Constrained cyano compounds

• US 7,786,163 B2
• Filed: 07/12/2005
• Issued: 08/31/2010
• Est. Priority Date: 07/12/2004
• Status: Expired due to Fees

• Current Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Original Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Inventors: Winn, David T., Campbell, David Alan, Betancort, Juan Manuel
• Primary Examiner(s): Saeed; Karmal A
• Assistant Examiner(s): BIANCHI, KRISTIN A
• Application Number:
  US11/179,797
• Publication Number:
  US 20060009518A1
• Time in Patent Office: 1,876 Days
• Field of Search: 514/522, 514/413, 558/410, 548/453
• US Class Current: 514/413
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/28 : Antiandrogens
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Certain constrained cyano compounds are useful as inhibitors of post-proline/alanine cleaving amino-dipeptidases. Accordingly, these compounds can be employed, alone or with another therapeutic agent, to treat diabetes (especially, Type II diabetes), hyperglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease.

Claims

1. A compound selected from the group consisting of:

6-Amino-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-methyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile,

6-Amino-6-ethyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-isopropyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclopentyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclohexyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-isobutyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-sec-butyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-5-oxo-6-phenethyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-benzyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclohexylmethyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-(4-fluoro-phenyl)-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride, and

6-Amino-5-oxo-6-phenyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

2. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier or diluent.

3. The compound of claim 1, wherein the compound is 6-Amino-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

4. The compound of claim 1, wherein the compound is 6-Amino-6-methyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile.

5. The compound of claim 1, wherein the compound is 6-Amino-6-ethyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

6. The compound of claim 1, wherein the compound is 6-Amino-6-isopropyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

7. The compound of claim 1, wherein the compound is 6-Amino-6-cyclopentyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

8. The compound of claim 1, wherein the compound is 6-Amino-6-cyclohexyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

9. The compound of claim 1, wherein the compound is 6-Amino-6-isobutyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

10. The compound of claim 1, wherein the compound is 6-Amino-6-sec-butyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

11. The compound of claim 1, wherein the compound is 6-Amino-5-oxo-6-phenethyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

12. The compound of claim 1, wherein the compound is 6-Amino-6-benzyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

13. The compound of claim 1, wherein the compound is 6-Amino-6-cyclohexylmethyl5oxo-hexahydro-pyrrolo[2,1-b]thiazole-3carbonitrile hydrochloride.

14. The compound of claim 1, wherein the compound is 6-Amino-6-(4-fluoro-phenyl)-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

15. The compound of claim 1, wherein the compound is 6-Amino-5-oxo-6-phenyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

33. A pharmaceutical composition comprising the compound of claim 1 and at least one compound selected from the group consisting of metformin, pioglitazone, a sulfonyl urea, and a thiazolidinedione.

16. A compound selected from the group consisting of compounds (i)-(xvi) and pharmaceutically acceptable salts thereof:

17. The compound of claim 16, wherein the compound is compound (i) or a pharmaceutically acceptable salt thereof.

18. The compound of claim 16, wherein the compound is compound (ii) or a pharmaceutically acceptable salt thereof.

19. The compound of claim 16, wherein the compound is compound (iii) or a pharmaceutically acceptable salt thereof.

20. The compound of claim 16, wherein the compound is compound (iv) or a pharmaceutically acceptable salt thereof.

21. The compound of claim 16, wherein the compound is compound (v) or a pharmaceutically acceptable salt thereof.

22. The compound of claim 16, wherein the compound is compound (vi) or a pharmaceutically acceptable salt thereof.

23. The compound of claim 16, wherein the compound is compound (vii) or a pharmaceutically acceptable salt thereof.

24. The compound of claim 16, wherein the compound is compound (viii) or a pharmaceutically acceptable salt thereof.

25. The compound of claim 16, wherein the compound is compound (ix) or a pharmaceutically acceptable salt thereof.

26. The compound of claim 16, wherein the compound is compound (x) or a pharmaceutically acceptable salt thereof.

27. The compound of claim 16, wherein the compound is compound (xi) or a pharmaceutically acceptable salt thereof.

28. The compound of claim 16, wherein the compound is compound (xii) or a pharmaceutically acceptable salt thereof.

29. The compound of claim 16, wherein the compound is compound (xiii) or a pharmaceutically acceptable salt thereof.

30. The compound of claim 16, wherein the compound is compound (xiv) or a pharmaceutically acceptable salt thereof.

31. The compound of claim 16, wherein the compound is compound (xv) or a pharmaceutically acceptable salt thereof.

32. The compound of claim 16, wherein the compound is compound (xvi) or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising the compound of claim 16 and at least one compound selected from the group consisting of metformin, pioglitazone, a sulfonyl urea, and a thiazolidinedione.