PROSTAGLANDIN ANALOGS AND USES THEREOF
20210139435 ยท 2021-05-13
Inventors
- Cheolhwan YOON (Seongnam-si, KR)
- Hongjun KANG (Seongnam-si, KR)
- Cheolkyu HAN (Seongnam-si, KR)
- Moonhwan Kim (Seongnam-si, KR)
- Jeongbeob SEO (Seongnam-si, KR)
- Jun Yeob Yoo (Singapore, SG)
- Rajan Sreekanth (Singapore, SG)
- Ho Sup YOON (Singapore, SG)
Cpc classification
C07C405/00
CHEMISTRY; METALLURGY
C07C405/0016
CHEMISTRY; METALLURGY
C07C259/14
CHEMISTRY; METALLURGY
C07C235/84
CHEMISTRY; METALLURGY
C07C233/75
CHEMISTRY; METALLURGY
C07C233/81
CHEMISTRY; METALLURGY
C07D241/42
CHEMISTRY; METALLURGY
International classification
C07D241/42
CHEMISTRY; METALLURGY
C07C233/81
CHEMISTRY; METALLURGY
C07C235/84
CHEMISTRY; METALLURGY
C07C69/738
CHEMISTRY; METALLURGY
Abstract
The present invention relates to pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, including, as an active ingredient, a prostaglandin analog or a pharmaceutically acceptable salt thereof, wherein the compound has excellent effects in inducing Nurr1, and thus, can be useful as a pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, in particular, cancer, autoimmune disease such as rheumatoid arthritis, schizophrenia, manic depression and neurodegenerative disease such as Alzheimers disease or Parkinson's disease.
Claims
1. A prostaglandin analog represented by the following Chemical Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof. ##STR00128## wherein, X is non-substituted or substituted (C1-C8)alkyl, [(C1-C8)alkoxy](C1-C8)alkyl-, (C1-C8)alkylcarboxylic acid (C1-C8)alkylcarboxylester, (C1-C8)akenyl, [(C1-C8)alkoxy](C1-C8)alkenyl, (C1-C8)alkenyl acid, (C1-C8)alkenyl ester, (C1-C8)alkylamide, or (C1-C8)alkenylamide; Y is (C1-C8) alkyl or (C1-C8) alkenyl, which is optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy, oxo, halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10) aryl, (C6-C10) aryloxy being optionally substituted with (C1-C3) alkyl or halo(C1-C3) alkyl, (C3-C10) cycloalkyl; A.sub.1 and A.sub.2 are each independently, CH, CH.sub.2, NH or N; Z is O, CH.sub.2, , or
; Z is O, CH.sub.2,
, or
, R.sub.d is H, (C1-C3) alkyl, (C1-C6)acylcarbonyl or tetrahydropyranyl, in the Chemical Formula, the notation
is a single bond or a double bond.
2. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein X is (C1-C8) alkyl or (C1-C8) alkenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, (C1-C6) alkoxy, C(O)OR.sub.a, C(O)NR.sub.aR.sub.b, where R.sub.a is H, (C1-C8) alkyl, (C6-C9) aryl, (C6-C9) aryloxy, NH(C6-C9)aryl, 5- to 12-membered heteroaryl having one or more heteroatom selected from the group consisting of N, O and S, said (C1-C8) alkyl, (C6-C9) aryl, 5- to 12-membered heteroaryl may be optionally substituted with halo, hydroxyl, cyano, nitro, amino, substituted amino, (C1-C6)acyl, ONO.sub.2, (C1-C8) alkoxy, (C1-C8)alkyl, substituted (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C7)cycloalkyl, (C1-C8)alkylcarboxy, NHC(O)R.sub.c, or C(O)R.sub.c, where R.sub.c is (C1-C8) alkyl or (C6-C9) aryl which may be optionally substituted with one or more substituents of halo, CF.sub.3, (C1-C6)acyl, amino, substituted amino, cyano, nitro, (C1-C8)alkyl, substituted (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C3)acyloxy, and (C6-C9)aryloxy 5- to 12-membered heterocycloalkyl having one or more heteroatoms selected from the group consisting of N, O and S; and R.sub.b is H or (C1-C6)alkyl.
3. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 2, wherein R.sub.a is one selected from the group consisting of below substituents: H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2OH, CH.sub.2CH(OH)CH.sub.2OH, CH(CH.sub.2OH).sub.2, SO.sub.2CH.sub.3, ##STR00129## ##STR00130## and R.sub.b is H or (C1-C3)alkyl.
4. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein, X is (C1-C8)alkyl-OH, (C1-C8)alkyl-O(C1-C6)alkyl, (C1-C8)alkyl-CO.sub.2H, (C1-C8)alkenyl-CO.sub.2H, (C1-C8)alkyl-CO.sub.2(C1-C6)alkyl, (C1-C8)alkyl-CO.sub.2R.sup.2, (C1-C8)alkenyl-CO.sub.2R.sup.2, (C1-C8)alkyl-CONR.sup.3R.sup.4, (C1-C8)alkyl-CONHOR.sup.4, (C1-C8)alkenyl-CONR.sup.3R.sup.4, or (C1-C8)alkyl-CONHOR.sup.4), where R.sup.2 is (C1-C6)alkyl, Ar, CH.sub.2Ar, ArNHCOAr, or ArCONHAr, said (C1-C6)alkyl is optionally with one to three substituents selected from the group consisting of (C1-C6) alkyl, hydroxyl, halogen (C1-C6)alkoxy or CF3; R.sup.3 is H or (C1-C6)alkyl; R.sup.4 is H, (C1-C6)alkyl, Ar, ArNHCOAr, or ArCONHAr; and Ar is a (C6-C10) aryl, 5- to 12 membered heteroaryl, or hetero-biaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF.sub.3.
5. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein X is CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2H, CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONR.sup.3R.sup.4, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4, CHCHCH2CH2CH2CONR.sup.3R.sup.4, or CHCHCH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4.
6. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein Y is (C1-C6) alkyl or (C1-C6) alkenyl, which is optionally substituted with one to three substituent(s) selected from the group consisting of hydroxy, oxo, halo, methyl, methoxy, phenyl, phenoxy being optionally substituted with CF.sub.3, cylobutyl and cyclohexyl.
7. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein, the prostaglandin analog of Chemical Formula I is represented by Formula II: ##STR00131## wherein X, Y and R.sub.d are the same as defined in Chemical formula I of claim 1.
8. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein, the prostaglandin analog of Chemical Formula I is represented by one of Chemical Formula IIIa, IIIb, IIIc, IIId, IIIe and IIIf: ##STR00132## wherein; R.sup.1 is CH.sub.2OH, CH.sub.2OCH.sub.3, CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, CO.sub.2R.sup.2, CONR.sup.3R.sup.4, or CONHOR.sup.4; R.sup.2 is (C1-C6)alkyl, Ar, CH.sub.2Ar, ArNHCOAr, or ArCONHAr, said (C1-C6)alkyl is optionally with one to three substituents selected from the group consisting of (C1-C6) alkyl, hydroxyl, halogen (C1-C6)alkoxy or CF3; R.sup.3 is H, (C1-C6)alkyl; R.sup.4 is H, (C1-C6)alkyl, Ar, ArNHCOAr, or ArCONHAr; Ar is a (C6-C10) aryl, 5- to 12 membered heteroaryl, or hetero-biaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF.sub.3.
9. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof according to claim 1, wherein, the prostaglandin analog of Chemical Formula I is represented by one of Chemical Formula IVa, IVb, IVc, and IVd, as below: ##STR00133## wherein, Y is (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)difluoroalkyl, (C1-C6)trifluoroalkyl, (C1-C6)hydroxyalkyl, (C2-C6)dihydroxyalkyl, or [(C1-C6)alkoxy](C1-C6)alkyl, which is optionally substituted with one to three substituents selected from the group consisting of (C1-C6) alkyl, halogen, hydroxyl, (C1-C6)alkoxy, or CF3. each R.sup.5 is independently selected from the group consisting of hydrogen, halogen, CF3, (C1-C6)acyl, amino, substituted amino, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkylcarboxy, cyano, nitro, and (C1-C6)alkoxy, each R.sup.6 is independently selected from the group consisting of hydrogen, halogen, CF3, (C1-C10)acyl, amino, substituted amino, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C1-C6)haloalkyl, cyano, nitro, (C1-C6)alkoxy, (C1-C3)acyloxy, and (C6-C10)aryloxy; and n is 0, 1, 2, 3, 4 or 5.
10. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1, wherein the prostaglandin analog is selected from the group consisting of the following compounds 2 to 15, 96 and 97: TABLE-US-00004 Compound # Structure 2
11. The prostaglandin analog, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1, wherein the prostaglandin analog is not the compound selected from the group consisting of the following compounds 1, 16 to 95, and 98 to 102: TABLE-US-00005 Compound # Structure 1
12. A pharmaceutical composition for modulating Nurr1, comprising a prostaglandin analog of Chemical Formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12, wherein the modulation of Nurr1 is activation of Nurr1.
14. A pharmaceutical composition for preventing or treating a disease, disorder, or condition associated with Nurr1, comprising a prostaglandin analog of Chemical Formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier:
15. The pharmaceutical composition of anyone of claims 12 to 14, wherein the prostaglandin analog is selected from the group consisting of the following compounds 1 to 102: TABLE-US-00006 Compound # Structure 1
16. The pharmaceutical composition of claim 14, wherein the a disease, disorder, or condition associated with Nurr1 is selected from the group consisting of cancer, autoimmune disease, schizophrenia, manic depression and neurodegenerative disease.
17. The pharmaceutical composition of claim 16, wherein the autoimmune disease is rheumatoid arthritis, and the neurodegenerative disease is Alzheimers disease or Parkinson's disease.
18. A method of modulating Nurr1, comprising administering an effective amount of the prostaglandin analog of Chemical Formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, to a subject in need of modulating Nurr1.
19. A method of for preventing or treating a disease, disorder, or condition associated with Nurr1, comprising administering an effective amount of the prostaglandin analog of Chemical Formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, to a subject in need of preventing or treating a disease, disorder, or condition associated with Nurr1.
20. The method of claim 19, wherein the a disease, disorder, or condition associated with Nurr1 is selected from the group consisting of cancer, rheumatoid arthritis, Alzheimers disease, schizophrenia, manic depression and Parkinson's disease.
21. The method of claim 20, wherein the autoimmune disease is rheumatoid arthritis, and the neurodegenerative disease is Alzheimers disease or Parkinson's disease.
21. The method of anyone of claims 18 to 21, wherein the prostaglandin analog is selected from the group consisting of the following compounds 1 to 102: TABLE-US-00007 Compound # Structure 1
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0026]
[0027]
[0028]
[0029]
[0030]
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0031] Hereinafter, the present invention will be described in detail.
[0032] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, although the invention has been described in conjunction with specific methods and samples, their analogs or equivalents should be within the scope of the present invention. Furthermore, the numerical values set forth herein are considered to include the meaning of about unless explicitly stated. All publications and other references mentioned herein are hereby incorporated by reference in their entirety.
[0033] The definition of residues used herein is described in detail. Unless otherwise indicated, each residue has the following definition and is used in the sense as commonly understood by one of ordinary skill in the art.
[0034] The term halo refers to F, Cl, Br, or I, and the term is compatibly used with the term halogen.
[0035] The term alkyl means a linear or branched hydrocarbon aliphatic saturated hydrocarbon group with a single bond, and may include, for example, C.sub.1-C.sub.8 alkyl, specifically C.sub.1-C.sub.6 alkyl, more specifically methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl. and the like.
[0036] The term haloalkyl refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above. Unless otherwise defined, the haloalkyl refers tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.
[0037] The term alkoxy means an oxygen group to which a linear or branched saturated hydrocarbon with a single bond is bonded, and may include, for example, C.sub.1-C.sub.8 alkoxy, specifically C.sub.1-C.sub.6 alkoxy, more specifically methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, and the like.
[0038] As used herein, the alkoxyalkyl refers to alkyl-O-alkyl group, and the alkyl group is defined as above. The unlimited example is methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.
[0039] As used herein, the term hydroxy or hydroxyl alone or in combination with other terms means OH.
[0040] As used herein, acyl refers to a group of C(O)-alkyl, where the alkyl group is as defined above. Examples thereof include, but are not limited to, acetyl, propanoyl, and acrylyl. Acyl groups may or may not be substituted with one or more suitable substituents.
[0041] The term cycloalkyl means a saturated hydrocarbon ring group with a single bond, and may include, for example, C.sub.3-C.sub.10 cycloalkyl depending on the number of carbon atoms, specifically C.sub.3-C.sub.8 cycloalkyl, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0042] The term heterocycloalkyl means a saturated hydrocarbon ring group with a single bond including one or more heteroatoms such as N, O, or S in addition to carbon atoms as ring members. Depending on the number and type of heteroatoms contained in the ring, and the number of carbon atoms, for example, the heterocycloalkyl includes 5- to 12-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkyl containing one or more, specifically, one or more heteroatoms selected from the group consisting of N, O and S, more specifically, aziridine, pyrrolidine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl or tetrahydropyranyl, and the like.
[0043] The term aryl means an aromatic substituent containing at least one ring having a shared pi-electron system, and includes monocyclic or fused ring polycyclic (i.e., rings that share pairs of adjacent carbon atoms) groups. For example, depending on the number of carbon atoms contained in the ring, the aryl is specifically C4-C.sub.10 aryl, more specifically C.sub.6-C.sub.10 aryl, and still more specifically phenyl, naphthyl, and the like.
[0044] The term heteroaryl means a monoheterocyclic or polyheterocyclic (e.g., diheterocyclic) aromatic hydrocarbon containing one or more heteroatoms such as N, O, or S in addition to a carbon atom as a ring member. For example, depending on the number and type of heteroatoms contained in the ring, and the number of carbon atoms, the heteroaryl includes C.sub.1-C.sub.10 heteroaryl, more specifically, C.sub.1-C.sub.8 heteroaryl, C.sub.2-C.sub.10 heteroaryl, or C.sub.2-C.sub.5 heteroaryl, containing one or more, specifically one or more heteroatoms selected from the group consisting of N, O, and S.
[0045] Examples of the heteroaryl include furanyl, pyranyl, oxazolyl, isoxazolyl, imidazole, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl, triazyl, and the like, but are not limited only thereto.
[0046] The term aryloxy means a group in which any one carbon forming an aromatic substituent is bonded to oxygen. For example, when oxygen is bonded to a phenyl group, it can be expressed as OC.sub.6H, C.sub.6H.sub.4O.
[0047] Accordingly, in a first embodiment, the present invention provides a prostaglandin analog represented by the following Chemical Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof.
##STR00002##
[0048] wherein,
[0049] X is non-substituted or substituted (C1-C8)alkyl, [(C1-C8)alkoxy](C1-C8)alkyl-, (C1-C8)alkylcarboxylic acid (C1-C8)alkylcarboxylester, (C1-C8)akenyl, [(C1-C8)alkoxy](C1-C8)alkenyl, (C1-C8)alkenyl acid, (C1-C8)alkenyl ester, (C1-C8)alkylamide, or (C1-C8)alkenylamide;
[0050] Y is (C1-C8) alkyl or (C1-C8) alkenyl, which may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halo, (C1-C6)alkyl, mono-, di-, or tri-halo(C1-C3) alkyl, (C1-C6)alkoxy, (C6-C10) aryl, (C6-C10) aryloxy and (C3-C10) cycloalkyl, said (C6-C10) aryloxy is optionally substituted with (C1-C3) alkyl, or mono-, di-, or tri-halo(C1-C3) alkyl;
[0051] A.sub.1 and A.sub.2 are each independently, CH, CH.sub.2, NH or N;
[0052] Z is O, CH.sub.2, , or
;
[0053] Z is O, CH.sub.2, , or
, R.sub.d is H, (C1-C3) alkyl, (C1-C6)acylcarbonyl or tetrahydropyranyl,
[0054] in the Chemical Formula, the notation is a single bond or a double bond.
[0055] Preferably, Y may be substituted with at least one hydroxyl or oxo group, and the substituents other than hydroxyl or oxo group.
[0056] In second embodiment of the present invention, in the Chemical Formula I,
[0057] X may be (C1-C8) alkyl or (C1-C8) alkenyl which is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, (C1-C6) alkoxy, C(O)OR.sub.a, C(O)NR.sub.aR.sub.b, NHC(O)Rc
[0058] where R.sub.a is H, (C1-C8) alkyl, (C6-C9) aryl, (C6-C9) aryloxy, NH(C6-C9)aryl, 5- to 12-membered heteroaryl having one or more heteroatom selected from the group consisting of N, O and S, said (C1-C8) alkyl, (C6-C9) aryl, 5- to 12-membered heteroaryl may be optionally substituted with halo, hydroxyl, cyano, nitro, amino, substituted amino, (C1-C6)acyl, ONO.sub.2, (C1-C8) alkoxy, (C1-C8)alkyl, substituted (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C7)cycloalkyl, (C1-C8)alkylcarboxy, NHC(O)R.sub.c, or C(O)R.sub.c, where R.sub.c is (C1-C8) alkyl or (C6-C9) aryl which may be optionally substituted with one or more substituents of halo, CF.sub.3, (C1-C6)acyl, amino, substituted amino, cyano, nitro, (C1-C8)alkyl, substituted (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C3)acyloxy, and (C6-C9)aryloxy 5- to 12-membered heterocycloalkyl having one or more heteroatoms selected from the group consisting of N, O and S; and
[0059] R.sub.b is H or (C1-C6)alkyl.
