948] Compound [8-c] can be produced by reacting compound [1-c] with compound [8-a] or compound [8-b] to sulfonylate or acylate the free amino of the N-terminal amino acid of the polypeptide moiety in compound [1-c].

(2) [Step 8-2]

[0949] Compound [8-e], in which ring A is directly substituted with ring B, can be produced by subjecting compound [8-c] to coupling reaction with compound [8-d] in the presence of a metal catalyst and a base. Examples of the metal catalyst may include tetrakis(triphenylphosphine)palladium, palladium acetate, and tris(dibenzylideneacetone)dipalladium. Examples of the base may include metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate, and potassium phosphate, cesium fluoride, potassium fluoride, and tetrabutylammonium fluoride.

(3) [Step 8-3]

[0950] Compound [8-f], one of the present inventive compounds, can be produced by using an acid on compound [8-e] obtained in (2) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0951] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0952] Compound [8-f] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0953] In the method described in Scheme 8, compound [8-a], compound [8-b], and compound [8-d] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them. Compound [1-c] can be produced with the method described in Scheme 1, or a method similar to it.

Method H: A Method for Producing Compound [9-f], which has the Substituent arylcarbonylamino (the Formula Ring BC(?O)NH) on Ring A

[0954] Compound [9-H] can be produced, for example, through solid-phase synthesis the summary of which is described in the following (Scheme 9).

##STR00181## [0955] wherein [0956] R.sup.A1, R.sup.A2, R.sup.B1, R.sup.B2, R.sup.B3, L.sup.N1, ring A, ring B, HZ.sup.xOH, x, m, Z.sup.x, and Y.sup.1 have the same definitions as those described above, [0957] Y.sup.2 represents hydroxy or a chlorine atom, and [0958] PG.sup.A represents a liposoluble protecting group protecting amino present on ring A, [0959] wherein examples of the liposoluble protecting group may include Fmoc.

(1) [Step 9-1]

[0960] As in step 8-1 of Scheme 8, compound [9-c] can be produced by reacting compound [1-c] with compound [9-a] or compound [9-b] to sulfonylate or acylate the free amino of the N-terminal amino acid of the polypeptide moiety in compound [1-c].

(2) [Step 9-2]

[0961] The liposoluble protecting group (PG.sup.A) in compound [9-c] obtained in (1) is subjected to deprotection.

(3) [Step 9-3]

[0962] Compound [9-e] can be produced by reacting the compound obtained in (2) with compound [9-d] for amidation (acylation) reaction between the free amino in the compound obtained in (2) and the carboxy in compound [9-d].

(4) [Step 9-4]

[0963] Compound [9-f], one of the present inventive compounds, can be produced by using an acid on compound [9-e] obtained in (3) to cleave the bond to the resin. Examples of the acid applicable in the present step may include TFA.

[0964] At that time, if a protected functional group is present in the side chain of an amino acid forming the polypeptide moiety, the protecting group of the functional group can be simultaneously deprotected.

[0965] Compound [9-f] obtained in the described manner can be isolate/purified by a known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[0966] In the method described in Scheme 9, compound [9-a], compound [9-b], and compound [9-d] to be used as raw material compounds can be obtained by producing with a method known per se, or purchasing commercially available products of them. Compound [1-c] can be produced with the method described in Scheme 1, or a method similar to it.

[0967] All kinds of amino acids can be used for the amino acids in the methods shown in Schemes 1 to 9 for producing compound [I] according to the present invention, and examples of the amino acids include natural proteogenic L-amino acids: Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, and Arg.

[0968] In addition, nonnatural amino acids including natural nonproteogenic amino acids and the D-forms of the natural proteogenic L-amino acids described above may be used in the present production methods.

[0969] Here, examples of nonnatural amino acids applicable in the present production methods include the following: [0970] (d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys [0971] ?-homoPro [0972] ?-Ala, GABA, Ape, Acp [0973] (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, (N-Me)Glu [0974] a group represented by formula [II-1] or formula [II-2]:

##STR00182##

wherein R.sup.A2 is hydroxy or amino; and [0975] the amino acids listed in Table 1 and Table 2

[0976] Examples of liposoluble protecting groups may include carbonate protecting groups, amide protecting groups, and alkyl protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyl (Bn), allyl (Allyl), allyloxycarbonyl (Alloc), and acetyl (Ac). Introduction of a liposoluble protecting group to an amino acid, for example, introduction of Fmoc, can be achieved by adding 9-fluorenylmethyl-N-succinidyl carbonate and sodium hydrogen carbonate for reaction. It is recommended to perform the reaction at 0 to 50? C., preferably at room temperature, for about 1 to 5 hours.

[0977] Commercially available amino acids protected with a liposoluble protecting group may be used. Examples thereof may include Fmoc-Ser-OH, Fmoc-Asn-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ala-OH, Fmoc-Tyr-OH, Fmoc-Gly-OH, Fmoc-Lys-OH, Fmoc-Arg-OH, Fmoc-His-OH, Fmoc-Asp-OH, Fmoc-Glu-OH, Fmoc-Gln-OH, Fmoc-Thr-OH, Fmoc-Cys-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Trp-OH, and Fmoc-Pro-OH.

[0978] Examples of amino acids protected with a liposoluble protecting group and having a protecting group introduced into the side chain may include Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, and Fmoc-Tyr(tBu)-OH.

[0979] The resin may be any resin commonly used for solid-phase synthesis, and, for example, 2-chlorotrityl chloride resin, which is functionalized with a chlorine atom, Wang resin, HMPA-PEGA resin, and Amino-PEGA resin, which is functionalized with amino, are applicable.

[0980] Solid-phase synthesis using resin for amide synthesis is recommended as a method for obtaining an amide formed at the C terminus of peptide. For example, Rink-Amide-AM resin, SAL-PEG resin, SAL-MBHA resin, or Rink-Amide-PEGA resin can be used. An amide formed at the C terminus of peptide can be obtained by cleaving off peptide from the resin.

[0981] To bond an amino acid whose amino has been protected with a liposoluble protecting group to resin, for example, in the case that resin having hydroxy or resin functionalized with a chlorine atom is used, the bonding can be achieved by allowing the carboxy of the amino acid to form an ester bond to the resin.

[0982] In the case that resin functionalized with amino is used, the bonding can be achieved by allowing the carboxy of the amino acid to form an amide bond to the resin.

[0983] In the case that 2-chlorotrityl chloride resin is used, esterification can be performed by using a base such as diisopropylethylamine (DIPEA), triethylamine, pyridine, and 2,4,6-collidine.

[0984] In the case that resin having hydroxy is used, a known dehydrating/condensing agent such as 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4,-triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC) can be used as an esterification catalyst. Regarding the usage ratio between an amino acid and a dehydrating/condensing agent, the amount of the latter is typically 1 to 10 equivalents, and preferably 2 to 5 equivalents per equivalent of the former.

[0985] For example, it is preferable to perform esterification reaction in such a manner that a resin is put in a solid-phase column, this resin is washed with a solvent, and a solution of an amino acid is then added thereto. Examples of the washing solvent may include chloroform, dimethylformamide (DMF), 2-propanol, and dichloromethane. Examples of the solvent to dissolve an amino acid therein include chloroform, dimethyl sulfoxide (DMSO), DMF, and dichloromethane. It is recommended to perform esterification reaction at 0 to 50? C., preferably at room temperature, for about 10 minutes to 30 hours, preferably for about 15 minutes to 24 hours.

[0986] At that time, it is also preferable to acetylate unreacted hydroxy on the solid phase by using acetic anhydride or the like for capping.

[0987] Elimination of a liposoluble protecting group can be performed, for example, by treating with a base. Examples of the base may include piperidine and morpholine. At that time, it is preferable that the elimination be performed in the presence of a solvent. Examples of the solvent may include DMF, DMSO, and methanol.

[0988] It is preferable to perform amidation reaction between the liberated amino and the carboxy of any amino acid whose amino has been protected with a liposoluble protecting group in the presence of an activator and a solvent.

[0989] Examples of the activator may include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(dimethylaminopropyl)carbodiimide-hydrochloride (WSC/HCl), diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI), diethylcyanophosphonate (DEPC), benzotriazol-1-yloxy-trispyrrolidinophosphonium (DIPCI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphonate (HATU), O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino (morpholino)]uronium hexafluorophosphate (COMU), and ethyl cyano(hydroxyimino)acetate (Oxyma).

[0990] It is preferable to set the amount of usage of the activator to 1 to 20 equivalents, preferably to 1 to 10 equivalents, more preferably to 1 to 5 equivalents, with respect to any amino acid whose amino has been protected with a protecting group having liposolubility.

[0991] Examples of the solvent may include DMF, DMSO, and dichloromethane. It is recommended to perform the reaction at 0 to 50? C., preferably at room temperature, for about 10 minutes to 30 hours, preferably for about 15 minutes to 2 hours.

[0992] Cleaving-off of a peptide chain from resin can be performed through treatment with an acid. Examples of the acid may include trifluoroacetic acid (TFA) and hydrogen fluoride (HF). It is recommended to perform the reaction for separation from resin at 0 to 50? C., preferably at room temperature, for about 10 minutes to 10 hours, preferably for about 30 minutes to 4 hours.

[0993] The present invention is described in more detail with reference to Examples, Reference Examples, and Test Examples below; however, these do not limit the present invention, and any modification may be made without departing from the scope of the present invention.

[0994] Abbreviations in the present specification are shown in the following. [0995] APCI: atmospheric pressure chemical ionization [0996] Arg (Pbf): N.sup.?-2,2,4,6,7-pentamethyldihydrobenzofuransulfonylarginine [0997] Bu: butyl [0998] BuOH: butanol [0999] Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-ethyl [1000] DMSO-d.sub.6: hexadeutrated dimethyl sulfoxide [1001] ELSD: evaporative light scattering detector [1002] ESI: electrospray ionization [1003] HPLC: high-performance liquid chromatography [1004] ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl [1005] LCMS: liquid chromatography/mass spectrometry [1006] NMP: 1-methyl-2-pyrrolidone [1007] Trt: trityl [1008] UV: ultraviolet ray

[1009] Herein, room temperature refers to 20 to 30? C., unless otherwise specified.

[1010] Under ice-cooling refers to 0 to 5? C., unless otherwise specified.

[1011] Herein, Biotage (registered trademark) SNAP Ultra manufactured by Biotage AB or REVELERIS (registered trademark) Silica 40 m manufactured by BUCHI Labortechnik AG was used for silica gel cartridge in purification with column chromatography.

[1012] In purification with reversed-phase column chromatography (hereinafter, occasionally referred to as preparative LCMS), an appropriate condition was selected from two conditions shown in the following, and purification was performed. [1013] Separation apparatus: used was Agilent 1260 Infinity and Agilent 6130 (ionization method: [1014] Electron Spray Ionization: ESI), or Agilent 385-ELSD when an ELSD detector was involved, each apparatus being from Agilent Technologies [1015] Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid [1016] Flow rate: 50 mL/min [1017] One of the following columns was used. [1018] Waters XBridge Prep C18, 5 ?m, 30?50 mm [1019] Waters XSelect CSH C18, 5 m, 30?50 mm

(Separation Condition A)

[1020] 0.0-0.5 min (solution A/solution B=90/10) [1021] 0.5-7.5 min (solution A/solution B=90/10 to 20/80) [1022] 7.5-7.95 min (solution A/solution B=20/80) [1023] 7.95-8.0 min (solution A/solution B=20/80 to 5/95) [1024] 8.0-9.0 min (solution A/solution B=5/95)

(Separation Condition B)

[1025] 0.0-0.5 min (solution A/solution B=95/5) [1026] 0.5-7.5 min (solution A/solution B=95/5 to 50/50) [1027] 7.5-7.95 min (solution A/solution B=50/50) [1028] 7.95-8.0 min (solution A/solution B=50/50 to 5/95) [1029] 8.0-9.0 min (solution A/solution B=5/95)

[1030] Instrumental data shown herein were determined with the following instruments. [1031] Microwave reactor: Initiator (Biotage AB) [1032] NMR spectra: [1H-NMR] 600 MHz: JNM-ECA600 (JEOL Ltd.), 400 MHz: AVANCE III HD 400 (Bruker)

[1033] Mass spectra of high-performance liquid chromatography (LCMS) and retention time (RT) in the present specification were determined under conditions shown in the following. [1034] Measurement apparatus: LCMS-2010EV, Shimadzu Corporation [1035] Column: Shimadzu XR-ODS, 2.2 m, 2.0?30 mm [1036] Ionization method: ESI/APCI dual source [1037] Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid [1038] Flow rate: 0.6 mL/min, detection method: UV 210 nm, 254 nm

(Analysis Condition A)

[1039] 0.0-1.0 min (solution A/solution B=90/10 to 60/40) [1040] 1.0-2.0 min (solution A/solution B=60/40 to 1/99) [1041] 2.0-2.6 min (solution A/solution B=1/99)

(Analysis Condition B)

[1042] 0.0-0.5 min (solution A/solution B=90/10) [1043] 0.5-1.5 min (solution A/solution B=90/10 to 70/30) [1044] 1.5-2.5 min (solution A/solution B=70/30 to 1/99) [1045] 2.5-5.0 min (solution A/solution B=1/99)

[1046] Compound names in Production Examples, Reference Examples, and Examples were given in accordance with ACD/Name 2019.1.2 (ACD Labs 2019.1.2, Advanced Chemistry Development Inc.).

Reference Example 1 4-(4-Carbamoylbenzamide)benzenesulfonyl chloride

[1047] ##STR00183##

[1048] To a solution of 4-carbamoylbenzoic acid (150 g) in DMF (180 mL), WSC monohydrochloride (209 g), HOBt monohydrate (167 g), and DIPEA (380 mL) were added. After stirring at room temperature for 5 minutes, aniline (99 mL) was added, and the resultant was stirred at room temperature for 72 hours. Water was added to the reaction solution, and a solid precipitated was collected through filtration to afford N-phenylterephthalamide (147 g) as a yellow amorphous.

[1049] To N-phenylterephthalamide obtained, chlorosulfonic acid (407 mL) was added, and the resultant was stirred at 60? C. for 1 hour with heating. The reaction mixture was ice-cooled, and then added to iced water. A solid precipitated was collected through filtration, washed with water, and then dried to afford the title compound (198 g) as a light-yellow solid.

[1050] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 7.54 (bs, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.96-8.09 (m, 4H), 8.14 (bs, 1H), 10.46 (s, 1H)

Reference Example 2 4-(4-(Trifluoromethoxy)benzamide)benzenesulfonyl chloride

[1051] ##STR00184##

[1052] With the same procedure as in Reference Example 1, the title compound was obtained as a yellow solid from the corresponding raw material.

[1053] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 7.52 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.72 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 10.42 (s, 1H)

Reference Example 3 4-(4-(Methylcarbamoyl)benzamide)benzenesulfonyl chloride

[1054] ##STR00185##

[1055] With the same procedure as in Reference Example 1, the title compound was obtained as a gray solid from the corresponding raw material.

[1056] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? ppm 2.81 (d, J=4.1 Hz, 3H), 7.57-7.61 (m, 2H), 7.72-7.78 (m, 2H), 7.96 (d, J=8.7 Hz, 2H), 8.03 (d, J=8.7 Hz, 2H), 8.62 (q, J=4.1, 1H), 10.42 (s, 1H)

Reference Example 4 4-(4-(Dimethylcarbamoyl)benzamide)benzenesulfonyl chloride

[1057] ##STR00186##

[1058] With the same procedure as in Reference Example 1, the title compound was obtained as a brown solid from the corresponding raw material.

[1059] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? ppm 2.91 (s, 3H), 3.01 (s, 3H), 7.54 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 8.01 (d, J=8.3 Hz, 2H), 10.41 (s, 1H)

Reference Example 5 4-(4-(Trifluoromethyl)benzamide)benzenesulfonyl chloride

[1060] ##STR00187##

[1061] With the same procedure as in Reference Example 1, the title compound was obtained as a white solid from the corresponding raw material.

[1062] .sup.1H NMR (400 MHz, CHLOROFORM-d) ? ppm 7.81 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.1 Hz, 2H), 8.01 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.1 Hz, 3H)

Reference Example 6 4-(4-Cyanobenzamide)benzenesulfonyl chloride

[1063] ##STR00188##

[1064] With the same procedure as in Reference Example 1, the title compound was obtained as a light brown solid from the corresponding raw material.

[1065] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? ppm 7.58 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.99 (d, J=8.3 Hz, 2H), 8.01 (d, J=8.3 Hz, 2H), 10.42 (s, 1H)

Reference Example 7 4-(4-(1,1,2,2-Tetrafluoroethoxy)benzamide)benzenesulfonyl chloride

[1066] ##STR00189##

[1067] With the same procedure as in Reference Example 1, the title compound was obtained as a yellow solid from the corresponding raw material.

[1068] .sup.1H NMR (400 MHz, CHLOROFORM-d) ? ppm 5.95 (tt, J=53.2 Hz, 2.8 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.92 (d, J=7.2 Hz, 2H), 7.94 (d, J=7.2 Hz, 2H), 8.05 (d, J=8.6 Hz, 2H), 8.12 (s, 1H)

Reference Example 8 4-(2-Fluorobenzamide)benzenesulfonyl chloride

[1069] ##STR00190##

[1070] With the same procedure as in Reference Example 1, the title compound was obtained as a white solid from the corresponding raw material.

[1071] .sup.1H NMR (400 MHz, CHLOROFORM-d) ? ppm 7.20-7.27 (m, 1H), 7.37 (dd, J=7.6 Hz, 7.6 Hz, 1H), 7.56-7.63 (m, 1H), 7.95 (d, J=9.1 Hz, 2H), 8.06 (d, J=9.1 Hz, 2H), 8.20 (td, J=8.0 Hz, 1.8 Hz, 1H), 8.75 (d, J=16.9 Hz, 1H)

Reference Example 9 2-Fluoro-4-phenoxybenzoic acid

[1072] ##STR00191##

[1073] To a solution of 2,4-difluorobenzaldehyde (250 mg) and phenol (199 mg) in DMF (10 mL), potassium carbonate (535 mg) was added, and the resultant was stirred at 120? C. for 4 hours with heating. After allowing to cool to room temperature, the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 2-fluoro-4-phenoxybenzaldehyde.

[1074] In tetrahydrofuran (5 mL) and water (5 mL), 2-fluoro-4-phenoxybenzaldehyde obtained was dissolved, to which sodium dihydrogen phosphate (844 mg), 2-methyl-2-butene (1.49 mL), and sodium chlorite (636 mg) were added, and the resultant was stirred at room temperature for 3 hours. Chloroform was added to the reaction solution, which was washed with water. The organic layer was allowed to pass through a Phase separator, and concentrated under reduced pressure to afford the title compound (182 mg) as a white solid.

[1075] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 6.75-6.92 (m, 2H), 7.17 (d, J=7.5 Hz, 2H), 7.24-7.33 (m, 1H), 7.43-7.55 (m, 2H), 7.83-7.97 (m, 1H), 13.0 (br s, 1H)

Reference Example 10 4-(4-Carbamoyl-2-fluorophenoxy)benzoic acid

[1076] ##STR00192##

[1077] With the same procedure as in Reference Example 9, the title compound was obtained as a white solid from the corresponding raw material.

[1078] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 7.12 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.40 (t, J=8.3 Hz, 1H), 7.53 (br s, 1H), 7.82 (t, J=8.3 Hz, 1H), 7.90-8.00 (m, 2H), 8.07 (br s, 1H), 9.95 (s, 1H)

Reference Example 11 3-Fluoro-4-(2-fluorophenoxy)benzoic acid

[1079] ##STR00193##

[1080] With the same procedure as in Reference Example 9, the title compound was obtained as a white solid from the corresponding raw material.

[1081] .sup.1H NMR (400 MHz, CHLOROFORM-d) ? ppm 6.89 (t, J=8.1 Hz, 1H), 7.10-7.25 (m, 4H), 7.80 (d, J=8.4 Hz, 1H), 7.89 (d, J=11.3 Hz, 1H)

Reference Example 12 5-((4-(4-Carbamoylphenoxy)phenyl)sulfonamide)pentanoic acid

[1082] ##STR00194##

[1083] To a solution of benzyl 5-aminopentanoate-tosilate (1.48 g) in chloroform (20 mL), triethylamine (2.3 mL) and 4-fluorobenzenesulfonyl chloride (800 mg) were added under ice-cooling, and the resultant was stirred under ice-cooling for 1 hour. After the completion of the reaction, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was allowed to pass through a Phase separator, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 50:50) to afford benzyl 5-((4-fluorophenyl)sulfonamide)pentanoate (1.24 g) as a colorless oily substance.

[1084] .sup.1H NMR (400 MHz, CHLOROFORM-d) ? ppm 1.46-1.56 (m, 2H), 1.58-1.68 (m, 2H), 2.33 (t, J=7.0 Hz, 2H), 2.96 (q, J=6.5 Hz, 2H), 4.40-4.47 (m, 1H), 5.09 (s, 2H), 7.18 (t, J=8.2 Hz, 2H), 7.31-7.39 (m, 5H), 7.86 (dd, J=7.6 Hz, 5.3 Hz, 2H)

##STR00195##

[1085] To a solution of benzyl 5-((4-fluorophenyl)sulfonamide)pentanoate (500 mg) obtained in (1) in DMF (13 mL), 4-hydroxybenzonitrile (179 mg) and potassium carbonate (567 mg) were added, and the resultant was stirred under microwave irradiation at 180? C. for 1 hour. After the reaction solution was allowed to cool, ethyl acetate and water were added to the reaction mixture for liquid separation. After the aqueous layer was washed with ethyl acetate, the pH was adjusted to 1 with 1 M hydrochloric acid aqueous solution, and extraction was performed with ethyl acetate/toluene mixed solvent. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (285 mg) as a white solid.

[1086] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 1.32-1.49 (m, 4H), 2.10-2.17 (m, 2H), 2.69-2.78 (m, 2H), 7.23-7.31 (m, 2H), 7.43 (t, J=8.7 Hz, 2H), 7.59-7.66 (m, 1H), 7.81-7.87 (m, 3H), 7.91 (d, J=8.3 Hz, 1H)

(3)

[1087] To a solution of 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (100 mg) obtained in (2) in DMSO (2 mL), potassium carbonate (81 mg) and 30% hydrogen peroxide solution (0.15 mL) were added, and the resultant was stirred at room temperature for 2 hours. After the completion of the reaction, sodium thiosulfate aqueous solution and 1 M hydrochloric acid aqueous solution were added, and extraction was performed with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the title compound (89 mg) as a white solid.

[1088] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 1.32-1.50 (m, 4H), 2.10-2.18 (m, 2H), 2.69-2.78 (m, 2H), 7.16 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.34 (br s, 1H), 7.43 (t, J=8.6 Hz, 2H), 7.52-7.58 (m, 1H), 7.59-7.66 (m, 1H), 7.86-7.79 (m 3H), 7.96 (d, J=7.7 Hz, 1H), 12.0 (br s, 1H)

Example 1 Synthesis of Compound of Compound No. 1: (N-[4-(4-carbamoylbenzamido)benzene-1-sulfonyl]-D-?-glutamyl-(4S)-4-amino-L-prolyl-L-1 eucyl-N-(5-amino-5-oxopentyl)-N.SUP.2.-methyl-L-?-glutamine)

[1089] ##STR00196##

[1090] Fmoc-Rink Amide AM resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin.

[1091] Subsequently, a solution of Fmoc-Ape-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce an Ape residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-(2S,4S)-(4-NHBoc)Pro-OH, and Fmoc-(d)-Glu-OtBu were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-?-(d)-Glu(OtBu)-(2S,4S)-(4-NHBoc)Pro-Leu-(N-Me)Glu(OtBu)-Ape-Rink Amide AM resin was synthesized.

(2)

[1092] To the resin obtained in (1), a solution of 4-(4-carbamoylbenzamide)benzenesulfonyl chloride (0.30 mmol) obtained in Reference Example 1 and DIPEA (0.60 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 1 hour. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(3)

[1093] To the resin obtained in (2), TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added, the mixture was shaken at room temperature for 1.5 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition B). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (46 mg) as a white powder.

Example 2 Synthesis of Compound of Compound No. 106: (N.SUP.2.-[4-(4-phenoxybenzamido)butanoyl]-L-asparaginyl-N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-L-?-asparagine)

[1094] ##STR00197##

[1095] Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-GABA-OH, and 4-phenoxybenzoic acid were sequentially condensed, and Ph-O-Ph-CO-GABA-Asn(Trt)-Asp(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-?-homoPro-NH-SAL-P EG resin was synthesized. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(2)

[1096] To the resin obtained in (1), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (14 mg) as a white powder.

Example 3 Synthesis of Compound of Compound No. 177: (N.SUP.2.-(4-{4-[4-(methylcarbamoyl)phenoxy]benzamido}butanoyl)-L-asparaginyl-L-?-aspartyl-L-alanyl-L-leucyl-L-methionyl-L-prolinamide)

[1097] ##STR00198##

[1098] Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a Pro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, and Fmoc-GABA-OH were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-GABA-Asn(Trt)-Asp(OtBu)-Ala-Leu-Met-Pro-NH-SAL-PEG resin was synthesized.

(2)

[1099] To the resin obtained in (1), a solution of 4,4-oxybisbenzoic acid (0.75 mmol), HATU (0.15 mmol), and DIPEA (2.0 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times).

(3)

[1100] To the resin obtained in (2), a solution of HATU (0.30 mmol), DIPEA (0.60 mmol), and methanol solution of methylamine (concentration: 9.8 mol/L, 0.30 mmol) in DMF (3 mL) was added, and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(4)

[1101] To the resin obtained in (3), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (30 mg) as a white powder.

Example 4 Synthesis of Compound of Compound No. 587: (N-{5-[(4-methylphenyl)ethynyl]thiophene-2-sulfonyl}-?-alanyl-L-asparaginyl-L-?-aspartyl-L-alanyl-L-leucyl-N-methyl-L-methionyl-L-prolinamide)

[1102] ##STR00199##

[1103] Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL) solution, a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a Pro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, and Fmoc-?-Ala-OH were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-?-Ala-Asn(Trt)-Asp(OtBu)-Ala-Leu-(N-Me)Met-Pro-NH-SAL-PEG resin was synthesized.

(2)

[1104] To the resin obtained in (1), a solution of 5-bromothiophene-2-sulfonyl chloride (0.20 mmol) and DIPEA (0.40 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(3)

[1105] To the resin obtained in (2), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition B). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford 5-Br-thiophene-2-SO.sub.2-?-Ala-Asn-Asp-Ala-Leu-(N-Me)Met-Pro-NH.sub.2 (27 mg) as a white powder.

(4)

[1106] The compound obtained in (3) was dissolved in DMF (0.5 mL), 4-ethinyltoluene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.01 mmol), triethylamine (0.18 mmol), and copper iodide (0.01 mmol) were added thereto, and the mixture was stirred under nitrogen atmosphere at 50? C. for 5 hours with heating. After allowing to cool to room temperature, the reaction solution was diluted with DMSO, filtered, and purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (4 mg) as a white powder.

Example 5 Synthesis of Compound of Compound No. 608: (N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-N.SUP.2.-[4-(1-phenyl-1H-1,2,3-triazol-4-yl)benzene-1-sulfonyl]-D-glutamine)

[1107] ##STR00200##

[1108] Fmoc-Rink Amide AM resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, and Fmoc-(d)-Glu-OtBu were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-?-(d)-Glu(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-?-homoPro-Rink Amide AM resin was synthesized.

(2)

[1109] To the resin obtained in (1), a solution of 4-bromobenzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (2 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times).

(3)

[1110] To the resin obtained in (2), a solution of trimethylsilylacetylene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol), and copper iodide (0.03 mmol) in DMF (2 mL) was added, and the mixture was stirred under microwave irradiation at 80? C. for 30 minutes with heating. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times) and chloroform (2 mL?three times).

[1111] To the resin obtained, tetrahydrofuran solution of tetrabutylammonium fluoride (concentration: 0.33 mol/L, 0.50 mmol) was added, and the mixture was shaken at room temperature for 1 hour. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times) and chloroform (2 mL?three times).

(4)

[1112] To the resin obtained in (3), a solution of azidobenzene (0.20 mmol), copper(II) sulfate pentahydrate (0.40 mmol), and ascorbic acid (0.40 mmol) in water (2 mL) and tBuOH (1 mL) was added, and the mixture was stirred under microwave irradiation at 60? C. for 1 hour with heating. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times) and chloroform (2 mL?three times).

(5)

[1113] To the resin obtained in (4), TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (12 mg) as a white powder.

Example 6 Synthesis of Compound of Compound No. 634: (N.SUP.2.-(4-acetyl[1,1-biphenyl]-4-sulfonyl)-N-[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-D-asparagine)

[1114] ##STR00201##

[1115] Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, and Fmoc-(d)-Asp-OtBu were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-?-(d)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-?-homoPro-NH-SAL-PEG resin was synthesized.

(2)

[1116] To the resin obtained in (1), a solution of 4-iodobenzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (2 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times) and chloroform (2 mL?three times).

(3)

[1117] To the resin obtained in (2), a solution of 4-acetylphenylboronic acid (0.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 mmol), and potassium phosphate (0.50 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added, and the mixture was stirred under microwave irradiation at 100? C. for 30 minutes with heating. After the completion of the reaction, the resulting resin was washed with DMF (2 mL?three times) and chloroform (2 mL?three times).

(4)

[1118] To the resin obtained in (3), TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (8 mg) as a white powder.

