PAR2-modulating compounds and their use

• US 20070123508A1
• Filed: 05/16/2006
• Published: 05/31/2007
• Est. Priority Date: 05/27/2005
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Seitzberg, Jimmi
• Application Number:
  US11/436,130
• Publication Number:
  US 20070123508A1
• Time in Patent Office: Days
• US Class Current: 514/212.30
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 207/277 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/335 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention relates to compounds, their uses for the elucidation of PAR2 activity and their uses for the treatment or prevention of diseases or disorders related to PAR2 activity, wherein the compound has the general chemical structure:

Claims

1. A compound having the chemical structure

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is 1, 2, or 3;

R₁ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4bR_4a, —

OC(═

Z)R₄, and —

SR₄;

R_1a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, halogen, hydroxyl, nitro, amino, sulfonyl, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a;

R₂ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl and unsubstituted or substituted heteroaryl; and

,

R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

NR₄NR_4aR_4b, —

NR₄N═

CR_4aR_4b, —

N(R₄)C(R_4a)═

NR_4b, —

N(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4bR_4a, and —

SR₄, wherein;

Z is oxygen or sulfur; and

,

R₄, R_4a and R_4b are independently selected from the group consisting of;

hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl.

2. The compound of claim 1, wherein:

R₃ is selected from the group consisting of —

CH₂R₅, —

OR_5a and —

NR_5bR_5c, wherein;

R₅ is selected from the group consisting of hydrogen;

alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, nitro, amino, halogen, sulfonyl, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

N═

CR₄R_4a, —

C(R₄)═

NR_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4aR_4b, —

OC(═

Z)R₄, and —

SR₄;

R_5a is selected from the group consisting of hydrogen;

alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and,

R_5b and R_5c, is selected from the group consisting of hydrogen;

alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, amino, sulphonate, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

N═

CR₄R_4a, —

C(R₄)═

NR_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4aR_4b, —

OC(═

Z)R₄, and —

SR₄.

3. The compound of claim 1, wherein:

R₃ is selected from the group consisting of

wherein;

R₆, R₇, and R₉ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, nitro, amino, halogen, sulfonate, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, N(R₄)—

C(═

Z)NR_4aR_4b, —

OC(═

Z)R₄, and —

SR₄;

R₈, R_8a and R_8b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl;

substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, nitro, amino, halogen, sulfonyl, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4aR_4b, —

OC(═

Z)R₄, and —

SR₄;

R₁₀ and R₁₁ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl;

substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, nitro, amino, halogen, sulfonyl, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

(R₄)—

C(═

Z)R_4a, —

N(R₄)—

C(═

Z)NR_4aR_4b, —

OC(═

Z)R₄, and —

SR₄;

r is 0, 1 or 2; and

s is 0, 1, 2, 3 or 4.

4. The compound of claim 1, wherein:

R₁ is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein if substituted, the substituent is one or more independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, nitro, amino, halogen, sulfonate, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R_4b)—

C(═

Z)NR₄R_4a, —

OC(═

Z)R₄, and —

SR₄.

5. The compound of claim 1, wherein:

R₃ is selected from the group consisting of;

wherein;

R₈ is hydrogen or alkyl;

X is NH, O or S;

each R₁₃ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxy, nitro, amino, halogen, sulfonyl, perhaloalkyl, —

OR₄, —

NR₄R_4a, —

CN, —

C(═

Z)R₄, —

C(═

Z)OR₄, —

C(═

Z)NR₄R_4a, —

N(R₄)—

C(═

Z)R_4a, —

N(R_4b)—

C(═

Z)NR₄R_4a, —

OC(═

Z)R₄, and —

SR4;

r is 0, 1, 2, 3,4 or 5;

s is 0, 1, 2, 3 or 4; and

,

t is 0, 1 or 2.

6. A method of treating or preventing a disease or disorder related to abnormal PAR2 activity, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

7. The method of claim 6, wherein the disease or disorder is selected from the group consisting of:

acute or chronic pain;

acute or chronic inflammation;

diseases or disorder of the pulmonary system;

diseases or disorders of the gastrointestinal system;

diseases or disorders of the musculoskeletal system;

diseases or disorders of the central nervous system;

diseases or disorders of the cardiovascular system;

disease or disorders of the renal system;

diseases or disorders of the hepatic system;

diseases of disorders of the eye;

diseases or disorders of the skin;

diseases or disorders of the prostrate;

diseases or disorders of the pancreas;

Sjogren'"'"'s syndrome; and

,

dry mouth.