[0060] Preferably, the substituted amino refers to amino group which may be substituted with (C1-C6)alkyl, and the substituted (C1-C6)alkyl refers to (C1-C6)alkyl group which may be substituted with halo, hydroxyl or (C1-C6)alkyl.
[0061] Preferably, R.sub.a may be one selected from the group consisting of below substituents:
[0062] H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2OH, CH.sub.2CH(OH)CH.sub.2OH, CH(CH.sub.2OH).sub.2, SO.sub.2CH.sub.3,
##STR00003## ##STR00004##
[0063] Preferably, R.sub.b is H or (C1-C3)alkyl.
[0064] In an another embodiment of the present invention, in the Chemical Formula I,
[0065] X may be (C1-C8)alkyl-OH, (C1-C8)alkyl-O(C1-C6)alkyl, (C1-C8)alkyl-CO.sub.2H, (C1-C8)alkenyl-CO.sub.2H, (C1-C8)alkyl-CO.sub.2(C1-C6)alkyl, (C1-C8)alkyl-CO.sub.2R.sup.2, (C1-C8)alkenyl-CO.sub.2R.sup.2, (C1-C8)alkyl-CONR.sup.3R.sup.4, (C1-C8)alkyl-CONHOR.sup.4, (C1-C8)alkenyl-CONR.sup.3R.sup.4, or (C1-C8)alkyl-CONHOR.sup.4),
[0066] wherein,
[0067] R.sup.2 is optionally substituted (i.e., non-substituted or at least one hydrogen being substituted with (C1-C6) alkyl (e.g., methyl), hydroxyl, dihydroxy, halogen (e.g., mono-, di-, or tri-F or -Cl), (C1-C6)alkoxy (e.g., methoxy), or CF3)) (C1-C6)alkyl, Ar, CH.sub.2Ar, ArNHCOAr, or ArCONHAr;
[0068] R.sup.3 is H or (C1-C6)alkyl;
[0069] R.sup.4 is H, (C1-C6)alkyl, Ar, ArNHCOAr, or ArCONHAr; and
[0070] Ar is a (C6-C10) aryl, 5- to 12 membered mono- or bi-heteroaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF.sub.3.
[0071] In an another embodiment of the present invention, in the Chemical Formula I,
[0072] X may be CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2H, CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONR.sup.3R.sup.4, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4, CHCHCH2CH2CH2CONR.sup.3R.sup.4, or CHCHCH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4.
[0073] In an another embodiment of the present invention, in the Chemical Formula I,
[0074] Y may be (C1-C6) alkyl or (C1-C6) alkenyl, which may be optionally substituted with one to three substituent(s) selected from the group consisting of hydroxy, oxo, halo, methyl, CF.sub.3, methoxy, phenyl, phenoxy being optionally substituted with CF.sub.3, cylobutyl, and cyclohexyl.
[0075] In a specific embodiment, in Formula I,
[0076] X may be CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONR.sup.3R.sup.4, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4, CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, CHCHCH2CH2CH2CONR.sup.3R.sup.4, or CHCHCH.sub.2CH.sub.2CH.sub.2CONHOR.sup.4, and
[0077] Y may be (C1-C6)hydroxyalkyl that is non-substituted or substituted with (C1-C6) alkyl (e.g., methyl),
[0078] wherein R.sup.2 and R.sup.4 may be independently Ar, ArNHCOAr, or ArCONHAr, and Ar may be a phenyl non-substituted or substituted with halogen (e.g., mono-, di-, or tri-F or -Cl), and
[0079] R.sup.3 is H or (C1-C6)alkyl (e.g., H),
[0080] with the proviso that if Y is 1-hydroxyhexyl, X is not CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2 or CHCHCH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.2, wherein R.sup.2 is ArNHCOAr and Ar is non-substituted phenyl.
[0081] In a specific embodiment, the prostaglandin analog of Chemical Formula I may be represented by one of Chemical Formula II, as below:
##STR00005##
[0082] wherein X, Y and R.sub.d are the same as defined in Chemical formula I above.
[0083] In an embodiment, the prostaglandin analog of Chemical Formula I may be represented by one of Chemical Formula IIIa, IIIb, IIIc, IIId, IIIe and IIIf, as below:
##STR00006##
[0084] wherein;
[0085] R.sup.1 is CH.sub.2OH, CH.sub.2OCH.sub.3, CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, CO.sub.2R.sup.2, CONR.sup.3R.sup.4, or CONHOR.sup.4.
[0086] R.sup.2 is (C1-C6)alkyl, Ar, CH.sub.2Ar, ArNHCOAr, or ArCONHAr, said (C1-C6)alkyl is optionally substituted with one or more selected from the group consisting of (C1-C6) alkyl, hydroxyl, halogen, (C1-C6)alkoxy, or CF3;
[0087] R.sup.3 is H or (C1-C6)alkyl;
[0088] R.sup.4 is H, (C1-C6)alkyl, Ar, ArNHCOAr, or ArCONHAr; and
[0089] Ar is a (C6-C10) aryl, 5- to 12 membered heteroaryl, or hetero-biaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF.sub.3.
[0090] In a specific embodiment, in Formula IIIa and IIIc, R.sup.1 may not be CO.sub.2R.sup.2, wherein R.sup.2 may be ArNHCOAr, and Ar is a non-substituted phenyl.
[0091] In another embodiment, the prostaglandin analog of Chemical Formula I may be represented by one of Chemical Formula IVa, IVb, IVc, and IVd, as below:
##STR00007##
[0092] wherein,
[0093] Y is (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)difluoroalkyl, (C1-C6)trifluoroalkyl, (C1-C6)hydroxyalkyl, (C2-C6)dihydroxyalkyl, or [(C1-C6)alkoxy](C1-C6)alkyl, which is optionally substituted with one to three substituents selected from the group consisting of (C1-C6) alkyl, halogen, hydroxyl, (C1-C6)alkoxy, or CF.sub.3.
[0094] each R.sup.5 is independently selected from the group consisting of hydrogen, halogen, CF.sub.3, (C1-C6)acyl, amino, substituted amino, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkylcarboxy, cyano, nitro, and (C1-C6) alkoxy,
[0095] each R.sup.6 is independently selected from the group consisting of hydrogen, halogen, CF.sub.3, (C1-C6)acyl, amino, substituted amino, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C1-C6)haloalkyl, cyano, nitro, (C1-C6)alkoxy, (C1-C3)acyloxy, and (C6-C10)aryloxy; and
[0096] n is 0, 1, 2, 3, 4 or 5.
[0097] Preferably, the substituted amino refers to amino group which may be substituted with (C1-C6)alkyl, and the substituted (C1-C6)alkyl refers to (C1-C6)alkyl group which may be substituted with halo, hydroxyl or (C1-C6)alkyl.
[0098] In a specific embodiment, in Formula IVa and IVb, if Y is 1-hydroxyhexyl, both of R.sup.5 and R.sup.6 are not hydrogen.
[0099] In the formula described herein, a number following C refers to the number of carbons; for example, the term (C1-C6) refers to comprising 1, 2, 3, 4, 5, or 6 carbons, the term (C2-C6) refers to comprising 2, 3, 4, 5, or 6 carbons, and the term (C3-C7) refers to comprising 3, 4, 5, 6, or 7 carbons. In the formula described herein, compounds (alkyl, acyl, alkoxy, acyloxy, aryloxy, and the like) without definition of carbon number may be one comprising 1, 2, 3, 4, 5, or 6 carbons, unless it is differently defined.
[0100] In the formula described herein, the term substituted compound may refer that at least one hydrogen of the compound is independently substituted with other chemical group, for example, one or more, preferably, one to three selected from the group consisting of (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF.sub.3, unless it is differently defined.
[0101] Further, in a more specific embodiment, the prostaglandin analog of the Chemical Formula I may be one selected from the group consisting of Compounds 2 to 15, 96 and 97, as shown in Table 1 as follows:
TABLE-US-00001 TABLE 1 Compound # Structure 2
[0102] In a specific embodiment, the prostaglandin analog of Chemical Formula I is not a compound selected from the group consisting of the following compounds shown in Table 2:
TABLE-US-00002 TABLE 2 Compound # Structure 1
[0103] Meanwhile, the compounds of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an addition salt formed by pharmaceutically acceptable free acids may be useful. The term pharmaceutically acceptable salt used herein refers to any organic or inorganic addition salt of the prostaglandin analog represented by Chemical Formula I, in which the adverse effect caused by the salt does not impair the beneficial effect of the compound at a concentration exhibiting relatively non-toxic and non-harmful effective activity to a patient.
