UREA DERIVATIVE OR PHARMACOLOGICALLY ACCEPTABLE SALT THEREOF

Abstract

The present invention provides a urea derivative or a pharmacologically acceptable salt thereof that has a formyl peptide receptor like 1 (hereinafter may be abbreviated as FPRL1) agonist effect, a pharmaceutical composition containing the urea derivative or the pharmacologically acceptable salt thereof, and a pharmaceutical use thereof. It has been found that a urea derivative N represented by the general formula (I) below or a pharmacologically acceptable salt thereof has a superior FPRL1 agonist effect. Compound (I) or a pharmacologically acceptable salt thereof is highly useful for treatment, prevention, or suppression of inflammatory diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, immune disorders and the like.

##STR00001##

Claims

1. A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof: ##STR00132## wherein, in the formula (I), Ar.sup.1 is a phenyl group optionally having substituent(S), a monocyclic aromatic heterocyclyl group optionally having substituent(S), or a bicyclic aromatic heterocyclyl group having 9 or 10 atoms and optionally having substituent(s); Ar.sup.2 is a phenyl group optionally having substituent(S) (provided that when A is A1, the phenyl group whose substituent(s) is only a halogen atom is excluded), a monocyclic aromatic heterocyclyl group optionally having substituent(S), or a bicyclic aromatic heterocyclyl group having 9 or 10 atoms and optionally having substituent(s); A is a group selected from the group consisting of the following A1), A2), A3), A4), and A5): ##STR00133## wherein R.sup.1 and R.sup.2 are independently a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or R.sup.1 and R.sup.2 together form a C.sub.2 to C.sub.6 alkylene group; R.sup.3 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S); X is an oxygen atom, a sulfur atom, or SO.sub.2; B is a heterocyclyl group optionally having substituent(S); and each carbon atom marked with an asterisk is an asymmetric carbon atom.

2. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), A is a group selected from the group consisting of the following A1a), A1b), and A1c): ##STR00134## wherein W.sup.1 is CR.sup.6 or a nitrogen atom; W.sup.2 is CR.sup.7R.sup.8 or NR.sup.9; W.sub.3 is CR.sup.10R.sup.11 or CO; W.sup.4 is CR.sup.12 or a nitrogen atom; W.sup.5 is CR.sup.13 or a nitrogen atom; W.sup.6 is CR.sup.14R.sup.15, an oxygen atom, or CO; W.sup.7 is CR.sup.16R.sup.17 or CO; R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sub.10 , R.sup.11, R.sup.14, R.sup.15, R.sup.16, and R.sup.17 are independently a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or R.sup.4 and R.sup.5, R.sup.7 and R.sup.8, R.sup.10 and R.sup.11, R.sup.14 and R.sup.15, or R.sup.16 and R.sup.17 may together form a C.sub.3 to C.sub.6 cycloalkyl group or a 3- to 10-membered heterocycloalkyl group; and R.sup.6, R.sup.9, R.sup.12, and R.sup.13 are independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkoxy group optionally having substituent(S), a C.sub.1 to C.sub.6 alkoxycarbonyl group optionally having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfanyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfinyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), a heterocyclyl group optionally having substituent(S), CONR.sup.18R.sup.19, or NR.sup.18R.sup.19, wherein when R.sup.6, R.sup.9, R.sup.12, and/or R.sup.13 are CONR.sup.18R.sup.19 or NR.sup.18R.sup.19, R.sup.18 is a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), or a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), and R.sup.19 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or R.sup.18 and R.sup.19 together form 3- to 10-membered heterocycloalkyl group.

3. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), A is a group selected from the group consisting of the following A1ba), A1bb), A1bc), A1ca), A1cb), A1cc), A1cd), A2), A3), A4), and A5): ##STR00135## ##STR00136## wherein R.sup.1 and R.sup.2 are independently a hydrogen atom or a C.sub.1 to C.sub.3 alkyl group; R.sup.3 is a hydrogen atom or a C.sub.1 to C.sub.3 alkyl group; R.sup.4, R.sup.5, R.sup.14, R.sup.15, R.sup.16, and R.sup.17 are independently a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group, or R.sup.4 and R.sup.5, R.sup.14 and R.sup.15, or R.sup.16 and R.sup.17 may together form a C.sub.3 to C.sub.6 cycloalkyl group or a 3- to 10-membered heterocycloalkyl group; R.sup.12 and R.sup.13 are independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C.sub.1 to C.sub.3 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, a C.sub.1 to C.sub.6 alkoxycarbonyl group, a C.sub.1 to C.sub.6 acyl group, a C.sub.1 to C.sub.6 alkylsulfanyl group, a C.sub.1 to C.sub.6 alkylsulfinyl group, a C.sub.1 to C.sub.6 alkylsulfonyl group, CONR.sup.18R.sup.19, or NR.sup.18R.sup.19, wherein when R.sup.12 and/or R.sup.13 are CONR.sup.18R.sup.19 or NR.sup.18R.sup.19, R.sup.18 is a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 acyl group, or a C.sub.1 to C.sub.6 alkylsulfonyl group, and R.sup.19 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group, or R.sup.18 and R.sup.19 together form 3- to 10-membered heterocycloalkyl group; and X is an oxygen atom or SO.sub.2.

4. The urea compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Ar.sup.2 is a group selected from the group consisting of the following B1), B2), B3), and B4): ##STR00137## wherein one of W.sup.8 and W.sup.9 is a nitrogen atom, and the other one is CH or a nitrogen atom; W.sup.10 is an oxygen atom, a sulfur atom, or NR.sup.22; W.sup.11 is CO, CH.sub.2, CF.sub.2, CHOH, NR.sup.23, an oxygen atom, or a sulfur atom; R.sup.20 is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkoxy group optionally having substituent(S), a halo-C.sub.1 to C.sub.6 alkoxy group having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfanyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfinyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), a heterocyclyl group optionally having substituent(S), CONR.sup.18R.sup.19, or NR.sup.18R.sup.19 , wherein when R.sup.20 is CONR.sup.18R.sup.19 or NR.sup.18R.sup.19, R.sup.18 is a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), or a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), and R.sup.19 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or R.sup.18 and R.sup.19 together form 3- to 10-membered heterocycloalkyl group; R.sup.21 is a hydrogen atom, a halogen atom, a hydroxy group, cyano group, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or a C.sub.1 to C.sub.6 alkoxy group optionally having sub stituent(S); R.sup.22 is a hydrogen atom, a halogen atom, or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S); m is 0 or 1; and provided that when Ar.sup.2 is B1), R.sup.20, R.sup.21, and R.sup.22 are not a combination of a hydrogen atom and a halogen atom.

5. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Ar.sup.1 is a group selected from the group consisting of the following C.sub.1), C.sub.2), C.sub.3), and C.sub.4): ##STR00138## wherein one of W.sup.12 and W.sup.13 is a nitrogen atom, and the other one is CH or a nitrogen atom; W.sup.14 is an oxygen atom, a sulfur atom or NR.sup.22; R.sup.23 is a hydrogen atom, a halogen atom, a cyano group, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkoxy group optionally having substituent(S), a C.sub.3 to C.sub.6 cycloalkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), a C.sub.2 to C.sub.6 alkenyl group optionally having substituent(S), an alkynyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkoxycarbonyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfanyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfinyl group optionally having substituent(S), a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), an aryloxy group optionally having substituent(S), a heterocyclyl group optionally having substituent(S), CONR.sup.18R.sup.19, or NR.sup.18R.sup.19, wherein when R.sup.23 is CONR.sup.18R.sup.19 or NR.sup.18R.sup.19, R.sup.18 is a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), a C.sub.1 to C.sub.6 acyl group optionally having substituent(S), or a C.sub.1 to C.sub.6 alkylsulfonyl group optionally having substituent(S), and R.sup.19 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group optionally having substituent(S), or R.sup.18 and R.sup.19 together form 3- to 10-membered heterocycloalkyl group; and R.sup.24 is a hydrogen atom, a halogen atom, hydroxy group, or a C.sub.1 to C.sub.6 alkyl group.

6. The urea compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Ar.sup.2 is a group selected from the group consisting of the following B1a), B3a), and B4a): ##STR00139## wherein R.sup.20 is a fluorine atom, a chlorine atom, a cyano group, a C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 alkoxy group, a halo-C.sub.1 to C.sub.6 alkoxy group, a C.sub.1 to C.sub.6 alkylsulfanyl group, a C.sub.1 to C.sub.6 alkylsulfinyl group, CONR.sup.18R.sup.19, or NR.sup.18R.sup.19, wherein when R.sup.20 is CONR.sup.18R.sup.19 or NR.sup.18R.sup.19, R.sup.18 is a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group, a C.sub.1 to C.sub.6 acyl group, or a C.sub.1 to C.sub.6 alkylsulfonyl group, and R.sup.19 is a hydrogen atom or a C.sub.1 to C.sub.6 alkyl group, or R.sup.18 and R.sup.19 together form 3- to 10-membered heterocycloalkyl group; R.sup.21 is a hydrogen atom or a halogen atom; R.sup.22 is a hydrogen atom or a halogen atom; m is 0 or 1; and provided that when Ar.sup.2 is B1a), R.sup.20, R.sup.21, and R.sup.22 are not a combination of a hydrogen atom and a halogen atom.

7. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Ar.sup.1 is C1): ##STR00140## wherein R.sup.23 is a hydrogen atom, a halogen atom, a cyano group, a trifluoromethyl group, or a C.sub.1 to C.sub.3 alkyl group; and R.sup.24 is a hydrogen atom, a halogen atom, or a hydroxy group.

8. The urea compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Ar.sup.2 is B1aa): ##STR00141## wherein R.sup.20 is a cyano group, an ethyl group, or a C.sub.1 to C.sub.3 alkoxy group; R.sup.21 is a hydrogen atom, a fluorine atom, or a chlorine atom; and R.sup.22 is a hydrogen atom, a fluorine atom, or a chlorine atom.

9. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the compound represented by the formula (I) is ()-cis-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(3-fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(2-fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(2,4-difluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(3,4-difluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(4-cyanophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-(5-chlorothiophen-2-yl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-cis-1-[4-(2,6-difluoro-4-methoxyphenyl)tetrahydrofuran-3-yl]-3-(4-fluorophenyl)urea, ()-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, ()-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1,1-dioxidotetrahydrothiophen-3-yl]urea, ()-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopiperidin-3-yl]urea, (+)-cis-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, (+)-cis-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea, (+)-cis-1-(4-fluorophenyl)3-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-yl]urea, ()-cis-1-[4-(4-chlorophenyl)tetrahydrofuran-3-yl]-3-(4-fluorophenyl)urea, ()-cis-1-[4-(4-fluorophenyl)tetrahydrofuran-3-yl]-3-(4-fluorophenyl)urea, ()-cis-1-[4-(4-cyanophenyl)tetrahydrofuran-3-yl]-3-(4-fluorophenyl)urea, ()-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxoxazolidin-3-yl]urea, ()-trans-1-(4-fluorophenyl)-3-[3-(4-methoxyphenyl)-5-oxopyrrolidin-2-yl]urea, ()-1-[(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-(4-fluorophenyl)urea, ()-1-[(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-(4-fluorophenyl)urea, ()-1-(4-fluorophenyl)-3-[(6R*,7S*)-6-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazol-7-yl]urea, ()-1-[(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazol-7-yl]-3-(4-fluorophenyl)urea, ()-1-[(6R*,7S*)-6-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazol-7-yl]-3-(4-fluorophenyl)urea, ()-1-[(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidin-8-yl]-3-(4-fluorophenyl)urea, 1-[(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]-3-(4-fluorophenyl)urea, ()-1-[(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]-3-(4-fluorophenyl)urea, ()-1-[(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-4-oxo-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidin-8-yl]-3-(4-fluorophenyl)urea, or 1-(4-fluorophenyl)-3-[(7R*,8S*)-7-(4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]urea.

10. A pharmaceutical comprising, as an active ingredient, the compound according to claim 1 or a pharmacologically acceptable salt thereof.

11. An FPRL1 agonist comprising, as an active ingredient, the compound according to claim 1 or a pharmacologically acceptable salt thereof.

12. A method of treatment or prevention of inflammatory diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders, comprising administering the compound according to claim 1 or a pharmacologically acceptable salt thereof.

13. Use of the compound according to claim 1 or a pharmacologically acceptable salt thereof to produce a pharmaceutical for treatment or prevention of inflammatory diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders.

14. A pharmaceutical composition containing the compound according to claim 1 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier, used for prevention or treatment of inflammatory diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders.

Description

EXAMPLES

[0475] Hereinafter, the present invention will be described in more detail on the basis of Test Examples, Examples, and Reference Examples. Starting materials used in production of Compound (I) include a novel compound, and therefore Production examples for the starting materials will be also described as Reference Examples. The present invention is not limited to compounds described in the following Examples, and may be modified without departing from the scope of the present invention.

[0476] Among symbols used in each Reference Example, each Example, and each Table; Ref. No. represents Reference Example Number, Ex. No. represents Example Number, P.D. represents physical chemical data, Str. represents a structural formula, and .sup.1 H-NMR represents a proton nuclear magnetic resonance spectrum. CDCl.sub.3 represents chloroform-d, and DMSO-d.sub.6 represents dimethyl sulfoxide-d.sub.6. MS(ESI.sup.+) represents mass spectral data measured by electron-spray ionization. An optical rotation represents a specific optical rotation, which measured in described solvent at described concentration and temperature using sodium D-line as light source.

[0477] Wedge-shaped solid line and dashed line in a structural formula represent relative configuration in an optically active substance, but do not represent absolute configuration. Thick solid line and dashed line represent relative configuration in a racemate and an optically active substance obtained by resolution of a racemate. A carbon atom marked with * represents an asymmetric carbon. A wavy line bond of carbon atom marked with * represents the presence of a racemate.