Example 7 Synthesis of Compound of Compound No. 692: (N-[(2S)-3-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-N.SUP.2.-[4-(4-methoxybenzamido)benzene-1-sulfonyl]-D-asparagine)

[1119] ##STR00202##

[1120] Fmoc-Rink Amide AM resin (0.10 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dap(Boc)-OH, and Fmoc-(d)-Asp-OtBu were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-?-(d)-Asp(OtBu)-Dap(Boc)-Leu-(N-Me)Ile-?-homoPro-Rink Amide AM resin, was synthesized.

(2)

[1121] To the resin obtained in (1), a solution of (9H-fluoren-9-yl)methyl (4-(chlorosulfonyl)phenyl)carbamate (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (3 mL) was added, and the mixture was shaken at room temperature for 1 hour. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times). Subsequently, DMF solution of piperidine (concentration: 20%, 3 mL) and Oxyma (0.01 mmol) were added, and the resultant was shaken at room temperature for 10 minutes.

(3)

[1122] To the resin obtained in (2), a solution of 4-methoxybenzoyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (2 mL) was added, and the mixture was shaken at room temperature for 3 hours. After the completion of the reaction, the resulting resin was washed with chloroform (3 mL?three times).

(4)

[1123] To the resin obtained in (3), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (12 mg) as a white powder.

Example 8 Synthesis of Compound of Compound No. 892: ([(2S,5S,8S,20S)-8-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxo pentan-2-yl}(methyl)carbamoyl]-5-methyl-3,6,14,17,21-pentaoxo-20-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butanamido}-1,4,7,13,16-pentaazacyclohenicosan-2-yl]acetic acid)

[1124] ##STR00203##

[1125] Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Lys(Dde)-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OAllyl)-OH, and Fmoc-GABA-OH were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-GABA-Glu(OAllyl)-Asp(OtBu)-Ala-Lys(Dde)-(N-Me)Ile-?-homoPro-SAL-PEG resin was synthesized.

(2)

[1126] To the resin obtained in (1), a solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 1.5 hours. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times).

(3)

[1127] To the resin obtained in (2), DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) and allyl alcohol (3.1 mmol) were added, and the mixture was shaken at room temperature for 30 minutes to deprotect the Dde of the Lys side chain. Subsequently, a solution of Fmoc-Gly-OH (0.48 mmol), COMU (0.48 mmol), Oxyma (0.48 mmol), and DIPEA (0.96 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 30 minutes to introduce a Gly residue. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(4)

[1128] To the resin obtained in (3), a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 mmol) and phenylsilane (0.60 mmol) in chloroform (4 mL) was added, and the mixture was shaken at room temperature for 1.5 hours to deprotect the Allyl of the Glu side chain. Subsequently, DMF solution of piperidine (concentration: 20%, 3 mL) was added, and the mixture was shaken at room temperature for 30 minutes to deprotect the Fmoc. After the completion of the reaction, the resulting residue was washed with DMF (3 mL?five times).

(5)

[1129] To the resin obtained in (4), a solution of PyBOP (0.36 mmol) and DIPEA (0.12 mmol) in DMF (4 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting residue was washed with DMF (3 mL?three times) and chloroform (3 mL?three times).

(6)

[1130] To the resin obtained in (5), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (10 mg) as a white powder.

Example 9 Synthesis of Compound of Compound No. 903: ((2S,5S,32R)-2-{[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]carbamoyl}-4,11,20,29,34-pentaoxo-5-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butanamido}-13,16,22,25-tetraoxa-3,10,19,28,33-pentaazaoctatetracontane-1,32,48-tricarboxylic acid)

[1131] ##STR00204##

[1132] Fmoc-Rink Amide AM resin (0.12 mmol) was treated with DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc on the resin. Subsequently, a solution of Fmoc-?-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a ?-homoPro residue. In the same manner, deprotection for Fmoc and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Dde)-OH, and Fmoc-GABA-OH were sequentially condensed, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by piperidine/DMF treatment in the above manner, and H-GABA-Lys(Dde)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-?-homoPro-Rink Amide AM resin was synthesized.

(2)

[1133] To the resin obtained in (1), a solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 2 hours. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?three times).

(3)

[1134] To the resin obtained in (2), DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) was added, and the mixture was shaken at room temperature for 30 minutes. This operation was repeated four times to deprotect the Dde of the Lys side chain. For the resulting resin, condensation and deFmoc were repeatedly performed: specifically, Fmoc-Adox-OH, Fmoc-Adox-OH, and Fmoc-Glu-OtBu were sequentially condensed to extend the Lys side chain with a peptide. Deprotection was performed for the N-terminal Fmoc of the Lys side chain by piperidine/DMF treatment.

(4)

[1135] To the resin obtained in (3), a solution of hexadecanedioic acid (0.96 mmol), COMU (0.18 mmol), Oxyma (0.18 mmol), and DIPEA (0.96 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 1 hour. After the completion of the reaction, the resulting resin was washed with DMF (3 mL?four times) and chloroform (3 mL?three times).

(5)

[1136] To the resin obtained in (4), TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, the mixture was shaken at room temperature for 2 hours, and the resin was removed through filtration. An operation in which cooled diethyl ether was added to the filtrate, a resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to afford a crude product of peptide. The crude product obtained was purified by preparative LCMS (separation condition A). The eluate was fractionated using test tubes, and eluted fractions containing the target product were collected and lyophilized to afford the title compound (29 mg) as a white powder.

[1137] The structures of compounds represented by formula [I-1], which were synthesized in Example 1 or with the same method as in Example 1, are shown in the following table.

##STR00205##

TABLE-US-00005 TABLE 5 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 1 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 2 ?-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 3 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 4 ?-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 5 ?-(d)-Glu (2S,4S)-(4-amino)Pro Val (N-Me)Glu Ape single bond 6 ?-(d)-Glu (2S,4S)-(4-amino)Pro Ile (N-Me)Glu Ape single bond 7 ?-(d)-Glu (2S,4S)-(4-amino)Pro Phe (N-Me)Glu Ape single bond 8 ?-(d)-Glu (2S,4S)-(4-amino)Pro Trp (N-Me)Glu Ape single bond 9 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Ile Ape single bond 10 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Val Ape single bond 11 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Leu Ape single bond 12 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Leu Ape single bond 13 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Phe Ape single bond 14 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Tyr Ape single bond 15 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Ser Ape single bond 16 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu Pro Ape single bond 17 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Asp ?-homoPro single bond 18 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Asp Pro single bond 19 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Asp (d)-Pro single bond 20 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu ?-homoPro single bond 21 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Pro single bond 22 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu ?-Ala single bond 23 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu GABA single bond 24 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Acp single bond 25 ?-(d)-Glu (2S,4S)-(4-amino)Pro Let (N-Me)Glu (d)-Pro single bond 26 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Lys single bond 27 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu (d)-Lys single bond 28 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Arg single bond 29 ?-(d)-Glu (2S,4S)-(4-amimo)Pro Leu (N-Me)Glu (d)-Arg single bond 30 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu single bond single bond 31 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu single bond single bond single bond 32 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape Pro 33 ?-(d)-Glu (26,4S)-(4-amino)Pro Leu (N-Me)Glu Ape Lys 34 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape (d)-Lys 35 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape Arg 36 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape (d)-Arg 37 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape (d)-Lys-(d)-Lys 38 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Ile ?-homoPro single bond 39 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Ile ?-homoPro single bond

[1138] The structure of a compound represented by formula [I-2], which was synthesized with the same method as in Example 1, is shown in the following table. [1139] [I-2]

TABLE-US-00006 TABLE 6 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 40 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond

[1140] The structure of a compound represented by formula [I-3], which was synthesized with the same method as in Example 1, is shown in the following table. [1141] [I-3]

TABLE-US-00007 TABLE 7 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 41 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond

[1142] The structure of a compound represented by formula [I-4], which was synthesized with the same method as in Example 1, is shown in the following table.

##STR00206##

TABLE-US-00008 TABLE 8 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 42 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond

[1143] The structure of a compound represented by formula [I-5], which was synthesized with the same method as in Example 1, is shown in the following table. [1144] [I-5]

TABLE-US-00009 TABLE 9 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 43 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond

[1145] The structure of a compound represented by formula [I-6], which was synthesized with the same method as in Example 1, is shown in the following table.

##STR00207##

TABLE-US-00010 TABLE 10 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 44 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond

[1146] The structures of compounds represented by formula [I-7], which were synthesized with the same method as in Example 1, are shown in the following table. [1147] [I-7]

TABLE-US-00011 TABLE 11 Compound No. AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c 45 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Ile Ape single bond 46 ?-(d)-Asp (S)-piperazine Leu (N-Me)Ile Ape single bond 47 ?-(d)-Asp (2S,4R)-(4-amino)Pro Leu (N-Me)Ile Ape single bond 48 ?-(d)-Asp (2S,4S)-(4-hydroxy)Pro Leu (N-Me)Ile ?-homoPro single bond 49 ?-(d)-Asp (2S,4R)-(4-hydroxy)Pro Leu (N-Me)Ile Ape single bond 50 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Glu ?-honoPro single bond 51 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Ile ?-homoPro single bond 52 ?-(d)-Asp (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 53 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Glu Ape single bond 54 ?-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Ile ?-homoPro single bond 66 ?-(d)-Glu (2S,4S)-(4-amino)Pro Leu (N-Me)Ile ?-homoPro single bond

[1148] The structures of compounds represented by formula [I-8], which were synthesized with the same method as in Example 1, are shown in the following table.

##STR00208##

TABLE-US-00012 TABLE 12 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 56 H GABA Asn Asp Ala Leu Met Pro single bond NH.sub.2 57 H GABA Asn Asp Ala Leu (N-Me)Val Pro single bond NH.sub.2 58 H GABA Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 59 H GABA Asn Asp Ala Leu (N-Me)Val ?-homoPro single bond NH.sub.2 60 H (N-Me)GABA Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 61 H GABA Asn Asp Dap Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 62 H GABA Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 63 H GABA Asn Asp Orn Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 64 H GABA Asn Asp Ala Leu Glu ?-homoPro single bond NH.sub.2 65 H GABA (N-Me)Asp Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 66 H GABA Asn Asp Ala Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 67 H GABA Asn Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 68 H GABA Asn Asp Dab Let (N-Me)Glu ?-homoPro single bond NH.sub.2 69 H GABA Asn Asp Deb Leu (N-Me)Glu Pro single bond NH.sub.2 70 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 71 H GABA (N-Me)Asn Asp Dab Let (N-Me)Ile Pro single bond NH.sub.2 72 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 73 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Glu Pro single bond NH.sub.2 74 H GABA Asn Asp Ala Dab (N-Me)Ile ?-homoPro single bond NH.sub.2 75 H GABA Asn Asp Ala Leu homoGlu ?-homoPro single bond NH.sub.2 76 H GABA Asn Asp Dab Let (N-Me)Glu ?-homoPro single bond OH 77 F Ape Glu Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 78 F Ape Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 79 F Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 80 H.sub.2NCO Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 81 H.sub.2NCO Ape Gln Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 82 H.sub.2NCO Ape (d)-Ser Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 83 H.sub.2NCO Ape homoSer Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 84 H Ape (d)-Thr Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 85 H Ape (d)-Thr Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 86 F Ape (d)-Thr Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 87 F Ape (d)-Thr Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 88 F Ape Arg Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 89 F Ape Arg Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 90 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro (d)-Lys NH.sub.2 91 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro (d)-Arg NH.sub.2

[1149] The structures of compounds represented by formula [I-9], which were synthesized in Example 2 or with the same method as in Example 2, are shown in the following table.

##STR00209##

TABLE-US-00013 TABLE 13 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 92 H GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 93 F GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 94 H GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 95 F GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 96 H GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Aib single bond NH.sub.2 97 F GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Aib single bond NH.sub.2 98 H GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Aib single bond NH.sub.2 99 F GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Aib single bond NH.sub.2 100 H (N-Me)GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 101 F (N-Me)GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 102 Me (N-Me)GABA (N-Me)Ala Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 103 H (N-Me)GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 104 F (N-Me)GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 105 Me (N-Me)GABA (N-Me)Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 106 H GABA Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 107 H GABA Asn Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 108 H GABA Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 109 H GABA Asn Asp Dab Leu (N-Me)Glu Pro single bond NH.sub.2 110 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 111 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 112 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 113 H GABA (N-Me)Asn Asp Dab Leu (N-Me)Glu Pro single bond NH.sub.2 114 H GABA (d)-Asn Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 115 H GABA (N-Me)Gly Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 116 H GABA Aze(2) Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 117 H GABA Pro Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 118 H GABA homoPro Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 119 H GABA (N-Me)Val Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 120 H GABA (N-Me)Leu Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 121 H GABA (N-Me)Ile Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 122 H GABA (N-Me)Met Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 123 H GABA (d)-Lys Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 124 H GABA (N-Me)Phe Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 125 H GABA (N-Me)Asp Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 126 H GABA (N-Me)Glu Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 127 H GABA (N-Me)Lys Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 128 H GABA Gln Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 129 H GABA (N-Me)Tyr Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 130 H GABA (N-Me)Trp Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 131 H GABA (N-Me)Thr Asp Ala Leu (N-Me)Ile Pro single bond NH.sub.2 132 H GABA Aze(2) Asp Dap Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 133 H GABA Aze(2) Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 134 H GABA (N-Me)Met Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 135 H GABA (N-Me)Val Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 136 H GABA (N-Me)Leu Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 137 F GABA (N-Me)Asn Asp Dab Leu (N-Me)Ile Pro single bond NH.sub.2 138 F GABA (N-Me)Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 139 F GABA (N-Me)Asn Asp Dab Leu (N-Me)Asp ?-homoPro single bond NH.sub.2 140 F GABA (N-Me)Asn Asp Dat Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 141 F GABA (N-Me)Asn Asp Dab Leu (N-Me)Asp Pro single bond NH.sub.2 142 F GABA (N-Me)Asn Asp Dab Leu (N-Me)Glu Pro single bond NH.sub.2 143 H GABA Val Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 144 H GABA Glu Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 145 H GABA Orn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 146 H GABA Val Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 147 H GABA Glu Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 148 H GABA Orn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 149 F GABA Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 150 F GABA Val Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 151 F GABA Glu Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 152 F GABA Orn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 153 F GABA Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 154 H GABA (N-Me)Asn Asp Dap(Me) Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 155 H GABA Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 156 H GABA Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2

[1150] The structures of compounds represented by formula [I-10], which were synthesized with the same method as in Example 9, are shown in the following table.

##STR00210##

TABLE-US-00014 TABLE 14 Compound No. R.sup.B1 L.sup.1 AA.sup.N5 AA.sup.N4 AA.sup.N3 AA.sup.N2 AA.sup.N1 n AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 157 H.sub.2NCO GABA ?-Glu Adox Adox single bond single bond 12 Asp Dab Leu (N-Me)Glu ?-homoPro 158 H.sub.2NCO GABA ?-Glu Adox Adox single bond single bond 14 Asp Dab Leu (N-Me)Glu ?-homoPro 159 H.sub.2NCO GABA (d)-Lys (d)-Lys (d)-Lys single bond single bond 12 Asp Dab Leu (N-Me)Glu ?-homoPro 160 H.sub.2NCO GABA (d)-Lys (d)-Lys (d)-Lys single bond single bond 14 Asp Dab Leu (N-Me)Glu ?-homoPro

[1151] The structures of compounds represented by formula [I-9], which were synthesized in Example 2 or with the same method as in Example 2, are shown in the following table.

##STR00211##

TABLE-US-00015 TABLE 15 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 161 F GABA Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond OH 162 F GABA Gln Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 163 F Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 164 F Ape Gln Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 165 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH 166 H Adox Asn Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 167 H Adox Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 168 MeSO.sub.2 Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 169 MeSO.sub.2 Ape (d)-Ser Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 170 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 171 F Ape Glu Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 172 F Ape (d)-Ser Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 173 H Ape (d)-Thr Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 174 H Ape (d)-Thr Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 175 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro (d)-Lys NH.sub.2 176 F Ape Gln Asp Dab Leu (N-Me)Ile ?-homoPro (d)-Arg NH.sub.2

[1152] The structures of compounds represented by formula [I-9], which were synthesized in Example 3 or with the same method as in Example 3, are shown in the following table.

##STR00212##

TABLE-US-00016 TABLE 16 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 177 MeHNCO GABA Asn Asp Ala Leu Met Pro single bond NH.sub.2 178 HO.sub.2CH.sub.2CHNCO Ape Asn Asp Ala Leu Met Pro single bond NH.sub.2 179 H.sub.2N(CH.sub.2).sub.2NHCO Ape Asu Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 180 H.sub.2N(CH.sub.2).sub.3NHCO Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 181 H.sub.2N(CH.sub.2).sub.4NHCO Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 182 HO(CH.sub.2).sub.3NHCO Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 183 HO.sub.2C(CH.sub.2).sub.2NHCO Ape Asn Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 184 MeNHCO Ape Lys Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 185 MeNHCO Ape Lys Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 186 MeNHCO Acp Lys Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 187 NeNHCO Acp Lys Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 188 MeNHCO Ape Arg Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 189 MeNHCO Ape Arg Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 190 MeNHCO Acp Arg Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 191 MeNHCO Acp Arg Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 192 EtNHCO Ape Lys Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 193 EtNHCO Ape Lys Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 194 EtNHCO Acp Lys Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 195 EtNHCO Acp Lys Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 196 EtNHCO Ape Arg Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 197 EtNHCO Ape Arg Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 198 EtNHCO Acp Arg Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 199 H.sub.2NCO(CH.sub.2).sub.4NHCO Ape Glu Asp Dab Leu (N-Me)Glu ?-homoPro single bond NH.sub.2 200 HO.sub.2C(CH.sub.2).sub.4NHCO Ape Glu Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2 201 H.sub.2NCO(CH.sub.2).sub.4NHCO Ape Glu Asp Dab Leu (N-Me)Ile ?-homoPro single bond NH.sub.2

[1153] The structure of a compound represented by formula [I-I1], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00213##

TABLE-US-00017 TABLE 17 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 202 GABA Asn Asp Ala Leu Met Pro single bond NH.sub.2

[1154] The structures of compounds represented by formula [I-12], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00214##

TABLE-US-00018 TABLE 18 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 203 Acp Asn Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond 204 Acp Gln Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond 205 Acp Ala Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond

[1155] The structures of compounds represented by formula [I-13], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00215##

TABLE-US-00019 TABLE 19 Compound No L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 206 Acp Asn Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond 207 Acp Gln Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond 208 Acp Ala Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond 209 Ape Asn Asp Dab Leu (NMe) ? -homo single NH.sub.2 Glu Pro bond

[1156] The structures of compounds represented by formula [I-14], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00216##

TABLE-US-00020 TABLE 20 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 210 GABA Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 211 GABA Val Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 212 GABA Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 213 GABA Orn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 214 GABA Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 215 GABA Val Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 216 GABA Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 217 GABA Orn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 218 GABA (NMe) Asp Dap Leu (NMe) ? - single NH.sub.2 Asn (Me) Ile homoPro bond 219 GABA (NMe) Asp Dap Leu (NMe) ? - single NH.sub.2 Asn (Me) Glu homoPro bond 220 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Asn (Me) Glu homoPro bond 221 ? -Ala Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 222 Ape Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 223 Ape Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 224 ? -Ala Asn Asp Dap Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 225 GABA Asn Asp Dap Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 226 Ape Asn Asp Dap Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 227 GABA Glu Asp Dap Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 228 Ape Asp Dap Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 229 ? -Ala Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 230 Ape Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 231 ? -Ala Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 232 Ape Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 233 Ape Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 234 Ape Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 235 GABA Asn Asp Dab Leu (NMe) ? - single OH Glu homoPro bond 236 GABA Asn Asp Dab Leu (NMe) ? - single OH Ile homoPro bond 237 GABA Gln Asp Dab Leu (NMe) ? - single OH Glu homoPro bond 238 GABA (d)- Asp Dab Leu (NMe) ? - single OH Asn Ile homoPro bond 239 GABA (d)- Asp Dab Leu (NMe) ? - single OH Asn Ile homoPro bond 240 GABA Asn Asp Dab Leu (NMe) ? - single OH Asp homoPro bond 241 GABA Asn Asp Dab Leu (NMe) ? - single OH Asn homoPro bond 242 GABA (d)- Asp Dab Leu (NMe) ? - single OH Gln Glu homoPro bond 243 GABA Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 244 GABA Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 245 ? -Lys Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 246 ? -Lys Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 247 ? -(d)- Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Ile homoPro bond 248 GABA Asn Asp Dab Leu (NMe) ? - single NH.sub.2 (Me).sub.2 Ile homoPro bond 249 GABA Gln Asp Dab Leu (NMe) ? - single NH.sub.2 (Me).sub.2 Ile homoPro bond 250 GABA (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Glu homoPro bond 251 GABA (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Ile homoPro bond 252 GABA Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Asp homoPro bond 253 GABA (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Gln Glu homoPro bond 254 Ape Asn Asp Dab Leu (NMe) ? - single NHEt Ile homoPro bond 255 Ape Asn Asp Dab Leu (NMe) ? - single piperidin- Ile homoPro bond 1-yl 256 Acp Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 257 Acp Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 258 Acp Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 259 Ape Asn Asp Dab Leu (NMe) ? - single OH Glu homoPro bond 260 Ape Gln Asp Dab Leu (NMe) ? - single OH Glu homoPro bond 261 Ape Gln Asp Dab Leu (NMe) ? - single OH Ile homoPro bond 262 Adox Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 263 Adox Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 264 Adox Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 265 Adox Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 266 Adox Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 267 Adox Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 268 Ape Asn Asp Dab Leu (NMe) ? - single NHMe Glu homoPro bond 269 Ape Asn Asp Dab Leu (NMe) ? - single azetidine- Glu homoPro bond 1-yl 270 Ape Asn Asp Dab Leu (NMe) ? - single pyrrolidin- Glu homoPro bond 1-yl 271 Ape Asn Asp Dab Leu (NMe) ? - single (4- Glu homoPro bond OH)piperidin- 1-yl 272 Ape Asn Asp Dab Leu (NMe) ? - single NH(CH.sub.2).sub.2OH Glu homoPro bond 273 Ape Asn Asp Dab Leu (NMe) ? - single azetidin- Ile homoPro bond 1-yl 274 Ape Asn Asp Dab Leu (NMe) ? - single (3- Ile homoPro bond OH)azetidin- 1-yl 275 Ape Asn Asp Dab Leu (NMe) ? - single pyrrolidin- Ile homoPro bond 1-yl 276 Ape Asn Asp Dab Leu (NMe) ? - single (4- Ile homoPro bond OH)piperidin- 1-yl 277 Ape Asn Asp Dab Leu (NMe) ? - single NH(CH.sub.2).sub.2OH Ile homoPro bond 278 Ape Glu Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 279 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Ile homoPro bond 280 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Glu homoPro bond 281 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Ile homoPro bond 282 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Glu homoPro bond 283 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Ile homoPro bond 284 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Asn Glu homoPro bond 285 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Glu homoPro bond 286 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ala Glu homoPro bond 287 Ape Phe Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 288 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Phe Glu homoPro bond 289 Ape Tyr Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 290 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Tyr Glu homoPro bond 291 ? -Dab Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 292 ? -(d)- Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Orn Glu homoPro bond 293 GABA ? -Dap Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 294 GABA ? -(d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Dap Glu homoPro bond 295 GABA ? -Ala Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 296 Ape Dab Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 297 Ape Dap Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 298 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Dab Glu homoPro bond 299 ? -(d)- Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Dab Glu homoPro bond 300 GABA Aze (2) Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 301 GABA Aze (2) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 302 Ape Aze (2) Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 303 Ape Aze (2) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 304 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu Ile homoPro bond 305 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu Glu homoPro bond 306 ? -Dap Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 307 ? -(d)- Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Dap Glu homoPro bond 308 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu Glu homoPro bond 309 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Ile Ile homoPro bond 310 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Ile homoPro bond 311 GABA (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Glu homoPro bond 312 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Ile homoPro bond 313 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Glu homoPro bond 314 NH(CH.sub.2).sub.2OCH.sub.2CO Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 315 NH(CH.sub.2).sub.2OCH.sub.2CO (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Ile homoPro bond

[1157] The structures of compounds represented by formula [I-15], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00217##

TABLE-US-00021 TABLE 21 Compound No L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 316 Ape Asn Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 317 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Ile homoPro bond

[1158] The structures of compounds represented by formula [I-14], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00218##