[0104] The acid addition salt may be prepared by a common method, for example, by dissolving a compound in an excess amount of aqueous acid solution and precipitating the resulting salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Alternatively, an equimolar amount of a compound and an acid in water or alcohol (e.g., glycol monomethyl ether) can be heated, and subsequently, the resulting mixture can be dried by evaporating, or precipitated salts can be filtered under suction.
[0105] In this case, the free acid may be an inorganic acid or an organic acid. Examples of the inorganic acids include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and stannic acid. Examples of the organic acids include, but are not limited to, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid.
[0106] In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt may be obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating the filtrate until dry. At this time, as the metal salts, particularly sodium, potassium or calcium salts are pharmaceutically suitable, but the present invention is not limited thereto. Also, the corresponding silver salts may be obtained by reacting an alkali metal or alkaline earth metal salt with a proper silver salt (e.g., silver nitrate).
[0107] Pharmaceutically acceptable salts of the compound of the present invention, unless otherwise indicated herein, include salts of acidic or basic groups, which may be present in the compound of Chemical Formula I. For example, the pharmaceutically acceptable salts include sodium, calcium and potassium salts of hydroxy group, and other pharmaceutically acceptable salts of amino group, including hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate). The salts may be prepared using a salt preparation method known in the art.
[0108] Salts of the compounds of Chemical Formula I of the present invention are pharmaceutically acceptable salts, and can be used without particular limitation as long as they are salts of the prostaglandin analogs of Chemical Formula I which can exhibit pharmacological activities equivalent to those of the prostaglandin analog of Chemical Formula I.
[0109] In addition, the prostaglandin analogs represented by Chemical Formula I according to the present invention include, but are not limited thereto, not only pharmaceutically acceptable salts thereof, but also all solvates or hydrates and all possible stereoisomers that can be prepared therefrom. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The racemic forms can be analyzed by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, salt formation with an optically active acid followed by crystallization.
[0110] The solvate and stereoisomer of the compound represented by Chemical Formula I may be prepared from the compound represented by Chemical Formula I using methods known in the art.
[0111] Furthermore, the prostaglandin analog represented by Chemical Formula I according to the present invention may be prepared either in a crystalline form or in a non-crystalline form, When the compound is prepared in a crystalline form, it may be optionally hydrated or solvated. In the present invention, the compound of Chemical Formula I may not only include a stoichiometric hydrate, but also include a compound containing various amounts of water. The solvate of the compound of Chemical Formula I according to the present invention includes both stoichiometric solvates and non-stoichiometric solvates.
[0112] In addition, the above compounds may be used as prodrugs, but is not limited thereto.
[0113] The term prodrug refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
[0114] In some embodiment, the compounds of the Chemical Formula I of the present invention, for example, Compound 11, but not limited thereto, may have pharmacological effect by themselves, and also act as prodrugs.
[0115] Another embodiment provides a pharmaceutical composition for modulating Nurr1, the composition comprising a compound of Chemical Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier. For example, the modulation of Nurr1 may be activation of Nurr1.
[0116] Another embodiment provides a method of modulating Nurr1, the method comprising administering an effective amount of a compound of Chemical Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, to a subject in need of modulating Nurr1. For example, the modulation of Nurr1 may be activation of Nurr1. In a specific embodiment, the method may further comprise a step of identifying a subject who is in need of modulating (e.g., activating) Nurr1, before the step of administration.
[0117] Another embodiment provides a pharmaceutical composition for preventing or treating a disease, disorder, or condition associated with Nurr1, the composition comprising a prostaglandin analog of Chemical Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
[0118] Another embodiment provides a method of for preventing or treating a disease, disorder, or condition associated with Nurr1, the method comprising administering an effective amount of a compound of Chemical Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, ester, tautomer, or prodrug thereof, to a subject in need of preventing or treating a disease, disorder, or condition associated with Nurr1. In a specific embodiment, the method may further comprise a step of identifying a subject who is in need of preventing or treating a disease, disorder, or condition associated with Nurr1, before the step of administering.
[0119] The term subject is used interchangeably with individual and patient herein and refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
[0120] The terms treating and treatment as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
[0121] In the pharmaceutical composition and the method for preventing or treating a disease, disorder, or condition associated with Nurr1, the disease, disorder, or condition associated with Nurr1 may be disease, disorder, or condition associated with modulated (e.g., inactivated, suppressed, inhibited, ablated, decreased, etc.) Nurr1 (protein and/or gene).
[0122] The disease, disorder, or condition may be any one associated with Nurr1 signaling, preferably selected from the group consisting of cancer, autoimmune disease such as rheumatoid arthritis, schizophrenia, manic depression and neurodegenerative diseases such as Alzheimer's disease, or Parkinson's disease, more preferably Parkinson's disease.
[0123] Other neurodegenerative diseases that may be treated with a compound or method described herein include Alexander's disease, Alper's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoffs disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, or Tabes dorsalis.
[0124] In the pharmaceutical composition and the method provided herein, the compound of Chemical Formula I may be the ones as described above.
[0125] In a specific embodiment, the pharmaceutical composition and the method provided herein comprises the compound of Chemical Formula II as described above.
[0126] In a specific embodiment, the pharmaceutical composition and the method provided herein comprises the compound of Chemical Formula IIIa, IIIb, IIIc, IIId, IIIe and IIIf as described above.
[0127] In a specific embodiment, the pharmaceutical composition and the method provided herein comprises the compound of Chemical Formula IVa, IVb, IVc, and IVd as described above.
[0128] In a specific embodiment, the pharmaceutical composition and the method provided herein comprises the compound selected from the group consisting of Compounds 1 to 102 shown above Tables 1 and 2.
[0129] The subject may be a mammal including human or a mammalian cell; for example, a mammal (e.g., human) suffering from the disease, disorder, or condition associated with Nurr1 as described above or a mammalian cell isolated therefrom.
[0130] The compound as an active ingredient or the pharmaceutical composition may be administered orally or parenterally. For example, the parenteral administration may be performed by any one of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, and the like.
[0131] The effective amount may refer to pharmaceutically and/or therapeutically effective amount, and may be prescribed depending on factors such as a type of preparation (formulation), administration route, the patient's age, body weight, gender, and/or pathologic conditions, and the like.
[0132] A pharmaceutically acceptable salt of the prostaglandin analog of the present invention may include addition salts formed by inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, or metaphosphate, addition salts formed by organic acids such as citrate, oxalate, benzoate, acetate, trifluoroacetate, propionate, succinate, fumarate, lactate, maleate, tartrate, glutarate, or sulfonate, or metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, but is not limited thereto.
[0133] The pharmaceutical composition according to the present invention can be formulated into a suitable form together with a commonly used pharmaceutically acceptable carrier. The pharmaceutically acceptable refers to being physiologically acceptable, and not usually causing an allergic reaction or a similar reaction such as gastrointestinal disorders and dizziness when administered to humans. Further, the pharmaceutical composition of the present invention may be used after being formulated into an oral preparation, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, etc., and a parental preparation, such as epidermal formulations, suppositories, or sterile injection solutions, in accordance with a conventional method.
[0134] Examples of carriers, excipients and diluents that can be included in the composition, may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, arabic gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. When formulated into a preparation, a diluting agent or an excipient, such as commonly-used fillers, stabilizing agents, binding agents, disintegrating agents, and surfactants can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations may be prepared by mixing the compound of the present invention with at least one excipient, for example, starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose or the like. In addition to the simple excipient, a lubricant such as magnesium stearate and talc are also used. Liquid preparations for oral administration include a suspension, a liquid for internal use, an emulsion, a syrup, etc. In addition to a commonly used simple diluent such as water and liquid paraffin, various excipients such as a humectant, a sweetener, an aromatic, a preservative, etc. may also be contained. Formulations for parenteral administration include a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized formulation and a suppository. The non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, etc. As a base of the suppository, witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc. may be used. In order to formulate the formulation for parenteral administration, the compound of Chemical Formula I or a pharmaceutically acceptable salt thereof may be mixed in water together with sterilized and/or contain adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powder or emulsifying accelerators, salt for controlling osmotic pressure and/or buffers and the like, and other therapeutically useful substances, to prepare a solution or suspension, which is then manufactured in the form of an ampoule or vial unit administration.
[0135] The pharmaceutical composition including the compound of Chemical Formula I disclosed herein as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes for the prevention or treatment of a disease, disorder, or condition associated with Nurr1.