[0478] Both R* and S* in the name of a compound represent relative steric configuration about an asymmetric carbon atom.

[0479] When both a substituent and a hydrogen atom are bonded to each of two positions of a pyrrolidine ring in a structural formula, the relative configuration of the substituents is expressed as cis or trans, and cis or trans is sometimes followed by a hyphen and the name of a compound.

[0480] When the pyrrolidine ring is considered as a face, cis means that the two adjacent substituents are on the same side, and trans means that the two adjacent substituents are on the respective opposite sides.

[0481] In order to represent isomers about a double bond and a double bond of imine in the name of a compound, a cis-isomer is expressed as Z, and a trans-isomer is expressed as E.

Reference Example 1-1

[0482] ##STR00036##

Methyl 2,2-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrofuran-3-carboxylate

[0483] Under an argon atmosphere, to ice-cooled diethyl ether (43 mL) were added sodium hydride (746 mg) and then methyl 2,2-dimethyl-4-oxotetrahydrofuran-3-carboxylate (2.36 g), and the mixture was stirred for 30 minutes. Then, trifluoromethanesulfonic anhydride (2.83 mL) was added to the mixture to produce a reaction solution. The reaction solution was stirred under ice-cooling for 4 hours. To water was added the reaction solution, the mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=20:1-1:1) to obtain the title compound as a colorless oil (3.43 g).

[0484] .sup.1H NMR (400 MHz, CDCl.sub.3) : 1.52 (6H, s), 3.84 (3H, s), 4.69 (2H, s).

Reference Example 1-2

[0485] ##STR00037##

Methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate

[0486] Using methyl 4-oxotetrahydrothiophene-3-carboxylate instead of methyl 2,2-dimethyl-4-oxotetrahydrofuran-3-carboxylate, the same method as in Reference Example 1-1 was performed to obtain the title compound.

[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.83 (3H, s), 3.94-3.99 (4H, m).

Reference Example 2-1

[0488] ##STR00038##

Methyl 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylate

[0489] Under an argon atmosphere, to a solution of methyl 2,2-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrofuran-3-carboxylate (3.41 g) in N,N-dimethylformamide (62 mL) were added (4-methoxyphenyl)boronic acid (1.70 g), triethylamine (4.68 mL), and tetrakis(triphenylphosphine)palladium (386 mg) to produce a reaction solution. The reaction solution was stirred at 100 C. for 3 hours. 1 mol/L Hydrochloric acid was added to the reaction solution to make the reaction solution acidic (pH: 1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=20:1-1:2) to obtain the title compound as a colorless oil (2.55 g).

[0490] .sup.1H NMR (400 MHz, CDCl.sub.3) : 1.53 (6H, s), 3.69 (3H, s), 3.83 (3H, s), 4.91 (2H, s), 6.89 (2H, d, J=9.1 Hz), 7.28 (2H, d, J=9.1 Hz).

[0491] The following Reference Examples 2-2 to 2-4 were obtained using each corresponding triflate and boronic acid in the same method as in Reference Example 2-1.

[0492] The structures and spectral data thereof are shown in Table 1.

TABLE-US-00001 TABLE 1 Ref. Chemical No Str. name P.D. 2-2 [00039] methyl 4-(4- methoxy- phenyl)- 2,5- dihydrofuran- 3-carboxylate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.72 (3H, s), 3.83 (3H, s), 4.99- 5.09 (4H, m), 6.91 (2H, d, J = 9.1 Hz), 7.51 (2H, c, J = 9.1 Hz) 2-3 [00040] methyl 4-(2,6- difluoro-4- methoxy- phenyl)- 2,5- dihydrofuran- 3-carboxylate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.69 (3H, s), 3.81 (3H, s), 4.94- 4.98 (2H, m), 4.99-5.02 (2H, m), 6.49 (2H, d, J = 9.8 Hz) 2-4 [00041] methyl 4-(4- methoxy- phenyl)- 2,5- dihydro- thiophene- 3-carboxylate .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.62 (3H, s), 3.82 (3H, s), 4.11- 4.18 (4H, m), 6.88 (2H, d, J = 9.1 Hz), 7.20 (2H, d, J = 9.1 Hz)

Reference Example 3-1

[0493] ##STR00042##

4-(4-Methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylic acid

[0494] To a solution of methyl 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylate (1.00 g) in methanol (7.6 mL) was added 2 mol/L aqueous potassium hydroxide (3.81 mL) to produce a reaction solution. The reaction solution was stirred at 50 C. for 4 hours. 1 mol/L hydrochloric acid was added to the reaction solution to make the reaction solution acidic (pH: 1), and the precipitated solid was collected by filtration and washed with water. The resulting solid was dried to obtain the title compound as a white solid (762 mg).

[0495] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.40 (6H, s), 3.76 (3H, s), 4.83 (2H, s), 6.92 (2H, d, J=9.1 Hz), 7.34 (2H, d, J=9.1 Hz), 12.64 (1H, s).

[0496] The following Reference Examples 3-2 to 3-3 were obtained using each corresponding ester in the same method as in Reference Example 3-1.

[0497] The structures and spectral data thereof are shown in Table 2.

TABLE-US-00002 TABLE 2 Ref. Chemical No Str. name P.D. 3-2 [00043] 4-(4- methoxy- phenyl)-2,5- dihydro- furan-3- carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.77 (3H, s), 4.85 (2H, t, J = 4.5 Hz), 5.00 (2H, t, J = 4.5 Hz), 6.93 (2H, dt, J = 8.5, 3.0 Hz), 7.54 (2H, dt, J = 8.5, 3.0 Hz), 12.65 (1H, s) 3-3 [00044] 4-(2,6- difluoro-4- methoxy- phenyl)- 2,5- dihydrofuran- 3-carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.79 (3H, s), 4.84 (4H, s), 6.80 (2H, d, J = 9.8 Hz), 12.79 (1H, br s)

Reference Example 4-1

[0498] ##STR00045##

()-cis-4-(4-Methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-carboxylic acid

[0499] To a solution of 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylic acid (750 mg) in ethanol (10 mL) was added 10% palladium carbon (75 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered over Celite, and the solvent was removed. The resulting crude product was washed with diisopropyl ether to obtain the title compound as a white solid (618 mg).

[0500] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.26 (3H, s), 1.31 (3H, s), 3.06 (1H, d, J=7.3 Hz), 3.70 (3H, s), 3.87-3.96 (1H, m), 4.11 (1H, t, J=7.3 Hz), 4.28 (1H, dd, J=10.9, 7.3 Hz), 6.83 (2H, d, J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz), 12.01 (1H, s).

[0501] The following Reference Examples 4-2 and 4-3 were obtained using each corresponding olefin in the same method as in Reference Example 4-1.

[0502] The structures and spectral data thereof are shown in Table 3.

TABLE-US-00003 TABLE 3 Ref. Chemical No Str. name P.D. 4-2 [00046] ()-cis-4-(4- methoxy- phenyl)- tetrahydro- furan- 3-carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.37- 3.44 (1H, m), 3.56- 3.63 (1H m), 3.70 (3H, s), 3.87 (1H, dd, J = 3.5, 5.4 Hz), 3.95 (1H, t, J = 8.5 Hz), 3.99-4.05 (2H, m), 6.82 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 12.10 (1H, s) 4-3 [00047] ()-cis-4- (2,6- difluoro-4- methoxy- phenyl)- tetrahydro- furan- 3-carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.30- 3.47 (1H, m), 3.74 (3H, s), 3.77-4.08 (4H, m), 4.11 (1H, t, J = 7.6 Hz), 6.67 (2H, d, J = 11.0 Hz), 12.14 (1H, br s)

Reference Example 5-1

[0503] ##STR00048##

Methyl ()-cis-4-(4-methoxyphenyl)tetrahydrofuran-3-carboxylate

[0504] Using methyl 4-(4-methoxyphenyl)-2,5-dihydrofuran-3-carboxylate instead of 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylic acid, the same method as in Reference Example 4-1 was performed to obtain the title compound.

[0505] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.34 (3H, s), 3.44-3.50 (1H, m), 3.66-3.71 (1H, m), 3.78 (3H, s), 4.07-4.17 (3H, m), 4.29 (1H, dd, J=9.1, 7.3 Hz), 6.82 (2H, dt, J=8.5, 1.8 Hz), 7.15 (2H, dt, J=8.5, 1.8 Hz).

Reference Example 6-1

[0506] ##STR00049##

()-trans-4-(4-Methoxyphenyl)tetrahydrofuran-3-carboxylic acid

[0507] Under an argon atmosphere, to a solution of methyl ()-cis-4-(4-methoxyphenyl)tetrahydrofuran-3-carboxylate (200 mg) in methanol (4.2 mL) was added sodium methoxide (20.0 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 18.5 hours. To the reaction solution was added 2 mol/L aqueous sodium hydroxide (0.847 mL), and the mixture was stirred at room temperature for 5 hours. 1 mol/L Hydrochloric acid was added to the reaction solution to make the reaction solution acidic (pH: 1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound as a colorless oil (182 mg).

[0508] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.04-3.13 (1H, m), 3.45-3.58 (2H, m), 3.71 (3H, s), 3.89 (1H, dd, J=8.2, 7.0 Hz), 4.06-4.14 (2H, m), 6.87 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 12.47 (1H, s).

Reference Example 7-1

[0509] ##STR00050##

()-4-(4-Methoxyphenyl)tetrahydrothiophene-3-carboxylic acid 1,1-dioxide

[0510] Using methyl 4-(4-methoxyphenyl)-2,5-dihydrothiophene-3-carboxylate instead of 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylic acid, the same method as in Reference Example 4-1 was performed to obtain a crude mixture of methyl ()-cis-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylate and methyl ()-trans-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylate (23 mg). To the solution of this crude mixture in dichloromethane (0.9 mL) was added metachloroperbenzoic acid (mCPBA) (49.4 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium thiosulfate, and the mixture was extracted with ethyl acetate. The extract was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate:hexane=1:20-1:1) to obtain a mixture of methyl ()-cis-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylate 1,1-dioxide and ()-trans-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylic acid 1,1-dioxide. Using the obtained mixture of methyl ()-cis-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylate 1,1-dioxide and ()-trans-4-(4-methoxyphenyl)tetrahydrothiophene-3-carboxylic acid 1,1-dioxide instead of methyl 4-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran-3-carboxylate, the same method as in Reference Example 3-1 was performed to obtain the title compound as a single racemic form.

[0511] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.21-3.29 (2H, m), 3.32-3.40 (1H, m), 3.52-3.70 (3H, m), 3.72 (3H, s), 6.88 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 12.77 (1H, s).

Reference Example 8-1

[0512] ##STR00051##

Dimethyl ()-2-[2-cyano-1-(4-methoxyphenyl)ethyl]malonate

[0513] Under an argon atmosphere, to a solution of dimethyl malonate (4.57 mL) in methanol (20 mL) was added sodium methoxide (378 mg), and the mixture was stirred at room temperature for 10 minutes, and then 3-(4-methoxyphenyl)acrylonitrile (2.9 mL) was added to the reaction mixture to produce a reaction solution. The reaction solution was stirred at room temperature for 2 hours, and then heated to reflux for 18 hours. The reaction solution was allowed to cool to room temperature, and then 10% hydrochloric acid was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound as a white solid (2.96 g).

[0514] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 2.84 (1H, dd, J=16.3, 4.8 Hz), 2.90 (1H, dd, J=16.3, 7.9 Hz), 3.54 (3H, s), 3.62-3.78 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 3.86 (1H, d, J=9.1 Hz), 6.88 (2H, d, J=9.1 Hz), 7.21 (2H, d, J=9.1 Hz).

Reference Example 9-1

[0515] ##STR00052##

Methyl ()-trans-4-(4-methoxyphenyl)-2-oxopiperidine-3-carboxylate

[0516] Under an argon atmosphere, to a solution of dimethyl ()-2-[2-cyano-1-(4-methoxyphenyl)ethyl]malonate (291 mg) in methanol (10 mL) was added nickel(II) chloride hexahydrate (238 mg) to produce a reaction solution. To the reaction solution under ice-cooling was added sodium borohydride (227 mg) in several times, then the reaction mixture was warmed to room temperatureand stirred for 1 hour. To the reaction solution were added a saturated aqueous ammonium chloride and ethyl acetate, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and then a brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1: 2) to obtain the title compound as a white solid (191 mg).

[0517] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.79 (1H, d, J=13.3 Hz), 1.90-2.02 (1H, m), 3,12-3.23 (2H, m), 3.24-3.30 (1H, m), 3.43 (3H, s), 3.51 (1H, d, J=11.5 Hz), 3.71 (3H, s), 6.84 (2H, d, J=8.5 Hz), 7.16 (2H, d, J=8.6 Hz), 7.87 (1H, d, J=2.4 Hz).

Reference Example 10-1

[0518] ##STR00053##

()-trans-4-(4-Methoxyphenyl)-2-oxopiperidine-3-carboxylic acid

[0519] To a solution of methyl ()-trans-4-(4-methoxyphenyl)-2-oxopiperidine-3-carboxylate (345 mg) in methanol (2.6 mL) was added 1 mol/L aqueous sodium hydroxide (2.62 mL) to produce a reaction solution. The reaction solution was stirred at 50 C. for 1 hour. 1 mol/L Hydrochloric acid was added to the reaction solution to make the reaction solution acidic (pH: 1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound as a white solid (200 mg).

[0520] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.78 (1H, d, J=13.3 Hz), 1.90-2.02 (1H, m), 3.08-3.46 (4H, m), 3.71 (3H, s), 6.85 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.6 Hz), 7.78 (1H, s), 12.17 (1H, s).