TABLE-US-00022 TABLE 22 Compound No L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 318 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Glu Ile homoPro bond 319 Ape Thr Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 320 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Glu homoPro bond 321 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Pro Glu homoPro bond 322 Ape Trp Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 323 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Leu Ile homoPro bond 324 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Leu Glu homoPro bond 325 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Met Ile homoPro bond 326 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Met Glu homoPro bond 327 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Trp Glu homoPro bond 328 Ape His Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 329 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 His Glu homoPro bond 330 Ape Cys Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 331 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Cys Glu homoPro bond 332 Ape Arg Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 333 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Arg Glu homoPro bond 334 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Glu Glu homoPro bond 335 NH(CH.sub.2).sub.2OCH.sub.2CO (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Glu homoPro bond 336 Ape Lys Asp Dab Leu (NMe) ? - single NH.sub.2 (Ac) Ile homoPro bond 337 Ape Lys Asp Dab Leu (NMe) ? - single NH.sub.2 (Ac) Glu homoPro bond 338 Ape Cit Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 339 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Cit Ile homoPro bond 340 Ape Cit Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 341 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Cit Glu homoPro bond 342 Ape ? -Asp Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 343 Ape ? -(d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Asp Glu homoPro bond 344 Ape Lys Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 345 Ape Met Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 346 Ape Met Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 347 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Ile homoPro bond 348 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Ile homoPro bond 349 Adox Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 350 Ape (d)- Asp Dab Leu (NMe) ? - (d)-Lys- NH.sub.2 Thr Glu homoPro (d)-Lys- (d)-Lys 351 Ape (d)- Asp Dab Leu (NMe) ? - (d)-Lys- NH.sub.2 Thr Ile homoPro (d)-Lys- (d)-Lys 352 GABA (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Glu homoPro bond 353 GABA (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Ile homoPro bond 354 Acp (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Glu homoPro bond 355 Acp (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Ile homoPro bond 356 Ape Arg Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 357 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Gln Ile homoPro bond 358 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Gln Glu homoPro bond 359 Ape Asn Asp Dab Phe (NMe) ? - single NH.sub.2 Ile homoPro bond 360 Ape Asn Asp Dab Phe (NMe) ? - single NH.sub.2 Glu homoPro bond 361 ? -Orn (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Glu homoPro bond 362 ? -Orn (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Glu homoPro bond 363 ? -Orn Lys Asp Dab Leu (NMe) ? - single NH.sub.2 Glu homoPro bond 364 ? -Orn (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Ser Ile homoPro bond 365 ? -Orn (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Thr Ile homoPro bond 366 ? -Orn Lys Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 367 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Arg Glu homoPro bond 368 Ape (NMe) Asp Dab Leu (NMe) ? - single NH.sub.2 Arg Ile homoPro bond 369 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Glu homoPro bond 370 Ape (d)- Asp Dab Leu (NMe) ? - single NH.sub.2 Lys Ile homoPro bond 371 Ape Lys Asp Dab Leu Dap ? - single NH.sub.2 homoPro bond 372 Ape Lys Asp Dab Leu Dab ? - single NH.sub.2 homoPro bond 373 Ape Lys Asp Dab Leu Orn ? - single NH.sub.2 homoPro bond 374 Ape Lys Asp Dab Leu (NMe) ? - single NH.sub.2 Arg homoPro bond 375 Ape Arg Asp Dab Leu Dap ? - single NH.sub.2 homoPro bond 376 Ape Arg Asp Dab Leu Dab ? - single NH.sub.2 homoPro bond 377 Ape Lys Asp Dab Leu Orn ? - single NH.sub.2 homoPro bond 378 Ape Arg Asp Dab Leu (NMe) ? - single NH.sub.2 Lys homoPro bond 379 Ape Gln Asp Dap Leu (NMe) single single NH.sub.2 Ile bond bond 380 Ape Gln Asp Dab Leu (NMe) single single NH.sub.2 Glu bond bond 381 Ape Gln Asp Dab Leu (NMe) single single NH.sub.2 Ile bond bond 382 Ape Gln Asp Dab Leu single single NH.sub.2 bond bond 383 Ape Gln aspartimide Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 384 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Glu homoPro Lys 385 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Ile homoPro Lys 386 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Glu homoPro Arg 387 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Ile homoPro Arg 388 Ape Arg Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Glu homoPro Lys 389 Ape Arg Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Ile homoPro Lys 390 Ape Arg Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Glu homoPro Arg 391 Ape Arg Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Ile homoPro Arg 392 Ape Gln Asp Dab Leu (NMe) Pro single NH.sub.2 Ile bond 393 Ape Gln Asp Dab Leu (NMe) Pro single NH.sub.2 Glu bond 394 Ape Glu Asp Dab Leu (NMe) Pro single NH.sub.2 Ile bond 395 Ape Glu Asp Dab Leu (NMe) Pro single NH.sub.2 Glu bond 396 Ape Arg Asp Dab Leu (NMe) Pro single NH.sub.2 Ile bond 397 Ape Arg Asp Dab Leu (NMe) Pro single NH.sub.2 Glu bond 398 Ape (d)- Asp Dab Leu (NMe) Pro single NH.sub.2 Thr Ile bond 399 Ape (d)- Asp Dab Leu (NMe) Pro single NH.sub.2 Thr Glu bond 400 Ape Gln Asp Dab Leu (NMe) Pro (d)- NH.sub.2 Glu Arg 401 Ape Gln Asp Dab Leu (NMe) Pro (d)- NH.sub.2 Ile Arg 402 Ape Gln Asp Dab Leu (NMe) Pro (d)- NH.sub.2 Glu Lys 403 Ape Gln Asp Dab Leu (NMe) Pro (d)- NH.sub.2 Ile Lys 404 Ape Gln Asp Dab Leu (NMe) Pro Lys NH.sub.2 Glu 405 Ape Gln Asp Dab Leu (NMe) Pro Lys NH.sub.2 Ile 406 Ape Gln Asp Dab Leu (NMe) Pro Arg NH.sub.2 Glu 407 Ape Gln Asp Dab Leu (NMe) Pro Arg NH.sub.2 Ile 408 Ape Gln Asp Dab Leu (NMe) Arg single NH.sub.2 Glu bond 409 Ape Gln Asp Dab Leu (NMe) Arg single NH.sub.2 Ile bond 410 Ape Gln Asp Dab Leu (NMe) Lys single NH.sub.2 Glu bond 411 Ape Gln Asp Dab Leu (NMe) Lys single NH.sub.2 Ile bond 412 Ape Gln Asp Dab Leu (NMe) ? -Ala single NH.sub.2 Glu bond 413 Ape Gln Asp Dab Leu (NMe) ? -Ala single NH.sub.2 Ile bond 414 Ape Gln Asp Dab Leu (NMe) GABA single NH.sub.2 Glu bond 415 Ape Gln Asp Dab Leu (NMe) GABA single NH.sub.2 Ile bond 416 Ape Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Glu bond 417 Ape Gln Asp Dab Leu (NMe) His single NH.sub.2 Glu bond 418 Ape Gln Asp Dab Leu (NMe) (d)- single NH.sub.2 Ile Arg bond 419 Ape Gln Asp Dab Leu (NMe) (d)- single NH.sub.2 Glu Arg bond 420 Ape Gln Asp Dab Leu (NMe) (d)- single NH.sub.2 Ile Lys bond 421 Ape Gln Asp Dab Leu (NMe) (d)- single NH.sub.2 Glu Lys bond 422 Ape Gln Asp Dab Leu (NMe) Dap single NH.sub.2 Glu bond 423 Ape Gln Asp Dab Leu (NMe) Dab single NH.sub.2 Glu bond 424 Ape Gln Asp Dab Leu (NMe) Orn single NH.sub.2 Ile bond 425 Ape Gln Asp Dab Leu (NMe) Orn single NH.sub.2 Glu bond 426 Ape Gln Asp Dab Leu (NMe) homoPro single NH.sub.2 Glu bond 427 Ape Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Ile bond 428 Ape Gln Asp Dab Leu (NMe) (2S, 4R) - single NH.sub.2 Ile (4-amino)Pro bond 429 Ape Gln Asp Dab Leu (NMe) ? - Arg- NH.sub.2 Glu homoPro Arg 430 Ape Gln Asp Dab Leu (NMe) ? - Arg- NH.sub.2 Ile homoPro Arg 431 Ape Gln Asp Dab Leu (NMe) Pro Arg- NH.sub.2 Glu Arg 432 Ape Gln Asp Dab Leu (NMe) Pro Arg- NH.sub.2 Ile Arg 433 Ape Gln Asp Dab Leu (NMe) ? - (d)-Arg- NH.sub.2 Glu homoPro (d)-Arg 434 Ape Gln Asp Dab Leu (NMe) ? - (d)-Arg- NH.sub.2 Ile homoPro (d)-Arg 435 Ape Gln Asp Dab Leu (NMe) Pro (d)-Arg- NH.sub.2 Glu (d)-Arg 436 Ape Gln Asp Dab Leu (NMe) Pro (d)-Arg- NH.sub.2 Ile (d)-Arg 437 Ape Gln Asp Dab Leu (NMe) ? -Dap single NH.sub.2 Ile bond 438 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Dap bond 439 Ape Gln Asp Dab Leu (NMe) ? -Dab single NH.sub.2 Ile bond 440 Ape Gln Asp Dab Leu (NMe) ? - Lys- NH.sub.2 Glu homoPro Lys 441 Apo Gln Asp Dab Leu (NMe) ? - Lys- NH.sub.2 Ile homoPro Lys 442 Ape Gln Asp Dab Leu (NMe) Pro Lys- NH.sub.2 Glu Lys 443 Ape Gln Asp Dab Leu (NMe) Pro Lys- NH.sub.2 Ile Lys 444 Ape Gln Asp Dab Leu (NMe) ? - (d)-Lys- NH.sub.2 Glu homoPro (d)-Lys 445 Ape Gln Asp Dab Leu (NMe) ? - (d)-Lys- NH.sub.2 Ile homoPro (d)-Lys 446 Ape Gln Asp Dab Leu (NMe) Pro (d)-Lys- NH.sub.2 Glu (d)-Lys 447 Ape Gln Asp Dab Leu (NMe) Pro (d)-Lys- NH.sub.2 Ile (d)-Lys 448 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Dap bond 449 Ape Gln Asp Dab Leu (NMe) ? -Orn single NH.sub.2 Ile bond 450 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Orn bond 451 Ape Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ile bond 452 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 453 Ape Gln ? -Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 454 Ape Gln Asp Dab Leu (NMe) Aze (2) single NH.sub.2 Ile bond 455 Ape Gln Asp Dab Leu (NMe) (d)- single NH.sub.2 Ile Aze (2) bond 456 Ape Gln Asp Dab Leu (NMe) (NMe)- single NH.sub.2 Ile ? -Ala bond 457 Ape Gln Asp Dab Leu (NMe) GABA Arg NH.sub.2 Ile 458 Ape Gln Asp Dab Leu (NMe) GABA (d)- NH.sub.2 Ile Arg 459 Ape Gln Asp Dab Leu (NMe) GABA Lys NH.sub.2 Ile 460 Ape Gln Asp Dab Leu (NMe) GABA (d)- NH.sub.2 Ile Lys 461 Ape Gln Asp Dab Leu (NMe) GABA Arg- NH.sub.2 Ile Arg 462 Ape Gln Asp Dab Leu (NMe) GABA (d)-Arg- NH.sub.2 Ile (d)-Arg 463 Ape Gln Asp Dab Leu (NMe) GABA (d)-Lys- NH.sub.2 Ile (d)-Lys 464 Ape Gln Asp Dab Leu (NMe) GABA Arg NH.sub.2 Glu 465 Ape Gln Asp Dab Leu (NMe) GABA (d)-Arg NH.sub.2 Glu 466 Ape Gln Asp Dab Leu (NMe) GABA Lys NH.sub.2 Glu 467 Ape Gln Asp Dab Leu (NMe) GABA (d)- NH.sub.2 Glu Lys 468 Ape Gln Asp Dab Leu (NMe) GABA Arg- NH.sub.2 Glu Arg 469 Ape Gln Asp Dab Leu (NMe) GABA (d)-Arg- NH.sub.2 Glu (d)-Arg 470 Ape Gln Asp Dab Leu (NMe) GABA Lys- NH.sub.2 Glu Lys 471 Ape Gln Asp Dab Leu (NMe) GABA (d)-Lys- NH.sub.2 Glu (d)-Lys 472 Ape Gln Asp Dab Leu (NMe) Ape Arg NH.sub.2 Ile 473 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Ile Arg 474 Ape Gln Asp Dab Leu (NMe) Ape Lys NH.sub.2 Ile 475 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Ile Lys 476 Ape Gln Asp Dab Leu (NMe) Ape Arg- NH.sub.2 Ile Arg 477 Ape Gln Asp Dab Leu (NMe) Ape (d)-Arg- NH.sub.2 Ile (d)-Arg 478 Ape Gln Asp Dab Leu (NMe) Ape Lys- NH.sub.2 Ile Lys 479 Ape Gln Asp Dab Leu (NMe) Ape (d)-Lys- NH.sub.2 Ile (d)-Lys 480 Ape Gln Asp Dab Leu (NMe) Acp single NH.sub.2 Ile bond 481 Ape Gln Asp Dab Ile (NMe) Ape single NH.sub.2 Glu bond 482 Ape Gln Asp Dab Ile (NMe) Ape single NH.sub.2 Ile bond 483 Ape Gln Asp Dab Leu (NMe) ? - Arg NH.sub.2 Ile homoPro 484 Ape Gln Asp Dab Leu (NMe) ? - Lys NH.sub.2 Ile homoPro 485 Ape Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Val bond 486 Ape Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Leu bond 487 Ape Gln Asp Dab Ile (NMe) Ape (d)- NH.sub.2 Ile Lys 488 Ape Gln Asp Dab Ile (NMe) Ape (d)- NH.sub.2 Ile Arg 489 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Val Arg 490 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Leu Lys 491 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Leu Arg 492 Ape Gln Asp Dab Leu (NMe) single single NH(CH.sub.2).sub.2NH.sub.2 Ile bond bond 493 Ape Gln Asp Dab Leu (NMe) Ape single NH(CH.sub.2).sub.2NH.sub.2 Ile bond 494 Ape Gln Asp Dab Leu (NMe) single single NH(CH.sub.2).sub.4NH.sub.2 Ile bond bond 495 Ape Gln Asp Dab Leu (NMe) single single NH(CH.sub.2).sub.5NH.sub.2 Ile bond bond 496 ? -Orn Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 497 ? -Orn Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Ile bond 498 ? -Orn Ala Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 499 ? -Orn Ala Asp Dab Leu (NMe) Ape single NH.sub.2 Ile bond 500 ? -Orn Lys Asp Dab Leu (NMe) ? - single NH.sub.2 (Ac) Ile homoPro bond 501 ? -Orn Lys Asp Dab Leu (NMe) Ape single NH.sub.2 (Ac) Ile bond 502 ? -Orn Dap Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 503 ? -Orn Dab Asp Dab Leu (NMe) Ape single NH.sub.2 Ile bond 504 ? -Orn Gly Asp Dab Leu (NMe) ? - single NH.sub.2 Ile homoPro bond 505 ? -Orn Gly Asp Dab Leu (NMe) Ape single NH.sub.2 Ile bond 506 ? -Orn Gln Asp Dab Leu (NMe) ? - single NH.sub.2 Val homoPro bond 507 ? -Orn Gln Asp Dab Leu (NMe) Ape single NH.sub.2 Val bond 508 Ape (d)- Asp Dab Leu (NMe) Pro single NH.sub.2 Thr Val bond 509 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Val homoPro Arg 510 Ape Gln Asp Dab Leu (NMe) ? - (d)- NH.sub.2 Val homoPro Lys 511 Ape Gln Asp Dab Leu (NMe) ? -Ala single NH.sub.2 Val bond 512 Ape Gln Asp Dab Leu (NMe) GABA single NH.sub.2 Val bond 513 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Lys bond 514 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Val Arg 515 Ape Gln Asp Dab Leu (NMe) Ape (d)- NH.sub.2 Val Lys 516 ? -Orn Dap Asp Dab Leu (NMe) ? - single NH.sub.2 Val homoPro bond 517 ? -Orn Dap Asp Dab Leu (NMe) Ape single NH.sub.2 Val bond 518 Ape Gln Asp Dab Leu (NMe) ? -(d)- (d)- NH.sub.2 Ile Lys Arg 519 Ape Gln Asp Dab Leu (NMe) ? -(d)- (d)- NH.sub.2 Ile Lys Lys 520 Ape Gln Asp Dab Leu (NMe) ? -Dab ? -Ala NH.sub.2 Ile 521 Ape Gln Asp Dab Leu (NMe) ? -Dab GABA NH.sub.2 Ile 522 ? -(d)- single Asp Dab Leu (NMe) Ape single NH.sub.2 Lys bond Ile bond 523 ? -Lys single Asp Dab Leu (NMe) Ape single NH.sub.2 bond Ile bond 524 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Lys bond 525 ? -Orn Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Val bond 526 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 527 ? -Orn Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ile bond 528 ? -Orn Arg Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 529 Ape Gln Asp Dab Leu (NMe) ? -Dap single NH.sub.2 Val bond 530 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Dap bond 531 Ape Gln Asp Dab Leu (NMe) ? -Dab single NH.sub.2 Val bond 532 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Dab bond 533 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Orn bond 534 Ape Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Val bond 535 ? -Orn Gln Asp Dab Leu (NMe) ? -Dap single NH.sub.2 Val bond 536 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Dap bond 537 ? -Orn Gln Asp Dab Leu (NMe) ? -Dab single NH.sub.2 Val bond 538 ? -Orn Gln Asp Dab Leu (NMe) ? -Orn single NH.sub.2 Val bond 539 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Orn bond 540 Ape Gln Asp Dab Leu (NMe) ? -Dab ? -Ala NH.sub.2 Val 541 Ape Gln Asp Dab Leu (NMe) ? -Dab GABA NH.sub.2 Val 542 Ape Gln Asp Dab Leu (NMe) ? -Orn single NH.sub.2 Val bond 543 Ape Arg Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ile bond 544 Ape Arg Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 545 Ape Arg Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Val bond 546 Ape Arg Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Lys bond 547 Ape (d)- Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Thr Ile bond 548 Ape (d)- Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Thr Ile Lys bond 549 Ape (d)- Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Thr Val bond 550 Ape (d)- Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Thr Val Lys bond 551 ? -Orn Arg Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ile bond 552 ? -Orn Arg Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Val bond 553 ? -Orn Arg Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Val Lys bond 554 ? -Orn (d)- Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Thr Ile bond 555 ? -Orn (d)- Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Thr Ile Lys bond 556 ? -Orn (d)- Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Thr Val bond 557 ? -Orn (d)- Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Thr Val Lys bond 558 Ape Gln Asp Dab Leu (NMe) ? -Dap ? -Ala NH.sub.2 Ile 559 ? -Orn Gln Asp Dab Leu (NMe) ? -Dap ? -Ala NH.sub.2 Ile 560 ? -Orn Gln Asp Dab Leu (NMe) ? -Dap ? -Ala NH.sub.2 Val 561 ? -Orn Gln Asp Dab Leu (NMe) ? -Dap single NH.sub.2 Ile bond 562 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Dap bond 563 ? -Orn Gln Asp Dab Leu (NMe) ? -Dab single NH.sub.2 Ile bond 564 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Dab bond 565 ? -Orn Gln Asp Dab Leu (NMe) ? -Orn single NH.sub.2 Ile bond 566 ? -Orn Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Orn bond 567 Ape Asn Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ile bond 568 Ape Asn Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 569 Ape Gln Asp Dap Leu (NMe) ? -Lys single NH.sub.2 Ile bond 570 Ape Gln Asp Dap Leu (NMe) ? -(d)- single NH.sub.2 Ile Lys bond 571 Ape Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Glu bond 572 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Glu Lys bond 573 Ape Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Ala bond 574 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Ala Lys bond 575 Ape Gln Asp Dab Leu (NMe) ? -Lys single NH.sub.2 Leu bond 576 Ape Gln Asp Dab Leu (NMe) ? -(d)- single NH.sub.2 Leu Lys bond 577 Ape Gln Asp Dab Leu (NMe) ? -(d)- single OH Ile Lys bond 578 Ape Gln Asp Dab Leu (NMe) Aze (2) single OH Ile bond 579 Ape Gln Asp Aze Leu (NMe) ? - single NH.sub.2 (2) Ile homoPro bond 580 Ape Lys Asp Aze Leu (NMe) Ape single NH.sub.2 (2) Ile bond 581 Ape Lys Asp Aze Leu (NMe) ? - single NH.sub.2 (2) Ile homoPro bond 582 Ape Arg Asp Aze Leu (NMe) Ape single NH.sub.2 (2) Ile bond 583 Ape Arg Asp Aze Leu (NMe) ? - single NH.sub.2 (2) Ile homoPro bond 584 Ape (d)- Asp Aze Leu (NMe) ? - single NH.sub.2 Ser (2) Ile homoPro bond 585 Ape (d)- Asp Aze Leu (NMe) Ape single NH.sub.2 Thr (2) Ile bond 586 Ape (d)- Asp Aze Leu (NMe) ? - single NH.sub.2 Thr (2) Ile homoPro bond indicates data missing or illegible when filed

[1159] The structures of compounds represented by formula [II-16], which were synthesized in Example 4 or with the same method as in Example 4, are shown in the following table.

##STR00219##

TABLE-US-00023 TABLE 23 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 587 ? -Ala Asn Asp Ala Leu (NMe) Pro single NH.sub.2 Met bond 588 GABA Asn Asp Ala Leu (NMe) Pro single NH.sub.2 Met bond 589 ? -Ala Asn Asp Ala Leu (NMe) Pro single NH.sub.2 Val bond

[1160] The structure of a compound represented by formula [I-17], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00220##

TABLE-US-00024 TABLE 24 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 590 Ape Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1161] The structure of a compound represented by formula [I-18], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00221##

TABLE-US-00025 TABLE 25 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 591 GABA Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1162] The structure of a compound represented by formula [I-19], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00222##

TABLE-US-00026 TABLE 26 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 592 Ape Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1163] The structure of a compound represented by formula [I-20], which was synthesized with the same method as in Example 1, is shown in the following table. [1164] [I-20]

TABLE-US-00027 TABLE 27 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 593 single single ? -(d)- Ala Leu (NMe) ? - single NH.sub.2 bond bond Asp Glu homoPro bond

[1165] The structures of compounds represented by formula [I-21], which were synthesized with the same method as in Example 1, are shown in the following table. [1166] [I-21]

TABLE-US-00028 TABLE 28 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 594 single single ?- Ala Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 595 single single ?- (2S,4S)-(4- Leu (NMe) Ape single NH.sub.2 bond bond (d)-Glu amino)Pro Glu bond

[1167] The structure of a compound represented by formula [I-22], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00223##

TABLE-US-00029 TABLE 29 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 596 GABA Asn Asp Dab Leu (NMe) Pro single NH.sub.2 Ile bond

[1168] The structure of a compound represented by formula [I-23], was synthesized with the same method as in Example 2, is shown in the following table.

##STR00224##

TABLE-US-00030 TABLE 30 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 597 GABA Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1169] The structure of a compound represented by formula [I-24], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00225##

TABLE-US-00031 TABLE 31 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 598 GABA Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1170] The structure of a compound represented by formula [I-25], which was synthesized with the same method as in Example 2, is shown in the following table.

##STR00226##

TABLE-US-00032 TABLE 32 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 599 GABA Asn Asp Ala Leu Met Pro single NH.sub.2 bond

[1171] The structures of compounds represented by formula [I-26], which were synthesized with the same method as in Example 2, are shown in the following table.

##STR00227##

TABLE-US-00033 TABLE 33 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 600 GABA Asn Asp Dab Leu (NMe) ?- single NH.sub.2 Ile homoPro bond 601 GABA Asn Asp Dab Leu (NMe) ?- single NH.sub.2 Glu homoPro bond

[1172] The structures of compounds represented by formula [I-27], which were synthesized with the same method as in Example 1, each are shown in the following table. [1173] [I-27]

TABLE-US-00034 TABLE 34 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 602 single single ?- Dap Leu (NMe) ?- single NH.sub.2 (d)-Asp Glu homoPro bond 603 single single ?- Dab Leu (NMe) ?- single NH.sub.2 (d)-Asp Glu homoPro bond 604 single single ?- Dap Leu (NMe) ?- single NH.sub.2 (d)-Asp Ile homoPro bond 605 single single ?- Dab Leu (NMe) ?- single NH.sub.2 (d)-Asp Ile homoPro bond

TABLE-US-00035 TABLE 35 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 606 single single ?- (2S,4S)-(4- Leu (NMe) Ape single OH bond bond (d)-Glu amino)Pro Glu bond

[1174] The structure of a compound represented by formula [I-29], which was synthesized with the same method as in Example 1, is shown in the following table.

##STR00228##

TABLE-US-00036 TABLE 36 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 607 single single ?- (2S,4S)-(4- Leu (NMe) Ape single OH bond bond (d-Glu) amino)Pro Glu bond

[1175] The structure of a compound represented by formula [I-30], which was synthesized with the same method as in Example 5, is shown in the following table.

##STR00229##

TABLE-US-00037 TABLE 37 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 608 single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Glu Ile homoPro bond

[1176] The structure of a compound represented by formula [I-31], which was synthesized with the same method as in Example 5, is shown in the following table.

##STR00230##

TABLE-US-00038 TABLE 38 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 609 single single ?- Dab Leu (NMe) Ape single NH.sub.2 bond bond (d)-Glu Glu bond

[1177] The structures of compounds represented by formula [I-32], which were synthesized with the same method as in Example 1, are shown in the following table.

##STR00231##

TABLE-US-00039 TABLE 39 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 610 MeO single single ?- Ala Ala(2- Met Pro single NH.sub.2 bond bond (d)-Asp Pyr) bond 611 MeO single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 612 MeO single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 613 MeO single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 614 MeO single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 615 F.sub.3CO single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 616 F.sub.3CO single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 617 MeO single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 618 MeO single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 619 MeO single single ?- Orn Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 620 H single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Glu homoPro bond 621 H single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Ile homoPro bond 622 MeO single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Glu homoPro bond 623 MeO single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Ile homoPro bond 624 F single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Glu homoPro bond 625 F single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Ile homoPro bond 626 Cl single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Glu homoPro bond 627 Cl single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Ile homoPro bond 628 Ac single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Glu homoPro bond 629 Ac single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp amino)Pro Ile homoPro bond 630 MeO single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Glu amino)Pro Glu homoPro bond 631 MeO single single ?- (2S,4S)-(4- Leu (NMe) ?- single NH.sub.2 bond bond (d)-Glu amino)Pro Ile homoPro bond 632 MeO single single ?- (2S,4S)-(4- Leu (NMe) Ape single NH.sub.2 bond bond (d)-Glu amino)Pro Glu bond 633 MeO single single ?- (2S,4S)-(4- Leu (NMe) single single NH.sub.2 bond bond (d)-Glu amino)Pro Glu bond bond

[1178] The structures of compounds represented by formula [I-32], which were synthesized in Example 6 or with the same method as in Example 6, are shown in the following table.

##STR00232##

TABLE-US-00040 TABLE 40 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 634 Ac single single ?- Ala Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 635 H.sub.2NCO single single ?- Ala Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 636 MeCONH single single ?- Ala Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 637 HOCH.sub.2 single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 638 HO(CH.sub.2).sub.2O single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 639 HOCH.sub.2 single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 640 HO(CH.sub.2).sub.2O single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Glu homoPro bond 641 HOCH.sub.2 single single ?- Dap Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond 642 HOCH.sub.2 single single ?- Dab Leu (NMe) ?- single NH.sub.2 bond bond (d)-Asp Ile homoPro bond

[1179] The structure of a compound represented by formula [I-33], which was synthesized with the same method as in Example 1, is shown in the following table. [1180] [I-33]

TABLE-US-00041 TABLE 41 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 643 single single ?- (2S,4S)-(4- Leu (NMe) Ape single OH bond bond (d)-Glu amino)Pro Glu bond

[1181] The structures of compounds represented by formula [I-34], which were synthesized with the same method as in Example 1, are shown in the following table.

##STR00233##

TABLE-US-00042 TABLE 42 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 644 H single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 645 H single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 646 H single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 647 H single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 648 H single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond Asp homoPro bond 649 H single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond Glu homoPro bond 650 H single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Glu homoPro bond 651 H single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Glu homoPro bond 652 H single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Glu homoPro bond 653 H single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Glu homoPro bond 654 F single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 655 F single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 656 F single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 657 F single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 658 Me single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 659 Me single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 660 Me single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 661 Me single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 662 CF.sub.3 single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 663 CF.sub.3 single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 664 CF.sub.3 single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 665 CF.sub.3 single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 666 Br single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 667 Br single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 668 CN single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 669 CN single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 670 H Ape Glu Asp Dab Leu (NMe)Ile ?- single NH.sub.2 homoPro bond 671 Br single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 672 CN single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 673 Br single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 674 HeNHCO single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 675 Me.sub.2NCO single single ?- Dap Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 676 MeNHCO single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 677 Me.sub.2NCO single single ?- Dab Leu (NMe)Ile ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 678 MeNHCO single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 679 Me.sub.2NCO single single ?- Dap Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 680 MeNHCO single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 681 Me.sub.2NCO single single ?- Dab Leu (NMe)Glu ?- single NH.sub.2 bond bond (d)-Asp homoPro bond 682 F single single ?- (2S,4S)-(4- Leu (NMe)Ile Ape single NH.sub.2 bond bond Glu amino)Pro bond 683 F single single ?- (2S,4S)-(4- Leu (NMe)Val Ape single NH.sub.2 bond bond Glu amino)Pro bond 684 H single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 685 F single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 686 Me single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 687 F.sub.3CO single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 688 F.sub.3C single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 689 F.sub.2HCCF.sub.2 single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond 690 CN single single ?- (2S,4S)-(4- Leu (NMe)Glu Ape single OH bond bond (d)-Glu amino)Pro bond

[1182] The structures of compounds represented by formula [I-34], which were synthesized in Example 7 or with the same method as in Example 7, are shown in the following table.

##STR00234##

TABLE-US-00043 TABLE 43 Compound No. R.sup.B1 L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 691 MeO single single ?-(d)- Dap Leu (NMe) ?-homo single NH.sub.2 bond bond Asp Glu Pro bond 692 MeO single single ?-(d)- Dap Leu (NMe) ?-homo single NH.sub.2 bond bond Asp Ile Pro bond 693 MeO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Asp Glu Pro bond 694 MeO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Asp Ile Pro bond 695 MeO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 696 n-PrO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 697 MeO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Glu Pro bond 698 EtO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 699 i-PrO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 700 c-PrO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 701 F.sub.3CO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Ile Pro bond 702 EtO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Glu Pro bond 703 c-PrO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Glu Pro bond 704 F.sub.3CO single single ?-(d)- Dab Leu (NMe) ?-homo single NH.sub.2 bond bond Glu Glu Pro bond

[1183] The structures of compounds represented by formula [I-35], which were synthesized with the same method as in Example 1, are shown in the following table. [1184] [I-35]