[0136] Pharmaceutical formulations described herein are administrable to a subject in a variety of by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, enfometrial or cerebrovascular injection), intranasal, buccal, topical or transdermal administration routes.
[0137] In some embodiments, the compounds of Chemical Formula I are administered orally.
[0138] In some embodiments, the compounds of Chemical Formula I are administered topically.
[0139] In another aspect, the compounds of Chemical Formula I are administered by intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.
[0140] Intranasal formulations are known in the art. Formulations, which include a compound of Chemical Formula I which are prepared according to these and other techniques well-known in the art are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions. The prostaglandin analogs of the present invention may show excellent pharmacological effects for preventing or treating a disease, disorder, or condition associated with Nurr1 when administered via intranasal route.
[0141] The dosage is varied depending on the age, sex, weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the duration of administration, the route of administration, the drug absorption, distribution and excretion rate, the types of other drugs used, the judgment of prescriber, and the like. Dosage determination based on such factors is within the standards of those skilled in the art.
[0142] Hereinafter, preferred examples of the present invention will be described in detail. However, the present invention is not limited to the examples described herein, and can also be embodied in other forms. Rather, the content presented herein will be thorough and complete, and will fully convey the scope of the present invention to those skilled in the art.
EXAMPLE
Preparation Examples
[0143] NMR spectra were recorded in CDCl.sub.3 solution in 5-mm o.d. tubes (Norell, Inc. 507-HP) at 30 C. and were collected on Varian VNMRS-400 at 400 MHz for .sup.1H. The chemical shifts (6) are relative to tetramethylsilane (TMS=0.00 ppm) and expressed in ppm. LC/MS was taken on Ion-trap Mass Spectrometer on FINNIGAN Thermo or ISQ EC, Thermo Fisher U3000 RSLC (Column: YMC Hydrosphere (C18, 4.650 mm, 3 m, 120 , 40 C.) operating in ESI(+) ionization mode; flow rate=1.0 mL/min. Mobile phase=0.01% heptafluorobutyric acid (HFBA) and 1.0% isopropyl alcohol (IPA) in water or CH.sub.3CN.
##STR00110##
Example 1: 4-Benzamidophenyl-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 1)
[0144] ##STR00111## ##STR00112##
[0145] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (10.8 mg, 0.0300 mmol) in DCM (2.0 mL) was added DMAP (3.72 mg, 0.0300 mmol) followed by N-(4-hydroxyphenyl)benzamide (9.10 mg, 0.0430 mmol) at 10 C. under Ar atmosphere. The mixture was stirred for 3 min at 10 C. After addition of EDCI (8.18 mg, 0.0430 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 4-benzamidophenyl-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl) heptanoate (12 mg, 71%) as a white solid.
[0146] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.87 (2H, d, J=6.8 Hz), 7.82 (1H, brs), 7.66 (2H, d, J=8.8 Hz), 7.59-7.49 (3H, m), 7.09 (2H, d, J=8.8 Hz), 5.71 (1H, dd, J=15.6, 6.0 Hz), 5.58 (1H, dd, J=15.0, 8.6 Hz), 4.14-4.07 (2H, m), 2.75 (1H, dd, J=18.0, 7.2 Hz), 2.54 (2H, t, J=7.4 Hz), 2.37 (1H, q, J=10.0 Hz), 2.24 (2H, dd, J=18.2, 9.8 Hz), 2.05-1.99 (1H, m), 1.73 (2H, qn, J=7.4 Hz), 1.61-1.26 (17H, m), 0.89 (3H, t, J=6.8 Hz).
Example 2: 4-Benzamidophenyl-7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-en-1-yl)-5-oxocyclopentyl)heptanoate (Compound 2)
[0147] ##STR00113## ##STR00114##
[0148] To a solution of DMAP (13.2 mg, 0.109 mmol) in DCM (2.0 mL) was added a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.109 mmol) in methyl acetate (4.0 mL) followed by N-(4-hydroxyphenyl)benzamide (32.4 mg, 0.152 mmol) at 10 C. under Ar atmosphere. The mixture was stirred for 3 min at 10 C. After addition of EDCI (29.1 mg, 0.152 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 4-benzamidophenyl-7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-en-1-yl)-5-oxocyclopentyl)heptanoate (2) (36 mg, 58%) as a colorless oil.
[0149] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.95 (1H, brs), 7.86 (2H, d, J=7.2 Hz), 7.64 (2H, d, J=8.8 Hz), 7.57-7.47 (3H, m), 7.07 (2H, d, J=8.4 Hz), 5.75-5.70 (1H, m), 5.44-5.34 (1H, m), 4.04 (1H, q, J=8.4 Hz), 2.72 (1H, dd, J=18.4, 7.2 Hz), 2.53 (2H, t, J=7.2 Hz), 2.38 (1H, q, J=8.8 Hz), 2.25-2.18 (3H, m), 2.04-1.97 (1H, m), 1.76-1.26 (18H, m), 1.17 (3H, s), 0.91 (3H, t, J=7.2 Hz).
Example 3: N-(4-(7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-en-1-yl)-5-oxocyclopentyl)heptanamido)phenyl)benzamide (Compound 3)
[0150] ##STR00115##
[0151] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl) heptanoic acid (10.5 mg, 0.0300 mmol) in DCM (2.0 mL) was added DMAP (3.62 mg, 0.0300 mmol) and EDCI (7.95 mg, 0.041 mmol) at 10 C. under Ar atmosphere. The mixture was stirred for 3 min at 10 C. After addition of N-(4-aminophenyl)benzamide (8.80 mg, 0.0410 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only to EtOAc:MeOH=20:1) to afford N-(4-(7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-en-1-yl)-5-oxocyclopentyl)heptanamido) phenyl)benzamide (7.6 mg, 46%) as a white solid.
[0152] .sup.1H-NMR (400 MHz, CD.sub.3OD): 7.92 (2H, d, J=7.6 Hz), 7.64 (2H, d, J=8.8 Hz), 7.57-7.49 (5H, m), 5.61 (2H, dd, J=6.0, 2.0 Hz), 4.05-4.01 (2H, m), 2.67 (1H, dd, J=20.0, 8.0 Hz), 2.36 (3H, t, J=6.0 Hz), 2.14-2.03 (2H, m), 1.70-1.65 (2H, m), 1.59-1.31 (17H, m), 0.89 (3H, t, J=5.6 Hz).
Example 4: 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-phenylheptanamide (Compound 4)
[0153] ##STR00116##
[0154] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (10.0 mg, 0.0280 mmol) in DCM (3.0 mL) was added DMAP (3.45 mg, 0.0280 mmol) followed by aniline (3.68 mg, 0.0390 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (7.57 mg, 0.0390 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only to EtOAc:MeOH=50:1) to afford 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-phenylheptanamide (10.6 mg, 87%) as a white solid.
[0155] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.72 (1H, brs), 7.51 (2H, d, J=7.2 Hz), 7.32 (2H, t, J=8.0 Hz), 7.17 (1H, brs), 7.10 (1H, t, J=8.0 Hz), 7.40 (1H, dd, J=15.2, 6.0 Hz), 5.60 (1H, dd, J=15.2, 8.8 Hz), 4.29-4.28 (1H, m), 4.17-4.05 (2H, m), 2.76 (1H, dd, J=18.4, 6.8 Hz), 2.41-2.32 (3H, m), 2.24 (1H, dd, J=18.4, 9.6 Hz), 2.05-2.00 (1H, m), 1.73-1.69 (2H, m), 1.49-1.26 (16H, m), 0.89-0.84 (3H, m).
Example 5: N-(4-chlorophenyl)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanamide (Compound 5)
[0156] ##STR00117##
[0157] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (10.0 mg, 0.0280 mmol) in DCM (3.0 mL) was added DMAP (3.45 mg, 0.0280 mmol) and 4-chloroaniline (5.04 mg, 0.0390 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (7.57 mg, 0.0390 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only) to afford N-(4-chlorophenyl)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanamide (9.20 mg, 70%) as a white solid.
[0158] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.47 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=10.4 Hz), 7.22 (1H, brs), 5.72 (1H, dd, J=15.6, 6.4 Hz), 5.59 (1H, dd, J=15.2, 8.4 Hz), 4.17-4.05 (2H, m), 2.75 (1H, dd, J=18.8, 6.4 Hz), 2.41-2.31 (3H, m), 2.23 (1H, dd, J=18.4, 9.6 Hz), 2.05-1.99 (1H, m), 1.72-1.66 (2H, m), 1.59-1.25 (18H, m), 0.91-0.87 (3H, m).
