Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)

• US 7,205,409 B2
• Filed: 09/07/2004
• Issued: 04/17/2007
• Est. Priority Date: 09/04/2003
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Sham, Hing L., Longenecker, Kenton L., Pei, Zhonghua, Li, Xiaofeng, Wiedeman, Paul E.
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US10/935,053
• Publication Number:
  US 20050131019A1
• Time in Patent Office: 952 Days
• Field of Search: 514/312, 514/343, 514/422, 546/153, 546/268.1, 548/518
• US Class Current: 546/153
• CPC Class Codes: C07D 207/16 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to compounds of formula (I),

which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

Claims

1. A compound of Formula (I)

2. The compound according to claim 1, wherein

3. The compound according to claim 1, wherein

4. The compound according to claim 1, wherein

5. The compound according to claim 1, wherein

6. The compound according to claim 1, wherein

7. The compound according to claim 1, wherein

8. The compound according to claim 1, wherein

9. The compound according to claim 1, wherein

10. The compound according to claim 1, wherein

11. The compound according to claim 1, wherein

12. The compound according to claim 1, wherein

13. The compound according to claim 1, wherein

14. The compound according to claim 1, wherein

15. The compound according to claim 1, wherein

16. The compound according to claim 1, wherein

17. The compound according to claim 1, wherein

18. The compound according to claim 1, wherein

19. The compound according to claim 1, wherein

20. The compound according to claim 1, wherein

21. The compound according to claim 1, wherein

22. The compound according to claim 1, wherein

23. The compound according to claim 1, wherein

24. The compound according to claim 1, wherein

25. The compound according to claim 1, that is selected from the group consisting of

(2S)-1-{(5R)-5-((2-chlorophenoxy)methyl)-L-prolyl}pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-(naphthalen-1-yloxymethyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-cyano-2-methoxyphenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((2-cyano-4-trifluoromethylphenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((2-chloro-4-cyanophenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((2-chloropyridyl-3-oxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-carboxy-2-methoxyphenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-carboxy-2-tert-butylphenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-carboxy-2-chlorophenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-carboxy-2-iso-propylphenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-([4-(tetrazol-5-yl)-2-chlorophenoxy]-methyl) L-prolyl}-pyrrolidin-2-carbonitrile;

(2S)-1-{(5R)-5-((5-carboxy-2-chlorophenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-(5-carboxynaphthalen-1-yloxymethyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((4-carboxynaphthalen-1-yloxy)methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((5-carboxy-3-chloropyridyl-2-oxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-{(5R)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl}-pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-methylphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-methoxyphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2,4-dichlorophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[2-bromo-4-(trifluoromethyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(4-bromo-2-methoxyphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-chloro-4-methoxyphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(4-bromo-2-chlorophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[(4-chloro-1-naphthyl)oxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(quinolin-4-yloxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(quinolin-5-yloxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[4-bromo-2-(1H-pyrazol-3-yl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-tert-butylphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-tert-butyl-4-cyanophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(4-bromo-2-tert-butylphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-isopropylphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

ethyl 3-tert-butyl-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoate;

{3-tert-butyl-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin--1 yl]carbonyl}pyrrolidin-2-yl)methoxy]phenoxy}acetic acid;

(2S)-1-[((2S,5R)-5-{[2-methoxy-4-(1H-tetraazol-5-yl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

3-tert-butyl-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzamide;

(2S)-1-[((2S,5R)-5-{[2-isopropyl-4-(1H-tetraazol-5-yl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]pyrrolidine-2-carboxylic acid;

(2S)-1-[((2S,5R)-5-{[4-(1-tert-butyl-1H-tetraazol-5-yl)-2-isopropylphenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[4-(1-tert-butyl-1H-tetraazol-5-yl)-2-chlorophenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

5-chloro-2-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoic acid;

{2-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}acetic acid;

3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4-fluorobenzoic acid;

3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4-isopropylbenzoic acid;

2-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-1-naphthoic acid;

3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-N,N-dimethylbenzamide;

(2S)-1-[((2S,5R)-5-{[(2-chloro-1-oxidopyridin-3-yl)oxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(2-chloro-4-morpholin-4-ylphenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-({(2S,5R)-5-[(4-amino-2-chlorophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoic acid;

6-chloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]nicotinic acid 1-oxide;

6-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-2-naphthoic acid;

(2S)-1-[((2S,5R)-5-{[2-chloro-4-(methylsulfonyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[4-chloro-2-(hydroxymethyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

5-chloro-6-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-2-naphthoic acid;

(2S)-1-[((2S,5R)-5-{[(6-chloro-1,3-benzodioxol-5-yl)oxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

N-{4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-1-naphthyl}methanesulfonamide;

(2S)-1-[((2S,5R)-5-{[2-bromo-4-(methylsulfonyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[(6-bromo-1,3-benzodioxol-5-yl)oxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

2-chloro-N-{3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}benzenesulfonamide;

N-{3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}methanesulfonamide;

N-{3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}acetamide;

(2S)-1-({(2S,5R)-5-[(1-benzothien-4-yloxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-[((2S,5R)-5-{[4-bromo-2-(methylsulfonyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}acetamide;

N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}methanesulfonamide;

N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}benzenesulfonamide;

N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-2-chlorobenzenesulfonamid;

methyl 2,3-dichloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoate;

3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4-methoxybenzoic acid;

2,3-dichloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoic acid;

(2S)-1-({(2S,5R)-5-[(2,4-dichloro-5-nitrophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

tert-butyl 2,3-dichloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoate;

ethyl 4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoate;

isopropyl 4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]benzoate;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}acetamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}acrylamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}benzamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-2-methoxyacetamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-2-(2-methoxyethoxy)acetamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}cyclopropanecarboxamide;

ethyl 2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenylcarbamate;

bis-[N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}]methanesulfonamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl)}-1-phenylmethanesulfonamide;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-N′

-phenylurea;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-N′

-(3,5-dimethoxyphenyl)urea;

N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]phenyl}-N′

-(4-nitrophenyl)urea;

(2S)-1-({(2S,5R)-5-[(5-amino-2,4-dichlorophenoxy)methyl]pyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile;

isopropyl 6-chloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]nicotinate;

(2S)-1-[((2S,5R)-5-{[2-chloro-3-(methylsulfonyl)phenoxy]methyl}pyrrolidin-2-yl)carbonyl]pyrrolidine-2-carbonitrile;

ethyl 3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4,5-difluorobenzoate;

3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4,5-difluorobenzoic acid; and

tert-butyl 3-[((2R,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}pyrrolidin-2-yl)methoxy]-4,5-difluorobenzoate.