TABLE-US-00044 TABLE 44 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 705 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Asp Glu homoPro bond 706 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 707 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Asp Glu homoPro bond 708 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 709 single single ?-(d)- Dap Leu (NMe) single single NH.sub.2 bond bond Asp Glu bond bond 710 single single ?-(d)- Dap Leu (NMe) single single NH.sub.2 bond bond Asp Ile bond bond 711 single single ?-(d)- Dab Leu (NMe) single single NH.sub.2 bond bond Asp Glu bond bond 712 single single ?-(d)- Dab Leu (NMe) single single NH.sub.2 bond bond Asp Ile bond bond 713 single single ?-(d)- Ala Leu (NMe) single single NH.sub.2 bond bond Asp Glu bond bond 714 single single ?-(d)- Ala Leu (NMe) ?- single NH.sub.2 bond bond Asp Glu homoPro bond 715 single single ?-(d)- Ala Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 716 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Glu Glu homoPro bond 717 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Glu Ile homoPro bond 718 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Glu Ile homoPro bond 719 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Glu Glu homoPro bond 720 single single ?-(d)- Dap Leu (NMe) ?- (d)-Lys NH.sub.2 bond bond Glu Ile homoPro 721 single single ?-(d)- Dap Leu (NMe) ?- (d)-Arg NH.sub.2 bond bond Glu Ile homoPro 722 single single ?-(d)- Dap Leu (NMe) ?- single NH(CH.sub.2).sub.2NH.sub.2 bond bond Glu Ile homoPro bond 723 single single ?-(d)- Dab Leu (NMe) ?- (d)-Lys NH.sub.2 bond bond Glu Ile homoPro 724 single single ?-(d)- Dab Leu (NMe) ?- (d)-Arg NH.sub.2 bond bond Glu Ile homoPro 725 single single ?-(d)- Dab Leu (NMe) ?- single NH(CH.sub.2).sub.2NH.sub.2 bond bond Glu Ile homoPro bond 726 single single ?-(d)- Dab Nle (NMe) ?- single NH.sub.2 bond bond Glu Ile homoPro bond 727 single single ?-(d)- Dab Leu (NMe) Ala single NH.sub.2 bond bond Glu Ile bond 728 single single ?-(d)- Dab Leu (NMe) Thr single NH.sub.2 bond bond Glu Ile bond 729 single single ?-(d)- Dab Leu (NMe) Phe single NH.sub.2 bond bond Glu Ile bond 730 single single ?-(d)- Dab Leu (NMe) Lys single NH.sub.2 bond bond Glu Ile bond 731 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH.sub.2 bond bond Glu Ile bond 732 single single ?-(d)- Dab Leu (NMe) GABA single NH.sub.2 bond bond Glu Ile bond 733 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Glu Ile bond 734 single single ?-(d)- Dab Leu (NMe) Acp single NH.sub.2 bond bond Glu Ile bond 735 single single ?-(d)- Dab Leu Lys (CO(CH.sub.2).sub.10CO.sub.2H) ?- single NH.sub.2 bond bond Glu homoPro bond 736 single single ?-(d)- Dab Leu Lys (CO(CH.sub.2).sub.12CO.sub.2H) ?- single NH.sub.2 bond bond Glu homoPro bond 737 single single ?-(d)- Dab Leu Lys (CO(CH.sub.2).sub.14CO.sub.2H) ?- single NH.sub.2 bond bond Glu homoPro bond 738 single single ?-(d)- Dab Leu (NMe) ?-Dap single NH.sub.2 bond bond Glu Ile bond 739 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Glu Ile Dap bond 740 single single ?-(d)- Dab Leu (NMe) ?-Dab single NH.sub.2 bond bond Glu Ile bond 741 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Glu Ile Dab bond 742 single single ?-(d)- Dab Leu (NMe) ?-Orn single NH.sub.2 bond bond Glu Ile bond 743 single single ?-(d)- Dab Leu (NMe) ?-Lys single NH.sub.2 bond bond Glu Ile bond 744 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Glu Ile Lys bond 745 single single ?-(d)- Dab Leu (NMe) ?-Lys single NH.sub.2 bond bond Glu Glu bond 746 single single ?-(d)- Dab Leu (NMe) single single NH(CH.sub.2).sub.4NH.sub.2 bond bond Glu Ile bond bond 747 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH(CH.sub.2).sub.2NH.sub.2 bond bond Glu Ile bond 748 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH(CH.sub.2).sub.3NH.sub.2 bond bond Glu Ile bond 749 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH(CH.sub.2).sub.4NH.sub.2 bond bond Glu Ile bond 750 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH(CH.sub.2).sub.5NH.sub.2 bond bond Glu Ile bond 751 single single ?-(d)- Dab Leu (NMe) GABA single NH(CH.sub.2).sub.2NH.sub.2 bond bond Glu Ile bond 752 single single ?-(d)- Dab Leu (NMe) GABA single NH(CH.sub.2).sub.3NH.sub.2 bond bond Glu Ile bond 753 single single ?-(d)- Dab Leu (NMe) GABA single NH(CH.sub.2).sub.4NH.sub.2 bond bond Glu Ile bond 754 single single ?-(d)- Dab Leu (NMe) GABA single NH(CH.sub.2).sub.5NH.sub.2 bond bond Glu Ile bond 756 single single ?-(d)- Dab Leu (NMe) Ape single NH(CH.sub.2).sub.2NH.sub.2 bond bond Glu Ile bond 756 single single ?-(d)- Dab Leu (NMe) Ape single NH(CH.sub.2).sub.3NH.sub.2 bond bond Glu Ile bond 757 single single ?-(d)- Dab Leu (NMe) Ape single NH(CH.sub.2).sub.4NH.sub.2 bond bond Glu Ile bond 758 single single ?-(d)- Dab Leu (NMe) Ape single NH(CH.sub.2).sub.5NH.sub.2 bond bond Glu Ile bond 759 single single ?-(d)- Dab Leu (NMe) (4) single NH.sub.2 bond bond Glu Ile Abz bond 760 single single ?-(d)- Dab Leu (NMe) Ape single (4- bond bond Glu Ile bond Me)piperazin- 1-yl 761 single single ?-(d)- Dab Leu (NMe) Ape single morpholin- bond bond Glu Ile bond 4-yl 762 single single ?-(d)- Dab Leu (NMe) Ape single [VI-8] bond bond Glu Ile bond 763 single single ?-(d)- Dab Leu (NMe) Ape single [VI-16] bond bond Glu Ile bond 764 single single ?-(d)- Dab Leu (NMe) Ape single [VI-18] bond bond Glu Ile bond 765 single single ?-(d)- Dab Leu homoSer Ape single NH.sub.2 bond bond Glu bond 766 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Ile 767 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Ile 768 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Ile (d)-Lys 769 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Ile (d)-Arg 770 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Ile (d)-Arg 771 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Ile (d)-Lys 772 single single ?-(d)- (S)- Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp piperazine Ile 773 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Glu (d)-Lys 774 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Glu (d)-Arg 775 single single ?-(d)- Deb Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Glu (d)-Arg 776 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Glu (d)-Lys 777 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Asp Ile Dab bond 778 single single ?-(d)- Dab Leu (NMe) ?-Orn single NH.sub.2 bond bond Asp Ile bond 779 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Asp Ile Orn bond 780 single single ?-(d)- Dab Leu (NMe) ?-Lys single NH.sub.2 bond bond Asp Ile bond 781 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Asp Ile Lys bond 782 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Val 783 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Leu 784 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Glu 785 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys OH bond bond Asp Ile 786 single single ?-(d)- (2S,4S)- Leu (NMe) Pro single NH.sub.2 bond bond Glu (4-amino) Glu bond Pro 787 single single ?-(d)- (2S,4S)- Leu (NMe) GABA single NH.sub.2 bond bond Glu (4-amino) Glu bond Pro 788 single single ?-(d)- (2S,4S)- Leu (NMe) Acp single NH.sub.2 bond bond Glu (4-amino) Glu bond Pro 789 single single ?-(d)- (2S,4S)- Leu (NMe) ?- single NH.sub.2 bond bond Glu (4-amino) Asp homoPro bond Pro 790 single single ?-(d)- (2S,4S)- Leu (NMe) Pro single NH.sub.2 bond bond Glu (4-amino) Asp bond Pro 791 single single ?-Glu (2S,4S)- Leu (NMe) Ape single NH.sub.2 bond bond (4-amino) Ile bond Pro

[1185] The structures of compounds represented by formula [I-36], which were synthesized with the same method as in Example 1, are shown in the following table.

##STR00235##

TABLE-US-00045 TABLE 45 Compound No. L.sup.1 L.sup.1 AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 W.sup.c R.sup.c 792 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Asp Glu homoPro bond 793 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Asp Glu homoPro bond 794 single single ?-(d)- Dap Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 795 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 796 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Glu Ile bond 797 single single ?-(d)- Dab Leu (NMe) Acp single NH.sub.2 bond bond Glu Ile bond 798 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Glu Glu bond 799 single single ?-(d)- Dab Leu (NMe) Acp single NH.sub.2 bond bond Glu Glu bond 800 single single ?-(d)- Dab Leu (NMe) ?-Dab single NH.sub.2 bond bond Glu Glu bond 801 single single ?-(d)- Dab Ala (NMe) Ape single NH.sub.2 bond bond Glu (cPropyl) Ile bond 802 single single ?-(d)- Dab Ala (NMe) Ape single NH.sub.2 bond bond Glu (4-Thz) Ile bond 803 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Ile 804 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Ile 805 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg- NH.sub.2 bond bond Asp Ile (d)-Lys 806 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Asp Ile (d)-Arg 807 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Asp Ile (d)-Lys 808 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Glu Ile 809 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Glu Ile (d)-Lys 810 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Glu Ile (d)-Arg 811 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Glu Ile (d)-Lys 812 single single ?-(d)- Dab Leu (NMe) Ape (d)-Lys NH.sub.2 bond bond Glu Ile 813 single single ?-(d)- Dab Leu (NMe) Ape (d)-Arg NH.sub.2 bond bond Glu Ile (d)-Arg 814 single single ?-(d)- Dab Leu (NMe) ?-(d) single NH.sub.2 bond bond Glu Ile Dap bond 815 single single ?-(d)- Dab Leu (NMe) ?-Orn single NH.sub.2 bond bond Glu Ile bond 816 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Glu Ile Orn bond 817 single single ?-(d)- Dab Leu (NMe) ?-Lys single NH.sub.2 bond bond Glu Ile bond 818 single single ?-(d)- Dab Leu (NMe) ?-(d)- single NH.sub.2 bond bond Glu Ile Lys bond 819 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Glu Ile homoPro bond 820 single single ?-(d)- Dab Leu (NMe) ?- (d)-Lys NH.sub.2 bond bond Glu Ile homoPro 821 single single ?-(d)- Dab Leu (NMe) ?- (d)-Arg NH.sub.2 bond bond Glu Ile homoPro 822 single single ?-(d)- Dab Leu (NMe) ?- (d)-Arg NH.sub.2 bond bond Glu Ile homoPro (d)-Lys 823 single single ?-(d)- Dab Leu (NMe) ?- (d)-Arg NH.sub.2 bond bond Glu Ile homoPro (d)-Arg 824 single single ?-(d)- Dab Leu (NMe) ?- (d)-Lys NH.sub.2 bond bond Glu Ile homoPro (d)-Arg 825 single single ?-(d)- Dab Leu (NMe) ?- (d)-Lys NH.sub.2 bond bond Glu Ile homoPro (d)-Lys 826 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Glu Val bond 827 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Glu Val homoPro bond 828 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Lys 829 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Arg 830 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Arg- (d)-Arg 831 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Lys (d)-Arg 832 single single ?-(d)- Dab Leu (NMe) Ape ?-Ala- NH.sub.2 bond bond Glu Ile (d)-Lys 833 single single ?-(d)- Dab Leu (NMe) Ape ?-Ala- NH.sub.2 bond bond Glu Ile (d)-Arg- (d)-Lys 834 single single ?-(d)- Dab Leu (NMe) Ape ?-Ala- NH.sub.2 bond bond Glu Ile (d)-Arg- (d)-Arg 835 single single ?-(d)- Dab Leu (NMe) Ape ?-Ala- NH.sub.2 bond bond Glu Ile (d)-Lys- (d)-Arg 836 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Arg- (d)-Lys 837 single single ?-(d)- Dab Leu (NMe) Ape Gly- NH.sub.2 bond bond Glu Ile (d)-Lys- (d)-Lys 838 single single ?-(d)- Dab Leu (NMe) ?- single NH.sub.2 bond bond Asp Ile homoPro bond 839 single single ?-(d)- Dab Leu (NMe) Pro single NH.sub.2 bond bond Asp Ile bond 840 single single ?-(d)- Dab Leu (NMe) ?-Ala single NH.sub.2 bond bond Asp Ile bond 841 single single ?-(d)- Dab Leu (NMe) GABA single NH.sub.2 bond bond Asp Ile bond 842 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Asp Ile bond 843 single single ?-(d)- Dab Leu (NMe) Acp single NH.sub.2 bond bond Asp Ile bond 844 single single ?-(d)- Dab Leu (NMe) ?-Dap single NH.sub.2 bond bond Asp Ile bond 845 single single ?-(d)- Dab Leu (NMe) Aze(2) single NH.sub.2 bond bond Glu Ile bond 846 single single ?-(d)- Dab Leu (NMe) (d)- single NH.sub.2 bond bond Glu Ile Aze(2) bond 847 single single ?-(d)- Dab Leu (NMe) Aze(3) single NH.sub.2 bond bond Glu Ile bond 848 single single ?-(d)- Dab Leu (NMe) cis- single NH.sub.2 bond bond Glu Ile NH(3)c bond Pen 849 single single ?-(d)- Dab Leu (NMe) cis- single NH.sub.2 bond bond Glu Ile NH(3)c bond Pen 850 single single ?-(d)- Dab Leu (NMe) single single [V]-14] bond bond Glu Ile bond bond 851 single single ?-(d)- (S)- Leu (NMe) Ape single NH.sub.2 bond bond Asp piperazine Ile bond 852 single single ?-Glu Dab Leu (NMe) Ape single NH.sub.2 bond bond Ile bond 853 single single ?-(d)- Dab Leu (NMe) Ape single NH.sub.2 bond bond Glu Leu bond 854 single single ?-(d)- Dab Leu (NMe) Ape single OH bond bond Glu Ile bond 855 single single ?-(d)- (S)- Leu (NMe) Ape single NH.sub.2 bond bond Glu piperazine Ile bond 856 single single ?-(d)- (S)- Leu (NMe) ?- single NH.sub.2 bond bond Asp piperazine Ile homoPro bond 857 single single ?-(d)- Pro Leu (NMe) Ape single NH.sub.2 bond bond Glu Glu bond 858 single single ?-(d)- (2S,4S)- Leu (NMe) Ape single OH bond bond Glu (4-amino) Glu bond Pro 859 single single ?-(d)- (2S,4S)- Leu (NMe) single single OH bond bond Glu (4-amino) Glu bond bond Pro 860 single single ?-(d)- (2S,4S)- Leu single Ape single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 861 single single ?-(d)- (2S,4S)- Leu single ?-Ala single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 862 single single ?-(d)- (2S,4S)- Leu single GABA single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 863 single single ?-(d)- (2S,4S)- Leu single Acp single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 864 single single ?-(d)- (2S,4S)- Leu single (d)- single NH.sub.2 bond bond Glu (4-amino) bond Lys bond Pro 865 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Asp (4-amino) Glu bond bond Pro 866 single single ?-Glu (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond (4-amino) Glu bond bond Pro 867 single single ?-(d)- (2S,4S)- Ile (NMe) single single NH.sub.2 bond bond Glu (4-amino) Glu bond bond Pro 868 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Ser bond bond Pro 869 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Tyr bond bond Pro 870 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Phe bond bond Pro 871 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Ala bond bond Pro 872 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Ile bond bond Pro 873 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Val bond bond Pro 874 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Leu bond bond Pro 875 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Asp bond bond Pro 876 single single ?-(d)- (2S,4S)- Leu (NMe) single single NH.sub.2 bond bond Glu (4-amino) Lys bond bond Pro 877 single single ?-(d)- (2S,4S)- Leu Gly single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 878 single single ?-(d)- (2S,4S)- Leu (d)-Arg single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 879 single single ?-(d)- (2S,4S)- Leu (d)-Pro single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 880 single single ?-(d)- (2S,4S)- Leu (d)-Ser single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 881 single single ?-(d)- (2S,4S)- Leu (d)-Tyr single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 882 single single ?-(d)- (2S,4S)- Leu (d)-Phe single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 883 single single ?-(d)- (2S,4S)- Leu (d)-Ala single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 884 single single ?-(d)- (2S,4S)- Leu (d)-Thr single single NH.sub.2 bond bond Glu (4-amino) bond bond Pro 885 single single ?-(d)- (2S,4S)- Lew (NMe) single single NH.sub.2 bond bond Glu (4-amino) Arg bond bond Pro 886 single single ?-(d)- (2S,4S)- Val (NMe) single single NH.sub.2 bond bond Glu (4-amino) Glu bond bond Pro 887 single single ?-(d)- (2S,4S)- Tyr (NMe) single single NH.sub.2 bond bond Glu (4-amino) Glu bond bond Pro 888 single single ?-(d)- (2S,4S)- Leu (d)- Ape single NH.sub.2 bond bond Glu (4-amino) (NMe) bond Pro Glu 889 single single ?-(d)- (2S,4S)- Leu Glu Ape single NH.sub.2 bond bond Glu (4-amino) bond Pro 890 single single ?-(d)- (2S,4S)- Leu (NMe) Ape Ape NH.sub.2 bond bond Glu (4-amino) Glu Pro

[1186] The structures of compounds represented by formula [I-37], which were synthesized in Example 8 or with the same method as in Example 8, are shown in the following table.

##STR00236##

TABLE-US-00046 TABLE 46 Compound No. R.sup.B1 L.sup.N1 AA.sup.2 L.sup.3 AA.sup.4 AA.sup.5 R.sup.c 891 H SO.sub.2 Ala Gly (NMe) ?- OH Ile homoPro 892 H SO.sub.2 Ala Gly (NMe) ?- NH.sub.2 Ile homoPro 893 H SO.sub.2 Ala GABA (NMe) ?- NH.sub.2 Ile homoPro 894 H SO.sub.2 Dab ?-Ala (NMe) ?- NH.sub.2 Ile homoPro 895 H SO.sub.2 Dab ?-Ala (NMe) ?- NH.sub.2 Asp homoPro 896 H SO.sub.2 Dab ?-Ala (NMe) single NH.sub.2 Ile bond 897 F CO Ala ?-Ala (NMe) ?- NH.sub.2 Ile homoPro 898 F CO Dab ?-Ala (NMe) ?- NH.sub.2 Ile homoPro 899 F CO Dab ?-Ala (NMe) ?- NH.sub.2 Asp homoPro

[1187] The structures of compounds represented by formula [I-38], which were synthesized in Example 9 or with the same method as in Example 9, are shown in the following table.

##STR00237##

TABLE-US-00047 TABLE 47 Compound No. L.sup.1 L.sup.1 AA.sup.N5 AA.sup.N4 AA.sup.N3 n AA.sup.1 AA.sup.2 AA.sup.3 AA.sup.4 AA.sup.5 900 GABA Lys ?-Glu Adox Adox 4 Asp Ala Leu (NMe) ?- Ile homoPro 901 GABA Lys ?-Glu Adox Adox 6 Asp Ala Leu (NMe) ?- Ile homoPro 902 GABA Lys Lys Lys Lys 8 Asp Ala Leu (NMe) ?- Ile homoPro 903 GABA Lys ?-Glu Adox Adox 14 Asp Ala Leu (NMe) ?- Ile homoPro 904 GABA Lys ?-Glu Adox Adox 16 Asp Ala Leu (NMe) ?- Ile homoPro 905 GABA Lys Lys Lys Lys 14 Asp Ala Leu (NMe) ?- Ile homoPro 906 GABA Lys ?-Glu Adox Adox 14 Asp Dab Leu (NMe) ?- Glu homoPro 907 GABA Lys Lys Lys Lys 14 Asp Dab Leu (NMe) ?- Glu homoPro 908 GABA Lys (d)-Lys (d)-Lys (d)-Lys 14 Asp Dab Leu (NMe) ?- Ile homoPro 909 GABA Lys (d)-Lys (d)-Lys (d)-Lys 14 Asp Dab Leu (NMe) ?- Glu homoPro 910 GABA (d)-Lys ?-Glu Adox Adox 14 Asp Dab Leu (NMe) ?- Glu homoPro 911 GABA (d)-Lys (d)-Lys (d)-Lys (d)-Lys 14 Asp Dab Leu (NMe) ?- Glu homoPro

[1188] The structures of compounds represented by formula [I-39], which were synthesized with the same method as in Example 9, are shown in the following table.

##STR00238##

TABLE-US-00048 TABLE 48 Compound No. R.sup.B1 L.sup.1 AA.sup.N5 AA.sup.N4 AA.sup.N3 AA.sup.N2 AA.sup.N1 n AA.sup.1 .sup.AA2 AA.sup.3 AA.sup.4 AA.sup.5 912 F GABA (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 913 F GABA (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Asp homoPro 914 H.sub.2NCO GABA ?-Glu Adox Adox single single 14 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 915 H.sub.2NCO GABA ?-Glu Adox Adox single single 14 Asp Dab Leu (NMe) ?- bond bond Asp homoPro 916 H.sub.2NCO GABA (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 917 H.sub.2NCO GABAA (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Asp homoPro 918 H.sub.2NCO Ape ?-Glu Adox Adox single single 14 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 919 H.sub.2NCO Ape ?-Glu Adox Adox single single 14 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 920 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 921 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 14 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 922 H.sub.2NCO Ape ?-Glu Adox Adox single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 923 H.sub.2NCO Ape ?-Glu Adox Adox single single 12 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 924 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 925 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 12 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 926 H.sub.2NCO Ape (d)-Lys single single single single 14 Asp Dab Leu (NMe) ?- bond bond bond bond Ile homoPro 927 H.sub.2NCO Ape (d)-Lys (d)-Lys single single single 14 Asp Dab Leu (NMe) ?- bond bond bond Ile homoPro 928 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys (d)-Lys single 14 Asp Dab Leu (NMe) ?- bond Ile homoPro 929 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys (d)-Lys (d)-Lys 14 Asp Dab Leu (NMe) ?- Ile homoPro 930 H.sub.2NCO Ape (d)-Lys single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond Glu homoPro 931 H.sub.2NCO Ape (d)-Lys (d)-Lys single single single 12 Asp Dab Leu (NMe) ?- bond bond bond Glu homoPro 932 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys (d)-Lys single 12 Asp Dab Leu (NMe) ?- bond Glu homoPro 933 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys (d)-Lys (d)-Lys 12 Asp Dab Leu (NMe) ?- 0 Glu homoPro 934 H.sub.2NCO Ape Lys Lys Lys single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 935 H.sub.2NCO Ape Arg Arg Arg single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 936 H.sub.2NCO Ape (d)-Arg (d)-Arg (d)-Arg single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 937 H.sub.2NCO Ape Adox Adox single single single 12 Asp Dab Leu (NMe) ?- bond bond bond Glu homoPro 938 H.sub.2NCO Ape Adox single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond Glu homoPro 939 H.sub.2NCO Ape ?-Glu single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond Glu homoPro 940 H.sub.2NCO Ape Adox Adox ?-Glu single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 941 H.sub.2NCO Ape single single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond bond Glu homoPro 942 H.sub.2NCO Ape (d)-Lys single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond Ile homoPro 943 H.sub.2NCO Ape (d)-Lys (d)-Lys single single single 12 Asp Dab Leu (NMe) ?- bond bond bond Ile homoPro 944 H.sub.2NCO Ape (d)-Lys single single single single 14 Asp Dab Leu (NMe) ?- bond bond bond bond Glu homoPro 946 H.sub.2NCO Ape (d)-Lys (d)-Lys single single single: 14 Asp Dab Leu (NMe) ?- bond bond bond Glu homoPro 946 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 10 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 947 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 10 Asp Dab Leu (NMe) ?- bond bond Ile homoPro 948 H.sub.2NCO Ape (d)-Arg single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond Glu homoPro 949 H.sub.2NCO Ape (d)-Arg (d)-Arg single single single 12 Asp Dab Leu (NMe) ?- bond bond bond Glu homoPro 950 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 12 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 951 H.sub.2NCO Ape single single single single single 12 Asp Dab Leu (NMe) ?- bond bond bond bond bond Ile homoPro 952 H.sub.2NCO Ape single single single single single 14 Asp Dab Leu (NMe) ?- bond bond bond bond bond Glu homoPro 953 H.sub.2NCO Ape single single single single single 14 Asp Dab Leu (NMe) ?- bond bond bond bond bond Ile homoPro 954 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 16 Asp Dab Leu (NMe) ?- bond bond Glu homoPro 956 H.sub.2NCO Ape (d)-Lys (d)-Lys (d)-Lys single single 16 Asp Dab Leu (NMe) ?- bond bond Ile homoPro

[1189] The structures of compounds represented by formula [I-40], which were synthesized with the same method as in Example 9, are shown in the following table:

##STR00239## [1190] wherein [1191] the structure represented by formula [VII-2]:

-AA.sup.WC1-AA.sup.WC2-AA.sup.WC3-AA.sup.WC4-AA.sup.WC5-[VII-2] [1192] corresponds to W.sup.C, which is linker consisting of one to three amino acids in the compound represented by formula [I], [1193] wherein [1194] AA.sup.WC1, AA.sup.WC2, AA.sup.WC4, and AA.sup.WC5 are same or different and each selected from the group consisting of a single bond and (d)-Lys, [1195] AA.sup.WC3 is Lys or (d)-Lys, and [1196] AA.sup.WC5 is a single bond or (d)-Lys.

TABLE-US-00049 TABLE 49 Compound No. AA.sup.4 AA.sup.5 AA .sup.C1 AA .sup.C2 AA .sup.C3 AA .sup.C4 AA .sup.C5 AA .sup.C n 956 (NMe) ?- (d)-Lys (d)-Lys Lys single single single 12 Ile homoPro bond bond bond 957 (NMe) ?- (d)-Lys (d)-Lys Lys single single single 14 Ile homoPro bond bond bond 958 (NMe) ?- (d)-Lys- (d)-Lys Lys single single single 14 Glu homoPro bond bond bond 959 (NMe) ?- (d)-Lys single Lys (d)-Lys single single 12 Ile homoPro bond bond bond 960 (NMe) ?- (d)-Lys single Lys (d)-Lys single single 14 Ile homoPro bond bond bond 961 (NMe) ?- (d)-Lys single Lys (d)-Lys single single 12 Glu homoPro bond bond bond 962 (NMe) ?- (d)-Lys single Lys (d)-Lys single single 14 Glu homoPro bond bond bond 963 (NMe) ?- single single Lys (d)-Lys (d)-Lys single 12 Ile homoPro bond bond bond 964 (NMe) ?- single single Lys (d)-Lys (d)-Lys single 14 Ile homoPro bond bond bond 965 (NMe) ?- single single Lys (d)-Lys (d)-Lys single 12 Glu homoPro bond bond bond 966 (NMe) ?- single single Lys (d)-Lys (d)-Lys single 14 Glu homoPro bond bond bond 967 (NMe) ?- single single Lys single single single 12 Ile homoPro bond bond bond bond bond 968 (NMe) ?- single single Lys single single single 14 Ile homoPro bond bond bond bond bond 969 (NMe) ?- single single (d)-Lys single single single 12 Ile homoPro bond bond bond bond bond 970 (NMe) ?- single single (d)-Lys single single single 14 Ile homoPro bond bond bond bond bond 971 (NMe) ?- single single Lys single single (d)-Lys 12 Ile homoPro bond bond bond bond 972 (NMe) ?- single single Lys single single (d)-Lys 14 Ile homoPro bond bond bond bond indicates data missing or illegible when filed

[1197] Mass spectra of high-performance liquid chromatography (LCMS), retention time (RT), and analysis conditions for the present inventive compounds are shown in the following table.