Example 6: 3-(7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl) heptanamido)-N-phenylbenzamide (Compound 6)
[0159] ##STR00118##
[0160] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (10.0 mg, 0.0280 mmol) in DCM (3.0 mL) was added DMAP (3.45 mg, 0.0280 mmol) and 3-amino-N-phenylbenzamide (8.38 mg, 0.0390 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (7.57 mg, 0.0390 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only to EtOAc:MeOH=50:1) to afford 3-(7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl) heptanamido)-N-phenylbenzamide (7.0 mg, 45%) as a white solid.
[0161] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.46 (1H, brs), 8.10 (1H, brs), 7.66 (3H, t, J=8.0 Hz), 7.61-7.59 (2H, m), 7.41 (1H, t, J=8.0 Hz), 7.37 (2H, t, J=7.6 Hz), 7.15 (1H, t, J=7.2 Hz), 5.71 (1H, dd, J=16.0, 6.4 Hz), 5.59 (1H, dd, J=15.2, 7.6 Hz), 4.11-4.04 (1H, m), 3.67 (1H, s), 2.73 (1H, dd, J=19.2, 7.2 Hz), 2.54 (1H, brs), 2.39-2.19 (4H, m), 2.03-2.00 (1H, m), 2.41-2.32 (3H, m), 1.71-1.10 (16H, m), 0.87-0.84 (3H, m). MS: m/z=531.3 (M+H.sup.+).
Example 7: 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-(quinoxalin-6-yl)heptanamide (Compound 7)
[0162] ##STR00119##
[0163] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (3.0 mL) and THF (1.0 mL) was successively added DIPEA (19.71 l, 0.113 mmol), HOBT (17.28 mg, 0.113 mmol) and quinoxalin-6-amine (22.9 mg, 0.158 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of HATU (42.9 mg, 0.113 mmol), the reaction mixture was stirred at room temperature 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc:Acetone=10:1 to Acetone only) to afford 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-(quinoxalin-6-yl)heptanamide (27 mg, 50%) as a yellow oil.
[0164] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.80 (1H, d, J=1.6 Hz), 8.76 (1H, d, J=2.0 Hz), 8.30 (1H, brs), 8.07-8.01 (2H, m), 7.91-7.86 (1H, m), 5.73 (1H, dd, J=15.2, 6.8 Hz), 5.60 (1H, dd, J=11.2, 8.8 Hz), 4.18-4.05 (2H, m), 2.74 (1H, dd, J=18.4, 6.8 Hz), 2.45-2.34 (3H, m), 2.25 (1H, dd, J=18.4, 10.0 Hz), 2.05-2.00 (1H, m), 2.05-2.00 (1H, m), 1.79-1.26 (19H, m), 0.87 (3H, t, J=6.8 Hz).
Example 8: 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-(quinolin-7-yl)heptanamide (Compound 8)
[0165] ##STR00120##
[0166] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (20.0 mg, 0.0560 mmol) in DCM (3.0 mL) and THF (1.0 mL) was successively added DIPEA (9.85 L, 0.0560 mmol), HOBT (8.64 mg, 0.0560 mmol) and quinolin-7-amine (24.40 mg, 0.169 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of HATU (32.2 mg, 0.0850 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc only to EtOAc:Acetone=10:1) to afford 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-(quinolin-7-yl)heptanamide (21 mg, 77%) as a yellow solid.
[0167] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.85 (1H, d, J=1.6 Hz), 8.13 (1H, d, J=7.6 Hz), 8.07-8.02 (2H, m), 7.86 (1H, brs), 7.79 (1H, d, J=8.4 Hz), 7.34 (1H, dd, J=8.0, 4.0 Hz), 5.74 (1H, dd, J=15.6, 6.8 Hz), 5.62 (1H, dd, J=15.6, 7.6 Hz), 4.18-4.05 (2H, m), 2.75 (1H, dd, J=18.4, 7.2 Hz), 2.44-2.36 (3H, m), 2.22 (1H, dd, J=18.4, 10.0 Hz), 2.05-2.01 (1H, m), 1.77-1.25 (20H, m), 0.86 (3H, t, J=7.2 Hz).
Example 9: 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-phenoxyheptanamide (Compound 9)
[0168] ##STR00121##
[0169] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (25.0 mg, 0.0710 mmol) in DCM (3.0 mL) and THF (1.0 mL) was successively added DIPEA (12.3 L, 0.0710 mmol), HOBT (10.8 mg, 0.0710 mmol) and O-phenylhydroxylamine (23.1 mg, 0.212 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of HATU (40.2 mg, 0.106 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc:Acetone=10:1 to Acetone only) to afford 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)-N-phenoxyheptanamide (27 mg, 88%) as a yellow oil.
[0170] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.84 (1H, brs), 7.32 (2H, brs), 7.07-7.05 (3H, m), 5.68 (1H, dd, J=12.8, 6.8 Hz), 5.55 (1H, dd, J=15.6, 8.8 Hz), 4.13-4.01 (2H, m), 2.73 (1H, dd, J=18.4, 7.6 Hz), 2.39-2.18 (4H, m), 2.02-1.96 (1H, m), 1.64-1.26 (20H, m), 0.88 (3H, t, J=7.0 Hz).
Example 10: 7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)-N-phenoxyheptanamide (Compound 10)
[0171] ##STR00122##
[0172] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoic acid (20.0 mg, 0.0540 mmol) in DCM (3.0 mL) and THF (1.0 mL) was successively added DIPEA (11.4 l, 0.0650 mmol), HOBT (8.31 mg, 0.0540 mmol) and O-phenylhydroxylamine (7.11 mg, 0.0650 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of HATU (28.9 mg, 0.0760 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was directly purified by column chromatography on SiO.sub.2 (EtOAc:Acetone=10:1 to Acetone only) to afford 7-((1R,2R,3R)-3-hydroxy-2-((E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)-N-phenoxyheptanamide (18 mg, 72%) as a yellow oil.
[0173] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.97 (1H, brs), 7.32-7.30 (2H, brs), 7.07-7.05 (3H, m), 5.78-5.70 (1H, m), 5.45-5.39 (1H, m), 4.05 (1H, q, J=8.4 Hz), 2.74 (1H, dd, J=16.0, 7.2 Hz), 2.41-2.05 (7H, m), 2.05-1.98 (2H, m), 1.63-1.26 (16H, m), 1.17 (3H, s), 0.91-0.83 (3H, m).
Example 11: 4-(4-fluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 11)
[0174] ##STR00123##
[0175] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (4.0 mL) were successively added 4-fluoro-N-(4-hydroxyphenyl)benzamide (36.5 mg, 0.158 mmol) and DMAP (13.8 mg, 0.113 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (30.3 mg, 0.158 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 4-(4-fluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclo-pentyl)heptanoate (45.0 mg, 70%) as a white solid.
[0176] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.89 (2H, dd, J=8.8, 5.2 Hz), 7.76 (1H, brs), 7.63 (2H, d, J=8.8 Hz), 7.48 (2H, t, J=8.4 Hz), 7.10 (2H, d, J=9.2 Hz), 5.71 (1H, dd, J=14.4, 6.4 Hz), 5.58 (1H, dd, J=14.4, 8.4 Hz), 4.15-4.05 (2H, m), 2.75 (1H, dd, J=14.4, 7.2 Hz), 2.54 (2H, t, J=7.2 Hz), 2.41-2.34 (1H, m), 2.24 (1H, dd, J=18.4, 9.6 Hz), 2.05-1.99 (1H, m), 1.73 (2H, q, J=6.4 Hz), 1.58-1.25 (18H, m), 0.88 (3H, t, J=6.4 Hz).
Example 12: 4-(3,4-difluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 12)
[0177] ##STR00124##
[0178] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (4.0 mL) was successively added 3,4-difluoro-N-(4-hydroxyphenyl)benzamide (39.4 mg, 0.158 mmol) and DMAP (13.8 mg, 0.113 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (30.3 mg, 0.158 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 4-(3,4-difluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (42.3 mg, 64%) as a white solid.
[0179] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.77-7.72 (2H, m), 7.62 (2H, d, J=9.2 Hz), 7.32-7.28 (1H, m), 7.10 (2H, d, J=9.2 Hz), 5.71 (1H, dd, J=14.7, 6.4 Hz), 5.58 (1H, dd, J=14.4, 8.0 Hz), 4.14-4.05 (2H, m), 2.75 (1H, dd, J=14.4, 7.2 Hz), 2.55 (2H, t, J=7.2 Hz), 2.45-2.34 (2H, m), 2.24 (1H, dd, J=18.4, 9.6 Hz), 2.05-2.01 (1H, m), 1.84 (1H, brs), 1.73 (2H, qn, J=6.8 Hz), 1.58-1.25 (17H, m), 0.89 (3H, t, J=6.8 Hz).