Reference Example 11-1

[0521] ##STR00054##

()-trans-4-(4-Chlorophenyl)tetrahydrofuran-3-ol

[0522] Under an argon atmosphere, to 1 mol/L 4-chlorophenylmagnesium bromide/diethyl ether (50 mL) under ice-cooling was added copper iodide(I) (476 mg) to produce a reaction solution. The reaction solution was stirred for 5 minutes, and a solution of 3,4-epoxytetrahydrofuran (4.30 g) in tetrahydrofuran (50 mL) was added to the reaction solution. The reaction mixture was stirred under ice-cooling for 10 minutes and at room temperature overnight. To the reaction solution was added a saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=6:1-ethyl acetate) to obtain the title compound as a colorless oil (4.19 g).

[0523] .sup.1H NMR (400 MHz, CDCl.sub.3) : 1.98 (1H, d, J=4.9 Hz), 3.26-3.32 (1H, m), 3.80 (1H, dd, J=9.8, 3.7 Hz), 3.90 (1H, dd, J=9.2, 5.5 Hz), 4.10 (1H, dd, J=9.8, 5.5 Hz), 4.33 (1H, dd, J=9.2, 7.3 Hz), 4.35-4.40 (1H, m), 7.20 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz).

[0524] The following Reference Examples 11-2 and 11-3 were obtained using each corresponding Grignard reagent and epoxy compound in the same method as in Reference Example 11-1.

[0525] The structures and spectral data thereof are shown in Table 4.

TABLE-US-00004 TABLE 4 Ref. Chemical No Str. name P.D. 11-2 [00055] ()-trans- 4-(4- fluoro- phenyl)- tetrahydro- furan- 3-ol .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.98 (1H, d, J = 4.2 Hz), 3.25-3.33 (1H, m), 3.80 (1H, dd, J = 9.7, 3.6 Hz), 3.90 (1H, dd, J = 9.1, 5.4 Hz), 4.08-4.13 (1H, m), 4.33 (1H, dd, J = 9.1, 7.3 Hz), 4.37 (1H, s), 7.02 (2H, t, J = 9.1 Hz), 7.22-7.24 (2H, m) 11-3 [00056] ()-trans- 4-{4- [(tetra- hydro- 2H-pyran- 2-yl)oxy]- phenyl} tetrahydro- .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.61- 1.76 (3H, m), 1.84-1.95 (3H, m), 1.98-2.08 (1H, m), 3.29 (1H, td, J = 6.7, 3.7 Hz), furan-3-ol 3.59-3.67 (1H, m), 3.82 (1H, dd, J = 9.8, 3.1 Hz), 3.89-3.97 (2H, m), 4.12 (1H, ddd, J = 9.8, 4.9, 1.8 Hz), 4.34 (1H, dd, J = 8.6, 7.3 Hz), 4.37-4.42 (1H, m), 5.42 (1H, J = 3.4 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz)

Reference Example 12-1

[0526] ##STR00057##

()-cis-2-[4-(4Chlorophenyl)tetrahydrofuran-3-yl]isoindoline-1,3-dione

[0527] Under an argon atmosphere, to a solution of ()-trans-4-(4-chlorophenyl)tetrahydrofuran-3-ol (4.00 g) in tetrahydrofuran (66 mL) under ice-cooling were added phthalimide (3.56 g) and triphenylphosphine (6.34 g) to produce a reaction solution. The reaction solution was stirred for 5 minutes, and then diisopropyl azodicarboxylate (4.67 mL) was added thereto. The reaction mixture was stirred under ice-cooling for 10 minutes, and then at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=4: 1) to obtain the title compound as a white solid (4.33 g).

[0528] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.76 (1H, td, J=9.8, 7.3 Hz), 4.29-4.37 (2H, m), 4.51-4.61 (2H, m), 5.22 (1H, td, J=8.6, 5.5 Hz), 7.05-7.12 (4H, m), 7.63-7.67 (2H, m), 7.67-7.70 (2H, m).

[0529] The following Reference Examples 12-2 and 12-3 were obtained using each corresponding hydroxy compound in the same method as in Reference Example 12-1.

[0530] The structures and spectral data thereof are shown in Table 5.

TABLE-US-00005 TABLE 5 Ref. No Str. Chemical name P.D. 12-2 [00058] ()-cis-2-[4-(4- fluorophenyl) tetrahydrofuran-3- yl]isoindoline- 1,3-dione .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.70- 3.80 (1H, m), 4.26- 4.35 (2H, m), 4.50-4.60 (2H, m), 5.18 (1H, td, J = 8.6, 5.5 Hz), 6.78 (2H, t, J = 7.9 Hz), 7.08-7.11 (2H, m), 7.58-7.68 (4H, m) 12-3 [00059] ()-cis-2-(4-{4- [(tetrahydro-2H- pyran-2-yl)oxy]- phenyl}tetra- hydrofuran-3- yl)isoindoline- 1,3-dione .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.46- 1.81 (5H, m), 1.84-1.96 (1H, m), 3.41-3.48 (1H, m), 3.67-3.79 (2H, m), 4.27-4.37 (2H, m), 4.52-4.60 (2H, m), 5.14-5.22 (2H, m), 6.79 (2H, d, J = 9.2 Hz), 7.04 (2H, d, J = 9.2 Hz), 7.59-7.64 (2H, m), 7.65-7.70 (2H, m)

Reference Example 13-1

[0531] ##STR00060##

()-cis-2-[4-(4-Hydroxyphenyl)tetrahydrofuran-3-yl]isoindoline-1,3-dione

[0532] Under an argon atmosphere, to a solution of ()-cis-2-(4-{4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl }tetrahydrofuran-3-yl)isoindoline-1,3-dione (3.22 g) in methanol (33 mL) under ice-cooling was added p-toluenesulfonic acid (1.56 g) to produce a reaction solution. The reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a white solid (2.38 g).

[0533] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.60-3.70 (1H, m), 4.13 (1H, t, J=7.6 Hz), 4.20 (1H, dd, J=9.5, 8.3 Hz), 4.28-4.36 (2H, m), 5.05 (1H, td, J=8.7, 4.7 Hz), 6.46 (2H, d, J=8.6 Hz), 6.84 (2H, d, J=8.6 Hz), 7.68-7.76 (4H, m), 9.10 (1H, s).

Reference Example 14-1

[0534] ##STR00061##

()-cis-2-{[4-(4-Trifluoromethanesulfonyloxy)phenyl]tetrahydrofuran-3-yl}isoindoline-1,3-dione

[0535] Under an argon atmosphere, to a solution of ()-cis-2-[4-(4-hydroxyphenyl)tetrahydrofuran-3-yl]isoindoline-1,3-dione (1.58 g) in dichloromethane (7.7 mL) under ice-cooling was added pyridine (4.12 mL) and a solution of trifluoromethanesulfonic anhydride (1.29 mL) in dichloromethane (2.6 mL) to produce a reaction solution. The reaction solution was stirred under ice-cooling for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a white solid (2.2 g).

[0536] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.76-3.87 (1H, m), 4.28-4.36 (2H, m), 4.56-4.63 (2H, m), 5.25 (1H, td, J=9.2, 5.5 Hz), 7.01 (2H, d, J=8.6 Hz), 7.23 (2H, d, J=8.6 Hz), 7.60-7.68 (4H, m).

Reference Example 15-1

[0537] ##STR00062##

()-cis-4-[4-(1,3-Dioxoisoindolin-2-yl)tetrahydrofuran-3-yl]benzonitrile

[0538] Under an argon atmosphere, to a solution of ()-cis-2-{[4-(4-trifluoromethanesulfonyloxy)phenyl]tetrahydrofuran-3-yl}isoindoline-1,3-dione (1.20 g) in N,N-dimethylformamide (10 mL) was added tetrakistriphenylphosphine palladium (316 mg) and zinc cyanide (1.27 g) to produce a reaction solution. The reaction solution was stirred at 100 C. for 3 hours. The reaction solution was filtered over Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a white solid (510 mg).

[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.83 (1H, dd, J=16.5, 9.2 Hz), 4.30-4.37 (2H, m), 4.55 (1H, dd, J=9.2, 5.5 Hz), 4.63 (1H, t, J=9.2 Hz), 5.28 (1H, td, J=8.9, 5.7 Hz), 7.26 (2H, d, J=7.9 Hz), 7.42 (2H, d, J=7.9 Hz), 7.64-7.70 (4H, m).

Reference Example 16-1

[0540] ##STR00063##

()-cis-4-(4Chlorophenyl)tetrahydrofuran-3-amine

[0541] Under an argon atmosphere, to a solution of ()-cis-2-[4-(4-chlorophenyl)tetrahydrofuran-3-yl]isoindoline-1,3-dione (1.00 g) in ethanol (15 mL) was added hydrazine monohydrate (1.48 mL) to produce a reaction solution. The reaction solution was heated to reflux for 3 hours. Water was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound as a colorless oil (608 mg).

[0542] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.42 (1H, q, J=6.7 Hz), 3.62 (1H, dd, J=9.1, 4.2 Hz), 3.78 (1H, td, J=6.1, 4.8 Hz), 4.08-4.22 (3H, m), 7.20 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=8.5 Hz).

[0543] The following Reference Examples 16-2 and 16-3 were obtained using each corresponding phthaloyl compound in the same method as in Reference Example 16-1.

[0544] The structures and spectral data thereof are shown in Table 6.

TABLE-US-00006 TABLE 6 Ref. No Str. Chemical name P.D. 16-2 [00064] ()-cis-4-(4- fluorophenyl)- tetrahydrofuran- 3-amine .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.43 (1H, q, J = 6.7 Hz), 3.60-3.66 (1H, m), 3.77 (1H, q, J = 5.5 Hz), 4.08-4.22 (3H, m), 7.03-7.08 (2H, m), 7.20-7.25 (2H, m) 16-3 [00065] ()-cis-4-(4- aminotetrahydro- furan-3- yl)benzonitrile .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.48 (1H, q, J = 6.7 Hz), 3.62 (1H, dd, J = 8.6, 4.3 Hz), 3.86 (1H, dd, J = 10.4, 5.5 Hz), 4.11-4.24 (3H, m), 7.40 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz)

Reference Example 17-1

[0545] ##STR00066##

()-3-Amino-4-(4-methoxyphenyl)oxazolidin-2-one

[0546] Under an argon atmosphere, to a solution of 4-(4-methoxyphenyl)oxazolidin-2-one (300 mg) in dioxane (8 mL) was added sodium hydride (65 mg) to produce a reaction solution. The reaction solution was stirred at 60 C. for 1 hour. O-(4-Nitrobenzoyl)hydroxylamine (311 mg) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain the title compound as a white solid (194 mg).

[0547] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.74 (3H, s), 3.95 (1H, dd, J=8.5, 6.7 Hz), 4.61 (1H, t, J=8.5 Hz), 4.86 (1H, dd, 8.5, 6.7 Hz), 6.94 (2H, d, J=9.1), 7.25 (2H, d, J=9.2), 8.09 (2H, s).

Reference Example 18-1

[0548] ##STR00067##

Ethyl ()-trans-1,3-bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate

[0549] To ethanol (7 mL) was added sodium (172 mg), and the mixture was stirred for 15 minutes. Then, a solution of dimethyl 2-[(4-methoxyphenyl)amino]malonate (2.0 g) in ethanol (35 mL) was added to the mixture at room temperature to produce a reaction solution. The reaction solution was stirred for 15 minutes. To the reaction solution was added ethyl 4-methoxycinnamate (2.20 g), and the reaction mixture was refluxed for 16 hours. To the reaction solution under ice-cooling was added acetic acid (1.0 mL), and the mixture was concentrated under reduced pressure. Water was added to the obtained resudue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the obtained residue were added dimethyl-sulfoxide (7.0 mL), water (0.26 mL), and then sodium chloride (420 mg), and the mixture was refluxed for 2 hours. The reaction solution was allowed to cool to room temperature, iced water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound as a white solid (633 mg).

[0550] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.20 (3H, t, J=7.0 Hz), 2.69 (1H, dd, J=17.0, 4.2 Hz), 3.15 (1H, dd, J=17.0, 9.1 Hz),3.54-3.60 (1H, m), 3.79 (3H, s), 3.81 (3H, s), 4.14-4.24 (2H, m), 4.54 (1H, d, J=3.6 Hz), 6.86-6.92 (4H, m), 7.22 (2H, d, J=11.5 Hz), 7.32 (2H, d, J=9.1 Hz).

Reference Example 19-1

[0551] ##STR00068##

()-trans-1,3-Bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylic acid

[0552] To a solution of ethyl ()-trans-1,3-bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate (570 mg) in methanol (7.7 mL) at room temperature was added 2 mol/L aqueous sodium hydroxide (1.5 mL) to produce a reaction solution. The reaction solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and then water and 2 mol/L hydrochloric acid were added to the residue to make the solution acidic (pH: 1). The precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound as a white solid (516 mg).

[0553] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8:2.53 (1H, dd, J=17.0, 6.7 Hz), 2.95 (1H, dd, J=17.0, 9.1 Hz), 3.54-3.62 (1H, m), 3.73 (3H, s), 3.73 (3H, s), 4.64 (1H, d, J=4.8 Hz), 6.88-6.94 (4H, m), 7.28 (2H, d, J=9.1 Hz), 7.36 (2H, d, J=9.1 Hz), 13.11 (1H, br s).

Reference Example 20-1

[0554] ##STR00069##

()-trans-1,3-Bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide

[0555] To a solution of ()-trans-1,3-bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylic acid (155 mg) in anhydrous N,N-dimethylformamide (7.4 mL) were added 1-hydroxybenzotriazole (245 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (308 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 1 hour. Then, aqueous ammonia (1.1 mL) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:methanol=20: 1) to obtain the title compound as a white solid (408 mg).