TABLE-US-00050 TABLE 50 LCMS analysis Compound MS MS Retention time Analysis No. (found) (calc.) RT (min) condition 1 916.7 [M + H].sup.+ 916.4 [M + H].sup.+ 0.97 A 2 902.5 [M + H].sup.+ 902.4 [M + H].sup.+ 0.98 A 3 902.5 [M + H].sup.+ 902.4 [M + H].sup.+ 0.99 A 4 916.4 [M + H].sup.+ 916.4 [M + H].sup.+ 0.94 A 5 902.4 [M + H].sup.+ 902.4 [M + H].sup.+ 0.81 A 6 916.4 [M + H].sup.+ 916.4 [M + H].sup.+ 0.90 A 7 950.4 [M + H].sup.+ 950.4 [M + H].sup.+ 0.99 A 8 989.4 [M + H].sup.+ 989.4 [M + H].sup.+ 1.01 A 9 900.6 [M + H].sup.+ 900.4 [M + H].sup.+ 1.08 A 10 886.4 [M + H].sup.+ 886.4 [M + H].sup.+ 1.02 A 11 900.5 [M + H].sup.+ 900.4 [M + H].sup.+ 1.10 A 12 858.4 [M + H].sup.+ 858.4 [M + H].sup.+ 0.98 A 13 934.4 [M + H].sup.+ 934.4 [M + H].sup.+ 1.20 A 14 950.5 [M + H].sup.+ 950.4 [M + H].sup.+ 1.02 A 15 874.4 [M + H].sup.+ 874.4 [M + H].sup.+ 0.88 A 16 870.4 [M + H].sup.+ 870.4 [M + H].sup.+ 0.96 A 17 914.5 [M + H].sup.+ 914.4 [M + H].sup.+ 0.99 A 18 900.4 [M + H].sup.+ 900.3 [M + H].sup.+ 0.95 A 19 900.3 [M + H].sup.+ 900.3 [M + H].sup.+ 0.92 A 20 928.6 [M + H].sup.+ 928.4 [M + H].sup.+ 1.01 A 21 914.4 [M + H].sup.+ 914.4 [M + H].sup.+ 0.94 A 22 888.3 [M + H].sup.+ 888.3 [M + H].sup.+ 0.87 A 23 902.4 [M + H].sup.+ 902.4 [M + H].sup.+ 0.89 A 24 930.4 [M + H].sup.+ 930.4 [M + H].sup.+ 0.99 A 25 914.4 [M + H].sup.+ 914.4 [M + H].sup.+ 0.91 A 26 945.5 [M + H].sup.+ 945.4 [M + H].sup.+ 0.69 A 27 945.4 [M + H].sup.+ 945.4 [M + H].sup.+ 0.69 A 28 973.4 [M + H].sup.+ 973.4 [M + H].sup.+ 0.70 A 29 973.4 [M + H].sup.+ 973.4 [M + H].sup.+ 0.71 A 30 817.3 [M + H].sup.+ 817.3 [M + H].sup.+ 0.89 A 31 674.1 [M + H].sup.+ 674.3 [M + H].sup.+ 0.85 A 32 1013.5 [M + H].sup.+ 1013.4 [M + H].sup.+ 1.00 A 33 1042.7 [M ? H].sup.? 1042.5 [M ? H].sup.? 0.74 A 34 1042.6 [M ? H].sup.? 1042.5 [M ? H].sup.? 0.74 A 35 1070.7 [M ? H].sup.? 1070.5 [M ? H].sup.? 0.75 A 36 1070.5 [M ? H].sup.? 1070.5 [M ? H].sup.? 0.76 A 37 587.0 [M + 2H].sup.2+ 586.8 [M + 2H].sup.2+ 0.64 A 38 898.7 [M + H].sup.+ 898.4 [M + H].sup.+ 1.07 A 39 912.6 [M + H].sup.+ 912.4 [M + H].sup.+ 1.06 A 40 830.3 [M + H].sup.+ 830.4 [M + H].sup.+ 1.28 A 41 860.4 [M + H].sup.+ 860.4 [M + H].sup.+ 1.27 A 42 864.4 [M + H].sup.+ 864.3 [M + H].sup.+ 1.38 A 43 848.4 [M + H].sup.+ 848.4 [M + H].sup.+ 1.30 A 44 846.4 [M + H].sup.+ 846.4 [M + H].sup.+ 1.28 A 45 877.5 [M + H].sup.+ 877.4 [M + H].sup.+ 1.46 A 46 877.5 [M + H].sup.+ 877.4 [M + H].sup.+ 1.47 A 47 875.5 [M ? H].sup.? 875.4 [M ? H].sup.? 1.48 A 48 888.5 [M ? H].sup.? 888.3 [M ? H].sup.? 1.74 A 49 876.5 [M ? H].sup.? 876.3 [M ? H].sup.? 1.71 A 50 905.6 [M + H].sup.+ 905.3 [M + H].sup.+ 1.36 A 51 889.5 [M + H].sup.+ 889.4 [M + H].sup.+ 1.44 A 52 893.5 [M + H].sup.+ 893.3 [M + H].sup.+ 1.32 A 53 907.5 [M + H].sup.+ 907.3 [M + H].sup.+ 1.29 A 54 903.6 [M + H].sup.+ 903.4 [M + H].sup.+ 1.40 A 55 903.6 [M + H].sup.+ 903.4 [M + H].sup.+ 1.40 A 56 976.4 [M + H].sup.+ 976.4 [M + H].sup.+ 1.66 A 57 956.6 [M ? H].sup.? 956.4 [M ? H].sup.? 1.63 A 58 970.7 [M ? H].sup.? 970.4 [M ? H].sup.? 1.65 A 59 970.6 [M ? H].sup.? 970.4 [M ? H].sup.? 1.64 A 60 985.0 [M ? H].sup.? 984.5 [M ? H].sup.? 1.72 A 61 1001.6 [M + H].sup.+ 1001.5 [M + H].sup.+ 1.37 A 62 1015.6 [M + H].sup.+ 1015.5 [M + H].sup.+ 1.35 A 63 1029.6 [M + H].sup.+ 1029.5 [M + H].sup.+ 1.35 A 64 988.6 [M + H].sup.+ 988.4 [M + H].sup.+ 1.59 A 65 984.6 [M ? H].sup.? 984.5 [M ? H].sup.? 1.66 A 66 1000.6 [M ? H].sup.? 1000.4 [M ? H].sup.? 1.58 A 67 1001.6 [M + H].sup.+ 1001.5 [M + H].sup.+ 1.33 A 68 1031.6 [M + H].sup.+ 1031.4 [M + H].sup.+ 1.29 A 69 1017.5 [M + H].sup.+ 1017.4 [M + H].sup.+ 1.29 A 70 1027.7 [M ? H].sup.? 1027.5 [M ? H].sup.? 1.40 A 71 1015.6 [M + H].sup.+ 1015.5 [M + H].sup.+ 1.37 A 72 1045.6 [M + H].sup.+ 1045.5 [M + H].sup.+ 1.31 A 73 1031.5 [M + H].sup.+ 1031.4 [M + H].sup.+ 1.30 A 74 973.6 [M + H].sup.+ 973.4 [M + H].sup.+ 1.31 A 75 1002.6 [M + H].sup.+ 1002.4 [M + H].sup.+ 1.60 A 76 1032.7 [M + H].sup.+ 1032.4 [M + H].sup.+ 1.35 A 77 1078.7 [M + H].sup.+ 1078.4 [M + H].sup.+ 1.39 A 78 1047.7 [M + H].sup.+ 1047.5 [M + H].sup.+ 1.44 A 79 1063.6 [M + H].sup.+ 1063.4 [M + H].sup.+ 1.37 A 80 1088.8 [M + H].sup.+ 1088.5 [M + H].sup.+ 1.06 A 81 1102.7 [M + H].sup.+ 1102.5 [M + H].sup.+ 1.06 A 82 1025.6 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.03 A 83 1037.7 [M ? H].sup.? 1037.5 [M ? H].sup.? 1.02 A 84 1032.8 [M + H].sup.+ 1032.5 [M + H].sup.+ 1.37 A 85 1016.7 [M + H].sup.+ 1016.5 [M + H].sup.+ 1.45 A 86 1050.7 [M + H].sup.+ 1050.5 [M + H].sup.+ 1.42 A 87 1034.7 [M + H].sup.+ 1034.5 [M + H].sup.+ 1.48 A 88 1103.8 [M ? H].sup.? 1103.5 [M ? H].sup.? 1.20 A 89 1089.8 [M + H].sup.+ 1089.5 [M + H].sup.+ 1.25 A 90 1188.1 [M ? H].sup.? 1187.6 [M ? H].sup.? 1.16 A 91 1216.0 [M ? H].sup.? 1215.6 [M ? H].sup.? 1.19 A 92 905.7 [M ? H].sup.? 905.5 [M ? H].sup.? 1.72 A 93 923.6 [M ? H].sup.? 923.5 [M ? H].sup.? 1.73 A 94 948.7 [M ? H].sup.? 948.5 [M ? H].sup.? 1.62 A 95 966.6 [M ? H].sup.? 966.5 [M ? H].sup.? 1.65 A 96 893.7 [M ? H].sup.? 893.5 [M ? H].sup.? 1.80 A 97 911.7 [M ? H].sup.? 911.5 [M ? H].sup.? 1.82 A 98 938.7 [M + H].sup.+ 938.5 [M + H].sup.+ 1.71 A 99 956.7 [M + H].sup.+ 956.5 [M + H].sup.+ 1.74 A 100 919.7 [M ? H].sup.? 919.5 [M ? H].sup.? 1.73 A 101 937.7 [M ? H].sup.? 937.5 [M ? H].sup.? 1.75 A 102 933.7 [M ? H].sup.? 933.5 [M ? H].sup.? 1.81 A 103 962.6 [M ? H].sup.? 962.5 [M ? H].sup.? 1.63 A 104 980.7 [M ? H].sup.? 980.5 [M ? H].sup.? 1.66 A 105 976.7 [M ? H].sup.? 976.5 [M ? H].sup.? 1.71 A 106 979.7 [M + H].sup.+ 979.5 [M + H].sup.+ 1.33 A 107 965.7 [M + H].sup.+ 965.5 [M + H].sup.+ 1.28 A 108 995.6 [M + H].sup.+ 995.5 [M + H].sup.+ 1.25 A 109 981.6 [M + H].sup.+ 981.5 [M + H].sup.+ 1.23 A 110 993.7 [M + H].sup.+ 993.5 [M + H].sup.+ 1.34 A 111 979.6 [M + H].sup.+ 979.5 [M + H].sup.+ 1.31 A 112 1009.6 [M + H].sup.+ 1009.5 [M + H].sup.+ 1.26 A 113 995.6 [M + H].sup.+ 995.5 [M + H].sup.+ 1.25 A 114 934.7 [M ? H].sup.? 934.5 [M ? H].sup.? 1.60 A 115 891.6 [M ? H].sup.? 891.5 [M ? H].sup.? 1.66 A 116 903.6 [M ? H].sup.? 903.5 [M ? H].sup.? 1.68 A 117 917.6 [M ? H].sup.? 917.5 [M ? H].sup.? 1.74 A 118 931.7 [M ? H].sup.? 931.5 [M ? H].sup.? 1.76 A 119 933.7 [M ? H].sup.? 933.5 [M ? H].sup.? 1.80 A 120 947.7 [M ? H].sup.? 947.5 [M ? H].sup.? 1.85 A 121 947.7 [M ? H].sup.? 947.5 [M ? H].sup.? 1.85 A 122 965.6 [M ? H].sup.? 965.5 [M ? H].sup.? 1.79 A 123 948.7 [M ? H].sup.? 948.5 [M ? H].sup.? 1.33 A 124 981.7 [M ? H].sup.? 981.5 [M ? H].sup.? 1.87 A 125 949.6 [M ? H].sup.? 949.5 [M ? H].sup.? 1.65 A 126 963.7 [M ? H].sup.? 963.5 [M ? H].sup.? 1.67 A 127 962.6 [M ? H].sup.? 962.5 [M ? H].sup.? 1.35 A 128 948.7 [M ? H].sup.? 948.5 [M ? H].sup.? 1.60 A 129 997.7 [M ? H].sup.? 997.5 [M ? H].sup.? 1.74 A 130 1020.6 [M ? H].sup.? 1020.5 [M ? H].sup.? 1.85 A 131 935.7 [M ? H].sup.? 935.5 [M ? H].sup.? 1.41 A 132 932.8 [M ? H].sup.? 932.5 [M ? H].sup.? 1.40 A 133 946.7 [M ? H].sup.? 946.5 [M ? H].sup.? 1.39 A 134 996.6 [M + H].sup.+ 996.5 [M + H].sup.+ 1.50 A 135 962.7 [M ? H].sup.? 962.5 [M ? H].sup.? 1.49 A 136 978.7 [M + H].sup.+ 978.6 [M + H].sup.+ 1.54 A 137 997.7 [M + H].sup.+ 997.5 [M + H].sup.+ 1.32 A 138 1011.8 [M + H].sup.+ 1011.5 [M + H].sup.+ 1.35 A 139 1013.6 [M + H].sup.+ 1013.5 [M + H].sup.+ 1.29 A 140 1027.7 [M + H].sup.+ 1027.5 [M + H].sup.+ 1.28 A 141 999.6 [M + H].sup.+ 999.5 [M + H].sup.+ 1.28 A 142 1013.6 [M + H].sup.+ 1013.5 [M + H].sup.+ 1.28 A 143 980.8 [M + H].sup.+ 980.5 [M + H].sup.+ 1.38 A 144 1010.7 [M + H].sup.+ 1010.5 [M + H].sup.+ 1.27 A 145 995.7 [M + H].sup.+ 995.5 [M + H].sup.+ 1.07 A 146 964.7 [M + H].sup.+ 964.5 [M + H].sup.+ 1.46 A 147 994.7 [M + H].sup.+ 994.5 [M + H].sup.+ 1.34 A 148 977.9 [M ? H].sup.? 977.6 [M ? H].sup.? 1.10 A 149 1013.7 [M + H].sup.+ 1013.5 [M + H].sup.+ 1.26 A 150 998.7 [M + H].sup.+ 998.5 [M + H].sup.+ 1.42 A 151 1028.6 [M + H].sup.+ 1028.5 [M + H].sup.+ 1.30 A 152 1013.6 [M + H].sup.+ 1013.5 [M + H].sup.+ 1.09 A 153 997.7 [M + H].sup.+ 997.5 [M + H].sup.+ 1.35 A 154 993.7 [M + H].sup.+ 993.5 [M + H].sup.+ 1.37 A 155 996.7 [M + H].sup.+ 996.5 [M + H].sup.+ 1.30 A 156 980.7 [M + H].sup.+ 980.5 [M + H].sup.+ 1.39 A 157 854.4 [M ? 2H].sup.2? 854.5 [M ? 2H].sup.2? 1.44 A 158 870.7 [M + 2H].sup.2+ 870.5 [M + 2H].sup.2+ 1.56 A 159 1675.3 [M ? H].sup.? 1675.0 [M ? H].sup.? 1.01 A 160 853.4 [M + 2H].sup.2+ 853.0 [M + 2H].sup.2+ 1.10 A 161 1012.6 [M ? H].sup.? 1012.5 [M ? H].sup.? 1.36 A 162 1025.7 [M ? H].sup.? 1025.5 [M ? H].sup.? 1.28 A 163 1026.0 [M ? H].sup.? 1025.5 [M ? H].sup.? 1.31 A 164 1041.8 [M + H].sup.+ 1041.5 [M + H].sup.+ 1.28 A 165 1025.8 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.35 A 166 1039.7 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.33 A 167 1055.7 [M + H].sup.+ 1055.5 [M + H].sup.+ 1.25 A 168 1087.7 [M + H].sup.+ 1087.5 [M + H].sup.+ 1.10 A 169 1060.6 [M + H].sup.+ 1060.5 [M + H].sup.+ 1.10 A 170 1059.6 [M ? H].sup.? 1059.5 [M ? H].sup.? 1.94 B 171 1062.6 [M + H].sup.+ 1062.5 [M + H].sup.+ 1.98 B 172 1020.6 [M + H].sup.+ 1020.5 [M + H].sup.+ 1.97 B 173 996.8 [M + H].sup.+ 996.5 [M + H].sup.+ 1.30 A 174 980.8 [M + H].sup.+ 980.5 [M + H].sup.+ 1.38 A 175 1152.0 [M ? H].sup.? 1151.6 [M ? H].sup.? 1.11 A 176 1180.0 [M ? H].sup.? 1179.6 [M ? H].sup.? 1.14 A 177 995.7 [M ? H].sup.? 995.4 [M ? H].sup.? 1.30 A 178 1055.4 [M + H].sup.+ 1055.4 [M + H].sup.+ 1.29 A 179 548.7 [M + 2H].sup.2+ 548.3 [M + 2H].sup.2+ 0.82 A 180 555.7 [M + 2H].sup.2+ 555.3 [M + 2H].sup.2+ 0.84 A 181 1121.8 [M ? H].sup.? 1121.6 [M ? H].sup.? 0.86 A 182 1110.7 [M + H].sup.+ 1110.5 [M + H].sup.+ 1.03 A 183 1124.7 [M + H].sup.+ 1124.5 [M + H].sup.+ 1.04 A 184 1079.0 [M ? H].sup.? 1078.6 [M ? H].sup.? 0.91 A 185 1063.4 [M ? H].sup.? 1062.6 [M ? H].sup.? 1.00 A 186 1093.0 [M ? H].sup.? 1092.6 [M ? H].sup.? 0.97 A 187 1077.0 [M ? H].sup.? 1076.6 [M ? H].sup.? 1.01 A 188 1106.9 [M ? H].sup.? 1106.6 [M ? H].sup.? 0.94 A 189 1090.9 [M ? H].sup.? 1090.6 [M ? H].sup.? 1.00 A 190 1121.1 [M ? H].sup.? 1120.6 [M ? H].sup.? 0.97 A 191 1105.0 [M ? H].sup.? 1104.6 [M ? H].sup.? 1.02 A 192 1093.1 [M ? H].sup.? 1092.6 [M ? H].sup.? 0.99 A 193 1077.0 [M ? H].sup.? 1076.6 [M ? H].sup.? 1.03 A 194 1106.9 [M ? H].sup.? 1106.6 [M ? H].sup.? 1.01 A 195 1091.0 [M ? H].sup.? 1090.6 [M ? H].sup.? 1.05 A 196 1121.0 [M ? H].sup.? 1120.6 [M ? H].sup.? 1.00 A 197 1105.0 [M ? H].sup.? 1104.6 [M ? H].sup.? 1.04 A 198 1118.9 [M ? H].sup.? 1118.6 [M ? H].sup.? 1.06 A 199 1164.8 [M ? H].sup.? 1164.6 [M ? H].sup.? 1.05 A 200 1151.7 [M + H].sup.+ 1151.6 [M + H].sup.+ 1.17 A 201 1150.7 [M + H].sup.+ 1150.6 [M + H].sup.+ 1.12 A 202 958.5 [M + H].sup.+ 958.4 [M + H].sup.+ 1.62 A 203 1059.7 [M + H].sup.+ 1059.5 [M + H].sup.+ 1.36 A 204 1073.7 [M + H].sup.+ 1073.5 [M + H].sup.+ 1.34 A 205 1016.7 [M + H].sup.+ 1016.5 [M + H].sup.+ 1.40 A 206 1084.7 [M + H].sup.+ 1084.5 [M + H].sup.+ 1.07 A 207 1098.7 [M + H].sup.+ 1098.5 [M + H].sup.+ 1.07 A 208 1041.7 [M + H].sup.+ 1041.5 [M + H].sup.+ 1.12 A 209 1070.6 [M + H].sup.+ 1070.5 [M + H].sup.+ 1.04 A 210 1038.7 [M + H].sup.+ 1038.5 [M + H].sup.+ 1.49 B 211 1023.7 [M + H].sup.+ 1023.5 [M + H].sup.+ 1.62 B 212 1053.7 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.52 B 213 1038.7 [M + H].sup.+ 1038.5 [M + H].sup.+ 1.33 B 214 1022.7 [M + H].sup.+ 1022.5 [M + H].sup.+ 1.57 B 215 1007.7 [M + H].sup.+ 1007.6 [M + H].sup.+ 1.70 B 216 1037.6 [M + H].sup.+ 1037.5 [M + H].sup.+ 1.59 B 217 1020.6 [M ? H].sup.? 1020.6 [M ? H].sup.? 1.44 B 218 1036.7 [M + H].sup.+ 1036.5 [M + H].sup.+ 1.08 A 219 1052.7 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.03 A 220 1066.6 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.03 A 221 1024.7 [M + H].sup.+ 1024.5 [M + H].sup.+ 0.98 A 222 1052.7 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.02 A 223 1067.7 [M + H].sup.+ 1067.5 [M + H].sup.+ 1.04 A 224 1010.6 [M + H].sup.+ 1010.5 [M + H].sup.+ 1.00 A 225 1024.5 [M + H].sup.+ 1024.5 [M + H].sup.+ 1.01 A 226 1038.6 [M + H].sup.+ 1038.5 [M + H].sup.+ 1.03 A 227 1039.6 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.03 A 228 1053.6 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 229 1008.7 [M + H].sup.+ 1008.5 [M + H].sup.+ 1.05 A 230 1036.7 [M + H].sup.+ 1036.5 [M + H].sup.+ 1.09 A 231 1023.7 [M + H].sup.+ 1023.5 [M + H].sup.+ 1.07 A 232 1051.7 [M + H].sup.+ 1051.5 [M + H].sup.+ 1.10 A 233 1066.6 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.02 A 234 1050.6 [M + H].sup.+ 1050.6 [M + H].sup.+ 1.07 A 235 1039.7 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.04 A 236 1023.7 [M + H].sup.+ 1023.5 [M + H].sup.+ 1.12 A 237 1053.7 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 238 1039.7 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.04 A 239 1023.7 [M + H].sup.+ 1023.5 [M + H].sup.+ 1.11 A 240 1025.6 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.04 A 241 1024.6 [M + H].sup.+ 1024.5 [M + H].sup.+ 1.02 A 242 1053.6 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 243 1052.6 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.00 A 244 1036.7 [M ? H].sup.+ 1036.5 [M ? H].sup.+ 1.05 A 245 1065.8 [M + H].sup.+ 1065.6 [M + H].sup.+ 0.95 A 246 1079.8 [M + H].sup.+ 1079.6 [M + H].sup.+ 0.95 A 247 533.6 [M + 2H].sup.2+ 533.3 [M + 2H].sup.2+ 0.90 A 248 1050.7 [M + H].sup.+ 1050.6 [M + H].sup.+ 1.06 A 249 1064.7 [M + H].sup.+ 1064.6 [M + H].sup.+ 1.07 A 250 1038.7 [M + H].sup.+ 1038.5 [M + H].sup.+ 0.99 A 251 1022.7 [M + H].sup.+ 1022.5 [M + H].sup.+ 1.05 A 252 1024.7 [M + H].sup.+ 1024.5 [M + H].sup.+ 1.00 A 253 1052.6 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.00 A 254 1064.8 [M + H].sup.+ 1064.6 [M + H].sup.+ 1.16 A 253 1104.8 [M + H].sup.+ 1104.6 [M + H].sup.+ 1.31 A 256 1066.7 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.04 A 257 1080.7 [M + H].sup.+ 1080.5 [M + H].sup.+ 1.04 A 258 1081.7 [M + H].sup.+ 1081.5 [M + H].sup.+ 1.07 A 259 1053.6 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.07 A 260 1067.7 [M + H].sup.+ 1067.5 [M + H].sup.+ 1.06 A 261 1051.6 [M + H].sup.+ 1051.5 [M + H].sup.+ 1.13 A 262 1082.7 [M + H].sup.+ 1082.5 [M + H].sup.+ 1.09 A 263 1098.6 [M + H].sup.+ 1098.5 [M + H].sup.+ 1.03 A 264 1097.7 [M + H].sup.+ 1097.5 [M + H].sup.+ 1.11 A 265 1113.6 [M + H].sup.+ 1113.5 [M + H].sup.+ 1.05 A 266 1096.6 [M + H].sup.+ 1096.6 [M + H].sup.+ 1.07 A 267 1112.7 [M + H].sup.+ 1112.5 [M + H].sup.+ 1.03 A 268 1066.7 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.03 A 269 1092.7 [M + H].sup.+ 1092.5 [M + H].sup.+ 1.06 A 270 1106.7 [M + H].sup.+ 1106.6 [M + H].sup.+ 1.11 A 271 1136.7 [M + H].sup.+ 1136.6 [M + H].sup.+ 1.03 A 272 1096.6 [M + H].sup.+ 1096.5 [M + H].sup.+ 1.01 A 273 1076.7 [M + H].sup.+ 1076.6 [M + H].sup.+ 1.16 A 274 1092.6 [M + H].sup.+ 1092.6 [M + H].sup.+ 1.07 A 275 1090.7 [M + H].sup.+ 1090.6 [M + H].sup.+ 1.22 A 276 1120.7 [M + H].sup.+ 1120.6 [M + H].sup.+ 1.10 A 277 1080.6 [M + H].sup.+ 1080.6 [M + H].sup.+ 1.07 A 278 1103.7 [M + H].sup.+ 1103.5 [M + H].sup.+ 1.09 A 279 1036.8 [M + H].sup.+ 1036.5 [M + H].sup.+ 1.06 A 280 1052.7 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.02 A 281 1050.7 [M + H].sup.+ 1050.6 [M + H].sup.+ 1.08 A 282 1066.7 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.03 A 283 1036.8 [M + H].sup.+ 1036.5 [M + H].sup.+ 1.06 A 284 1052.6 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.00 A 285 1025.7 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.02 A 286 1007.7 [M ? H].sup.? 1007.5 [M ? H].sup.? 1.04 A 287 1085.7 [M + H].sup.+ 1085.5 [M + H].sup.+ 1.22 A 288 1085.7 [M + H].sup.+ 1085.5 [M + H].sup.+ 1.21 A 289 1101.7 [M + H].sup.+ 1101.5 [M + H].sup.+ 1.11 A 290 1101.5 [M + H].sup.+ 1101.5 [M + H].sup.+ 1.11 A 291 527.6 [M + 2H].sup.2+ 527.3 [M + 2H].sup.2+ 0.83 A 292 534.5 [M + 2H].sup.2+ 534.3 [M + 2H].sup.2+ 0.80 A 293 505.9 [M + 2H].sup.2+ 505.8 [M + 2H].sup.2+ 0.86 A 294 506.0 [M + 2H].sup.2+ 505.8 [M + 2H].sup.2+ 0.86 A 295 993.5 [M ? H].sup.? 993.5 [M ? H].sup.? 1.03 A 296 520.0 [M + 2H].sup.2+ 519.8 [M + 2H].sup.2+ 0.85 A 297 513.1 [M + 2H].sup.2+ 512.8 [M + 2H].sup.2+ 0.87 A 298 1036.8 [M ? H].sup.? 1036.5 [M ? H].sup.? 0.86 A 299 1051.8 [M ? H].sup.? 1051.5 [M ? H].sup.? 0.76 A 300 991.7 [M + H].sup.+ 991.5 [M + H].sup.+ 1.11 A 301 1007.6 [M + H].sup.+ 1007.5 [M + H].sup.+ 1.04 A 302 1005.6 [M + H].sup.+ 1005.5 [M + H].sup.+ 1.12 A 303 1021.6 [M + H].sup.+ 1021.5 [M + H].sup.+ 1.06 A 304 1051.7 [M + H].sup.+ 1051.5 [M + H].sup.+ 1.11 A 305 534.5 [M + 2H].sup.2+ 534.2 [M + 2H].sup.2+ 1.05 A 306 1037.7 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.78 A 307 1037.7 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.75 A 308 1081.8 [M + H].sup.+ 1081.5 [M + H].sup.+ 1.07 A 309 1035.8 [M + H].sup.+ 1035.6 [M + H].sup.+ 1.31 A 310 1048.9 [M ? H].sup.? 1048.6 [M ? H].sup.? 0.98 A 311 1066.8 [M + H].sup.+ 1066.6 [M + H].sup.+ 0.88 A 312 1062.8 [M ? H].sup.? 1062.6 [M ? H].sup.? 1.00 A 313 1078.9 [M ? H].sup.? 1078.6 [M ? H].sup.? 0.91 A 314 1038.7 [M + H].sup.+ 1038.5 [M + H].sup.+ 1.06 A 315 1011.7 [M + H].sup.+ 1011.5 [M + H].sup.+ 1.07 A 316 1071.7 [M + H].sup.+ 1071.5 [M + H].sup.+ 1.18 A 317 1044.7 [M + H].sup.+ 1044.5 [M + H].sup.+ 1.18 A 318 1065.7 [M + H].sup.+ 1065.6 [M + H].sup.+ 1.11 A 319 1039.8 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.04 A 320 1039.7 [M + H].sup.+ 1039.5 [M + H].sup.+ 1.03 A 321 1035.7 [M + H].sup.+ 1035.5 [M + H].sup.+ 1.09 A 322 1124.7 [M + H].sup.+ 1124.5 [M + H].sup.+ 1.22 A 323 1049.8 [M + H].sup.+ 1049.6 [M + H].sup.+ 1.32 A 324 1064.8 [M + H].sup.+ 1065.6 [M + H].sup.+ 1.24 A 325 1067.8 [M + H].sup.+ 1067.6 [M + H].sup.+ 1.26 A 326 1082.7 [M + H].sup.+ 1083.5 [M + H].sup.+ 1.17 A 327 1124.7 [M + H].sup.+ 1124.5 [M + H].sup.+ 1.21 A 328 538.6 [M + 2H].sup.2+ 538.3 [M + 2H].sup.2+ 0.85 A 329 1073.8 [M ? H].sup.? 1073.5 [M ? H].sup.? 0.85 A 330 1041.7 [M + H].sup.+ 1041.5 [M + H].sup.+ 1.08 A 331 1041.7 [M + H].sup.+ 1041.5 [M + H].sup.+ 1.07 A 332 1092.7 [M ? H].sup.? 1092.6 [M ? H].sup.? 0.86 A 333 1092.9 [M ? H].sup.? 1092.6 [M ? H].sup.? 0.86 A 334 534.6 [M + 2H].sup.2+ 534.3 [M + 2H].sup.2+ 1.03 A 335 1027.7 [M + H].sup.+ 1027.5 [M + H].sup.+ 1.00 A 336 1092.8 [M + H].sup.+ 1092.6 [M + H].sup.+ 1.09 A 337 1108.7 [M + H].sup.+ 1108.6 [M + H].sup.+ 1.05 A 338 1079.8 [M + H].sup.+ 1079.6 [M + H].sup.+ 1.06 A 339 1079.8 [M + H].sup.+ 1079.6 [M + H].sup.+ 1.05 A 340 1095.7 [M + H].sup.+ 1095.5 [M + H].sup.+ 1.01 A 341 1095.7 [M + H].sup.+ 1095.5 [M + H].sup.+ 1.01 A 342 1053.7 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 343 1053.6 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 344 1048.9 [M ? H].sup.? 1048.6 [M ? H].sup.? 0.92 A 345 1053.7 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.20 A 346 1069.7 [M + H].sup.+ 1069.5 [M + H].sup.+ 1.14 A 347 1009.8 [M + H].sup.+ 1009.5 [M + H].sup.+ 1.06 A 348 1023.8 [M + H].sup.+ 1023.5 [M + H].sup.+ 1.08 A 349 984.6 [M + H].sup.+ 984.5 [M + H].sup.+ 1.04 A 350 1422.4 [M ? H].sup.? 1421.8 [M ? H].sup.? 0.60 A 351 470.1 [M + 3H].sup.3+ 469.9 [M + 3H].sup.3+ 0.67 A 352 1025.7 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.02 A 353 1009.7 [M + H].sup.+ 1009.5 [M + H].sup.+ 1.07 A 354 1053.7 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.06 A 355 1037.7 [M + H].sup.+ 1037.6 [M + H].sup.+ 1.13 A 356 1076.8 [M ? H].sup.? 1076.6 [M ? H].sup.? 0.99 A 357 1064.7 [M + H].sup.+ 1064.6 [M + H].sup.+ 1.09 A 358 1080.7 [M + H].sup.+ 1080.5 [M + H].sup.+ 1.04 A 359 1070.6 [M + H].sup.+ 1070.5 [M + H].sup.+ 1.07 A 360 1086.6 [M + H].sup.+ 1086.5 [M + H].sup.+ 1.04 A 361 1038.9 [M ? H].sup.? 1038.5 [M ? H].sup.? 0.80 A 362 1052.7 [M ? H].sup.? 1052.5 [M ? H].sup.? 0.83 A 363 1079.8 [M ? H].sup.? 1079.6 [M ? H].sup.? 0.71 A 364 513.1 [M + 2H].sup.2+ 512.8 [M + 2H].sup.2+ 0.91 A 365 520.1 [M + 2H].sup.2+ 519.8 [M + 2H].sup.2+ 0.98 A 366 1064.0 [M ? H].sup.? 1063.6 [M ? H].sup.? 0.78 A 367 1107.0 [M ? H].sup.? 1106.6 [M ? H].sup.? 0.94 A 368 1091.1 [M ? H].sup.? 1090.6 [M ? H].sup.? 1.00 A 369 1064.9 [M ? H].sup.? 1064.5 [M ? H].sup.? 0.86 A 370 1049.1 [M ? H].sup.? 1048.6 [M ? H].sup.? 0.99 A 371 1009.9 [M + H].sup.+ 1009.5 [M + H].sup.+ 0.66 A 372 1021.8 [M ? H].sup.? 1021.5 [M ? H].sup.? 0.66 A 373 1035.9 [M ? H].sup.? 1035.6 [M ? H].sup.? 0.62 A 374 1092.0 [M ? H].sup.? 1091.6 [M ? H].sup.? 0.73 A 375 1035.9 [M ? H].sup.? 1035.5 [M ? H].sup.? 0.68 A 376 1049.9 [M ? H].sup.? 1049.6 [M ? H].sup.? 0.68 A 377 1065.8 [M + H].sup.+ 1065.6 [M + H].sup.+ 0.67 A 378 1093.8 [M + H].sup.+ 1093.6 [M + H].sup.+ 0.73 A 379 925.5 [M + H].sup.+ 925.5 [M + H].sup.+ 1.13 A 380 955.5 [M + H].sup.+ 955.5 [M + H].sup.+ 1.00 A 381 939.6 [M + H].sup.+ 939.5 [M + H].sup.+ 1.13 A 382 812.5 [M + H].sup.+ 812.4 [M + H].sup.+ 0.97 A 383 1032.7 [M + H].sup.+ 1032.6 [M + H].sup.+ 1.09 A 384 1192.9 [M ? H].sup.? 1192.6 [M ? H].sup.? 0.86 A 385 1176.9 [M ? H].sup.? 1176.6 [M ? H].sup.? 0.89 A 386 1221.0 [M ? H].sup.? 1220.6 [M ? H].sup.? 0.85 A 387 1204.9 [M ? H].sup.? 1204.6 [M ? H].sup.? 0.93 A 388 1220.9 [M ? H].sup.? 1220.6 [M ? H].sup.? 0.72 A 389 1205.0 [M ? H].sup.? 1204.7 [M ? H].sup.? 0.80 A 390 1249.0 [M ? H].sup.? 1248.6 [M ? H].sup.? 0.74 A 391 1232.9 [M ? H].sup.? 1232.7 [M ? H].sup.? 0.81 A 392 1036.7 [M + H].sup.+ 1036.5 [M + H].sup.+ 1.05 A 393 1052.7 [M + H].sup.+ 1052.5 [M + H].sup.+ 1.01 A 394 1037.7 [M + H].sup.+ 1037.5 [M + H].sup.+ 1.07 A 395 1053.6 [M + H].sup.+ 1053.5 [M + H].sup.+ 1.04 A 396 1062.9 [M ? H].sup.? 1062.6 [M ? H].sup.? 0.93 A 397 1078.9 [M ? H].sup.? 1078.5 [M ? H].sup.? 0.85 A 398 1009.7 [M + H].sup.+ 1009.5 [M + H].sup.+ 1.06 A 399 1025.7 [M + H].sup.+ 1025.5 [M + H].sup.+ 1.02 A 400 1206.8 [M ? H].sup.? 1206.6 [M ? H].sup.? 0.83 A 401 1191.0 [M ? H].sup.? 1190.6 [M ? H].sup.? 0.90 A 402 1178.9 [M ? H].sup.? 1178.6 [M ? H].sup.? 0.82 A 403 1163.0 [M ? H].sup.? 1162.6 [M ? H].sup.? 0.86 A 404 1179.0 [M ? H].sup.? 1178.6 [M ? H].sup.? 0.83 A 405 1163.1 [M ? H].sup.? 1162.6 [M ? H].sup.? 0.86 A 406 1206.9 [M ? H].sup.? 1206.6 [M ? H].sup.? 0.84 A 407 1191.0 [M ? H].sup.? 1190.6 [M ? H].sup.? 0.88 A 408 1110.0 [M ? H].sup.? 1109.5 [M ? H].sup.? 0.79 A 409 1093.9 [M ? H].sup.? 1093.6 [M ? H].sup.? 0.99 A 410 1081.9 [M ? H].sup.? 1081.5 [M ? H].sup.? 0.78 A 411 1065.7 [M ? H].sup.? 1065.6 [M ? H].sup.? 0.98 A 412 1026.7 [M + H].sup.+ 1026.5 [M + H].sup.+ 0.97 A 413 1010.7 [M + H].sup.+ 1010.5 [M + H].sup.+ 1.09 A 414 1040.7 [M + H].sup.+ 1040.5 [M + H].sup.+ 0.99 A 415 1024.8 [M + H].sup.+ 1024.5 [M + H].sup.+ 1.10 A 416 1054.7 [M + H].sup.+ 1054.5 [M + H].sup.+ 1.01 A 417 1092.7 [M + H].sup.+ 1092.5 [M + H].sup.+ 0.81 A 418 1093.9 [M ? H].sup.? 1093.6 [M ? H].sup.? 0.97 A 419 1109.9 [M ? H].sup.? 1109.5 [M ? H].sup.? 0.81 A 420 1065.8 [M ? H].sup.? 1065.6 [M ? H].sup.? 0.95 A 421 1081.8 [M ? H].sup.? 1081.5 [M ? H].sup.? 0.78 A 422 1039.8 [M ? H].sup.? 1039.5 [M ? H].sup.? 0.79 A 423 1053.7 [M ? H].sup.? 1053.5 [M ? H].sup.? 0.78 A 424 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.97 A 425 1067.8 [M ? H].sup.? 1067.5 [M ? H].sup.? 0.77 A 426 1066.7 [M + H].sup.+ 1066.5 [M + H].sup.+ 1.07 A 427 1038.8 [M + H].sup.+ 1038.6 [M + H].sup.+ 1.11 A 428 1049.8 [M ? H].sup.? 1049.5 [M ? H].sup.? 0.85 A 429 1377.2 [M ? H].sup.? 1376.7 [M ? H].sup.? 0.75 A 430 1361.0 [M ? H].sup.? 1360.7 [M ? H].sup.? 0.80 A 431 680.9 [M ? 2H].sup.2? 680.8 [M ? 2H].sup.2? 0.72 A 432 1347.1 [M ? H].sup.? 1346.7 [M ? H].sup.? 0.75 A 433 1376.8 [M ? H].sup.? 1376.7 [M ? H].sup.? 0.74 A 434 1361.2 [M ? H].sup.? 1360.7 [M ? H].sup.? 0.80 A 435 1363.0 [M ? H].sup.? 1362.7 [M ? H].sup.? 0.73 A 436 1347.1 [M ? H].sup.? 1346.7 [M ? H].sup.? 0.77 A 437 1025.8 [M + H].sup.+ 1025.5 [M + H].sup.+ 0.96 A 438 1023.8 [M ? H].sup.? 1023.5 [M ? H].sup.? 0.96 A 439 1038.1 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.95 A 440 1321.1 [M ? H].sup.? 1320.7 [M ? H].sup.? 0.72 A 441 1305.1 [M ? H].sup.? 1304.7 [M ? H].sup.? 0.76 A 442 1307.1 [M ? H].sup.? 1306.7 [M ? H].sup.? 0.71 A 443 1291.1 [M ? H].sup.? 1290.7 [M ? H].sup.? 0.73 A 444 1321.1 [M ? H].sup.? 1320.7 [M ? H].sup.? 0.70 A 445 1305.1 [M ? H].sup.? 1304.7 [M ? H].sup.? 0.75 A 446 1307.0 [M ? H].sup.? 1306.7 [M ? H].sup.? 0.70 A 447 1291.2 [M ? H].sup.? 1290.7 [M ? H].sup.? 0.73 A 448 1037.9 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.97 A 449 1053.8 [M + H].sup.+ 1053.6 [M + H].sup.+ 0.97 A 450 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.98 A 451 1065.8 [M ? H].sup.? 1065.6 [M ? H].sup.? 0.99 A 452 1065.9 [M ? H].sup.? 1065.6 [M ? H].sup.? 0.97 A 453 1050.8 [M + H].sup.+ 1050.6 [M + H].sup.+ 1.08 A 454 1020.8 [M ? H].sup.? 1020.5 [M ? H].sup.? 1.04 A 455 1020.9 [M ? H].sup.? 1020.5 [M ? H].sup.? 1.08 A 456 1022.9 [M ? H].sup.? 1022.5 [M ? H].sup.? 1.05 A 457 1179.0 [M ? H].sup.? 1178.6 [M ? H].sup.? 1.00 A 458 1179.0 [M ? H].sup.? 1178.6 [M ? H].sup.? 0.98 A 459 1150.9 [M ? H].sup.? 1150.6 [M ? H].sup.? 0.98 A 460 1151.0 [M ? H].sup.? 1150.6 [M ? H].sup.? 0.98 A 461 1335.1 [M ? H].sup.? 1334.7 [M ? H].sup.? 0.85 A 462 669.1 [M + 2H].sup.2+ 668.9 [M + 2H].sup.2+ 0.86 A 463 1279.3 [M ? H].sup.? 1278.7 [M ? H].sup.? 0.82 A 464 1194.9 [M ? H].sup.? 1194.6 [M ? H].sup.? 0.82 A 465 1195.0 [M ? H].sup.? 1194.6 [M ? H].sup.? 0.83 A 466 1167.1 [M ? H].sup.? 1166.6 [M ? H].sup.? 0.80 A 467 1166.9 [M ? H].sup.? 1166.6 [M ? H].sup.? 0.79 A 468 1351.2 [M ? H].sup.? 1350.7 [M ? H].sup.? 0.71 A 469 1351.1 [M ? H].sup.? 1350.7 [M ? H].sup.? 0.70 A 470 1295.1 [M ? H].sup.? 1294.7 [M ? H].sup.? 0.69 A 471 1295.0 [M ? H].sup.? 1294.7 [M ? H].sup.? 0.68 A 472 1193.0 [M ? H].sup.? 1192.7 [M ? H].sup.? 0.99 A 473 1193.0 [M ? H].sup.? 1192.7 [M ? H].sup.? 0.99 A 474 1165.1 [M ? H].sup.? 1164.6 [M ? H].sup.? 0.99 A 475 1165.0 [M ? H].sup.? 1164.6 [M ? H].sup.? 0.99 A 476 1349.2 [M ? H].sup.? 1348.8 [M ? H].sup.? 0.87 A 477 1349.5 [M ? H].sup.? 1348.8 [M ? H].sup.? 0.86 A 478 1293.1 [M ? H].sup.? 1292.7 [M ? H].sup.? 0.84 A 479 648.0 [M + 2H].sup.2+ 647.9 [M + 2H].sup.2+ 0.83 A 480 1052.9 [M + H].sup.