Example 13: 4-(3,5-difluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 13)
[0180] ##STR00125##
[0181] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (4.0 mL) was successively added 3,5-difluoro-N-(4-hydroxyphenyl)benzamide (39.4 mg, 0.158 mmol) and DMAP (13.8 mg, 0.113 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (30.3 mg, 0.158 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 4-(3,5-difluorobenzamido)phenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (45.3 mg, 69%) as a white solid.
[0182] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.77 (1H, s), 7.63 (2H, d, J=9.2 Hz), 7.40 (2H, d, J=6.4 Hz), 7.11 (2H, d, J=9.2 Hz), 7.04-6.99 (1H, m), 5.73 (1H, dd, J=15.6, 6.4 Hz), 5.58 (1H, dd, J=14.4, 8.4 Hz), 4.14-4.05 (2H, m), 2.76 (1H, dd, J=14.4, 6.8 Hz), 2.55 (2H, t, J=7.2 Hz), 2.41-2.34 (2H, m), 2.24 (1H, dd, J=18.8, 10.0 Hz), 2.05-1.99 (1H, m), 1.81 (1H, brs), 1.73 (2H, qn, J=7.2 Hz), 1.58-1.25 (16H, m), 0.88 (3H, t, J=6.4 Hz).
Example 14: 3,4,5-trimethoxyphenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 14)
[0183] ##STR00126##
[0184] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (2.0 mL) were successively added DMAP (13.8 mg, 0.113 mmol) and 3,4,5-trimethoxyphenol (29.1 mg, 0.158 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (30.3 mg, 0.158 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO.sub.2 (EtOAc only) to afford 3,4,5-trimethoxyphenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (48.6 mg, 83%) as a colorless oil.
[0185] .sup.1H-NMR (400 MHz, CDCl.sub.3): 6.32 (2H, s), 5.70 (1H, dd, J=14.7, 6.4 Hz), 5.57 (1H, dd, J=14.4, 8.4 Hz), 4.16-4.05 (2H, m), 3.84 (6H, s), 3.83 (3H, s), 2.76 (1H, dd, J=18.8, 7.2 Hz), 2.67 (1H, brs), 2.53 (2H, t, J=7.6 Hz), 2.41-2.34 (1H, m), 2.23 (1H, dd, J=18.8, 10.0 Hz), 2.05-1.99 (1H, m), 1.73 (2H, qn, J=7.2 Hz), 1.61-1.25 (17H, m), 0.89 (3H, t, J=6.8 Hz).
Example 15: benzyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 15)
[0186] ##STR00127##
[0187] To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (50.0 mg, 0.141 mmol) in DCM (2.0 mL) were successively added DMAP (17.2 mg, 0.141 mmol) and benzyl alcohol (20.5 L, 0.197 mmol) at 10 C. under Ar atmosphere. The mixture was stirred at 10 C. for 3 minutes. After addition of EDC (37.9 mg, 0.197 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO.sub.2 (EtOAc only) to afford benzyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (53.5 mg, 85%) as a colorless oil.
[0188] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.39-7.32 (5H, m), 5.71 (1H, dd, J=12.0, 6.8 Hz), 5.57 (1H, dd, J=14.4, 8.8 Hz), 5.11 (2H, s), 4.16-4.10 (2H, m), 2.75 (1H, dd, J=14.4, 8.0 Hz), 2.51 (1H, brs), 2.40-2.32 (3H, m), 2.23 (1H, dd, J=18.8, 9.6 Hz), 2.03-1.97 (1H, m), 1.62-1.27 (19H, m), 0.89 (3H, t, J=6.4 Hz).
Examples 16 to 102: Compounds 16 to 102
[0189] Compounds 16 to 102 as shown in Tables 1 and 2 were synthesized referring to the methods disclosed in Examples 1 to 15.
EXPERIMENTAL EXAMPLES
Experimental Example 1: Structure-Based Design of PG Analogs
[0190] Cyclopentenone prostaglandin's A1/A2 are dehydrated metabolites of their precursors, the cyclopentanone prostaglandins E1/E2. In PGE1/E2, a hydroxyl group is attached to the C11 atom, which is responsible for the covalent attachment between PGA1 and Nurr1. This is evident from the electron density observed between the PGA1/A2's C11 atom (Rajan, S. et al. Nat Chem Biol 16, 876-886 (2020); U.S. patent application Ser. No. 16/334,550) and Nurr1's Cys566 sulphur, a characteristic feature of PGA1/A2 binding. Our NMR titration revealed that both PGA1 and PGE1 interact at same binding site on Nurr1-LBD corroborating with that in the crystal structure. Based on these one could conclude that both PGA1 and PGE1 can be used to design analogs, preferably using PGE1 which is better suited for chemic synthesis and modifications as it lacks the reactive C11 site, concealed by the hydroxyl group (Rajan, S. et al. Nat Chem Biol 16, 876-886 (2020)). In a similar way, addition of hydroxyl or methyl groups to PGE1 along the two hydrophobic tails has also been shown to prolong its metabolic degradation. One such is the misoprostol, which enhanced Nurr1's transcription function. Thus, we chose PGE1 and Misoprostol as the candidate molecules to make modification.
[0191] In this direction, the inventors of the present invention compared Nurr1-LBD crystal structures in the apo and PGA1-bound form. PGA1 interacts with Nurr1 residues Glu440, Phe443, Leu444, Arg515, His516, Arg563, Thr567, Cys566, Leu570, Ile573, Leu591, Phe592, Thr595 and Pro597 from helices 4, 11 and 12 (WO2018056905A1; U.S. patent application Ser. No. 16/334,550) constituting the primary binding site in Nurr1-LBD. A closer inspection revealed the presence of a ligand-induced surface pocket in Nurr1-LBD, lined by residues Glu445, Leu446, Leu509, Ala510, Thr513, Glu514, Arg515, Gln528, Val532, Leu556, Leu559, Pro560 and Arg563 from helices 9 and 11, forming the H9-H11 wedge. We have coined this pocket as the secondary site and our hypothesis was to identify prostaglandin analogs, in which chemical fragments can be linked to the lead molecule, enabling it to occupy the secondary site and enhance the activity. The carboxyl group of PGA1 is oriented toward this secondary site and could serve as the point of modification for linking the fragment molecules. The secondary site could accommodate small fragments ranging between 100 and 120 Da. In this direction, a chemical synthesis protocol was adopted to link small fragments to the carboxyl (C1) end of PGE1 and misoprostol.
Experimental Example 2: Activation of Nurr1-Mediated Transcription by the PG Analogs of the Present Invention
[0192] To investigate whether the PG analogs of the present invention activate Nurr1 function, the inventors of the present invention employed an reporter gene assay and examined the transcriptional activation as described in Kim, C.-H. et al., Proceedings of the National Academy of Sciences 112, 8756-8761, doi:10.1073/pnas.1509742112 (2015).
[0193] The gene assay was performed by Luciferase assay as described below:
[0194] [Protocol for Luciferase Assay to Determine Nurr1 Transcriptional Activity] [0195] 1. SK-N-BE2C cells were maintained in HyClone DMEM High Glucose (Cat. No.: SH30022.01) with 10% (v/v) fetal bovine serum (FBS), 100 units/ml penicillin and 100 g/ml streptomycin. [0196] 2. Seed 1.510.sup.5 SK-N-BE2C cells/well into a 24-well plate and incubate at 37 C. with 5% CO.sub.2 for 24 hours. [0197] 3. After 24 hours, transfect cells with pcDNA3.1 Myc/His mouse Nurr1 full-length construct, firefly luciferase reporter vector (pGL-3 basic from Promega, Cat. No.:E1751; with appropriate response element cloned in) and Renilla luciferase control vector (pRL-null from Promega, Cat. No.:E2271) in the ratio of 8:1:1 (Nurr1: firefly: renilla) or 400 ng, 50 ng and 50 ng respectively, amounting to a total of 500 ng in the 50 l transfection mix for 1 well. [0198] 4. To make the transfection mix, first prepare the DNA with P3000 reagent by adding the appropriate amount of DNA with 1 l P3000 reagent and top up with Opti-MEM I Reduced-Serum Media (from ThermoFisher Scientific [Cat. No.: 31985070]) to 25 l. Incubate for 5 minutes at room temperature. [0199] 5. Make another mix consisting of 1 l Lipofectamine 3000 reagent with 24 l Opti-MEM I Reduced-Serum Media per well. Add this Lipofectamine mix to the previous DNA-P3000 mix (after the previous 5 minute incubation) and incubate them for 15 minutes at room temperature. [P3000:Lipofectamine=1:1]. [0200] 6. In the meantime, change the media in the sample wells with fresh DMEM media without antibiotics. [0201] 7. After 15 minutes incubation, add the 50 l transfection mix into each well and incubate the plate for 24 hours at 37 C. with 5% CO.sub.2. [0202] 8. After 24 hours, change the media to normal DMEM media with antibiotics and add various doses of compounds into designated wells and incubate the plate for another 24 hours at 37 C. with 5% CO.sub.2. [0203] 9. Following the 24-hour incubation period, luciferase assay can be conducted using Dual-Glo Luciferase kit from Promega (Cat. No.: E2920). [0204] 10. Lyse each tested wells for 15 minutes with 75 l of passive lysis buffer provided in the Dual-Luciferase kit from Promega (Cat. No.: E1910). [Alternatively, add 75 l of PBS and 75 l of Dual-Glo Luciferase Reagent and incubate for 10 minutes at room temperature (cover the plate with foil to protect from light). Transfer the entire sample in each well to a Greiner CELLSTAR 96-well white polystyrene plate then proceed to step 13]. [0205] 11. After 15 minutes, transfer each lysed sample to a Greiner CELLSTAR 96-well white polystyrene plate (Cat. No.:655083). [0206] 12. To each well of lysed cells, add 75 l of Dual-Glo Luciferase Reagent and incubate for 10 minutes at room temperature (cover the plate with foil to protect from light). [0207] 13. Set the measurement with a 10-second integrated measurement period. [0208] 14. Add 75 l of Dual-Glo Stop & Glo reagent into each well and incubate for 10 minutes before commencing with the same parameters as before to determine the RLU for the Renilla luciferase. [0209] 15. The averaged reading for wells corresponding to non-transfected cells can be subtracted from each RLU reading and duplicate/triplicate readings can then be averaged. Normalization of the luminescence reading for each well can be carried out by dividing the firefly luciferase RLU with the corresponding Renilla luciferase RLU. Each drug-treated well can then be normalized against the averaged DMSO-treated well reading.