[0556] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 2.71 (1H, dd, J=17.0, 5.5 Hz), 3.15 (1H, dd, J=17.0, 9.1 Hz), 3.60-3.70 (1H, m), 3.79 (3H, s), 3.81 (3H, s), 4.45 (1H, d, J=3.6 Hz), 5.42 (1H, br s), 5.64 (1H, br s), 6.87-6.93 (4H, m), 7.23 (2H, d, J=9.1 Hz), 7.39 (2H, d, J=9.1 Hz).

Reference Example 21-1

[0557] ##STR00070##

tert-Butyl ()-trans-(1,3-bis(4-methoxyphenyl)-5-oxopyrrolidine-2-yl)carbamate

[0558] To a solution of ()-trans-1,3-bis(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (155 mg) in tert-butanol (1.2 mL) was added pyridine (1.2 mL) at room temperatureand then [bis(trifluoroacetoxy)iodo]benzene (293 mg) at room temperature to produce a reaction solution. The reaction solution was stirred at 90 C. for 4 hours. The reaction solution was allowed to cool to room temperature, iced water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:1) to obtain the title compound as a white solid (94 mg).

[0559] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.30 (9H, s), 2.70 (1H, dd, J=17.1, 7.9 Hz), 3.07 (1H, dd, J=17.1, 8.6 Hz), 3.30-3.39 (1H, m), 3.79 (3H, s), 3.82 (3H, s), 4.80-4.94 (1H, m), 5.60-5.73 (1H, m), 6.90 (4H, d, J=7.9 Hz), 7.22-7.33 (4H, m).

Reference Example 22-1

[0560] ##STR00071##

tert-Butyl ()-trans-[3-(4-methoxyphenyl)-5-oxopyrrolidin-2-yl]carbamate

[0561] To a solution of tert-butyl ()-trans-(1,3-bis(4-methoxyphenyl)-5-oxopyrrolidin-2-yl)carbamate (71.0 mg) in acetonitrile (3.5 mL) under ice-cooling was added a solution of ammonium cerium(IV) nitrate (189 mg) in water (3.5 mL) to produce a reaction solution. The reaction solution was stirred under ice-cooling for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=6:1-3:1) to obtain the title compound as a white solid (29 mg).

[0562] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.43 (9H, s), 2.49 (1H, dd, J=17.1, 7.9 Hz), 2.84 (1H, dd, J=17.7, 9.2 Hz), 3.20 (1H, td, J=7.9, 6.4 Hz), 3.80 (3H, s), 4.97-5.11 (1H, m), 5.19-5.29 (1H, m), 6.06-6.21 (1H, m), 6.89 (2H, d, J=8.6 Hz), 7.18 (2H, d, J=8.6 Hz).

Reference Example 23-1

[0563] ##STR00072##

(E)-1,3-Difluoro-5-methoxy-2-(2-nitrovinyl)benzene

[0564] Under an argon atmosphere, to a solution of 2,6-difluoro-4-methoxybenzaldehyde (14.7 g) in acetic acid (85 mL) were added ammonium acetate (11.2 g) and nitromethane (22.9 mL) to produce a reaction solution. The reaction solution was stirred at 100 C. for 6 hours. The reaction solution was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration and washed with water. The resulting solid was dried to obtain the title compound as a yellow solid (17.5 g).

[0565] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.87 (3H, s), 6.54-6.59 (2H, m), 7.77 (1H, d, J=13.4 Hz), 8.11 (1H, d, J=13.4 Hz).

Reference Example 23-2

[0566] ##STR00073##

(E)-6-Fluoro-5-(2-nitrovinyl)-2,3-dihydrobenzofuran

[0567] Using 6-fluoro-2,3-dihydrobenzofuran-5-carbaldehyde instead of 2,6-difluoro-4-methoxybenzaldehyde, the same method as in Reference Example 23-1 was performed to obtain the title compound.

[0568] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.23 (2H, t, J=8.9 Hz), 4.72 (2H, t, J=8.9 Hz), 6.60 (1H, d, J=11.6 Hz) 7.30 (1H, d, J=6.7 Hz), 7.62 (1H, d, J=13.4 Hz), 8.03 (1H, d, J=13.4 Hz).

Reference Example 24-1

[0569] ##STR00074##

Dimethyl ()-(R*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonate

[0570] Under an argon atmosphere, to a solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (500 mg) in toluene (2.8 mL) were added dimethyl malonate (0.36 mL) and nickel(II) bis[(S,S)-N,N-dibenzylcyclohexane-1,2-diamine]bromide (68 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:hexane=4:1) to obtain the title compound as a colorless liquid (865 mg).

[0571] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.57 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.83 (1H, d, J=9.1 Hz), 4.16-4.22 (1H, m), 4.83 (1H, dd, J=12.7, 9.1 Hz), 4.89 (1H, dd, J=12.7, 5.1 Hz), 6.84 (2H, d, J=9.1 Hz), 7.14 (2H, d, J=9.1 Hz).

[0572] [].sub.D.sup.2520 (c 0.26, EtOH)

[0573] The following Reference Examples 24-2 and 24-3 were obtained using each corresponding nitrostyrene in the same method as in Reference Example 24-1.

[0574] The structures and spectral data thereof are shown in Table 7.

TABLE-US-00007 TABLE 7 Ref. No Str. Chemical name P.D. 24-2 [00075] dimethyl ()- (R*)-2-[1-(2,6- difluoro-4- methoxyphenyl)-2- nitroethyl]- malonate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.57 (3H, s), 3.77 (3H, s), 3.80 (3H, s), 3.93 (1H, d, J = 10.4 Hz), 4.63- 4.70 (1H, m), 4.81 (1H, dd, J = 13.1, 10.1 Hz), 4.91 (1H, dd, J = 13.1, 4.7 Hz), 6.41- 6.47 (2H, m) [].sub.D.sup.24 25 (c 0.11, EtOH) 24-3 [00076] dimethyl ()- (R*)-2-[1-(6- fluoro-2,3- dihydro- benzofuran-5-yl)- 2-nitroethyl]- malonate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.13 (2H, t, J = 8.9 Hz), 3.58 (3H, s), 3.77 (3H, s), 3.96 (1H, d, J = 9.8 Hz), 4.29-4.35 (1H, m), 4.59 (2H, t, J = 8.9 Hz), 4.87 (2H, d, J = 7.3 Hz), 6.48 (1H, d, J = 11.6 Hz), 6.99 (1H, d, J = 7.3 Hz) [].sub.D.sup.26 20 (c 0.31, EtOH)

Reference Example 25-1

[0575] ##STR00077##

Methyl ()-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylate

[0576] Under an argon atmosphere, to a solution of dimethyl (R*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonate (1.7 g) in methanol (110 mL) was added nickel(II) chloride hexahydrate (1.3 g) to produce a reaction solution. To the reaction solution under ice-cooling was added sodium borohydride (1.03 g) in several times, and then the reaction mixture was warmed to room temperatureand stirred for 2 hours. To the reaction solution were added a saturated aqueous ammonium chloride and ethyl acetate, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and then the resulting crude product was washed with ethanol-diisopropyl ether to obtain the title compound as a white solid (840 mg).

[0577] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.40 (1H, t, J=9.1 Hz), 3.53 (1H, d, J=9.7 Hz), 3.76-3.81 (1H, m), 3.78 (3H, s), 3.80 (3H, s), 4.08 (1H, q, J=8.9 Hz), 5.85 (1H, brs), 6.88 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz).

[0578] [].sub.D.sup.2596 (c 0.19, EtOH)

[0579] The following Reference Examples 25-2 and 25-3 were obtained using each corresponding nitro compound in the same method as in Reference Example 25-1.

[0580] The structures and spectral data thereof are shown in Table 8.

TABLE-US-00008 TABLE 8 Ref. No Str. Chemical name P.D. 25-2 [00078] methyl ()- (3S*,4R*)-4-(2,6- difluoro-4- methoxyphenyl)-2- oxopyrrolidine-3- carboxylate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.51 (1H, t, J = 9.2 Hz), 3.64-3.70 (1H, m), 3.78 (6H, s), 3.78-3.81 (1H, m), 4.46 (1H, q, J = 9.4 Hz), 6.24 (1H, brs), 6.43-6.50 (2H, m) [].sub.D.sup.23 120 (c 0.11, EtOH) 25-3 [00079] methyl ()- (3S*,4R*)-4-(6- fluoro-2,3- dihydrobenzofuran- 5-yl)-2- oxopyrrolidine-3- carboxylate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.15 (2H, t, J = 8.9 Hz), 3.41 (1H, t, J = 8.6 Hz), 3.66 (1H, d, J = 9.8 Hz), 3.74-3.79 (1H, m), 3.79 (3H, s), 4.19 (1H, q, J = 8.6 Hz), 4.61 (2H, t, J = 8.9 Hz), 5.68 (1H, brs), 6.52 (1H, d, J = 11.6 Hz), 7.03 (1H, d, J = 7.9 Hz) [].sub.D.sup.26 121 (c 0.20, EtOH)

Reference Example 26-1

[0581] ##STR00080##

()-(3S*,4W)-4-(4-Methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid

[0582] To a solution of methyl ()-(3S*,4R*-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylate (130 mg) in methanol (2.6 mL) was added 2 mol/L aqueous sodium hydroxide (0.52 mL) to produce a reaction solution. The reaction solution was stirred at 60 C. for 1 hour. 1 mol/L Hydrochloric acid was added to the reaction solution to make the reaction solution acidic (pH: 1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and then the resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain the title compound as a white solid (112 mg).

[0583] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.16 (1H, t, J=9.4 Hz), 3.42 (1H, d, J=10.9 Hz), 3.55 (1H, t, J=8.2 Hz), 3.72 (3H, s), 3.79 (1H, q, J=9.5 Hz), 6.88 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 8.03 (1H, s), 12.54 (1H, brs).

[0584] [].sub.D.sup.2768 (c 0.15, EtOH)

[0585] The following Reference Examples 26-2 and 26-3 were obtained using each corresponding ester in the same method as in Reference Example 26-1.

[0586] The structures and spectral data thereof are shown in Table 9.

TABLE-US-00009 TABLE 9 Ref. No Str. Chemical name P.D. 26-2 [00081] ()-(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-2- oxopyrrolidine-3- carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.25 (1H, t, J = 9.2 Hz), 3.43 (1H, d, J = 10.4 Hz), 3.56 (1H, t, J = 9.2 Hz), 3.76 (3H, s), 4.14 (1H, q, J = 9.4 Hz), 6.73-6.80 (2H, m), 8.20 (1H, s), 12.77 (1H, brs) [].sub.D.sup.23 121 (c 0.10, EtOH) 26-3 [00082] ()-(3S*,4R*)-4- (6-fluoro-2,3- dihydrobenzofuran- 5-yl)-2- oxopyrrolidine-3- carboxylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.09-3.19 (3H, m), 3.46 (1H, d. J = 10.4 Hz), 3.52 (1H, t, J = 8.9 Hz), 3.94-4.03 (1H, m), 4.55 (2H, t, J = 8.6 Hz), 6.65 (1H, d, J = 11.0 Hz), 7.31 (1H, d, J = 7.9 Hz), 8.09 (1H, s), 12.65 (1H, brs) [].sub.D.sup.27 114 (c 0.30, EtOH)

Reference Example 27-1

[0587] ##STR00083##

Benzyl ()-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamate

[0588] To a solution of ()-(3S*,4W)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (6.04 g) in toluene (128 mL) were added triethylamine (3.95 mL) and diphenylphosphoryl azide (6.2 mL) to produce a reaction solution. The reaction solution was stirred at room temperature for 4.5 hours. The reaction solution was heated to 80 C., and stirred for 30 minutes. Then, benzyl alcohol (13.3 mL) was added to the reaction solution, and the reaction mixture was stirred at 120 C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10: 1) to obtain the title compound as a white solid (6.3 g).

[0589] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.36 (1H, t, J=9.1 Hz), 3.49-3.70 (2H, m), 3.80 (3H, s), 4.42 (1H, dd, J=11.5, 8.5 Hz), 5.07 (2H, s), 5.16 (1H, brs), 5.98 (1H, brs), 6.89 (2H, d, J=7.9 Hz), 7.22 (2H, d, J=7.9 Hz), 7.20-7.40 (5H, m).

[0590] [].sub.D.sup.2779 (c 0.17, EtOH)

[0591] The following Reference Examples 27-2 and 27-3 were obtained using each corresponding carboxylic acid in the same method as in Reference Example 27-1.

[0592] The structures and spectral data thereof are shown in Table 10.