+ 1052.6 [M + H].sup.+ 1.13 A 481 1052.9 [M ? H].sup.? 1052.5 [M ? H].sup.? 1.01 A 482 1037.0 [M ? H].sup.? 1036.6 [M ? H].sup.? 1.07 A 483 1205.2 [M ? H].sup.? 1204.7 [M ? H].sup.? 0.94 A 484 1177.2 [M ? H].sup.? 1176.6 [M ? H].sup.? 0.91 A 485 1022.9 [M ? H].sup.? 1022.5 [M ? H].sup.? 1.08 A 486 1037.0 [M ? H].sup.? 1036.6 [M ? H].sup.? 1.15 A 487 1164.9 [M ? H].sup.? 1164.7 [M ? H].sup.? 0.91 A 488 1193.0 [M ? H].sup.? 1192.7 [M ? H].sup.? 0.96 A 489 1178.9 [M ? H].sup.? 1178.6 [M ? H].sup.? 0.97 A 490 1165.1 [M ? H].sup.? 1164.6 [M ? H].sup.? 1.01 A 491 1193.1 [M ? H].sup.? 1192.7 [M ? H].sup.? 1.01 A 492 980.9 [M ? H].sup.? 980.5 [M ? H].sup.? 1.00 A 493 1080.1 [M ? H].sup.? 1079.6 [M ? H].sup.? 0.99 A 494 1008.9 [M ? H].sup.? 1008.6 [M ? H].sup.? 0.98 A 495 1023.0 [M ? H].sup.? 1022.6 [M ? H].sup.? 0.99 A 496 1063.9 [M ? H].sup.? 1063.6 [M ? H].sup.? 0.92 A 497 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.98 A 498 1006.9 [M ? H].sup.? 1006.5 [M ? H].sup.? 0.94 A 499 994.8 [M ? H].sup.? 994.5 [M ? H].sup.? 0.99 A 500 1105.7 [M ? H].sup.? 1105.6 [M ? H].sup.? 0.96 A 501 1093.8 [M ? H].sup.? 1093.6 [M ? H].sup.? 1.00 A 502 1021.9 [M ? H].sup.? 1021.6 [M ? H].sup.? 0.77 A 503 1009.9 [M ? H].sup.? 1009.6 [M ? H].sup.? 0.81 A 504 992.9 [M ? H].sup.? 992.5 [M ? H].sup.? 0.91 A 505 980.8 [M ? H].sup.? 980.5 [M ? H].sup.? 0.98 A 506 1050.0 [M ? H].sup.? 1049.5 [M ? H].sup.? 0.86 A 507 1037.9 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.87 A 508 993.9 [M ? H].sup.? 994.5 [M ? H].sup.? 1.04 A 509 1191.0 [M ? H].sup.? 1190.6 [M ? H].sup.? 0.88 A 510 1163.0 [M ? H].sup.? 1162.6 [M ? H].sup.? 0.87 A 511 994.8 [M ? H].sup.? 994.5 [M ? H].sup.? 1.04 A 512 1008.8 [M ? H].sup.? 1008.5 [M ? H].sup.? 1.05 A 513 1052.0 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.92 A 514 1179.0 [M ? H].sup.? 1178.6 [M ? H].sup.? 0.94 A 515 1150.9 [M ? H].sup.? 1150.6 [M ? H].sup.? 0.92 A 516 1007.7 [M ? H].sup.? 1007.5 [M ? H].sup.? 0.76 A 517 995.7 [M ? H].sup.? 995.5 [M ? H].sup.? 0.77 A 518 1221.9 [M ? H].sup.? 1221.7 [M ? H].sup.? 0.84 A 519 1193.9 [M ? H].sup.? 1193.7 [M ? H].sup.? 0.83 A 520 1109.0 [M ? H].sup.? 1108.6 [M ? H].sup.? 0.93 A 521 1123.0 [M ? H].sup.? 1122.6 [M ? H].sup.? 0.93 A 522 937.8 [M ? H].sup.? 937.5 [M ? H].sup.? 1.00 A 523 937.8 [M ? H].sup.? 937.5 [M ? H].sup.? 1.01 A 524 1067.1 [M ? H].sup.? 1066.6 [M ? H].sup.? 0.72 A 525 1067.0 [M ? H].sup.? 1066.6 [M ? H].sup.? 0.72 A 526 1080.8 [M ? H].sup.? 1080.6 [M ? H].sup.? 0.77 A 527 1080.5 [M ? H].sup.? 1080.6 [M ? H].sup.? 0.77 A 528 1108.9 [M ? H].sup.? 1108.6 [M ? H].sup.? 0.68 A 529 1009.9 [M ? H].sup.? 1009.5 [M ? H].sup.? 0.88 A 530 1009.9 [M ? H].sup.? 1009.5 [M ? H].sup.? 0.89 A 531 1023.8 [M ? H].sup.? 1023.5 [M ? H].sup.? 0.88 A 532 1023.9 [M ? H].sup.? 1023.5 [M ? H].sup.? 0.88 A 533 1037.9 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.89 A 534 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.89 A 535 514.3 [M + 2H].sup.2+ 513.8 [M + 2H].sup.2+ 0.73 A 536 514.2 [M + 2H].sup.2+ 513.8 [M + 2H].sup.2+ 0.69 A 537 521.2 [M + 2H].sup.2+ 520.8 [M + 2H].sup.2+ 0.69 A 538 1053.0 [M ? H].sup.? 1052.6 [M ? H].sup.? 0.72 A 539 1052.9 [M ? H].sup.? 1052.6 [M ? H].sup.? 0.70 A 540 1095.0 [M ? H].sup.? 1094.6 [M ? H].sup.? 0.88 A 541 1108.9 [M ? H].sup.? 1108.6 [M ? H].sup.? 0.88 A 542 1038.0 [M ? H].sup.? 1037.5 [M ? H].sup.? 0.87 A 543 1094.0 [M ? H].sup.? 1093.6 [M ? H].sup.? 0.82 A 544 1094.0 [M ? H].sup.? 1093.6 [M ? H].sup.? 0.82 A 545 1080.0 [M ? H].sup.? 1079.6 [M ? H].sup.? 0.76 A 546 1079.8 [M ? H].sup.? 1079.6 [M ? H].sup.? 0.78 A 547 1038.8 [M ? H].sup.? 1038.6 [M ? H].sup.? 0.99 A 548 1038.9 [M ? H].sup.? 1038.6 [M ? H].sup.? 1.00 A 549 1024.9 [M ? H].sup.? 1024.6 [M ? H].sup.? 0.93 A 550 1024.9 [M ? H].sup.? 1024.6 [M ? H].sup.? 0.98 A 551 1109.0 [M ? H].sup.? 1108.6 [M ? H].sup.? 0.71 A 552 1095.0 [M ? H].sup.? 1094.6 [M ? H].sup.? 0.64 A 553 1095.0 [M ? H].sup.? 1094.6 [M ? H].sup.? 0.66 A 554 1053.7 [M ? H].sup.? 1053.6 [M ? H].sup.? 0.80 A 555 1053.8 [M ? H].sup.? 1053.6 [M ? H].sup.? 0.80 A 556 1039.8 [M ? H].sup.? 1039.6 [M ? H].sup.? 0.74 A 557 1039.8 [M ? H].sup.? 1039.6 [M ? H].sup.? 0.74 A 558 1094.9 [M ? H].sup.? 1094.6 [M ? H].sup.? 0.99 A 559 1109.9 [M ? H].sup.? 1109.6 [M ? H].sup.? 0.78 A 560 1095.8 [M ? H].sup.? 1095.6 [M ? H].sup.? 0.72 A 561 1039.0 [M ? H].sup.? 1038.5 [M ? H].sup.? 0.77 A 562 1038.8 [M ? H].sup.? 1038.5 [M ? H].sup.? 0.76 A 563 1053.0 [M ? H].sup.? 1052.6 [M ? H].sup.? 0.76 A 564 1052.9 [M ? H].sup.? 1052.6 [M ? H].sup.? 0.75 A 565 1066.9 [M ? H].sup.? 1066.6 [M ? H].sup.? 0.75 A 566 1067.0 [M ? H].sup.? 1066.6 [M ? H].sup.? 0.75 A 567 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.99 A 568 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.99 A 569 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.99 A 570 1051.9 [M ? H].sup.? 1051.6 [M ? H].sup.? 0.99 A 571 1081.9 [M ? H].sup.? 1081.5 [M ? H].sup.? 0.82 A 572 1081.9 [M ? H].sup.? 1081.5 [M ? H].sup.? 0.80 A 573 1023.9 [M ? H].sup.? 1023.5 [M ? H].sup.? 0.82 A 574 1023.9 [M ? H].sup.? 1023.5 [M ? H].sup.? 0.82 A 575 1065.9 [M ? H].sup.? 1065.6 [M ? H].sup.? 1.02 A 576 1065.8 [M ? H].sup.? 1065.6 [M ? H].sup.? 0.99 A 577 1066.9 [M ? H].sup.? 1066.6 [M ? H].sup.? 1.05 A 578 1021.8 [M ? H].sup.? 1021.5 [M ? H].sup.? 1.10 A 579 1031.9 [M ? H].sup.? 1031.5 [M ? H].sup.? 1.30 A 580 1019.8 [M ? H].sup.? 1019.6 [M ? H].sup.? 1.14 A 581 1031.8 [M ? H].sup.? 1031.6 [M ? H].sup.? 1.12 A 582 1047.8 [M ? H].sup.? 1047.6 [M ? H].sup.? 1.17 A 583 1059.8 [M ? H].sup.? 1059.6 [M ? H].sup.? 1.14 A 584 990.8 [M ? H].sup.? 990.5 [M ? H].sup.? 1.32 A 585 992.7 [M ? H].sup.? 992.5 [M ? H].sup.? 1.38 A 586 1004.7 [M ? H].sup.? 1004.5 [M ? H].sup.? 1.35 A 587 1002.7 [M ? H].sup.? 1002.4 [M ? H].sup.? 1.81 A 588 1016.7 [M ? H].sup.? 1016.4 [M ? H].sup.? 1.83 A 589 970.7 [M ? H].sup.? 970.4 [M ? H].sup.? 1.79 A 590 939.5 [M ? H].sup.? 939.4 [M ? H].sup.? 1.08 A 591 941.6 [M + H].sup.+ 941.4 [M + H].sup.+ 0.89 A 592 939.4 [M ? H].sup.? 939.4 [M ? H].sup.? 1.49 A 593 801.3 [M + H].sup.+ 801.2 [M + H].sup.+ 1.89 B 594 774.5 [M ? H].sup.? 774.4 [M ? H].sup.? 1.53 A 595 835.3 [M + H].sup.+ 835.4 [M + H].sup.+ 1.04 A 596 989.6 [M + H].sup.+ 989.5 [M + H].sup.+ 1.34 A 597 974.5 [M ? H].sup.? 974.4 [M ? H].sup.? 1.65 A 598 974.5 [M ? H].sup.? 974.4 [M ? H].sup.? 1.63 A 599 958.6 [M + H].sup.+ 958.4 [M + H].sup.+ 1.64 A 600 991.7 [M + H].sup.+ 991.5 [M + H].sup.+ 1.22 A 601 1007.7 [M + H].sup.+ 1007.5 [M + H].sup.+ 1.15 A 602 844.6 [M ? H].sup.? 844.3 [M ? H].sup.? 0.98 A 603 858.5 [M ? H].sup.? 858.4 [M ? H].sup.? 0.97 A 604 828.4 [M ? H].sup.? 828.4 [M ? H].sup.? 1.06 A 605 842.5 [M ? H].sup.? 842.5 [M ? H].sup.? 1.04 A 606 872.7 [M ? H].sup.? 872.4 [M ? H].sup.? 1.07 A 607 872.5 [M ? H].sup.? 872.4 [M ? H].sup.? 0.87 A 608 881.6 [M + H].sup.+ 881.4 [M + H].sup.+ 1.38 A 609 928.6 [M + H].sup.+ 928.4 [M + H].sup.+ 1.07 A 610 826.4 [M + H].sup.+ 826.3 [M + H].sup.+ 1.39 A 611 830.8 [M ? H].sup.? 830.3 [M ? H].sup.? 1.37 A 612 846.5 [M + H].sup.+ 846.4 [M + H].sup.+ 1.34 A 613 816.5 [M + H].sup.+ 816.4 [M + H].sup.+ 1.45 A 614 830.5 [M + H].sup.+ 830.4 [M + H].sup.+ 1.42 A 615 870.4 [M + H].sup.+ 870.4 [M + H].sup.+ 1.63 A 616 884.4 [M + H].sup.+ 884.4 [M + H].sup.+ 1.61 A 617 846.4 [M + H].sup.+ 846.4 [M + H].sup.+ 1.48 A 618 860.4 [M + H].sup.+ 860.4 [M + H].sup.+ 1.45 A 619 858.5 [M + H].sup.+ 858.4 [M + H].sup.+ 1.51 A 620 826.5 [M ? H].sup.? 826.4 [M ? H].sup.? 1.35 A 621 810.5 [M ? H].sup.? 810.4 [M ? H].sup.? 1.44 A 622 856.5 [M ? H].sup.? 856.4 [M ? H].sup.? 1.36 A 623 840.6 [M ? H].sup.? 840.4 [M ? H].sup.? 1.43 A 624 844.5 [M ? H].sup.? 844.3 [M ? H].sup.? 1.40 A 625 828.5 [M ? H].sup.? 828.4 [M ? H].sup.? 1.47 A 626 860.5 [M ? H].sup.? 860.3 [M ? H].sup.? 1.49 A 627 844.6 [M ? H].sup.? 844.3 [M ? H].sup.? 1.55 A 628 868.6 [M ? H].sup.? 868.4 [M ? H].sup.? 1.28 A 629 852.6 [M ? H].sup.? 852.4 [M ? H].sup.? 1.36 A 630 870.5 [M ? H].sup.? 870.4 [M ? H].sup.? 1.33 A 631 854.6 [M ? H].sup.? 854.4 [M ? H].sup.? 1.40 A 632 858.5 [M ? H].sup.? 858.4 [M ? H].sup.? 1.29 A 633 759.3 [M ? H].sup.? 759.3 [M ? H].sup.? 1.28 A 634 811.6 [M ? H].sup.? 811.4 [M ? H].sup.? 1.67 A 635 812.6 [M ? H].sup.? 812.4 [M ? H].sup.? 1.38 A 636 826.5 [M ? H].sup.? 826.4 [M ? H].sup.? 1.50 A 637 832.6 [M + H].sup.+ 832.3 [M + H].sup.+ 1.14 A 638 862.5 [M + H].sup.+ 862.4 [M + H].sup.+ 1.16 A 639 846.6 [M + H].sup.+ 846.4 [M + H].sup.+ 1.12 A 640 876.6 [M + H].sup.+ 876.4 [M + H].sup.+ 1.15 A 641 816.5 [M + H].sup.+ 816.4 [M + H].sup.+ 1.22 A 642 830.5 [M + H].sup.+ 830.4 [M + H].sup.+ 1.20 A 643 889.6 [M ? H].sup.? 889.4 [M ? H].sup.? 1.10 A 644 845.5 [M + H].sup.+ 845.3 [M + H].sup.+ 1.22 A 645 827.6 [M ? H].sup.? 827.4 [M ? H].sup.? 1.32 A 646 859.5 [M + H].sup.+ 859.4 [M + H].sup.+ 1.21 A 647 843.5 [M + H].sup.+ 843.4 [M + H].sup.+ 1.29 A 648 845.5 [M + H].sup.+ 845.3 [M + H].sup.+ 1.71 B 649 843.5 [M + H].sup.+ 843.4 [M + H].sup.+ 1.79 B 650 859.5 [M + H].sup.+ 859.4 [M + H].sup.+ 1.70 B 651 843.5 [M + H].sup.+ 843.4 [M + H].sup.+ 1.80 B 652 873.6 [M + H].sup.+ 873.4 [M + H].sup.+ 1.71 B 653 857.6 [M + H].sup.+ 857.4 [M + H].sup.+ 1.79 B 654 863.5 [M + H].sup.+ 863.3 [M + H].sup.+ 1.27 A 655 847.6 [M + H].sup.+ 847.4 [M + H].sup.+ 1.35 A 656 877.6 [M + H].sup.+ 877.3 [M + H].sup.+ 1.25 A 657 861.6 [M + H].sup.+ 861.4 [M + H].sup.+ 1.33 A 658 859.5 [M + H].sup.+ 859.4 [M + H].sup.+ 1.32 A 659 843.6 [M + H].sup.+ 843.4 [M + H].sup.+ 1.44 A 660 873.6 [M + H].sup.+ 873.4 [M + H].sup.+ 1.30 A 661 857.6 [M + H].sup.+ 857.4 [M + H].sup.+ 1.39 A 662 913.5 [M + H].sup.+ 913.3 [M + H].sup.+ 1.48 A 663 897.5 [M + H].sup.+ 897.4 [M + H].sup.+ 1.54 A 664 927.6 [M + H].sup.+ 927.3 [M + H].sup.+ 1.45 A 665 911.6 [M + H].sup.+ 911.4 [M + H].sup.+ 1.51 A 666 921.5 [M ? H].sup.? 921.4 [M ? H].sup.? 1.42 A 667 937.3 [M + H].sup.+ 937.3 [M + H].sup.+ 1.36 A 668 870.5 [M + H].sup.+ 870.3 [M + H].sup.+ 1.23 A 669 884.6 [M + H].sup.+ 884.4 [M + H].sup.+ 1.21 A 670 1071.7 [M + H].sup.+ 1071.5 [M + H].sup.+ 1.28 A 671 907.3 [M + H].sup.+ 907.3 [M + H].sup.+ 1.48 A 672 852.5 [M ? H].sup.? 852.4 [M ? H].sup.? 1.32 A 673 921.3 [M + H].sup.+ 921.3 [M + H].sup.+ 1.44 A 674 886.5 [M + H].sup.+ 886.4 [M + H].sup.+ 1.13 A 675 900.6 [M + H].sup.+ 900.4 [M + H].sup.+ 1.18 A 676 900.6 [M + H].sup.+ 900.4 [M + H].sup.+ 1.12 A 677 912.6 [M ? H].sup.? 912.4 [M ? H].sup.? 1.17 A 678 902.5 [M + H].sup.+ 902.4 [M + H].sup.+ 1.06 A 679 916.5 [M + H].sup.+ 916.4 [M + H].sup.+ 1.11 A 680 914.6 [M ? H].sup.? 914.4 [M ? H].sup.? 1.05 A 681 930.5 [M + H].sup.+ 930.4 [M + H].sup.+ 1.10 A 682 848.4 [M + H].sup.+ 848.4 [M + H].sup.+ 1.44 A 683 834.4 [M + H].sup.+ 834.4 [M + H].sup.+ 1.39 A 684 871.6 [M ? H].sup.? 871.4 [M ? H].sup.? 1.10 A 685 889.6 [M ? H].sup.? 889.4 [M ? H].sup.? 1.15 A 686 885.6 [M ? H].sup.? 885.4 [M ? H].sup.? 1.19 A 687 955.6 [M ? H].sup.? 955.4 [M ? H].sup.? 1.36 A 688 939.7 [M ? H].sup.? 939.4 [M ? H].sup.? 1.34 A 689 987.6 [M ? H].sup.? 987.4 [M ? H].sup.? 1.38 A 690 898.4 [M + H].sup.+ 898.4 [M + H].sup.+ 1.10 A 691 875.4 [M + H].sup.+ 875.4 [M + H].sup.+ 1.26 A 692 859.5 [M + H].sup.+ 859.4 [M + H].sup.+ 1.35 A 693 889.4 [M + H].sup.+ 889.4 [M + H].sup.+ 1.24 A 694 873.4 [M + H].sup.+ 873.4 [M + H].sup.+ 1.33 A 695 887.6 [M + H].sup.+ 887.4 [M + H].sup.+ 1.31 A 696 915.6 [M + H].sup.+ 915.5 [M + H].sup.+ 1.51 A 697 903.5 [M + H].sup.+ 903.4 [M + H].sup.+ 1.23 A 698 901.6 [M + H].sup.+ 901.4 [M + H].sup.+ 1.37 A 699 915.6 [M + H].sup.+ 915.5 [M + H].sup.+ 1.46 A 700 913.6 [M + H].sup.+ 913.4 [M + H].sup.+ 1.43 A 701 941.5 [M + H].sup.+ 941.4 [M + H].sup.+ 1.51 A 702 917.6 [M + H].sup.+ 917.4 [M + H].sup.+ 1.31 A 703 929.6 [M + H].sup.+ 929.4 [M + H].sup.+ 1.36 A 704 957.5 [M + H].sup.+ 957.4 [M + H].sup.+ 1.45 A 705 879.5 [M + H].sup.+ 879.3 [M + H].sup.+ 1.39 A 706 863.5 [M + H].sup.+ 863.3 [M + H].sup.+ 1.47 A 707 893.5 [M + H].sup.+ 893.3 [M + H].sup.+ 1.37 A 708 877.5 [M + H].sup.+ 877.4 [M + H].sup.+ 1.45 A 709 768.4 [M + H].sup.+ 768.2 [M + H].sup.+ 1.37 A 710 752.4 [M + H].sup.+ 752.3 [M + H].sup.+ 1.53 A 711 782.4 [M + H].sup.+ 782.3 [M + H].sup.+ 1.35 A 712 766.4 [M + H].sup.+ 766.3 [M + H].sup.+ 1.52 A 713 751.2 [M ? H].sup.? 751.2 [M ? H].sup.? 1.64 A 714 864.5 [M + H].sup.+ 864.3 [M + H].sup.+ 1.65 A 715 846.3 [M ? H].sup.? 846.3 [M ? H].sup.? 1.75 A 716 893.5 [M + H].sup.+ 893.3 [M + H].sup.+ 1.34 A 717 877.5 [M + H].sup.+ 877.4 [M + H].sup.+ 1.43 A 718 891.5 [M + H].sup.+ 891.4 [M + H].sup.+ 1.43 A 719 907.5 [M + H].sup.+ 907.3 [M + H].sup.+ 1.34 A 720 1003.8 [M ? H].sup.? 1003.5 [M ? H].sup.? 1.15 A 721 1031.7 [M ? H].sup.? 1031.5 [M ? H].sup.? 1.17 A 722 918.7 [M ? H].sup.? 918.4 [M ? H].sup.? 1.16 A 723 1017.8 [M ? H].sup.? 1017.5 [M ? H].sup.? 1.15 A 724 1045.8 [M ? H].sup.? 1045.5 [M ? H].sup.? 1.17 A 725 932.7 [M ? H].sup.? 932.4 [M ? H].sup.? 1.15 A 726 891.6 [M + H].sup.+ 891.4 [M + H].sup.+ 1.40 A 727 851.5 [M + H].sup.+ 851.3 [M + H].sup.+ 1.46 A 728 881.5 [M + H].sup.+ 881.4 [M + H].sup.+ 1.47 A 729 927.5 [M + H].sup.+ 927.4 [M + H].sup.+ 1.58 A 730 906.6 [M ? H].sup.? 906.4 [M ? H].sup.? 1.21 A 731 851.5 [M + H].sup.+ 851.3 [M + H].sup.+ 1.45 A 732 865.5 [M + H].sup.+ 865.4 [M + H].sup.+ 1.47 A 733 879.5 [M + H].sup.+ 879.4 [M + H].sup.+ 1.47 A 734 893.6 [M + H].sup.+ 893.4 [M + H].sup.+ 1.48 A 735 1104.7 [M + H].sup.+ 1104.5 [M + H].sup.+ 1.61 A 736 1132.8 [M + H].sup.+ 1132.5 [M + H].sup.+ 1.68 A 737 1159.0 [M ? H].sup.? 1158.6 [M ? H].sup.? 1.77 A 738 864.5 [M ? H].sup.? 864.4 [M ? H].sup.? 1.27 A 739 864.5 [M ? H].sup.? 864.4 [M ? H].sup.? 1.23 A 740 878.7 [M ? H].sup.? 878.4 [M ? H].sup.? 1.22 A 741 878.6 [M ? H].sup.? 878.4 [M ? H].sup.? 1.21 A 742 892.6 [M ? H].sup.? 892.4 [M ? H].sup.? 1.20 A 743 906.6 [M ? H].sup.? 906.4 [M ? H].sup.? 1.20 A 744 906.6 [M ? H].sup.? 906.4 [M ? H].sup.? 1.18 A 745 922.6 [M ? H].sup.? 922.4 [M ? H].sup.? 1.10 A 746 849.6 [M ? H].sup.? 849.4 [M ? H].sup.? 1.23 A 747 892.6 [M ? H].sup.? 892.4 [M ? H].sup.? 1.20 A 748 906.6 [M ? H].sup.? 906.4 [M ? H].sup.? 1.22 A 749 920.7 [M ? H].sup.? 920.4 [M ? H].sup.? 1.20 A 750 934.9 [M ? H].sup.? 934.4 [M ? H].sup.? 1.23 A 751 906.6 [M ? H].sup.? 906.4 [M ? H].sup.? 1.22 A 752 920.6 [M ? H].sup.? 920.4 [M ? H].sup.? 1.22 A 753 934.7 [M ? H].sup.? 934.4 [M ? H].sup.? 1.22 A 754 948.6 [M ? H].sup.? 948.4 [M ? H].sup.? 1.24 A 755 920.6 [M ? H].sup.? 920.4 [M ? H].sup.? 1.21 A 756 934.7 [M ? H].sup.? 934.4 [M ? H].sup.? 1.23 A 757 948.7 [M ? H].sup.? 948.6 [M ? H].sup.? 1.23 A 758 962.7 [M ? H].sup.? 962.7 [M ? H].sup.? 1.24 A 759 899.6 [M + H].sup.+ 899.4 [M + H].sup.+ 1.55 A 760 960.7 [M ? H].sup.? 960.6 [M ? H].sup.? 1.22 A 761 949.5 [M + H].sup.+ 949.4 [M + H].sup.+ 1.53 A 762 990.8 [M ? H].sup.? 990.5 [M ? H].sup.? 1.23 A 763 975.6 [M + H].sup.+ 975.4 [M + H].sup.+ 1.54 A 764 972.7 [M ? H].sup.? 972.6 [M ? H].sup.? 1.23 A 765 853.5 [M + H].sup.+ 853.3 [M + H].sup.+ 1.26 A 766 991.7 [M ? H].sup.? 991.8 [M ? H].sup.? 1.22 A 767 1019.8 [M ? H].sup.? 1019.6 [M ? H].sup.? 1.23 A 768 1147.9 [M ? H].sup.? 1147.9 [M ? H].sup.? 1.09 A 769 1175.9 [M ? H].sup.? 1175.7 [M ? H].sup.? 1.11 A 770 1147.9 [M ? H].sup.? 1147.9 [M ? H].sup.? 1.08 A 771 1119.7 [M ? H].sup.? 1119.7 [M ? H].sup.? 1.09 A 772 1003.7 [M ? H].sup.? 1003.5 [M ? H].sup.? 1.22 A 773 1164.0 [M ? H].sup.? 1163.7 [M ? H].sup.? 1.00 A 774 595.5 [M ? 2H].sup.2? 595.3 [M ? 2H].sup.2? 1.01 A 775 1163.9 [M ? H].sup.? 1163.7 [M ? H].sup.? 1.00 A 776 1136.0 [M ? H].sup.? 1135.6 [M ? H].sup.? 0.98 A 777 864.5 [M ? H].sup.? 864.6 [M ? H].sup.? 1.25 A 778 878.5 [M ? H].sup.? 878.6 [M ? H].sup.? 1.23 A 779 878.5 [M ? H].sup.? 878.6 [M ? H].sup.? 1.23 A 780 892.7 [M ? H].sup.? 892.5 [M ? H].sup.? 1.23 A 781 892.5 [M ? H].sup.? 892.5 [M ? H].sup.? 1.23 A 782 977.8 [M ? H].sup.? 977.4 [M ? H].sup.? 1.19 A 783 991.8 [M ? H].sup.? 991.4 [M ? H].sup.? 1.27 A 784 1007.8 [M ? H].sup.? 1007.4 [M ? H].sup.? 1.11 A 785 992.8 [M ? H].sup.? 992.4 [M ? H].sup.? 1.28 A 786 905.5 [M + H].sup.+ 905.3 [M + H].sup.+ 1.30 A 787 893.5 [M + H].sup.+ 893.3 [M + H].sup.+ 1.26 A 788 921.5 [M + H].sup.+ 921.4 [M + H].sup.+ 1.32 A 789 905.5 [M + H].sup.+ 905.3 [M + H].sup.+ 1.31 A 790 891.4 [M + H].sup.+ 891.3 [M + H].sup.+ 1.31 A 791 864.4 [M + H].sup.+ 864.4 [M + H].sup.+ 1.51 A 792 888.6 [M + H].sup.+ 888.5 [M + H].sup.+ 1.03 A 793 902.6 [M + H].sup.+ 902.4 [M + H].sup.+ 1.02 A 794 870.5 [M ? H].sup.? 870.6 [M ? H].sup.? 1.10 A 795 886.5 [M + H].sup.+ 886.6 [M + H].sup.+ 1.08 A 796 888.6 [M + H].sup.+ 888.4 [M + H].sup.+ 1.13 A 797 902.7 [M + H].sup.+ 902.7 [M + H].sup.+ 1.15 A 798 904.6 [M + H].sup.+ 904.7 [M + H].sup.+ 1.00 A 799 918.6 [M + H].sup.+ 918.5 [M + H].sup.+ 1.02 A 800 903.7 [M ? H].sup.? 903.5 [M ? H].sup.? 0.77 A 801 884.6 [M ? H].sup.? 884.6 [M ? H].sup.? 1.05 A 802 927.5 [M ? H].sup.? 927.5 [M ? H].sup.? 1.02 A 803 1000.8 [M ? H].sup.? 1000.5 [M ? H].sup.? 1.00 A 804 1028.7 [M ? H].sup.? 1028.8 [M ? H].sup.? 1.00 A 805 1156.9 [M ? H].sup.? 1156.8 [M ? H].sup.? 0.89 A 806 1184.9 [M ? H].sup.? 1184.6 [M ? H].sup.? 0.91 A 807 1129.0 [M ? H].sup.? 1128.7 [M ? H].sup.? 0.87 A 808 1043.0 [M ? H].sup.? 1042.5 [M ? H].sup.? 1.00 A 809 1171.0 [M ? H].sup.? 1170.7 [M ? H].sup.? 0.85 A 810 1171.0 [M ? H].sup.? 1170.7 [M ? H].sup.? 0.84 A 811 1142.8 [M ? H].sup.? 1142.6 [M ? H].sup.? 0.83 A 812 1014.8 [M ? H].sup.? 1014.7 [M ? H].sup.? 0.99 A 813 1199.0 [M ? H].sup.? 1198.6 [M ? H].sup.? 0.86 A 814 873.5 [M ? H].sup.? 873.4 [M ? H].sup.? 1.01 A 815 901.6 [M ? H].sup.? 901.4 [M ? H].sup.? 1.00 A 816 901.7 [M ? H].sup.? 901.4 [M ? H].sup.? 0.99 A 817 915.8 [M ? H].sup.? 915.7 [M ? H].sup.? 0.99 A 818 915.6 [M ? H].sup.? 915.7 [M ? H].sup.? 0.99 A 819 900.6 [M + H].sup.+ 900.4 [M + H].sup.+ 1.08 A 820 1026.8 [M ? H].sup.? 1026.7 [M ? H].sup.? 0.90 A 821 1054.7 [M ? H].sup.? 1054.5 [M ? H].sup.? 0.92 A 822 1183.0 [M ? H].sup.? 1182.7 [M ? H].sup.? 0.75 A 823 1211.0 [M ? H].sup.? 1210.6 [M ? H].sup.? 0.76 A 824 1183.1 [M ? H].sup.? 1182.7 [M ? H].sup.? 0.75 A 825 1155.0 [M ? H].sup.? 1154.6 [M ? H].sup.? 0.73 A 826 874.6 [M + H].sup.+ 874.6 [M + H].sup.+ 1.07 A 827 886.6 [M + H].sup.+ 886.6 [M + H].sup.+ 1.04 A 828 1072.0 [M ? H].sup.? 1071.8 [M ? H].sup.? 0.99 A 829 1099.9 [M ? H].sup.? 1099.5 [M ? H].sup.? 1.00 A 830 1256.0 [M ? H].sup.? 1255.6 [M ? H].sup.? 0.86 A 831 1228.1 [M ? H].sup.? 1227.6 [M ? H].sup.? 0.82 A 832 1085.8 [M ? H].sup.? 1085.6 [M ? H].sup.? 0.99 A 833 1242.1 [M ? H].sup.? 1241.7 [M ? H].sup.? 0.83 A 834 1270.1 [M ? H].sup.? 1269.8 [M ? H].sup.? 0.85 A 835 1242.1 [M ? H].sup.? 1241.7 [M ? H].sup.? 0.83 A 836 1228.0 [M ? H].sup.? 1227.9 [M ? H].sup.? 0.86 A 837 1199.8 [M ? H].sup.? 1199.6 [M ? H].sup.? 0.85 A 838 884.5 [M ? H].sup.? 884.6 [M ? H].sup.? 1.09 A 839 872.5 [M + H].sup.+ 872.6 [M + H].sup.+ 1.06 A 840 844.5 [M ? H].sup.? 844.5 [M ? H].sup.? 1.13 A 841 858.5 [M ? H].sup.? 858.6 [M ? H].sup.? 1.13 A 842 872.8 [M ? H].sup.? 872.6 [M ? H].sup.? 1.14 A 843 886.7 [M ? H].sup.? 886.4 [M ? H].sup.? 1.16 A 844 859.6 [M ? H].sup.? 859.6 [M ? H].sup.? 1.00 A 845 870.5 [M ? H].sup.? 870.6 [M ? H].sup.? 1.06 A 846 872.5 [M + H].sup.+ 872.6 [M + H].sup.+ 1.09 A 847 872.5 [M + H].sup.+ 872.6 [M + H].sup.+ 1.06 A 848 900.5 [M + H].sup.+ 900.4 [M + H].sup.+ 1.17 A 849 900.6 [M + H].sup.+ 900.4 [M + H].sup.+ 1.20 A 850 914.6 [M + H].sup.+ 914.7 [M + H].sup.+ 1.10 A 851 886.5 [M + H].sup.+ 886.4 [M + H].sup.+ 1.12 A 852 886.7 [M ? H].sup.? 886.4 [M ? H].sup.? 1.11 A 853 886.7 [M ? H].sup.? 886.4 [M ? H].sup.? 1.13 A 854 887.7 [M ? H].sup.? 887.4 [M ? H].sup.? 1.18 A 855 891.6 [M + H].sup.+ 891.4 [M + H].sup.+ 1.45 A 856 887.6 [M ? H].sup.? 887.4 [M ? H].sup.? 1.44 A 857 901.4 [M + H].sup.+ 901.4 [M + H].sup.+ 1.24 A 858 915.5 [M ? H].sup.? 915.4 [M ? H].sup.? 1.02 A 859 816.3 [M ? H].sup.? 816.3 [M ? H].sup.? 0.96 A 860 771.3 [M ? H].sup.? 771.3 [M ? H].sup.? 0.90 A 861 743.2 [M ? H].sup.? 743.3 [M ? H].sup.? 0.82 A 862 757.2 [M ? H].sup.? 757.3 [M ? H].sup.? 0.86 A 863 785.4 [M ? H].sup.? 785.3 [M ? H].sup.? 0.94 A 864 800.4 [M ? H].sup.? 800.3 [M ? H].sup.? 0.64 A 865 803.3 [M + H].sup.+ 803.3 [M + H].sup.+ 0.93 A 866 817.4 [M + H].sup.+ 817.3 [M + H].sup.+ 0.91 A 867 817.4 [M + H].sup.+ 817.3 [M + H].sup.+ 0.86 A 868 775.3 [M + H].sup.+ 775.3 [M + H].sup.+ 0.84 A 869 851.4 [M + H].sup.+ 851.3 [M + H].sup.+ 1.01 A 870 835.3 [M + H].sup.+ 835.3 [M + H].sup.+ 1.22 A 871 759.3 [M + H].sup.+ 759.3 [M + H].sup.+ 0.96 A 872 799.4 [M ? H].sup.? 799.4 [M ? H].sup.? 1.08 A 873 787.4 [M + H].sup.+ 787.3 [M + H].sup.+ 1.03 A 874 801.4 [M + H].sup.+ 801.4 [M + H].sup.+ 1.12 A 875 803.3 [M + H].sup.+ 803.3 [M + H].sup.+ 0.89 A 876 816.4 [M + H].sup.+ 816.4 [M + H].sup.+ 0.68 A 877 729.3 [M ? H].sup.? 729.3 [M ? H].sup.? 0.85 A 878 828.3 [M ? H].sup.? 828.3 [M ? H].sup.? 0.64 A 879 769.5 [M ? H].sup.? 769.3 [M ? H].sup.? 1.01 A 880 759.5 [M ? H].sup.? 759.3 [M ? H].sup.? 0.81 A 881 835.3 [M ? H].sup.? 835.3 [M ? H].sup.? 1.00 A 882 819.3 [M ? H].sup.? 819.3 [M ? H].sup.? 1.20 A 883 743.3 [M ? H].sup.? 743.3 [M ? H].sup.? 0.94 A 884 773.3 [M ? H].sup.? 773.3 [M ? H].sup.? 0.89 A 885 844.4 [M + H].sup.+ 844.4 [M + H].sup.+ 0.72 A 886 803.3 [M + H].sup.+ 803.3 [M + H].sup.+ 0.78 A 887 867.4 [M + H].sup.+ 867.3 [M + H].sup.+ 0.77 A 888 914.7 [M ? H].sup.? 914.4 [M ? H].sup.? 0.92 A 889 900.6 [M ? H].sup.? 900.4 [M ? H].sup.? 0.83 A 890 1015.5 [M + H].sup.+ 1015.4 [M + H].sup.+ 0.96 A 891 1054.7 [M ? H].sup.? 1054.5 [M ? H].sup.? 1.67 A 892 1053.7 [M ? H].sup.? 1053.5 [M ? H].sup.? 1.62 A 893 1105.8 [M + Na].sup.+ 1105.5 [M + Na].sup.+ 1.60 A 894 1098.6 [M + H].sup.+ 1098.5 [M + H].sup.+ 1.26 A 895 1100.6 [M + H].sup.+ 1100.5 [M + H].sup.+ 1.19 A 896 987.6 [M + H].sup.+ 987.5 [M + H].sup.+ 1.29 A 897 1073.6 [M + Na].sup.+ 1073.5 [M + Na].sup.+ 1.59 A 898 1080.8 [M + H].sup.+ 1080.5 [M + H].sup.+ 1.23 A 899 1082.7 [M + H].sup.+ 1082.5 [M + H].sup.+ 1.17 A 900 1546.2 [M ? H].sup.? 1545.8 [M ? H].sup.? 1.64 A 901 1598.2 [M + Na].sup.+ 1597.8 [M + Na].sup.+ 1.67 A 902 785.1 [M + 2H].sup.2+ 785.0 [M + 2H].sup.2+ 1.17 A 903 1686.5 [M ? H].sup.? 1685.9 [M ? H].sup.? 1.95 A 904 1714.3 [M ? H].sup.? 1713.9 [M ? H].sup.? 2.06 A 905 1651.7 [M ? H].sup.? 1651.0 [M ? H].sup.? 1.40 A 906 1733.4 [M + H].sup.+ 1732.9 [M + H].sup.+ 1.67 A 907 1696.5 [M ? H].sup.? 1696.0 [M ? H].sup.? 1.21 A 908 841.6 [M + 2H].sup.2+ 841.5 [M + 2H].sup.2+ 1.25 A 909 1696.4 [M ? H].sup.? 1696.0 [M ? H].sup.? 1.22 A 910 1733.2 [M + H].sup.+ 1732.9 [M + H].sup.+ 1.67 A 911 1695.9 [M ? H].sup.? 1696.0 [M ? H].sup.? 1.23 A 912 1662.8 [M ? H].sup.? 1662.1 [M ? H].sup.? 1.23 A 913 1664.4 [M ? H].sup.? 1664.0 [M ? H].sup.? 1.20 A 914 1724.6 [M + H].sup.+ 1724.0 [M + H].sup.+ 2.05 B 915 1726.5 [M + H].sup.+ 1725.9 [M + H].sup.+ 1.54 A 916 1687.6 [M ? H].sup.? 1687.1 [M ? H].sup.? 1.10 A 917 1689.6 [M ? H].sup.? 1689.0 [M ? H].sup.? 1.06 A 918 1754.5 [M + H].sup.+ 1753.9 [M + H].sup.+ 2.05 B 919 1736.6 [M ? H].sup.? 1736.0 [M ? H].sup.? 2.07 B 920 1717.6 [M ? H].sup.? 1717.0 [M ? H].sup.? 1.60 B 921 1701.2 [M ? H].sup.? 1701.1 [M ? H].sup.? 1.63 B 922 1723.9 [M ? H].sup.? 1723.9 [M ? H].sup.? 1.95 B 923 1710.6 [M + H].sup.+ 1710.0 [M + H].sup.+ 1.97 B 924 1689.5 [M ? H].sup.? 1689.0 [M ? H].sup.? 1.53 B 925 1673.0 [M ? H].sup.? 1673.0 [M ? H].sup.? 1.57 B 926 1445.0 [M ? H].sup.? 1444.9 [M ? H].sup.? 1.94 B 927 1573.7 [M ? H].sup.? 1573.0 [M ? H].sup.? 1.77 B 928 1829.7 [M ? H].sup.? 1829.2 [M ? H].sup.? 1.56 B 929 1957.9 [M ? H].sup.? 1957.3 [M ? H].sup.? 1.52 B 930 1433.4 [M ? H].sup.? 1432.8 [M ? H].sup.? 1.77 B 931 1561.4 [M ? H].sup.? 1560.9 [M ? H].sup.? 1.63 B 932 1817.3 [M ? H].sup.? 1817.1 [M ? H].sup.? 1.49 B 933 1945.8 [M ? H].sup.? 1945.2 [M ? H].sup.? 1.39 B 934 1689.7 [M ? H].sup.? 1689.0 [M ? H].sup.? 1.52 B 935 1773.7 [M ? H].sup.? 1773.0 [M ? H].sup.? 1.55 B 936 886.3 [M ? 2H].sup.2? 886.0 [M ? 2H].sup.2? 1.60 B 937 1597.3 [M + H].sup.+ 1596.9 [M + H].sup.+ 1.97 B 938 1452.3 [M + H].sup.+ 1451.8 [M + H].sup.+ 1.98 B 939 1434.3 [M ? H].sup.? 1433.8 [M ? H].sup.? 1.97 B 940 1726.5 [M + H].sup.+ 1725.9 [M + H].sup.+ 1.98 B 941 1307.0 [M + H].sup.+ 1306.7 [M + H].sup.+ 2.01 B 942 1417.5 [M ? H].sup.? 1416.9 [M ? H].sup.? 1.32 A 943 1545.6 [M ? H].sup.? 1545.0 [M ? H].sup.? 1.16 A 944 1461.0 [M ? H].sup.? 1460.9 [M ? H].sup.? 1.39 A 945 1589.7 [M ? H].sup.? 1588.9 [M ? H].sup.? 1.21 A 946 1661.6 [M ? H].sup.? 1661.0 [M ? H].sup.? 0.97 A 947 1645.8 [M ? H].sup.? 1645.0 [M ? H].sup.? 1.00 A 948 1461.3 [M ? H].sup.? 1460.8 [M ? H].sup.? 1.29 A 949 1617.2 [M ? H].sup.? 1616.9 [M ? H].sup.? 1.14 A 950 1675.4 [M ? H].sup.? 1675.0 [M ? H].sup.? 1.03 A 951 1291.0 [M + H].sup.+ 1290.8 [M + H].sup.+ 1.55 A 952 1335.1 [M + H].sup.+ 1334.8 [M + H].sup.+ 1.61 A 953 1319.1 [M + H].sup.+ 1318.8 [M + H].sup.+ 1.64 A 954 1745.5 [M ? H].sup.? 1745.1 [M ? H].sup.? 1.20 A 955 1729.8 [M ? H].sup.? 1729.1 [M ? H].sup.? 1.23 A 956 839.2 [M + 2H].sup.2+ 838.5 [M + 2H].sup.2+ 1.18 A 957 1702.8 [M ? H].sup.? 1702.0 [M ? H].sup.? 1.30 A 958 1718.3 [M ? H].sup.? 1718.0 [M ? H].sup.? 1.26 A 959 1674.3 [M ? H].sup.? 1674.0 [M ? H].sup.? 1.16 A 960 1702.4 [M ? H].sup.? 1702.0 [M ? H].sup.? 1.25 A 961 1690.2 [M ? H].sup.? 1690.0 [M ? H].sup.? 1.15 A 962 1719.3 [M ? H].sup.? 1719.0 [M ? H].sup.? 1.28 A 963 1675.2 [M ? H].sup.? 1675.0 [M ? H].sup.? 1.21 A 964 1703.4 [M ? H].sup.? 1703.0 [M ? H].sup.? 1.34 A 965 1691.1 [M ? H].sup.? 1691.0 [M ? H].sup.? 1.20 A 966 1719.4 [M ? H].sup.? 1719.0 [M ? H].sup.? 1.32 A 967 1418.0 [M ? H].sup.? 1417.8 [M ? H].sup.? 1.54 A 968 1448.0 [M + H].sup.+ 1447.8 [M + H].sup.+ 1.63 A 969 1420.0 [M + H].sup.+ 1419.8 [M + H].sup.+ 1.53 A 970 1446.1 [M ? H].sup.? 1445.8 [M ? H].sup.? 1.63 A 971 1546.3 [M ? H].sup.? 1545.9 [M ? H].sup.? 1.30 A 972 1573.9 [M ? H].sup.? 1573.9 [M ? H].sup.? 1.41 A