[0210] The results are shown in below Table 3. Notably, tested PG analogs of the present invention stimulated Nurr1-dependent transcriptional activity through its LBD in a dose-dependent manner as they induced Nurr1 LBD-based reporter activity up to 0.52.9-fold:
TABLE-US-00003 TABLE 3 Transcription Assays Data Fold activity: Relative activity over control (luminescence value; 1.0) A: above 2.0 (high activity), B: 1.1~2.0 (moderate), C: below 1.0 (low activity) Comp. Fold activity # (1 uM) 1 A Example 1 2 A Example 2 3 B Example 3 4 A Example 4 5 A Example 5 6 B Example 6 7 A Example 7 8 A Example 8 9 A Example 9 10 A Example 10 11 A Example 11 12 A Example 12 13 A Example 13 14 A Example 14 15 A Example 15 16 A 15(R)-Prostaglandin D2 17 B Prostaglandin D2-1-glyceryl ester 18 A Prostaglandin E1 Ethanolamide 19 B 15-keto Prostaglandin E1 20 A Prostaglandin E2 21 B 11b-Prostaglandin E2 22 B Sulprostone 23 B 11-keto Fluprostenol 24 A Prostaglandin E2-1-glyceryl ester 25 B 11-deoxy-11-methylene Prostaglandin D2 26 A Prostaglandin E1 Alcohol 27 A 15(S)-15-methyl Prostaglandin E1 28 A Prostaglandin E2 methyl ester 29 B 13,14-dihydro-15-keto Prostaglandin E2 30 A 16-phenyl tetranor Prostaglandin E2 31 B (R)-Butaprost (free acid) 32 C Prostaglandin D2 serinol amide 33 B 13,14-dihydro-15-keto Prostaglandin D2 34 B 1a,1b-dihomo Prostaglandin E1 35 B (R)-Butaprost 36 B Prostaglandin E2 Ethanolamide 37 B 15(R)-Prostaglandin E2 38 B 17-phenyl trinor Prostaglandin E2 39 B Prostaglandin E2-biotin 40 C Prostaglandin E2 serinol amide 41 C D12-Prostaglandin D2 42 A 6-keto Prostaglandin E1 43 B CAY10408 44 A Prostaglandin E2 p-acetamidophenyl ester 45 B 15-keto Prostaglandin E2 46 C tetranor-PGEM 47 B ent-Prostaglandin E2 48 C Prostaglandin D1 49 C 15(R)-15-methyl Prostaglandin D2 50 A 8-iso Prostaglandin E1 51 A 16,16-dimethyl Prostaglandin E1 52 A Prostaglandin E2 p-benzamidophenyl ester 53 B 15(R)-15-methyl Prostaglandin E2 54 A 19(R)-hydroxy Prostaglandin E2 55 C Prostaglandin D2 methyl ester 56 C Prostaglandin D1 Alcohol 57 B 15(S)-15-methyl Prostaglandin D2 58 A 13,14-dihydro Prostaglandin E1 59 B 16-phenyl tetranor Prostaglandin E1 60 B 5-trans Prostaglandin E2 61 A 15(S)-15-methyl Prostaglandin E2 62 A 20-ethyl Prostaglandin E2 63 B 3-methoxy Limaprost 64 B Prostaglandin D2 65 C 17-phenyl trinor Prostaglandin D2 66 B 13,14-dihydro-15(R)-Prostaglandin E1 67 A Limaprost 68 A 8-iso Prostaglandin E2 69 A 16,16-dimethyl Prostaglandin E2 70 A Prostaglandin E3 71 B 8-iso-16-cyclohexyl-tetranor Prostaglandin E2 72 C Prostaglandin D2 Ethanolamide 73 A Prostaglandin E1 74 B 13,14-dihydro-15-keto Prostaglandin E1 75 A Misoprostol 76 A 8-iso Prostaglandin E2 isopropyl ester 77 A 16,16-dimethyl Prostaglandin E2 p-(p- acetamidobenzamido) phenyl ester 78 A 17-trans Prostaglandin E3 79 C 13,14-dihydro-15-keto Prostaglandin D1 80 C 17-phenyl trinor PGF2a methyl amide 81 C 11-Misoprostol 82 B 8-iso-15-keto Prostaglandin E2 83 B 19(R)-hydroxy Prostaglandin E1 84 B 16,16-dimethyl-6-keto Prostaglandin E1 85 C 11b-Prostaglandin E1 86 C Carboprost 87 C 15(R)-PGE1 88 B Alprostadil Ethanolamide 89 A 1,11a,15S-Trihydroxy-prost-13E-EN- 9-ONE 90 A BW245C 91 B Latanoprost 92 B DinoprostTromethanol 93 C 2,3-DINOR PGE1 94 B Misoprostol acid 95 C Latanoprostene bunod 96 C 97 B 98 99 Enprostil 100 Rioprostol 101 Ornoprostol 102 Gemeprost
Experimental Example 3: Structural Models of PG Analogs Bound to Nurr1-LBD
[0211] The inventors of the present invention then modelled the two PG analogs, Compound 1 and Compound 2 (
Experimental Example 4: Intranasal Administration of the Present Invention for Treating 6-OHDA Parkinson's Disease Model
[0212] Mice were randomly divided into four groups: Control (n=4); 6-OHDA (6-hydroxydopamine)+(n=7), 6-OHDA+PGE1 (n=8); 6-OHDA+BSC15 (the compound of the present invention) (n=8); 6-OHDA+BSC19 (the compound of the present invention) (n=7).
[0213] Week 9-10 C57BL/6 mice were intranasally administered daily with 0.2 mg/ml of compounds to be tested for 3 days before 6-OHDA injection. Stereotaxic surgery was performed by injecting 7.5 g of 6-OHDA into the left striatum (AP: +0.5 mm, ML: 2.0 mm, VD: 3.5 mm) of the mouse. Compounds to be tested, i.e., PGE1, BSC15 and BSC19 were prepared by double emulsion solvent evaporation of 1:4 molar ratio with 2-hydroxypropyl--cyclodextrin. After surgical recovery, the daily intranasal administration continued with a weekly assessment of apomorphine (0.5 mg/kg) induced rotational behavior. Animal care and handling were performed according to the protocol approved by Nanyang Technological University's Institutional Animal Care and Use Committee.
[0214] Mice treated with PGE1, BSC15 and BSC19 showed a significant reduction in rotation number, suggesting a substantial recovery from the 6-OHDA-induced behavioral deficit. (
CONCLUSION
[0215] As shown above, the PG analogs of the present invention could enhance the activity of Nurr1, and show remarkable effect in treating Parkinson's disease. The invention can be expanded to cancer, rheumatoid arthritis, Alzheimers disease, schizophrenia, manic depression or any disease, disorder, or condition associated with Nurr1. Systematic approach from structure to synthesis and characterization has been provided here to claim that the PG analogs of the present invention could serve as potent therapeutic agents toward treatment of a disease, disorder, or condition associated with Nurr1.