TABLE-US-00010 TABLE 10 Ref. No Str. Chemical name P.D. 27-2 [00084] benzyl ()- [(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-2- oxopyrrolidine-3- yl]carbamate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.48-3.62 (2H, m), 3.79 (3H, s), 3.80-3.96 (1H, m), 4.67-4.75 (1H, m), 5.05 (2H, s), 5.38 (1H, brd, J = 8.0 Hz), 6.42-6.53 (2H, m), 6.60 (1H, s), 7.26-7.36 (5H, m) [].sub.D.sup.24 107 (c 0.10, EtOH) 27-3 [00085] benzyl ()- [(3S*,4R*)-4-(6- fluoro-2,3- dihydrobenzofuran- 5-yl)-2- oxopyrrolidine-3- yl]carbamate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.05-3.25 (2H, m), 3.37 (1H, t, J = 9.2 Hz), 3.55-3.80 (2H, m), 4.50-4.65 (3H, m), 5.04-5.14 (3H, m), 5.83 (1H, s), 6.50 (1H, d, J = 10.4 Hz), 7.10-7.22 (1H, m), 7.26-7.40 (5H, m) [].sub.D.sup.29 185 (c 0.16, EtOH)

Reference Example 28-1

[0593] ##STR00086##

Benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-ethoxy-3-methyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate

[0594] To a suspension of benzyl ()-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamate (605 mg) in dichloromethane (8 mL) was added triethyloxonium hexafluorophosphate (595 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain benzyl [(3S*,4R*)-5-ethoxy-3-(2,6-difluoro-4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate that is an intermediate as a yellow oil. To a solution of benzyl [(3R*,4S*)-5-ethoxy-3-(2,6-difluoro-4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate (40 mg) in ethanol (0.7 mL) were added ammonium chloride (0.5 mg) and hydrazine monohydrate (23 L) to produce a reaction solution. The reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (0.8 mL). To the ethanol solution was added ethyl orthoacetate (28 L), and the mixture was heated to reflux for 3 hours. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound as a colorless oil (27 mg).

[0595] .sup.1H NMR (400 MHz, CDCl.sub.3) : 1.30 (3H, t, J=7.3 Hz), 2.06 (3H, s), 3.52-3.72 (3H, m), 3.77 (3H, s), 4.12 (2H, q, J=7.3 Hz), 5.02 (2H, s), 5.09 (1H, dd, J=10.4, 7.3 Hz), 5.24 (1H, s), 5.62 (1H, s), 6.40-6.49 (2H, m), 7.30 (5H, s).

Reference Example 29-1

[0596] ##STR00087##

Benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate

[0597] To a solution of benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-ethoxy-3-methyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate (27 mg) in toluene (1 mL) was added p-toluenesulfonic acid (1 mg) to produce a reaction solution. The reaction solution was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:methanol=4:1) to obtain the title compound as a colorless oil (10 mg).

[0598] .sup.1H NMR (400 MHz, CDCl.sub.3) : 2.45 (3H, s), 3.81 (3H, s), 3.98-4.09 (1H, m), 4.17-4.30 (1H, m), 4.40-4.50 (1H, m), 5.00-5.13 (2H, m), 5.39-5.48 (2H, m), 6.52 (2H, d, J=10.4 Hz), 7.29-7.39 (5H, m).

Reference Example 30-1

[0599] ##STR00088##

[0600] Benzyl [(6R*,7S*)-6-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazol-7-yl]carbamate

[0601] To a suspension of benzyl ()-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamate (500 mg) in dichloromethane (3.7 mL) was added triethyloxonium hexafluorophosphate (446 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain benzyl [(3R*,4S*)-5-ethoxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate that is an intermediate as a yellow oil. To a solution of benzyl [(3R*,4S*)-5-ethoxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate (325 mg) in acetic acid (1.2 mL) was added sodium azide (177 mg) to produce a reaction solution. The reaction solution was stirred at 60 C. for 5 hours. To the reaction solution under ice-cooling were added ethyl acetate and aqueous potassium carbonate to make the reaction solution basic (pH: 9), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a colorless oil (160 mg).

[0602] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.75 (3H, s), 4.21-4.36 (2H, m), 4.89 (1H, dd, J=9.7, 7.9 Hz), 5.00 (1H, d, J=12.7 Hz), 5.05 (1H, d, J=12.7 Hz), 5.34 (1H, m), 6.94 (2H, d, J=8.5 Hz), 7.25-7.38 (5H, m), 7.42 (2H, d, J=8.5 Hz), 8.14 (1H, d, J=9.1 Hz).

[0603] The following Reference Examples 30-2 and 30-3 were obtained using each corresponding Cbz compound in the same method as in Reference Example 30-1.

[0604] The structures and spectral data thereof are shown in Table 11.

TABLE-US-00011 TABLE 11 Ref. No Str. Chemical name P.D. 30-2 [00089] benzyl [(6R*,7S*)-6- (2,6-difluoro-4- methoxyphenyl)- 6,7-dihydro-5H- pyrrolo[1,2- d]tetrazol-7- yl]carbamate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.81 (3H, s), 4.36- 4.46 (1H, m), 4.67-4.76 (1H, m), 4.76-4.84 (1H, m), 5.03- 5.13 (2H, m), 5.36 (1H, t, J = 7.3 Hz), 5.45 (1H, br s), 6.53 (2H, d, J = 10.4 Hz), 7.27-7.38 (5H, m) 30-3 [00090] benzyl [(6R*,7S*)-6-(6- fluoro-2,3- dihydrobenzo- furan-5-yl)-6,7- dihydro-5H- pyrrolo[1,2- d]tetrazol-7- yl]carbamate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.17 (2H, t, J = 8.9 Hz), 4.28-4.36 (1H, m), 4.40- 4.52 (1H, m), 4.64 (2H, t, J = 8.9 Hz), 4.80- 4.90 (1H, m), 5.08 (2H, s), 5.30 (1H, t, J = 7.6 Hz), 5.41 (1H, brs), 6.57 (1H, d, J = 10.4 Hz), 7.05 (1H, brs), 7.28-7.38 (5H, m)

Reference Example 31-1

[0605] ##STR00091##

Benzyl {(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-[(2,2-dimethoxyethyl)amino]-3,4-dihydro-2H-pyrrol-4-yl }carbamate

[0606] To a solution of benzyl [(3R*,4S*)-5-ethoxy-3-(2,6-difluoro-4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate (56 mg) that was obtained in the same method as in Reference Example 28-1 in ethanol (0.7 mL) were added ammonium chloride (0.4 mg) and aminoacetaldehyde dimethyl acetal (18 L) to produce a reaction solution. The reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a colorless oil (51 mg).

[0607] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.40-3.62 (9H, m), 3.66-3.76 (1H, m), 3.79 (3H, s), 3.86-3.98 (1H, m), 4.54 (1H, t, J=5.2 Hz), 4.98 (1H, d, J=7.3 Hz), 5.04-5.16 (3H, m), 6.47 (2H, d, J=9.8 Hz), 7.30-7.42 (5H, m).

[0608] The following Reference Examples 31-2 to 31-4 were obtained using each corresponding amine in the same method as in Reference Example 31-1.

[0609] The structures and spectral data thereof are shown in Table 12.

TABLE-US-00012 TABLE 12 Ref. No Str. Chemical name P.D. 31-2 [00092] benzyl {(3S*,4R*,Z)-4- (2,6-difluoro-4- methoxyphenyl)-2- [(2-hydroxy- ethoxy)imino]- pyrrolidin-3- yl}carbamate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 2.87 (1H, brs), 3.50- 3.64 (2H, m), 3.65-3.80 (4H, m), 3.83-3.90 (2H, m), 4.08 (1H, dd, J = 4.3, 4.3 Hz), 4.80- 5.15 (3H, m), 5.13 (1H, dd, J = 9.8, 8.0 Hz), 5.25 (1H, s), 6.40-6.50 (2H, m), 7.26-7.32 5H, m) 31-3 [00093] ethyl 2-(((Z)- {(3S*,4R*)-3- [(benzyloxy- carbonyl)amino]- 4-(2,6-difluoro- 4-methoxyphenyl)- pyrrolidin-2- ylidene}amino)- oxy)acetate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.29 (3H, t, J = 7.3 Hz), 3.56-3.77 (5H, m), 4.22 (2H, q, J = 7.3 Hz), 4.50 (2H, s), 4.93-5.19 (3H, m), 5.43 (1H, s), 5.88 (1H, s), 6.45 (2H, d, J = 10.4 Hz), 7.27-7.36 (5H, m) 31-4 [00094] ethyl 3-((Z)- {(3S*,4R*)-3- [(benzyloxy- carbonyl)amino]- 4-(2,6-difluoro- 4-methoxyphenyl)- pyrrolidin-2- ylidene}amino)- propionate .sup.1H-NMR (400 MHz, CDCl.sub.3) : 1.28 (3H, t, J = 7.3 Hz), 2.64-2.78 1H, m), 3.50- 4.20 (9H, m), 4.02-4.09 (1H, m), 4.65-4.75 (1H, m), 4.95- 5.20 (3H, m), 5.75 (1H, brs), 6.42-6.52 (2H, m), 7.27-7.37 (5H, m)

Reference Example 32-1

[0610] ##STR00095##

[0611] Benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]carbamate

[0612] To benzyl {(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-[(2,2-dimethoxyethyl)amino]-3,4-dihydro-2H-pyrrol-4-yl}carbamate (51 mg) was added 1 mol/L hydrochloric acid (1.1 mL) to produce a reaction solution. The reaction solution was heated to reflux for 6 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by aminopropylated silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound as a colorless oil (13 mg).

[0613] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.79 (3H, s), 4.17-4.27 (1H, m), 4.27-4.35 (1H, m), 5.00-5.08 (2H, m), 5.30-5.42 (2H, m), 6.49 (2H, d, J=9.8 Hz), 6.93 (1H, s), 7.15 (1H, s), 7.34 (5H, t, J=14.4 Hz).

Reference Example 33-1

[0614] ##STR00096##

Benzyl {(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-iodoethoxy)imino] pyrrolidin-3-yl}carbamate

[0615] Under an argon atmosphere, a solution of benzyl {(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}carbamate (44 mg) in tetrahydrofuran (1.0 mL) under ice-cooling were added imidazole (14 mg), triphenylphosphine (53 mg) and iodine (51 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 2 hours. An aqueous saturated sodium thiosulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound as a colorless oil (40 mg).

[0616] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.32-3.50 (2H, m), 3.58-3.71 (1H, m), 3.77 (3H, s), 3.97-4.05 (2H, m), 4.83-4.99 (3H, m), 6.67-6.86 (3H, m), 7.21-7.36 (5H, m), 7.70 (1H, d, J=9.2 Hz).

Reference Example 34-1

[0617] ##STR00097##

Benzyl [(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]carbamate

[0618] Under an argon atmosphere, to a solution of benzyl {(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-iodoethoxy)imino]pyrrolidin-3-yl}carbamate (40 mg) in N,N-dimethylformamide (1.5 mL) under ice-cooling was added potassium tert-butoxide (16.5 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane : ethyl acetate=1 : 1) to obtain the title compound as a colorless oil (23 mg).

[0619] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.27-3.40 (4H, m), 3.49-3.72 (2H, m), 3.77 (3H, s), 3.82-3.90 (1H, m), 4.89-4.99 (3H, m), 6.76 (2H, d, J=11.0 Hz), 7.22-7.35 (5H, m), 7.76 (1H, d, J=9.2 Hz).

Reference Example 35-1

[0620] ##STR00098##

Benzyl [(7R*,8S*)-7-(2,6-difluoro-4-methoxyphenyl)-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidin-8-yl]carbamate

[0621] To a solution of benzyl [(3R*,4S*)-5-ethoxy-3-(2,6-difluoro-4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate (59 mg) that was obtained in the same method as in Reference Example 28-1 in ethanol (0.3 mL) were added ammonium chloride (1 mg) and 3-bromopropylamine hydrobromide (35 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 2 hours. Then, potassium carbonate (61 mg) was added to the reaction solution, and the reaction mixture was stirred for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by aminopropylated silica gel column chromatography (ethyl acetate:methanol=4:1) to obtain the title compound as a colorless oil (27 mg).

[0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.60-1.73 (2H, m), 3.09-3.24 (4H, m), 3.32-3.44 (2H, m), 3.47-3.61 (1H, m), 3.76 (3H, s), 4.66 (1H, t, J=9.8 Hz), 4.92 (2H, s), 6.74 (2H, d, J=11.0 Hz), 7.22-7.35 (5H, m), 7.49 (1H, d, J=9.2 Hz).

Reference Example 36-1

[0623] ##STR00099##

Benzyl ((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)carbamate

[0624] Benzyl [(3R*,4S*)-5-ethoxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamate that was obtained in the same method as in Reference Example 30-1 was subjected to react with O-(tert-butyldimethylsilyl)hydroxylamine as a reacting reagent instead of aminoacetaldehyde dimethyl acetal according to the same method as in Reference Example 31-1 to obtain the title compound.

[0625] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.05 (6H, s), 0.90 (9H, s), 3.18 (1H, t, J=9.1 Hz), 3.22-3.40 (1H, m), 3.49 (1H, t, J=8.2 Hz), 3.72 (3H, s), 4.55 (1H, t, J=9.7 Hz), 4.91 (1H, d, J=13.3 Hz), 5.03 (1H, d, J=13.3 Hz), 6.49 (1H, s), 6.86 (2H, d, J=8.5 Hz), 7.20-7.33 (7H, m), 7.58 (1H, d, J=9.1 Hz).

Reference Example 37-1

[0626] ##STR00100##

1-((3S*,4W,Z)-2-{[(tert-Butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea

[0627] Using benzyl ((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl )carbamate instead of benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate, the same method as in Example 7-1 was performed to obtain the title compound.

[0628] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 3.17 (1H, t, J=8.8 Hz), 3.28-3.37 (1H, m), 3.53 (1H, t, J=8.5 Hz), 3.71 (3H, s), 4.74 (1H, t, J=9.1 Hz), 6.34 (1H, d, J=9.1 Hz), 6.56 (1H, s), 6.86 (2H, d, J=8.5 Hz), 7.00-7.04 (2H, m), 7.27 (2H, d, J=8.5 Hz), 7.30-7.34 (2H, m), 8.45 (1H, s).

Reference Example 38-1

[0629] ##STR00101##

()-1-(4-Fluorophenyl)-3-[(3S*,4W,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea

[0630] To a solution of 1-((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea (290 mg) in 1,4-dioxane (1.5 mL) were added water (1.35 mL) and trifluoroacetic acid (135 L) to produce a reaction solution. The reaction solution was stirred at room temperature for 30 minutes. To the reaction solution under ice-cooling was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with diisopropyl ether to obtain the title compound as a white solid (212 mg).