[1198] The inhibitory effects of the present inventive compounds on MMP2 were determined with the method described in Test Examples 1-1 and 1-2 shown below.

Test Example 1-1: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP2 (Method 1)

[1199] The human-MMP2-inhibitory effects of the compounds were determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 100 ?g/mL human recombinant MMP2 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate were mixed together, and reacted at 37? C. for 60 minutes. The human MMP2 activated through the reaction was poured into a 96-well microplate to reach a final concentration of 0.7 or 7 ng/mL. Further, the compounds of the present invention, which had been diluted to different concentrations, were added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 was added to reach a final concentration of 5 or 16 ?mol/L, and enzymatic reaction was initiated. After reacting at room temperature for 2 hours, fluorescence intensity (Ex 320 nm/Em 400 nm) was measured by using a microplate reader. Enzyme inhibition rates (%) were calculated with the measured fluorescence values in accordance with the following formula, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds were calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1200] A: Fluorescence value with addition of compound [1201] B: Fluorescence value without addition of compound and enzyme [1202] C: Fluorescence value without addition of compound

Test Example 1-2: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP2 (Method 2)

[1203] The human-MMP2-inhibitory effects of the compounds were determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 12.5 ?g/mL human recombinant MMP2 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate were mixed together, and reacted at 37? C. for 60 minutes. The human MMP2 activated through the reaction was poured into a 384-well microplate to reach a final concentration of 7 or 2.8 ng/mL. Further, the compounds of the present invention, which had been diluted to different concentrations, were added, and left to stand at room temperature for 10 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 was added to reach a final concentration of 16 or 5 ?mol/L, and enzymatic reaction was initiated. After reacting at room temperature for 1 to 2 hours, fluorescence intensity (Ex 320 nm/Em 405 nm) was measured by using a microplate reader. Enzyme inhibition rates (%) were calculated with the measured fluorescence values in accordance with the following formula, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds were calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1204] A: Fluorescence value with addition of compound [1205] B: Fluorescence value without addition of compound and enzyme [1206] C: Fluorescence value without addition of compound

[1207] The results on the inhibitory effects of the present inventive compounds on human MMP2 enzyme activity are shown in the following tables.