8. The method of claim 7, wherein the disease or disorder of the pulmonary system is selected from the group consisting of asthma, chronic obstructive pulmonary disease, lung cancer and pneumonitis.

9. The method of claim 7, wherein the disease or disorder of the gastrointestinal system is selected from the group consisting of gastric ulcers, colitis, inflammatory bowel syndrome, Crohn'"'"'s disease, gastric and intestinal motility, colon cancer, cancer of the stomach, and cancer of the intestine.

10. The method of claim 7, wherein the disease or disorder of the musculoskeletal system is selected from the group consisting of rheumatoid arthritis, osteoporosis and Paget'"'"'s disease.

11. The method of claim 7, wherein the disease or disorder of the central nervous system is selected from the group consisting of Alzheimer'"'"'s disease, encephalitis, meningitis, ischemia and stroke.

12. The method of claim 7, wherein the disease or disorder of the cardiovascular system is selected from the group consisting of hypertension, atherosclerosis, angina, congestive heart failure, myocarditus and cardiac ischemia.

13. The method of claim 7, wherein the disease or disorder of the renal system is selected from the group consisting of glomerular kidney disease, kidney cancer and renal failure.

14. The method of claim 7, wherein the disease or disorder of the hepatic system is selected from the group consisting hepatitis and liver cancer.

15. The method of claim 7, wherein the disease or disorder of the eye is selected from the group consisting of glaucoma, retinitis pigmentosa, cataracts, macular degeneration and dry eye.

16. The method of claim 7, wherein the disease or disorder of the skin is selected from the group consisting of dermatitis, psoriasis, pruritis, dermatitis, eczema, seborrhea, wounds, and melanoma.

17. The method of claim 7, wherein the disease or disorder of the pancreatic system is selected from the group consisting of pancreatitus, pancreatic cancer and diabetes.

18. The method of claim 7, wherein the disease or disorder is dry mouth.

19. The method of claim 7, wherein the the disease or disorder is Sjogren'"'"'s syndrome.

20. The method of claim 7, wherein the disease or disorder is acute or chronic pain.

21. The method of claim 7, wherein the disease or disorder is acute or chronic inflammation.

22. The method of claim 7, wherein the disease of disorder of the prostatic system is selected from the group consisting of benign prostatic hyperplasia and prostatic cancer.

23. The method of claim 7, wherein the disease or disorder of the pancreatic system is selected from the group consisting of pancreatitis, diabetes and pancreatic cancer.

24. The method of claim 1 wherein the compound is selected from the group consisting of:

2Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(3-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide (3)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(5-bromo-thiophen-2-yl)-(E/Z)-ethylidene]-hydrazide (4)

2-Oxo-4-phenyl-3-pyrrolidinecarboxyqic acid [1-(thiophen-2-yl)-(E/Z)-ethylidene]-hydrazide (5)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(4-bromo-thiophen-2-yl)-(E/Z)-ethylidene]-hydrazide (6)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(5-bromo-pyridine-3-yl)-(E/Z)-ethylidene]-hydrazide (7)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(4-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide (8)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(2-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide (9)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(3-methoxy-phenyl)-(E/Z)-ethylidene]-hydrazide (10)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(toluen-3-yl)-(E/Z)-ethylidene]-hydrazide (11)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(3-trifluoromethyl-phenyl)-(E/Z)-ethylidene]-hydrazide (12)

2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid N′

-[1-(3-bromo-phenyl)-(E/Z)-ethyl]-hydrazide (13)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3,5-dimethylphenyl)ethylidene]hydrazide (14)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-7-bromo-2,3-dihydro-4-methyl-1H-inden-1-ylidene]hydrazide (15)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-5-(acetylamino)-2,3-dihydro-1H-inden-1-ylidene]hydrazide (16)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(5-carboxy-2-thienyl)ethylidene]hydrazide (17)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(4-chlorophenyl)-3-(dimethylamino)propylidene]hydrazide (18)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(1H-pyrrol-2-yl)ethylidene]hydrazide (19)