[0631] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.19 (1H, t, J=9.1 Hz), 3.30 (1H, q, J=8.7 Hz), 3.55 (1H, t, J=8.2 Hz), 3.76 (3H, s), 4.80 (1H, t, J=9.4 Hz), 6.37 (1H, d, J=9.1 Hz), 6.43 (1H, s), 6.92 (2H, d, J=8.5 Hz), 7.04-7.10 (2H, m), 7.32 (2H, d, J=8.5 Hz), 7.36-7.40 (2H, m), 8.49 (1H, s), 8.89 (1H, s).

[0632] MS (ESI+) m/z: 359 (MH.sup.+).

Reference Example 39-1

[0633] ##STR00102##

Ethyl 3-((Z)-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]pyrrolidin-2-ylidene}amino)propionate

[0634] Using ethyl 3-((Z)-{(3S*,4R*)-3-[(benzyloxycarbonyl)amino]-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-ylidene}amino)propionate instead of benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate, the same method as in Example 7-1 was performed to obtain the title compound.

[0635] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.17 (3H, t, J=7.3 Hz), 2.65 (2H, t, J=7.3 Hz), 3.42-3.53 (2H, m), 3.57-3.66 (1H, m), 3.75 (3H, s), 3.86-3.93 (1H, m), 3.97-4.10 (3H, m), 5.18 (1H, t, J=8.6 Hz), 6.70 (1H, d, J=8.6 Hz), 6.77 (2H, d, J=11.0 Hz), 7.04 (2H, t, J=8.6 Hz), 7.33-7.37 (2H, m), 8.99 (1H, s).

Example 1-1

[0636] ##STR00103##

()-cis-1-(4-Chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea

[0637] Under an argon atmosphere, to a solution of ()-cis-4-(4-methoxyphenyl)tetrahydrofuran-3-carboxylic acid (447 mg) in toluene (6.7 mL) were added triethylamine (336 L) and diphenylphosphoryl azide (476 L) to produce a reaction solution. The reaction solution was stirred at room temperature for 2 hours and then at 100 C. for 30 minutes. The reaction solution was allowed to cool to room temperature, then 4-chloroaniline (256 mg) was added thereto, and the reaction mixture was heated to reflux for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:20) to obtain a crude product, and the crude product was washed with diisopropyl ether to obtain the title compound as a white solid (502 mg).

[0638] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.49-3.59 (2H, m), 3.70 (3H, s), 3.89 (1H, t, J=7.9 Hz), 4.00 (1H, dd, J=8.5, 6.1 Hz), 4.15 (1H, t, J=8.5 Hz), 4.51-4.57 (1H, m), 5.89 (1H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=9.1 Hz), 7.28 (2H, d, J=9.1 Hz), 8.43 (1H, s).

[0639] MS (ESI+) m/z: 347 (MH).sup.+.

[0640] The following Examples 1-2 to 1-11 were obtained using each corresponding aromatic amine in the same method as in Example 1-1.

[0641] The structures and spectral data thereof are shown in Tables 13 to 16.

TABLE-US-00013 TABLE 13 Ex. No Str. Chemical name P.D. 1-2 [00104] ()-cis-1-(3- fluorophenyl)-3-[4- (4-methoxy- phenyl)tetrahydro- furan-3-yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.49-3.60 (2H, m), 3.69 (3H, s), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.01 (1H, dd, J = 8.6, 5.5 Hz), 4.15 (1H, dd, J = 8.6, 7.3 Hz), 4.50-4.58 (1H, m), 5.94 (1H, d, J = 8.6 Hz), 6.66 (1H, td, J = 8.6, 2.4 Hz), 6.87 (3H, d, J = 8.6 Hz), 7.13-7.23 (3H, m), 7.33 (1H, dt, J = 12.2, 2.4 Hz), 8.52 (1H, s) MS (ESI+) m/z: 331 (MH.sup.+) 1-3 [00105] ()-cis-1-(2- fluorophenyl)-3-[4- (4-methoxy- phenyl)tetrahydro- furan-3-yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.48-3.60 (2H, m), 3.69 (3H, s), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.00 (1H, dd, J = 8.6, 5.8 Hz), 4.15 (1H, dd, J = 8.6, 7.3 Hz), 4.50-4.59 (1H, m), 5.94 (1H, d, J = 8.6 Hz), 6.66 (1H, td, J = 8.6, 1.8 Hz), 6.87 (3H, d, J = 8.6 Hz), 7.12-7.22 (3H, m), 7.33 (1H, dt, J = 12.2, 2.4 Hz), 8.52 (1H, s) MS (ESI+) m/z: 331 (MH.sup.+) 1-4 [00106] ()-cis-1-(2,4- difluorophenyl)-3- [4-(4-methoxy- phenyl)tetrahydro- furan-3-yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.47-3.59 (2H, m), 3.69 (3H, s), 3.88 (1H, dd, J = 8.6, 7.9 Hz), 4.00 (1H, dd, J = 8.6, 6.1 Hz), 4.16 (1H, dd, J = 8.6, 7.3 Hz), 4.51-4.58 (1H, m), 6.40 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.90-6.96 (1H, m), 7.14 (2H, d, J = 8.6 Hz), 7.17-7.22 (1H, m), 7.95 (1H, td, J = 9.2, 6.1 Hz), 8.15 (1H, d, J = 1.8 Hz) MS (ESI+) m/z: 349 (MH.sup.+)

TABLE-US-00014 TABLE 14 Ex. No Str. Chemical name P.D. 1-5 [00107] ()-cis-1-(3,4- difluorophenyl)-3- [4-(4-methoxy- phenyl)tetrahydro- furan-3-yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.49-3.59 (2H, m), 3.70 (3H, s), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.00 (1H, dd, J = 8.6, 6.1 Hz), 4.14 (1H, dd, J = 8.6, 7.3 Hz), 4.49-4.58 (1H, m), 5.93 (1H, d, J = 8.6 Hz), 6.87 (3H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.22 (1H, dt, J = 11.0, 9.2 Hz), 7.49 (1H, ddd, J = 13.4, 7.3, 2.4 Hz), 8.50 (1H, s) MS (ESI+) m/z: 349 (MH.sup.) 1-6 [00108] ()-cis-1-(4- cyanophenyl)-3-[4- (4-methoxyphenyl)- tetrahydrofuran-3- yl]urea 1H-NMR (400 MHz, DMSO- d.sub.6) : 3.50-3.62 (2H, m), 3.69 (3H, s), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.01 (1H, dd, J = 8.6, 5.8 Hz), 4.16 (1H, dd, J = 8.6, 7.3 Hz), 4.51-4.59 (1H, m), 6.10 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.81 (1H, s) MS (ESI+) m/z: 338 (MH.sup.+) 1-7 [00109] ()-cis-1-(5- chlorothiophen-2- yl)-3-[4-(4- methoxyphenyl)- tetrahydrofuran-3- yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.49-3.60 (2H, m), 3.70 (3H, s), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.00 (1H, dd, J = 8.6, 6.1 Hz), 4.13 (1H, dd, J = 8.6, 7.3 Hz), 4.47-4.56 (1H, m), 5.99 (1H, d, J = 8.6 Hz), 6.12 (1H, d, J = 3.7 Hz), 6.70 (1H, d, J = 3.7 Hz), 6.87 (2H, d, J = 9.2 Hz), 7.13 (2H, d, J = 9.2 Hz), 9.38 (1H, s) MS (ESI) m/z: 353 (MH.sup.)

TABLE-US-00015 TABLE 15 Ex. No Str. Chemical name P.D. 1-8 [00110] ()-cis-1-[4-(2,6- difluoro-4- methoxyphenyl)- tetrahydrofuran-3- yl]-3-(4- fluorophenyl)urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.54 (1H, dd, J = 9.2, 4.9 Hz), 3.69 (3H, s), 3.76 (1H, q, J = 8.4 Hz), 3.98 (1H, t, J = 8.9 Hz), 4.04-4.12 (2H, m), 4.51-4.60 (1H, m), 6.04 (1H, d, J = 9.2 Hz), 6.66 (2H, d, J = 10.4 Hz), 6.98 (2H, t, J = 9.2 Hz), 7.14-7.21 (2H, m), 8.36 (1H, s) MS (ESI+) m/z: 367 (MH.sup.+) 1-9 [00111] ()-trans-1-(4- chlorophenyl)-3- [4-(4-methoxy- phenyl)tetrahydro- furan-3-yl]urea .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.21 (1H, m), 3.51 (1H, dd, J = 8.6, 5.5 Hz), 3.66 (1H, t, J = 8.0 Hz), 3.71 (3H, s), 4.02-4.15 (2H, m), 4.18- 4.24 (1H, m), 6.57 (1H, d, J = 7.3 Hz), 6.88 (2H, d, J = 9.2 Hz), 7.20-7.26 (4H, m), 7.34 (2H, d, J = 9.2 Hz), 8.51 (1H, s) MS (ESI+) m/z: 347 (MH.sup.+) 1-10 [00112] ()-1-(4-chloro- phenyl)-3-[4-(4- methoxyphenyl)- 1,1-dioxide- terrahydro- thiophen-3-yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.10 (1H, ddd, J = 13.3, 6.7, 1.2 Hz), 3.31 (1H, dd, J = 13.3, 9.7 Hz), 3.52-3.59 (1H, m), 3.63-3.71 (1H, m), 3.74-3.80 (1H, m), 3.81 (3H, s), 4.57-4.66 (1H, m), 5.14 (1H, d, J = 6.7 Hz), 6.43 (1H, s), 6.91 (2H, d, J = 9.1 Hz), 7.16 (2H, d, J = 9.1 Hz), 7.22-7.27 (4H, m) MS (ESI+) m/z: 395 (MH.sup.)

TABLE-US-00016 TABLE 16 Ex. No Str. Chemical name P.D. 1-11 [00113] ()-trans-1-(4- chlorophenyl)-3- [4-(4-methoxy- phenyl)-2- oxopiperidin-3- yl]urea 1H-NMR (400 MHz, DMSO-d.sub.6) : 1.80- 1.89 (1H, m), 1.95-2.06 (1H, m), 3.14-3.30 (3H, m), 3.69 (3H, s), 4.13 (1H, dd, J = 12.1, 8.5 Hz), 6.17 (1H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.60 (1H, s), 8.52 (1H, s) MS (ESI+) m/z: 374 (MH.sup.+)

Example 2-1

[0642] ##STR00114##

(+)-cis-1-(4Chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea

()-cis-1-(4Chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea

[0643] ()-cis-1-(4Chlorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea that was obtained in Example 1-1 was subjected to optical resolution by high performance liquid chromatography (methyl tert-butyl ether : ethanol : hexane=65:3:32, flow rate: 20.0 mL) using a column for separation of enantiomers (CHIRALPAK ID) to obtain the title compounds of two isomers as a white solid: Isomer A (+) with a retention time of 26.20 minutes, and Isomer B () with a retention time of 41.76 minutes.

[0644] Isomer A (+):

[0645] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.49-3.59 (2H, m), 3.70 (3H, s), 3.89 (1H, t, J=7.9 Hz), 4.00 (1H, dd, J=8.5, 6.1 Hz), 4.15 (1H, t, J=8.5 Hz), 4.51-4.57 (1H, m), 5.89 (1H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=9.1 Hz), 7.28 (2H, d, J=9.1 Hz), 8.43 (1H, s).

[0646] MS (ESI+) m/z: 347 (MH).sup.+.

[0647] [].sub.D.sup.24+130 (c 0.35, EtOH).

[0648] Isomer B ():

[0649] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.49-3.59 (2H, m), 3.70 (3H, s), 3.89 (1H, t, J=7.9 Hz), 4.00 (1H, dd, J=8.5, 6.1 Hz), 4.15 (1H, t, J=8.5 Hz), 4.51-4.57 (1H, m), 5.89 (1H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=9.1 Hz), 7.28 (2H, d, J=9.1 Hz), 8.43 (1H, s).

[0650] MS (ESI+) m/z: 347 (MH).sup.+.

[0651] [].sub.D.sup.24129 (c 0.35, EtOH).

Example 3-1

[0652] ##STR00115##

(+)-cis-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea

()-cis-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea

[0653] ()-cis-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)tetrahydrofuran-3-yl]urea that was obtained in the same method as in Example 1-1 using 4-fluoroaniline instead of 4-chloroaniline was subjected to optical resolution by high performance liquid chromatography (methyl tert-butyl ether : ethanol=95 : 5, flow rate: 20.0 mL) using a column for separation of enantiomers (CHIRALPAK ID) to obtain the title compounds of two isomers as a white solid: Isomer A (+) with a retention time of 11.44 minutes, and Isomer B () with a retention time of 14.50 minutes.

[0654] Isomer A (+):

[0655] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.49-3.58 (2H, m), 3.70 (3H, s), 3.89 (1H, dd, J=8.5, 7.3 Hz), 4.00 (1H, dd, J=8.5, 6.1 Hz), 4.15 (1H, dd, J=8.5, 7.3 Hz), 4.50-4.57 (1H, m), 5.82 (1H, d, J=9.1 Hz), 6.87 (2H, d, J=9.1 Hz), 6.96-7.03 (2H, m), 7.15 (2H, d, J=9.1 Hz), 7.22-7.28 (2H, m), 8.32 (1H, s).

[0656] MS (ESI+) m/z: 331 (MH).sup.+.

[0657] [].sub.D.sup.24+101 (c 0.35, EtOH).

