3-(Imidazolyl)-2-aminopropanoic acids

• US 20030191107A1
• Filed: 01/22/2003
• Published: 10/09/2003
• Est. Priority Date: 01/22/2002
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Allerton, Charlotte Moira Norfor, Steele, John, Bunnage, Mark Edward
• Granted Patent: US 6,759,426 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compounds according to formula (I) wherein n is 1-4, R¹ is optionally substituted C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, Heterocycle, Aromatic heterocycle, Aryl or hydrogen and R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen and optionally substituted C_1-6 alkyl are novel. They are useful in the treatment of thrombotic conditions and other pathologies associated with fibrin deposition.

Claims

1. A compound according to formula (I)

2. A compound according to claim 1 wherein the substitution pattern of the imidazole is as depicted in formula (ID¹)

3. A compound according to claim 1 wherein the stereochemistry is as depicted in formula (IA)

4. A compound according to any preceding claim wherein n is 2 or 3.

5. A compound according to claim 4 wherein n is 2.

6. A compound according to any preceding claim wherein R¹ is hydrogen, Aryl or C_1-6 alkyl optionally substituted by C_3-7 cycloalkyl or Aryl.

7. A compound according to claim 6 wherein R¹ is hydrogen, Aryl or C_1-6 alkyl optionally substituted by cyclohexyl or Aryl.

8. A compound according to claim 7 wherein R¹ is hydrogen, phenyl, C_1-5 alkyl or C_1-3 alkyl substituted by cyclohexyl or phenyl.

9. A compound according to claim 7 wherein R¹ is hydrogen, Aryl or propyl.

10. A compound according to claim 8 or claim 9 wherein R¹ is propyl.

11. A compound according to any preceding claim wherein R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen or C_1-3 alkyl.

12. A compound according to claim 11 wherein R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are all hydrogen.

13. A compound according to claim 1, selected from:

(+)-(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-(1H-imidazol-4-yl)propanoic acid;

(+)-(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-(1-propyl-1H-imidazol-4-yl)propanoic acid;

(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-(1-isopentyl-1H-imidazol-4-yl)propanoic acid;

(+)-(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-[1-(2-cyclohexylethyl)-1H-imidazol-4-yl]propanoic acid;

(+)-(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-[1-(2-phenylethyl)-1H-imidazol-4-yl]propanoic acid; and

(+)-(2S)-2-[(3S)-3-aminopyrrolidinyl]-3-[1-phenyl-1H-imidazol-4-yl]propanoic acid, and pharmaceutically acceptable salts thereof.

14. A compound according to any of claims 1 to 12 for use as a medicament.

15. A compound according to any of claims 1 to 12 for use as a medicament for the treatment of a condition selected from thrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in the body.

16. A pharmaceutical composition comprising a compound according to any of claims 1 to 13 and a pharmaceutically acceptable carrier.

17. The use of a compound according to any of claims 1 to 13 for the preparation of a medicament for the treatment of a condition selected from thrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in the body.

18. A use according to claim 17 wherein the medicament is for the treatment of a thrombotic condition.

19. A method of treatment of a condition selected from thrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in the body, comprising administration of a compound according to any of claims 1 to 13 to a subject in need of such treatment.

20. A process for the preparation of a compound according to formula (I)

21. A process for the preparation of a compound according to formula (I)