TABLE-US-00051 TABLE 51-1 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 1 0.22 1-1 2 2.04 1-2 3 0.25 1-1 4 0.128 1-2 5 0.608 1-2 6 0.198 1-2 7 0.898 1-2 8 3.15 1-2 9 0.29 1-1 10 0.107 1-2 11 0.109 1-2 12 0.109 1-2 13 0.0784 1-2 14 0.0897 1-2 15 0.108 1-2 16 0.119 1-2 17 0.199 1-2 18 0.135 1-2 19 0.148 1-2 20 0.20 1-1 21 0.101 1-2 22 0.109 1-2 23 0.0923 1-2 24 0.105 1-2 25 0.178 1-2 26 0.151 1-2 27 0.152 1-2 28 0.136 1-2 29 0.140 1-2 30 0.107 1-2 31 0.199 1-2 32 0.0996 1-2 33 0.144 1-2 34 0.130 1-2 35 0.147 1-2 36 0.152 1-2 37 0.178 1-2 38 0.27 1-1 39 0.27 1-1 40 0.451 1-2 41 0.0719 1-2 42 0.113 1-2 43 0.594 1-2 44 4.75 1-2 45 0.32 1-1 46 0.31 1-1 47 4.1 1-1 48 0.0740 1-2 49 0.113 1-2 50 0.089 1-1 51 0.21 1-1 52 0.12 1-1 53 0.0702 1-2 54 0.095 1-1 55 0.13 1-1

TABLE-US-00052 TABLE 51-2 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 56 0.083 1-1 57 0.078 1-1 58 0.097 1-1 59 0.046 1-1 60 0.97 1-1 61 0.13 1-1 62 0.090 1-1 63 0.61 1-1 64 0.060 1-1 65 0.083 1-1 66 0.047 1-1 67 0.11 1-1 68 0.068 1-1 69 0.19 1-1 70 0.34 1-1 71 0.89 1-1 72 0.52 1-1 73 1.9 1-1 74 8.1 1-1 75 0.097 1-1 76 0.055 1-1 77 0.25 1-1 78 0.037 1-1 79 0.091 1-1 80 0.22 1-1 81 0.48 1-1 82 0.83 1-1 83 0.37 1-1 84 0.17 1-1 85 0.49 1-1 86 0.40 1-1 87 0.84 1-1 88 0.97 1-1 89 0.58 1-1 90 1.4 1-1 91 1.5 1-1 92 0.31 1-1 93 0.34 1-1 94 0.088 1-1 95 0.13 1-1 96 0.74 1-1 97 0.84 1-1 98 0.27 1-1 99 0.33 1-1 100 1.2 1-1 101 1.2 1-1 102 0.55 1-1 103 0.67 1-1 104 0.51 1-1 105 0.30 1-1 106 0.16 1-1 107 0.32 1-1 108 0.19 1-1 109 0.70 1-1 110 0.37 1-1 111 0.96 1-1 112 0.55 1-1 113 2.2 1-1 114 0.072 1-1 115 0.42 1-1

TABLE-US-00053 TABLE 51-3 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 116 0.055 1-1 117 0.55 1-1 118 0.40 1-1 119 0.17 1-1 120 0.21 1-1 121 0.19 1-1 122 0.16 1-1 123 1.11 1-1 124 0.31 1-1 125 0.47 1-1 126 0.29 1-1 127 0.24 1-1 128 0.15 1-1 129 0.46 1-1 130 0.36 1-1 131 0.36 1-1 132 0.43 1-1 133 0.88 1-1 134 2.0 1-1 135 9.3 1-1 136 4.7 1-1 137 0.60 1-1 138 0.26 1-1 139 1.1 1-1 140 0.43 1-1 141 1.0 1-1 142 2.1 1-1 143 2.6 1-1 144 0.26 1-1 145 0.72 1-1 146 1.7 1-1 147 0.14 1-1 148 0.48 1-1 149 0.11 1-1 150 3.3 1-1 151 0.33 1-1 152 0.85 1-1 153 0.066 1-1 154 0.44 1-1 155 0.19 1-1 156 0.088 1-1 157 1.24 1-1 158 1.38 1-1 159 0.37 1-1 160 0.68 1-1 161 0.33 1-1 162 0.60 1-1 163 0.12 1-1 164 0.37 1-1 165 0.23 1-1 166 0.39 1-1 167 0.58 1-1 168 1.2 1-1 169 2.5 1-1 170 0.072 1-1 171 0.068 1-1 172 0.13 1-1 173 0.19 1-1 174 0.55 1-1 175 2.0 1-1

TABLE-US-00054 TABLE 51-4 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 176 1.9 1-1 177 0.21 1-1 178 3.6 1-1 179 3.5 1-1 180 2.6 1-1 181 3.1 1-1 182 0.49 1-1 183 7.0 1-1 184 0.61 1-1 185 1.0 1-1 186 2.0 1-1 187 2.8 1-1 188 0.81 1-1 189 0.86 1-1 190 1.8 1-1 191 2.7 1-1 192 1.9 1-1 193 1.7 1-1 194 3.7 1-1 195 2.7 1-1 196 1.7 1-1 197 2.6 1-1 198 5.1 1-1 199 1.4 1-1 200 7.4 1-1 201 1.4 1-1 202 0.097 1-1 203 0.13 1-1 204 0.42 1-1 205 0.80 1-1 206 0.101 1-1 207 0.49 1-1 208 0.61 1-1 209 0.094 1-1 210 0.17 1-1 211 2.9 1-1 212 0.62 1-1 213 1.9 1-1 214 0.096 1-1 215 2.6 1-1 216 0.21 1-1 217 0.72 1-1 218 0.32 1-1 219 0.47 1-1 220 0.12 1-1 221 0.53 1-1 222 0.051 1-1 223 0.20 1-1 224 1.1 1-1 225 0.33 1-1 226 0.12 1-1 227 0.49 1-1 228 0.19 1-1 229 0.39 1-1 230 0.103 1-1 231 1.1 1-1 232 0.18 1-1 233 0.17 1-1 234 0.14 1-1 235 0.22 1-1

TABLE-US-00055 TABLE 51-5 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 236 0.10 1-1 237 0.53 1-1 238 0.11 1-1 239 0.108 1-1 240 0.44 1-1 241 0.32 1-1 242 6.3 1-1 243 0.33 1-1 244 0.27 1-1 245 0.16 1-1 246 0.64 1-1 247 1.9 1-1 248 6.0 1-1 249 8.9 1-1 250 0.093 1-1 251 0.18 1-1 252 0.31 1-1 253 3.5 1-1 254 0.18 1-1 255 0.072 1-1 256 0.13 1-1 257 0.68 1-1 258 0.94 1-1 259 0.083 1-1 260 0.15 1-1 261 0.13 1-1 262 0.14 1-1 263 0.17 1-1 264 0.97 1-1 265 2.0 1-1 266 1.5 1-1 267 1.6 1-1 268 0.16 1-1 269 0.15 1-1 270 0.12 1-1 271 0.084 1-1 272 0.13 1-1 273 0.071 1-1 274 0.12 1-1 275 0.096 1-1 276 0.103 1-1 277 0.12 1-1 278 0.71 1-1 279 0.084 1-1 280 0.15 1-1 281 0.047 1-1 282 0.059 1-1 283 0.046 1-1 284 0.064 1-1 285 0.091 1-1 286 1.15 1-1 287 0.35 1-1 288 1.9 1-1 289 0.29 1-1 290 1.3 1-1 291 0.11 1-1 292 0.14 1-1 293 2.8 1-1 294 2.1 1-1 295 2.8 1-1

TABLE-US-00056 TABLE 51-6 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 296 0.96 1-1 297 0.35 1-1 298 3.4 1-1 299 0.62 1-1 300 0.86 1-1 301 2.0 1-1 302 0.29 1-1 303 0.21 1-1 304 1.05 1-1 305 1.9 1-1 306 2.2 1-1 307 3.7 1-1 308 0.48 1-1 309 1.4 1-1 310 3.2 1-1 311 4.5 1-1 312 0.29 1-1 313 0.57 1-1 314 0.11 1-1 315 0.54 1-1 316 1.06 1-1 317 2.3 1-1 318 0.15 1-1 319 0.75 1-1 320 0.061 1-1 321 5.8 1-1 322 0.27 1-1 323 0.17 1-1 324 7.8 1-1 325 0.17 1-1 326 1.9 1-1 327 0.92 1-1 328 0.43 1-1 329 2.5 1-1 330 0.22 1-1 331 0.22 1-1 332 0.14 1-1 333 0.84 1-1 334 0.63 1-1 335 0.56 1-1 336 0.13 1-1 337 0.17 1-1 338 0.13 1-1 339 0.62 1-1 340 0.16 1-1 341 0.77 1-1 342 3.9 1-1 343 7.0 1-1 344 0.13 1-1 345 0.10 1-1 346 0.11 1-1 347 0.059 1-1 348 0.083 1-1 349 1.4 1-1 350 0.21 1-1 351 0.34 1-1 352 0.26 1-1 353 0.28 1-1 354 0.076 1-1 355 0.12 1-1

TABLE-US-00057 TABLE 51-7 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 356 0.19 1-1 357 0.10 1-1 358 0.14 1-1 359 5.1 1-1 360 2.5 1-1 361 0.20 1-1 362 0.27 1-1 363 0.24 1-1 364 0.25 1-1 365 0.49 1-1 366 0.33 1-1 367 0.17 1-1 368 0.28 1-1 369 0.76 1-1 370 1.2 1-1 371 2.1 1-1 372 6.5 1-1 373 4.7 1-1 374 1.9 1-1 375 2.4 1-1 376 3.4 1-1 377 2.8 1-1 378 2.6 1-1 379 0.20 1-1 380 0.75 1-1 381 0.23 1-1 382 5.3 1-1 383 6.3 1-1 384 0.13 1-1 385 0.17 1-1 386 0.12 1-1 387 0.12 1-1 388 0.20 1-1 389 0.39 1-1 390 0.36 1-1 391 0.37 1-1 392 0.15 1-1 393 0.28 1-1 394 0.17 1-1 395 0.48 1-1 396 0.40 1-1 397 0.61 1-1 398 0.12 1-1 399 0.13 1-1 400 0.43 1-1 401 0.43 1-1 402 0.31 1-1 403 0.20 1-1 404 0.42 1-1 405 0.15 1-1 406 0.45 1-1 407 0.15 1-1 408 2.0 1-1 409 1.8 1-1 410 1.1 1-1 411 0.59 1-1 412 0.30 1-1 413 0.13 1-1 414 0.27 1-1 415 0.082 1-1

TABLE-US-00058 TABLE 51-8 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 416 0.29 1-1 417 1.5 1-1 418 2.1 1-1 419 1.8 1-1 420 1.5 1-1 421 2.6 1-1 422 1.8 1-1 423 1.9 1-1 424 0.44 1-1 425 0.62 1-1 426 0.27 1-1 427 0.073 1-1 428 1.0 1-1 429 0.15 1-1 430 0.071 1-1 431 0.69 1-1 432 0.38 1-1 433 0.19 1-1 434 0.23 1-1 435 0.45 1-1 436 0.30 1-1 437 0.21 1-1 438 0.26 1-1 439 0.16 1-1 440 0.28 1-1 441 0.29 1-1 442 0.67 1-1 443 0.32 1-1 444 0.17 1-1 445 0.24 1-1 446 0.46 1-1 447 0.50 1-1 448 0.19 1-1 449 0.17 1-1 450 0.24 1-1 451 0.16 1-1 452 0.14 1-1 453 30 1-1 454 0.19 1-1 455 0.46 1-1 456 0.61 1-1 457 0.24 1-1 458 0.27 1-1 459 0.25 1-1 460 0.29 1-1 461 0.29 1-1 462 0.33 1-1 463 0.76 1-1 464 0.79 1-1 465 0.82 1-1 466 1.1 1-1 467 0.85 1-1 468 0.52 1-1 469 0.85 1-1 470 0.81 1-1 471 1.6 1-1 472 0.21 1-1 473 0.18 1-1 474 0.30 1-1 475 0.19 1-1

TABLE-US-00059 TABLE 51-9 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 476 0.20 1-1 477 0.46 1-1 478 0.53 1-1 479 0.66 1-1 480 0.45 1-1 481 2.4 1-1 482 0.90 1-1 483 0.22 1-1 484 0.26 1-1 485 0.096 1-1 486 0.39 1-1 487 1.4 1-1 488 1.8 1-1 489 0.27 1-1 490 0.86 1-1 491 0.81 1-1 492 0.68 1-1 493 0.55 1-1 494 0.37 1-1 495 0.44 1-1 496 0.23 1-1 497 0.24 1-1 498 0.32 1-1 499 0.31 1-1 500 0.25 1-1 501 0.32 1-1 502 0.30 1-1 503 0.45 1-1 504 0.34 1-1 505 0.38 1-1 506 0.15 1-1 507 0.16 1-1 508 0.30 1-1 509 0.28 1-1 510 0.40 1-1 511 0.20 1-1 512 0.15 1-1 513 0.18 1-1 514 0.22 1-1 515 0.29 1-1 516 1.3 1-1 517 1.3 1-1 518 1.4 1-1 519 1.6 1-1 520 0.32 1-1 521 0.41 1-1 522 3.1 1-1 523 1.9 1-1 524 0.12 1-1 525 0.15 1-1 526 0.21 1-1 527 0.32 1-1 528 0.23 1-1 529 0.49 1-1 530 0.42 1-1 531 0.35 1-1 532 0.31 1-1 533 0.34 1-1 534 0.29 1-1 535 0.31 1-1

TABLE-US-00060 TABLE 51-10 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 536 0.35 1-1 537 0.28 1-1 538 0.22 1-1 539 0.23 1-1 540 0.29 1-1 541 0.35 1-1 542 0.45 1-1 543 1.3 1-1 544 1.3 1-1 545 1.0 1-1 546 0.98 1-1 547 0.59 1-1 548 0.67 1-1 549 0.52 1-1 550 0.52 1-1 551 0.92 1-1 552 0.62 1-1 553 1.1 1-1 554 0.89 1-1 555 0.87 1-1 556 0.55 1-1 557 0.44 1-1 558 0.66 1-1 559 0.42 1-1 560 0.42 1-1 561 0.74 1-1 562 0.58 1-1 563 0.49 1-1 564 0.44 1-1 565 0.42 1-1 566 0.59 1-1 567 0.54 1-1 568 0.92 1-1 569 0.93 1-1 570 1.0 1-1 571 1.7 1-1 572 1.8 1-1 573 4.3 1-1 574 4.8 1-1 575 2.0 1-1 576 2.8 1-1 577 0.34 1-1 578 0.36 1-1 579 0.249 1-2 580 0.436 1-2 581 0.412 1-2 582 0.254 1-2 583 0.217 1-2 584 1.82 1-2 585 1.20 1-2 586 1.03 1-2 587 0.19 1-1 588 0.12 1-1 589 0.12 1-1 590 3.2 1-1 591 0.98 1-1 592 0.38 1-1 593 2.6 1-1 594 1.8 1-1 595 3.83 1-2

TABLE-US-00061 TABLE 51-11 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 596 1.3 1-1 597 0.27 1-1 598 4.1 1-1 599 0.39 1-1 600 0.98 1-1 601 1.03 1-1 602 0.59 1-1 603 1.6 1-1 604 0.94 1-1 605 0.80 1-1 606 0.355 1-2 607 2.68 1-2 608 0.34 1-1 609 0.24 1-1 610 0.70 1-1 611 0.15 1-1 612 0.31 1-1 613 0.12 1-1 614 0.35 1-1 615 0.18 1-1 616 0.36 1-1 617 0.087 1-1 618 0.17 1-1 619 0.30 1-1 620 0.132 1-2 621 0.0867 1-2 622 <0.05 1-2 623 <0.05 1-2 624 0.159 1-2 625 0.103 1-2 626 0.18 1-1 627 <0.05 1-2 628 0.0914 1-2 629 0.0655 1-2 630 0.11 1-1 631 <0.05 1-2 632 0.0682 1-2 633 0.135 1-2 634 0.13 1-1 635 0.83 1-1 636 0.94 1-1 637 0.48 1-1 638 0.14 1-1 639 1.0 1-1 640 0.38 1-1 641 0.57 1-1 642 1.6 1-1 643 0.320 1-2 644 0.26 1-1 645 0.41 1-1 646 0.29 1-1 647 0.35 1-1 648 5.9 1-1 649 0.70 1-1 650 1.6 1-1 651 2.0 1-1 652 1.1 1-1 653 0.74 1-1 654 0.21 1-1 655 0.27 1-1

TABLE-US-00062 TABLE 51-12 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 656 0.72 1-1 657 0.56 1-1 658 0.055 1-1 659 0.065 1-1 660 0.12 1-1 661 0.11 1-1 662 0.093 1-1 663 0.13 1-1 664 0.19 1-1 665 0.17 1-1 666 0.035 1-1 667 0.079 1-1 668 0.25 1-1 669 0.37 1-1 670 5.3 1-1 671 0.069 1-1 672 0.23 1-1 673 0.061 1-1 674 0.22 1-1 675 3.7 1-1 676 0.49 1-1 677 6.3 1-1 678 0.20 1-1 679 1.5 1-1 680 0.33 1-1 681 4.1 1-1 682 1.68 1-2 683 1.86 1-2 684 0.126 1-2 685 0.134 1-2 686 0.0488 1-2 687 0.0577 1-2 688 0.0513 1-2 689 0.0319 1-2 690 0.0974 1-2 691 0.065 1-1 692 0.068 1-1 693 0.079 1-1 694 0.094 1-1 695 0.53 1-1 696 0.22 1-1 697 0.28 1-1 698 0.31 1-1 699 0.27 1-1 700 0.41 1-1 701 0.27 1-1 702 0.25 1-1 703 0.33 1-1 704 0.42 1-1 705 0.066 1-1 706 0.080 1-1 707 0.14 1-1 708 0.16 1-1 709 0.41 1-1 710 0.29 1-1 711 1.0 1-1 712 0.27 1-1 713 0.11 1-1 714 0.065 1-1 715 0.069 1-1

TABLE-US-00063 TABLE 51-13 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 716 0.48 1-1 717 0.80 1-1 718 0.43 1-1 719 0.55 1-1 720 0.72 1-1 721 0.43 1-1 722 0.66 1-1 723 0.41 1-1 724 0.45 1-1 725 0.51 1-1 726 2.4 1-1 727 0.39 1-1 728 1.9 1-1 729 1.4 1-1 730 2.9 1-1 731 0.20 1-1 732 0.16 1-1 733 0.11 1-1 734 0.10 1-1 735 0.65 1-1 736 1.2 1-1 737 4.5 1-1 738 1.2 1-1 739 1.0 1-1 740 1.4 1-1 741 0.61 1-1 742 0.57 1-1 743 0.78 1-1 744 1.0 1-1 745 1.7 1-1 746 1.0 1-1 747 0.88 1-1 748 0.96 1-1 749 1.1 1-1 750 0.78 1-1 751 1.4 1-1 752 1.6 1-1 753 1.7 1-1 754 2.3 1-1 755 1.9 1-1 756 1.3 1-1 757 1.4 1-1 758 0.86 1-1 759 2.1 1-1 760 1.4 1-1 761 1.5 1-1 762 1.1 1-1 763 0.78 1-1 764 1.7 1-1 765 1.7 1-1 766 0.27 1-1 767 0.29 1-1 768 0.35 1-1 769 0.34 1-1 770 0.31 1-1 771 0.44 1-1 772 0.81 1-1 773 5.4 1-1 774 5.1 1-1 775 4.4 1-1

TABLE-US-00064 TABLE 51-14 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 776 5.2 1-1 777 1.0 1-1 778 1.1 1-1 779 1.3 1-1 780 0.97 1-1 781 1.8 1-1 782 0.41 1-1 783 2.1 1-1 784 2.1 1-1 785 0.51 1-1 786 0.0830 1-2 787 0.0670 1-2 788 0.0645 1-2 789 0.0553 1-2 790 0.0605 1-2 791 0.584 1-2 792 0.11 1-1 793 0.23 1-1 794 0.15 1-1 795 0.19 1-1 796 0.22 1-1 797 0.30 1-1 798 0.59 1-1 799 0.72 1-1 800 1.6 1-1 801 1.3 1-1 802 1.4 1-1 803 0.46 1-1 804 0.32 1-1 805 0.46 1-1 806 0.28 1-1 807 1.0 1-1 808 0.55 1-1 809 1.9 1-1 810 0.99 1-1 811 0.82 1-1 812 1.3 1-1 813 1.6 1-1 814 1.5 1-1 815 0.98 1-1 816 1.3 1-1 817 0.93 1-1 818 1.1 1-1 819 0.42 1-1 820 0.70 1-1 821 1.2 1-1 822 1.1 1-1 823 0.95 1-1 824 1.0 1-1 825 1.1 1-1 826 0.32 1-1 827 0.58 1-1 828 1.4 1-1 829 1.5 1-1 830 1.7 1-1 831 1.1 1-1 832 1.1 1-1 833 1.4 1-1 834 1.2 1-1 835 1.2 1-1

TABLE-US-00065 TABLE 51-15 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 836 1.2 1-1 837 1.0 1-1 838 0.61 1-1 839 0.62 1-1 840 0.80 1-1 841 0.74 1-1 842 0.82 1-1 843 1.1 1-1 844 1.4 1-1 845 1.3 1-1 846 2.3 1-1 847 2.1 1-1 848 1.1 1-1 849 1.3 1-1 850 0.92 1-1 851 0.66 1-1 852 0.64 1-1 853 0.57 1-1 854 0.89 1-1 855 0.67 1-1 856 0.19 1-1 857 0.307 1-2 858 0.17 1-1 859 0.25 1-1 860 0.108 1-2 861 0.124 1-2 862 0.114 1-2 863 0.118 1-2 864 0.107 1-2 865 0.150 1-2 866 0.137 1-2 867 0.213 1-2 868 0.143 1-2 869 0.106 1-2 870 0.124 1-2 871 0.140 1-2 872 0.123 1-2 873 0.135 1-2 874 0.133 1-2 875 0.191 1-2 876 0.158 1-2 877 0.136 1-2 878 0.124 1-2 879 0.133 1-2 880 0.146 1-2 881 0.106 1-2 882 0.0996 1-2 883 0.143 1-2 884 0.153 1-2 885 0.128 1-2 886 1.09 1-2 887 1.34 1-2 888 0.153 1-2 889 0.170 1-2 890 0.158 1-2 891 1.6 1-1 892 1.7 1-1 893 1.15 1-1 894 1.1 1-1 895 1.3 1-1

TABLE-US-00066 TABLE 51-16 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 896 1.2 1-1 897 0.87 1-1 898 6.4 1-1 899 4.2 1-1 900 0.055 1-1 901 0.054 1-1 902 0.049 1-1 903 0.127 1-1 904 0.20 1-1 905 0.092 1-1 906 0.19 1-1 907 0.080 1-1 908 0.049 1-1 909 0.13 1-1 910 2.5 1-1 911 3.1 1-1 912 0.111 1-1 913 0.38 1-1 914 0.23 1-1 915 1.19 1-1 916 0.19 1-1 917 0.61 1-1 918 0.31 1-1 919 0.18 1-1 920 0.18 1-1 921 0.085 1-1 922 0.27 1-1 923 0.13 1-1 924 0.096 1-1 925 0.16 1-1 926 0.090 1-1 927 0.090 1-1 928 0.081 1-1 929 0.12 1-1 930 0.074 1-1 931 0.081 1-1 932 0.077 1-1 933 0.084 1-1 934 0.086 1-1 935 0.079 1-1 936 0.11 1-1 937 0.13 1-1 938 0.21 1-1 939 0.20 1-1 940 0.26 1-1 941 0.22 1-1 942 0.080 1-1 943 0.081 1-1 944 0.15 1-1 945 0.11 1-1 946 0.093 1-1 947 0.082 1-1 948 0.12 1-1 949 0.12 1-1 950 0.19 1-1 951 0.088 1-1 952 0.29 1-1 953 0.21 1-1 954 0.11 1-1 955 0.17 1-1

TABLE-US-00067 TABLE 51-17 Compound Human MMP2, Test Example No. IC.sub.50 (nmol/L) No. 956 0.18 1-1 957 0.12 1-1 958 0.35 1-1 959 0.23 1-1 960 0.28 1-1 961 0.28 1-1 962 0.38 1-1 963 0.26 1-1 964 0.27 1-1 965 0.50 1-1 966 0.37 1-1 967 0.18 1-1 968 0.23 1-1 969 0.14 1-1 970 0.25 1-1 971 0.16 1-1 972 0.36 1-1

[1208] The inhibitory effects of the present inventive compounds on different types of MMP can be determined with the methods described in Test Examples 2 to 9.

Test Example 2: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP1

[1209] The human-MMP1-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 50 ?g/mL human recombinant MMP1 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate are mixed together, and reacted at 37? C. for 120 minutes. The human MMP1 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 8 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 is added to reach a final concentration of 11 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1210] A: Fluorescence value with addition of compound [1211] B: Fluorescence value without addition of compound and enzyme [1212] C: Fluorescence value without addition of compound

Test Example 3: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP3

[1213] The human-MMP3-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 3 ?g/mL human recombinant MMP3 enzyme and g/mL Chymotrypsin are mixed together. After reacting at 37? C. for 30 minutes, PMSF is added to reach 2 mmol/L, thereby terminating the reaction. The human MMP3 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 52 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH.sub.2 is added to reach a final concentration of 26 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1214] A: Fluorescence value with addition of compound [1215] B: Fluorescence value without addition of compound and enzyme [1216] C: Fluorescence value without addition of compound

Test Example 4: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP7

[1217] The human-MMP7-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 50 ?g/mL human recombinant MMP7 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate are mixed together, and reacted at 37? C. for 60 minutes. The human MMP7 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 18 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 is added to reach a final concentration of 22 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1218] A: Fluorescence value with addition of compound [1219] B: Fluorescence value without addition of compound and enzyme [1220] C: Fluorescence value without addition of compound

Test Example 5: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP8

[1221] The human-MMP8-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 100 ?g/mL human recombinant MMP8 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate are mixed together, and reacted at 37? C. for 60 minutes. The human MMP8 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 149 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 is added to reach a final concentration of 25 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1222] A: Fluorescence value with addition of compound [1223] B: Fluorescence value without addition of compound and enzyme [1224] C: Fluorescence value without addition of compound

Test Example 6: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP9

[1225] The human-MMP9-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 50 ?g/mL human recombinant MMP9 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate are mixed together, and reacted at 37? C. for 24 hours. The human MMP9 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 58 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 is added to reach a final concentration of 3 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1226] A: Fluorescence value with addition of compound [1227] B: Fluorescence value without addition of compound and enzyme [1228] C: Fluorescence value without addition of compound

Test Example 7: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP12

[1229] The human-MMP12-inhibitory effects of the compounds were determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2, 0.05% Brij L23], 50 ?g/mL human recombinant MMP12 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate were mixed together, and reacted at 37? C. for 4 or 24 hours. The human MMP12 activated through the reaction was poured into a 96-well microplate to reach a final concentration of 17 or 5.2 ng/mL. Further, the compounds of the present invention, which had been diluted to different concentrations, were added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 was added to reach a final concentration of 5 or 14 ?mol/L, and enzymatic reaction was initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) was determined by using a microplate reader. Enzyme inhibition rates (%) were calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds were calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1230] A: Fluorescence value with addition of compound [1231] B: Fluorescence value without addition of compound and enzyme [1232] C: Fluorescence value without addition of compound

[1233] The results on the inhibitory effects of the present inventive compounds on human MMP12 enzyme activity are shown in the following table.

TABLE-US-00068 TABLE 52 Compound Human MMP12, No. IC.sub.50 (nmol/L) 1 253 3 502 9 160 20 254 52 190 149 4478 223 1367 230 1270 320 1897 347 2769 666 80 691 101 701 169 766 756 796 411

Test Example 8: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP13

[1234] The human-MMP13-inhibitory effects of the compounds were determined through enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl.sub.2), 0.05% Brij L23], 50 ?g/mL human recombinant MMP13 enzyme and 1 mmol/L 4-Aminophenylmercuric acetate were mixed together, and reacted at 37? C. for 2 hours. The human MMP13 activated through the reaction was poured into a 96-well microplate to reach a final concentration of 5 ng/mL. Further, the compounds of the present invention, which had been diluted to different concentrations, were added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 was added to reach a final concentration of 6 ?mol/L, and enzymatic reaction was initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) was determined by using a microplate reader. Enzyme inhibition rates (%) were calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds were calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1235] A: Fluorescence value with addition of compound [1236] B: Fluorescence value without addition of compound and enzyme [1237] C: Fluorescence value without addition of compound

[1238] The results on the inhibitory effects of the present inventive compounds on human MMP13 enzyme activity are shown in the following table.

TABLE-US-00069 TABLE 53 Compound Human MMP13, No. IC.sub.50 (nmol/L) 1 240 3 732 9 250 20 224 52 679 149 1293 223 174 230 114 320 94 347 162 666 81 691 142 701 116 766 699 796 685

Test Example 9: Evaluation Test for Inhibitory Effects of Compounds of Present Invention on Human MMP14

[1239] The human-MMP14-inhibitory effects of the compounds are determined through enzyme assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 200 mmol/L NaCl, 5 mmol/L CaCl.sub.2, mol/L ZnSO.sub.4, 0.05% Brij L23], 100 ?g/mL human recombinant MMP14 enzyme and g/mL trypsin are mixed together. After reacting at room temperature for 25 minutes, a trypsin inhibitor is added to reach 25 ?g/mL, thereby terminating the reaction. The human MMP14 activated through the reaction is poured into a 96-well microplate to reach a final concentration of 6 ng/mL. Further, the compounds of the present invention, which have been diluted to different concentrations, are added, and left to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH.sub.2 is added to reach a final concentration of 5 ?mol/L, and enzymatic reaction is initiated. After reacting at room temperature for 1 hour, fluorescence intensity (Ex 320 nm/Em 400 nm) is determined by using a microplate reader. Enzyme inhibition rates (%) are calculated with the measured fluorescence values in accordance with the following formulation, and the 50% inhibitory concentrations (IC.sub.50 values) of the inventive compounds are calculated.

Enzyme inhibition rate (%)=[1?(A?B)/(C?B)]*100 [1240] A: Fluorescence value with addition of compound [1241] B: Fluorescence value without addition of compound and enzyme [1242] C: Fluorescence value without addition of compound

INDUSTRIAL APPLICABILITY

[1243] The compounds of the present invention have a superior effect to inhibit MMP2, and the present invention can provide a pharmaceutical product effective for preventing or treating cancerous disease and organ fibrosis, and symptoms relating to cancerous disease and organ fibrosis, and is expected to reduce burdens on patients, thereby contributing to the development of the pharmaceutical industry.