[0658] Isomer B ():

[0659] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 3.49-3.58 (2H, m), 3.70 (3H, s), 3.89 (1H, dd, J=8.5, 7.3 Hz), 4.00 (1H, dd, J=8.5, 6.1 Hz), 4.15 (1H, dd, J=8.5, 7.3 Hz), 4.50-4.57 (1H, m), 5.82 (1H, d, J=9.1 Hz), 6.87 (2H, d, J=9.1 Hz), 6.96-7.03 (2H, m), 7.15 (2H, d, J=9.1 Hz), 7.22-7.28 (2H, m), 8.32 (1H, s). MS (ESI+) m/z: 331 (MH).sup.+.

[0660] [].sub.D.sup.24104 (c 0.35, EtOH).

Example 4-1

[0661] ##STR00116##

(+)-cis-1-(4-Fluorophenyl)3-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-yl]urea

()-cis-1-(4-Fluorophenyl)3-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-yl]urea

[0662] ()-cis-1-(4-Fluorophenyl)3-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-yl]urea that was obtained in the same method as in Example 1-1 using ()-cis-4-(4-methoxyphenyl)-2,2-dimethyltetrahydrofuran-3-carboxylic acid instead of ()-cis-4-(4-methoxyphenyl)tetrahydrofuran-3-carboxylic acid was subjected to optical resolution by high performance liquid chromatography (ethanol : hexane=20:80, flow rate: 10.0 mL) using a column for separation of enantiomers (CHIRALPAK IA) to obtain the title compounds of two isomers as a white solid: Isomer A (+) with a retention time of 12 minutes, and Isomer B ()with a retention time of 14 minutes.

[0663] Isomer A (+):

[0664] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 1.09 (3H, s), 1.28 (3H, s), 3.69 (3H, s), 3.73-3.81 (1H, m), 3.89 (1H, t, J=8.8 Hz), 4.12 (1H, dd, J=8.8, 7.3 Hz), 4.27 (1H, dd, J=10.3, 6.7 Hz), 5.86 (1H, d, J=10.3 Hz), 6.85 (2H, d, J=8.5 Hz), 6.96-7.03 (2H, m), 7.15 (2H, d, J=8.5 Hz), 7.24-7.28 (2H, m), 8.32 (1H, s).

[0665] MS (FD+) m/z: 358 (M).sup.+.

[0666] [].sub.D.sup.24+102 (c 0.33, EtOH).

[0667] Isomer B ():

[0668] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8 1.09 (3H, s), 1.28 (3H, s), 3.69 (3H, s), 3.73-3.81 (1H, m), 3.89 (1H, t, J=8.8 Hz), 4.12 (1H, dd, J=8.8, 7.3 Hz), 4.27 (1H, dd, J=10.3, 6.7 Hz), 5.86 (1H, d, J=10.3 Hz), 6.85 (2H, d, J=8.5 Hz), 6.96-7.03 (2H, m), 7.15 (2H, d, J=8.5 Hz), 7.24-7.28 (2H, m), 8.32 (1H, s).

[0669] MS (FD+) m/z: 358 (M).sup.+.

[0670] [].sub.D.sup.24103 (c 0.37, EtOH).

Example 5-1

[0671] ##STR00117##

()-cis-1-[4-(4-Chlorophenyl)tetrahydrofuran-3-yl]-3-(4-fluorophenyl)urea

[0672] Under an argon atmosphere, to a solution of ()-cis-4-(4-chlorophenyl)tetrahydrofuran-3-amine (200 mg) in tetrahydrofuran (5 mL) under ice-cooling was added 4-fluorophenyl isocyanate (0.115 mL) to produce a reaction solution. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound as a white solid (270 mg).

[0673] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 8 3.53-3.62 (2H, m), 3.91 (1H, dd, J=8.5, 7.3 Hz), 4.02 (1H, dd, J=8.5, 6.7 Hz), 4.16 (1H, dd, J=8.5, 7.3 Hz), 4.55-4.64 (1H, m), 5.91 (1H, d, J=8.5 Hz), 7.00 (2H, t, J=8.5 Hz), 7.20-7.27 (4H, m), 7.36(2H, d, J=8.5 Hz), 8.24 (1H, s).

[0674] MS (ESI+) m/z: 335 (MH).sup.+.

[0675] The following Examples 5-2 to 5-4 were obtained using each corresponding aromatic amine in the same method as in Example 5-1.

[0676] The structures and spectral data thereof are shown in Table 17.

TABLE-US-00017 TABLE 17 Ex. No Str. Chemical name P.D. 5-2 [00118] ()-cis-1-[4-(4- fluorophenyl)- tetrahydrofuran-3- yl]-3-(4- fluorophenyl)urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.53-3.62 (2H, m), 3.89 (1H, dd, J = 8.6, 7.3 Hz), 4.00 (1H, dd, J = 8.6, 6.1 Hz), 4.14 (1H, dd, J = 8.6, 7.3 Hz), 4.52-4.61 (1H, m), 5.91 (1H, d, J = 8.6 Hz), 6.99 (2H, t, J = 8.6 Hz), 7.11 (2H, t, J = 8.6 Hz), 7.20-7.27 (4H, m), 8.23 (1H, s) MS (ESI+) m/z: 319 (MH.sup.+) 5-3 [00119] ()-cis-1-[4-(4- cyanophenyl)tetra- hydrofuran-3-yl]-3- (4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.59 (1H, dd, J = 8.6, 4.3 Hz), 3.70 (1H, q, J = 7.3 Hz), 3.95 (1H, dd, J = 8.6, 7.3 Hz), 4.03 (1H, dd, J = 8.6, 6.1 Hz), 4.17 (1H, dd, J = 8.6, 7.3 Hz), 4.61-4.69 (1H, m), 6.02 (1H, d, J = 8.6 Hz), 7.00 (2H, t, J = 9.2 Hz), 7.18-7.25 (2H, m), 7.43 (2H, d, J = 7.9 Hz), 7.77 (2H, d, J = 8.6 Hz), 8.18 (1H, s) MS (ESI+) m/z: 326 (MH.sup.+) 5-4 [00120] ()-1-(4-chloro- phenyl)-3-[4-(4- methoxyphenyl)-2- oxooxazolidin-3- yl]urea .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 3.72 (3H, s), 4.09 (1H, s), 4.70 (1H, t, J = 8.5 Hz), 5.02 (1H, s), 6.93 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.43 (4H, d, J = 8.5 Hz), 8.51 (1H, s), 8.89 (1H, s). MS (ESI+) m/z: 362 (MH.sup.+)

Example 6-1

[0677] ##STR00121##

()-trans-1-(4-Fluorophenyl)-3-[3-(4-methoxyphenyl)-5-oxopyrrolidin-2-yl]urea

[0678] To a solution of tert-butyl ()-trans-[43-(4-methoxyphenyl)-5-oxopyrrolidin-2-yl]carbamate (30 mg) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) to produce a reaction solution. The reaction solution was stirred under ice-cooling for 1.5 hours. The reaction solution was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the pH in the aqueous layer thereof was adjusted to 9. To the bilayer solution was added 4-fluorophenyl isocyanate (20 L), and the reaction mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate:hexane=4:1-ethyl acetate-ethyl acetate : methanol=95:5) to obtain the title compound as a white solid (26 mg).

[0679] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 2.33 (1H, dd, J=16.5, 9.2 Hz), 2.61 (1H, dd, J=16.5, 9.2 Hz), 3.22-3.35 (1H, m), 3.71 (3H, s), 5.24 (1H, t, J=9.2 Hz), 6.84-6.94 (3H, m), 7.04 (2H, t, J=8.9 Hz), 7.24 (2H, d, J=8. 6 Hz), 7.37 (2H, dd, J=9.2, 5.5 Hz), 8.18 (1H, s), 8.52 (1H, s).

Example 7-1

[0680] ##STR00122##

()-1-[(6R*,7S*)-6-(2,6-Difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-3-(4-fluorophenyl)urea

[0681] To a solution of benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate (10 mg) in ethanol (0.5 mL) was added 10% palladium carbon (2 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered over Celite, and the solvent of the filtrate was removed to obtain (6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-amine that is an intermediate compound as a colorless oil. To a solution of the obtained (6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-amine (7.3 mg) in tetrahydrofuran (0.5 mL) was added 4-fluorophenyl isocyanate (2.7 L) to produce a reaction solution. The reaction solution was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=4:1-ethyl acetate) to obtain the title compound as a white solid (5.4 mg).

[0682] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 2.32 (3H, s), 3.77 (3H, s), 3.91 (1H, dd, J=10.4, 8.6 Hz), 4.31-4.46 (2H, m), 5.38 (1H, t, J=7.9 Hz), 6.79 (2H, d, J=11.0 Hz), 6.88-6.95 (1H, m), 7.03 (2H, t, J=9.2 Hz), 7.32-7.37 (2H, m), 8.85 (1H, s).

[0683] MS (ESI+) m/z: 418 (MH).sup.+.

[0684] [].sub.D.sup.2779 (c 0.20, EtOH).

[0685] The following Examples 7-2 to 7-7 were obtained using each corresponding Cbz compound in the same method as in Example 7-1.

[0686] The structures and spectral data thereof are shown in Tables 18 and 19.

TABLE-US-00018 TABLE 18 Ex. No Str. Chemical name P.D. 7-2 [00123] ()-1-[(6R*,7S*)-6- (2,6-difluoro-4- methoxyphenyl)- 6,7-dihydro-5H- pyrrolo[1,2- a]imidazol-7-yl]- 3-(4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.78 (3H, s), 3.93 (1H, dd, J = 10.4, 8.6 Hz), 4.22 (1H, q, J = 8.6 Hz), 4.43 (1H, t, J = 10.4 Hz), 5.30 (1H, t, J = 7.9 Hz), 6.74- 6.83 (3H, m), 7.00 (1H, s), 7.04 (2H, t, J = 8.6 Hz), 7.16 (1H, s), 7.31- 7.38 (2H, m), 8.67 (1H, s) MS (ESI+) m/z; 403 (MH.sup.+) [].sub.D.sup.29 121 (c 0.098, EtOH) 7-3 [00124] ()-1-(4-fluoro- phenyl)-3- [(6R*,7S*)-6-(4- methoxyphenyl)- 6,7-dihydro-5H- pyrrolo[1,2- d]tetrazol-7- yl]urea 1H-NMR (400 MHz, DMSO-d.sub.6) : 3.74 (3H, s), 4.28-4.41 (2H, m), 4.86 (1H, dd, J = 9.7, 7.3 Hz), 5.50 (1H, dd, J = 9.1, 9.1 Hz), 6.90-6.95 (3H, m), 7.04 (2H, m), 7.37 (2H, m), 7.43 (2H, d, J = 8.5 Hz), 8.83 (1H, s) MS (ESI+) m/z: 369 (MH.sup.+) [].sub.D.sup.28.5 183 (c 0.311, EtOH) 7-4 [00125] ()-1-[(6R*,7S*)-6- (2,6-difluoro-4- methoxyphenyl)- 6,7-dihydro-5H- pyrrolo[1,2- d]tetrazol-7-yl]- 3-(4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.77 (3H, s), 4.36 (1H, dd, J = 11.6, 7.9 Hz), 4.64-4.72 (1H, m), 4.89 (1H, J = 11.6 Hz), 5.42 (1H, t, J = 7.9 Hz), 6.81 (2H, d, J = 10.4 Hz), 6.99- 7.07 (3H, m), 7.30- 7.36 (2H, m), 9.10 (1H, s) MS (ESI+) m/z: 405 (MH.sup.+) [].sub.D.sup.29 51 (c 0.067, EtOH

TABLE-US-00019 TABLE 19 Ex. No Str. Chemical name P.D. 7-5 [00126] ()-1-[(6R*,7S*)-6- (6-fluoro-2,3- dihydrobenzofuran- 5-yl)-6,7-dihydro- 5H-pyrrolo[1,2- d]tetrazol-7-yl]- 3-(4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, CDCl.sub.3) : 3.18 (2H, t, J = 8.9 Hz), 4.35 (1H, dd, J = 11.0, 7.9 Hz), 4.55-4.60 (1H, m), 4.63 (2H, t, J = 8.9 Hz), 4.83-4.89 (1H, m), 5.38 (1H, t, J = 7.6 Hz), 6.49 (1H, d, J = 7.3 Hz), 6.56 (1H, d, J = 11.0 Hz), 6.78-6.83 (2H, m), 7.09-7.14 (3H, m), 7.33 (1H, s) MS (ESI+) m/z: 399 (MH.sup.+) [].sub.D.sup.24 107 (c 0.15, EtOH) 7-6 [00127] ()-1-[(7R*,8S*)-7- (2,6-difluoro-4- methoxyphenyl)- 2,3,4,6,7,8- hexahydropyrrolo [1,2-a]pyrimidin-8- yl]-3-(4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.19- 1.31 (2H, m), 1.66- 1.79 (2H, m), 3.15- 3.60 (5H, m), 3.76 (3H, s), 4.84-4.86 (1H, m), 6.24- 6.43 (1H, m), 6.73 (2H, d, J = 11 Hz), 7.02 (2H, t, J = 8.6 Hz), 7.26-7.34 (2H, m), 8.75 (1H, s) MS (ESI+) m/z: 419 (MH.sup.+) [].sub.D.sup.29 261 (c 0.12, EtOH) 7-7 [00128] 1-[(7R*,8S*)-7- (2,6-difluoro-4- methoxyphenyl)- 4,6,7,8- tetrahydro-3H- pyrrolo[2,1- c][1,2,4]- oxadiazin-8-yl]-3- (4-fluoro- phenyl)urea .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.35- 3.38 (3H, m), 3.55 (1H, t, J = 9.1 Hz), 3.61-3.70 (2H, m), 3.75 (3H, s), 3.83-3.90 (1H, m), 5.13 (1H, t, J = 9.4 Hz), 6.55 (1H, d, J = 7.9 Hz), 6.73 (2H, d, J = 10.9 Hz), 7.00 (2H, t, J = 9.1 Hz), 7.27-7.33 (2H, m), 8.62 (1H, s) MS (ESI+) m/z: 421 (MH.sup.+)

Example 8-1

[0687] ##STR00129##

()-1-[(7R*,8S*)-7-(2,6-Difluoro-4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]-3-(4-fluorophenyl)urea

[0688] Using ethyl 2-(((Z)-{(3S*,4R*)-3-[(benzyloxycarbonyl)amino]-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-ylidene}amino)oxy)acetate instead of benzyl [(6R*,7S*)-6-(2,6-difluoro-4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]carbamate, the same method as in Example 7-1 was performed to obtain the title compound.