2-oxo-N′

-[(E/Z)-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethylidene]-4-phenyl-3-pyrrolidinecarbohydrazide (20)

N′

-[(4 E/Z)-2,3-dihydro-4H-chromen-4-ylidene]-2-oxo-4-phenyl-3-pyrrolidinecarbohydrazide (21)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-fluorophenyl)ethylidene]hydrazide (22)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-chlorophenyl)ethylidene]hydrazide (23)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-cyanophenyl)ethylidene]hydrazide (24)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-hydroxyphenyl)ethylidene]hydrazide (25)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3,5-dimethoxyphenyl)ethylidene]hydrazide (26)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-[3,5-bis(trifluoromethyl)phenyl]ethylidene]hydrazide (27)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3,5-difluorophenyl)ethylidene]hydrazide (28)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3,4-dimethylphenyl)ethylidene]hydrazide (29)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(1,3-benzodioxol-5-yl)ethylidene]hydrazide (30)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethylidene]hydrazide (31)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethylidene]hydrazide (32)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,3-dihydro-2-oxo-6-benzothiazolyl)ethylidene]hydrazide (33)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,5-dichloro-3-thienyl)ethylidene]hydrazide (34)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,5-dimethyl-3-thienyl)ethylidene]hydrazide (35)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,5-dimethyl-3-furanyl)ethylidene]hydrazide (36)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,5-dimethyl-3-furanyl)ethylidene]hydrazide (37)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(5-chloro-2-thienyl)ethylidene]hydrazide (38)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(5-methyl-2-thienyl)ethylidene]hydrazide (39)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(5-cyano-2-thienyl)ethylidene]hydrazide (40)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(5-bromo-2-hydroxyphenyl)ethylidene]hydrazide (41)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(4-methyl-2-thienyl)ethylidene]hydrazide (42)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-2,3-dihydro-5-methoxy-1H-inden-1-ylidene]hydrazide (43)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-2,3-dihydro-5,6-dimethoxy-1H-inden-1-ylidene]hydrazide (44)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-5-fluoro-2,3-dihydro-1H-inden-1-ylidene]hydrazide (45)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-2,3-dihydro-6-methoxy-1H-inden-1-ylidene]hydrazide (46)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-5-bromo-2,3-dihydro-1H-inden-1-ylidene]hydrazide (47)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-2,3-dihydro-6-methyl-1H-inden-1-ylidene]hydrazide (48)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-2,3-dihydro-4,5-dimethoxy-1H-inden-1-ylidene]hydrazide (49)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,4-dimethoxyphenyl)ethylidene]hydrazide (50)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,6-difluorophenyl)ethylidene]hydrazide (51)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-fluoro-4-methoxyphenyl)ethylidene]hydrazide (52)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3,4-difluorophenyl)ethylidene]hydrazide (53)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(4 E/Z)-6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-ylidene]hydrazide (54)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,3-difluorophenyl)ethylidene]hydrazide (55)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(4 E/Z)-2,3-dihydro-6-methyl-4H-1-benzopyran-4-ylidene]hydrazide (56)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,3,4,5,6-pentafluorophenyl)ethylidene]hydrazide (57)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-[3-(acetylamino)phenyl]ethylidene]hydrazide (58)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(1-methyl-1H-pyrrol-3-yl)ethylidene]hydrazide (59)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(2,4-dimethyl-1H-pyrrol-3-yl)ethylidene]hydrazide (60)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(1-methyl-1H-pyrrol-2-yl)ethylidene]hydrazide (61)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(E/Z)-1-(3-thienyl)ethylidene]hydrazide (62)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-3,4-dihydro-7-nitronaphthalenylidene]hydrazide (63)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-6-bromo-2,3-dihydro-1H-inden-1-ylidene]hydrazide (64)

2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid 2-[(1 E/Z)-5-chloro-2,3-dihydro-6-methoxy-1H-inden-1-ylidene]hydrazide (65)

25. A method for the treatment or prevention of a disease or disorder related to abnormal PAR2 activity comprising administering to a patient in need thereof a compound of claim 24.