[0689] .sup.1H NMR (400 MHz, CDCl.sub.3) : 3.77 (3H, s), 3.78-3.86 (2H, m), 4.06-4.18 (2H, m), 4.25-4.34 (1H, m), 5.03-5.10 (1H, m), 6.47 (2H, d, J=10.4 Hz), 6.88-6.96 (2H, m), 7.34-7.40 (2H, m), 7.70 (1H, d, J=2.4 Hz), 8.69 (1H, s).

[0690] MS (ESI+) m/z: 435 (MH.sup.+).

[0691] [].sub.D.sup.2589 (c 0.12, EtOH).

Example 9-1

[0692] ##STR00130##

()-1-[(7R*,8S*)-7-(2,6-Difluoro-4-methoxyphenyl)-4-oxo-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidin-8-yl]-3-(4-fluorophenyl)urea

[0693] To a solution of ethyl 3-((Z)-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]pyrrolidin-2-ylidene}amino)propionate (12 mg) in N,N-dimethylformamide (0.3 mL) was added cesium carbonate (9.8 mg), and the mixture was stirred at room temperature for a day. To the reaction solution was added ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with diisopropyl ether to obtain the title compound as a white solid (10 mg).

[0694] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 2.51-2.59 (2H, m), 3.70-3.74 (4H, m), 3.75 (3H, s), 4.12 (1H, d, J=9.2 Hz), 5.22 (1H, s), 6.50 (2H, d, J=10.4 Hz), 6.88-6.96 (2H, m), 7.13-7.21 (2H, m).

[0695] MS (ESI+) m/z: 433 (MH).sup.+.

[0696] [].sub.D.sup.25108 (c 0.10, EtOH).

Example 10-1

[0697] ##STR00131##

1-(4-Fluorophenyl)-3-[(7R*,8S*)-7-(4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]oxadiazin-8-yl]urea

[0698] To a solution of ()-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea (84 mg) in N,N-dimethylformamide (0.6 mL) was added cesium carbonate (91 mg) to produce a reaction solution. The reaction solution was stirred at room temperature for 30 minutes. Then, ethyl bromoacetate (31 L) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 1 day. To the reaction solution was added ethyl acetate. The organic layer was washed with water and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with diisopropyl ether to obtain the title compound as a white solid (59 mg).

[0699] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.44-3.58 (2H, m), 3.72 (3H, s), 4.11 (1H, m), 4.21 (1H, d, J=15.7 Hz), 4.44 (1H, d, J=15.7 Hz), 5.30 (1H, m), 6.64 (1H, d, J=9.1 Hz), 6.91 (2H, d, J=9.1 Hz), 7.03 (2H, m), 7.31-7.37 (4H, m), 8.65 (1H, s).

[0700] MS (ESI+) m/z: 399 (MH).sup.+.

[0701] Next, results in support of utility of the compound of the present invention will be shown with reference to Test Examples.

Test Example 1

[0702] Measurement test of agonist activity on human FPRL1

[0703] (1-1) Construction of Human FPRL1 Expression Vector

[0704] Human FPRL (SEQ ID NO: 3) was amplified in a PCR reaction from cDNA derived from a monocytic leukemia cell line THP-1 (TIB-202, ATCC) as a template using a forward primer shown in SEQ ID NO: 1, a reverse primer shown in SEQ ID NO: 2, and KOD-plus-ver. 2 (KOD-211, TOYOBO CO., LTD.). The amplified PCR product and pCMV-script vector (212220, STRATAGENE) were digested with Hind III (1060A, Takara Bio Inc.) and XhoI (1094A, Takara Bio Inc.), and the resultant digest was ligated with Ligation high ver. 2 (LGK-201, TOYOBO CO., LTD.). The ligation product was transformed into DH5 (DNA-901, TOYOBO CO., LTD.), cultured on a 100 g/mL kanamycin-containing LB medium, and purified with HiSpeed Plasmid Maxi Kit (12662, QIAGEN).

[0705] (1-2) Construction of Human G15 Expression Vector

[0706] Human G15 (SEQ ID NO: 6) was amplified in a PCR reaction from cDNA derived from a myeloid leukemia cell line HL-60 (CCL-240, ATCC) as a template using a forward primer shown in SEQ ID NO: 4, a reverse primer shown in SEQ ID NO: 5, and KOD-plus-ver. 2. The amplified PCR product and pCMV-script vector were digested with Hind III and XhoI, and the resultant digest was ligated with Ligation high ver. 2. The ligation product was transformed into DH5, cultured on a 100 g/mL kanamycin-containing LB medium, and purified with HiSpeed Plasmid Maxi Kit.

[0707] (2-1) Method for Culturing and Subculturing HEK293

[0708] HEK293 (JCRB9068, NIBIO) was cultured in an incubator at 5% CO.sub.2 and 37 C. using DMEM (11885-092, GIBCO) containing 10% FBS and 1cPenicillin-Streptomycin (15140-122, GIBCO). Subculture was carried out as followings: The cells that reached 80 to 90% confluency were washed with PBS(), separated using 0.25% Trypsin-EDTA (25200-072, GIBCO), centrifuged, resuspended in a fresh medium, and then seeded in Collagen Type 1 Coated dish (4020-010, IWAKI) at a split ratio of 1:8 (cultured for 3 days).

[0709] (2-2) Introduction of Human FPRL1 and Gal5 Expression Vectors

[0710] HEK293 that reached 80 to 90% confluency was washed with PBS(), separated using 0.25% Trypsin-EDTA, centrifuged, and re-suspended in a fresh medium excluding 1Penicillin-Streptomycin. The cells were inoculated in a Collagen Type 1 coated 6-well plate (4810-010, IWAKI) to 510.sup.5 cells/2.5 mL/well and cultured overnight. On the next day, human FPRL1 and G15 expression vectors were introduced using Lipofectamine 2000 transfection reagent (11668-019, Life technologies). First, the human FPRL1 and Gal5 expression vectors were diluted with Opti-MEM I Reduced Serum Medium (31985-070, GIBCO) to 2 g/250 L/well and Lipofectamine 2000 transfection reagent was diluted with Opti-MEM I Reduced Serum Medium to be 4 L/250 L/well. The vectors and reagent were softly diffused, and incubated at room temperature for 5 minutes. The vector solution was mixed with Lipofectamine 2000 transfection reagent in equal amounts. In order to form a complex of the vectors and Lipofectamine 2000 transfection reagent, the mixture was incubated at room temperature for 20 minutes, and added at 500 L/well to the medium of inoculated cells. The treated cells were cultured for 24 hours, inoculated in Poly-D-Lysine coated 96-well plate (356640, BD Biosciences) at a cell density of 710.sup.4 cells/100 L/well, and cultured for another 24 hours. The resultant cells were used in a measurement test of calcium mobilization in the cells.

[0711] (3) Evaluation of Agonist Activity on Human FPRL1 (Test of Calcium Mobilization in Cell)

[0712] An appropriate amount of each test compound was first weighed, and dissolved to 10.sup.2 M by addition of dimethyl sulfoxide (DMSO). For calculation of an EC.sub.50 value for agonist activity, each compound solution was serially diluted with DMSO by 10-fold increments to make eight solutions having a concentration of 10.sup.2 M to 10.sup.9 M. The formed compound solution having each concentration was diluted 100 times with an assay buffer that was contained in Fluo-4 NW Calcium Assay Kit (F36206, Life technologies), and dispensed in an amount of 100 L into a 96-well plate with a V-bottom shape. The plate dispensed with compound solutions was set in Flexstation (Molecular Devices, LLC.) until measurement.

[0713] Subsequently, 10 mL of assay buffer and 100 L of probenecid solution (dissolved by addition of 1 mL of assay buffer to a 250 mM stock) were sufficiently mixed and dissolved in Fluo-4 NW dye mix. The medium of cells inoculated on the previous day was removed, the dissolved Fluo-4 NW dye mix was added in an amount of 90 L/well, and a reaction was caused in the dark at 37 C. for 45 minutes. The cells after the reaction and chips for addition of the compound were set in Flexstation, and variation in fluorescence intensity over time after addition of the compound was measured [amount of added compound=10 L (final concentration: 10.sup.5 M to 10.sup.12 M), excitation wavelength: 485 nm, measured wavelength: 525 nm, 1.5 sec54 read]. A value was calculated by subtracting a base value during addition of DMSO from the maximum value of relative fluorescence unit, and analyzed. All the measurement data were analyzed with Prism 4 that was a data analysis tool. As an EC.sub.50 value, a molar concentration that resulted in 50% maximum activation was calculated. The EC.sub.50 values of the resultant test compounds are shown in Table I.

TABLE-US-00020 TABLE I Compound to be tested Efficacy EC.sub.50 (nM) Example 1-1 0.25 Example 1-5 12 Example 1-6 10 Example 1-7 5.2 Example 1-8 3.78 Example 1-9 2.3 Example 1-10 0.29 Example 1-11 0.11 Example 2-1 Isomer A 0.54 Example 3-1 Isomer A 0.62 Example 5-1 14 Example 5-4 2.6 Example 6-1 5.6 Example 7-1 0.05 Example 7-2 0.25 Example 7-3 0.6 Example 7-4 0.36 Example 7-5 2.5 Example 7-6 0.97 Example 7-7 0.02 Example 8-1 0.03 Example 9-1 0.03 Example 10-1 0.29

[0714] As seen from Table I, the compounds (I) of the present invention or pharmacologically acceptable salts thereof show a superior FPRL1 agonist effect.

Test Example 2

[0715] Effect of lipopolysaccharide induction on neutrophilic infiltration in mouse lung A compound to be tested was orally administrated to a mouse (BALB/c, male), and after 30 minutes, the mouse was placed in a plastic container. Lipopolysaccharide (0.3 mg/mL) dissolved in physiological saline was aerosolized with an ultrasonic wave nebulizer (NE-U17, OMRON Corporation), and exposed to the mouse for 10 minutes. After 5 hours, the anesthetized mouse was sacrificed by exsanguination. A cannula was inserted in the respiratory tract and bronchoalveolar lavage (BAL) with 1 mL of 0.85% NaCl liquid containing 0.4% sodium citrate was carried out. This operation was repeated 3 times, to obtain a BAL fluid. The BAL fluid was centrifuged at 4 C. and 200 g for 5 minutes, and the pellet was suspended in a physiological saline containing 0.1% BSA. The number of white blood cells was counted using Turks solution with a microscope, and the total white blood cell count was calculated. The white blood cells were fixed on a glass slide using Cytospin 3 (Thermo BioAnalysis Japan K. K.). The cells were stained with Diff-Quik (SYSMEX INTERNATIONAL REAGENTS CO., LTD.), and the number thereof was counted with a microscope, and the neutrophil ratio was calculated. The neutrophil ratio was multiplied by the total white blood cell count to calculate the total neutrophil count. An effect of the compound to be tested represents a percentage (%) of suppression ratio relative to the neutrophil count in a control. The suppression ratios of the resultant test compounds are shown in Table II.

TABLE-US-00021 TABLE II Compound to be tested Suppression Ratio (% ) Dose (mg/kg) Example 2-1 Isomer A 82 3 Example 3-1 Isomer A 80 3 Example 7-7 97 1

[0716] As seen from Table II, the compounds (I) of the present invention or pharmacologically acceptable salts thereof had a superior action of suppressing neutrophil infiltration.

INDUSTRIAL APPLICABILITY

[0717] The compound of the present invention has a superior action of suppressing neutrophil infiltration due to a superior FPRL1 agonist effect, and therefore is useful as a therapeutic or prophylactic agent for inflammatory disease, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, immune disorders and the like.

SEQUENCE LISTING FREE TEXT

[0718] <Sequence Listing 1>

[0719] SEQ ID NO: 1 is a sequence of a forward primer used for amplification of DNA of human FPRL1 (SEQ ID NO: 3), and is supplemented with a Hind III recognition site.

[0720] <Sequence Listing 2>

[0721] SEQ ID NO: 2 is a sequence of a reverse primer used for amplification of DNA of human FPRL1 (SEQ ID NO: 3), and is supplemented with an XhoI recognition site.

[0722] <Sequence Listing 3>

[0723] SEQ ID NO: 3 is an open reading frame (ORF) of human FPRL1, and is a DNA sequence of a site translated into an amino acid.

[0724] <Sequence Listing 4>

[0725] SEQ ID NO: 4 is a sequence of a forward primer used for amplification of DNA of human G15 (SEQ ID NO: 6), and is supplemented with a Hind III recognition site.

[0726] <Sequence Listing 5>

[0727] SEQ ID NO: 5 is a sequence of a reverse primer used for amplification of DNA of human G15 (SEQ ID NO: 6), and is supplemented with an XhoI recognition site.

[0728] <Sequence Listing 6>

[0729] SEQ ID NO: 6 is an open reading frame (ORF) of human G15, and is a DNA sequence of a site translated into an amino acid.