Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV

• US 7,767,828 B2
• Filed: 05/01/2006
• Issued: 08/03/2010
• Est. Priority Date: 11/12/2003
• Status: Active Grant

• Current Assignee: Phenomix Corporation
• Original Assignee: Phenomix Corporation
• Inventors: Winn, David T., Campbell, David Alan, Betancort, Juan Manuel
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US11/381,090
• Publication Number:
  US 20060264401A1
• Time in Patent Office: 1,555 Days
• Field of Search: 548/405
• US Class Current: 548/405
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention is directed to pyrrolidinylaminoacetyl pyrrolidine boronic acid compounds that display selective, potent dipeptidyl peptidase IV inhibitory activity. These compounds are useful for the treatment of disorders that can be regulated or normalized via inhibition of DPP-IV including those characterized by impaired glycemic control such as Diabetes Mellitus and related conditions. The compounds can be administered alone or with another medicament that displays pharmacological activity for treatment of these and other diseases.

Claims

1. A pyrrolidine compound represented by formula I:

2. A pyrrolidine compound of claim 1 having an R configuration at C^a.

3. The pyrrolidine compound of claim 2 having an R configuration at C^b.

4. The pyrrolidine compound of claim 2 having an S configuration at C^b.

5. An optically enriched stereoisomer of the pyrrolidine compound of claim 1.

6. A stereomeric mixture of two or more stereoisomers of the pyrrolidine compound of claim 1, wherein at least one of the asymmetric carbons, C^a or C^b, has both R and S configurations.

7. A stereomeric mixture of claim 6, which is a mixture of two diastereoisomers, an enantiomeric pair, a racemic mixture, a mixture of an enantiomeric pair plus a diastereomer, or an optically active mixture of at least two stereoisomers.

8. A stereomeric mixture of claim 6, wherein one stereoisomer predominates and the predominant isomer has an R configuration at C^a and an R or S configuration at C^b.

9. A stereomeric mixture of claim 8, wherein the predominant isomer has an R configuration at C^b.

10. A stereomeric mixture of claim 6, wherein two optical isomers predominate, one having R configurations at C^a and C^b, and one having an R configuration at C^a and an S configuration at C^b.

11. A pyrrolidine compound of claim 1 of the structure:

12. A pyrrolidine compound of claim 11 having a stereomeric purity of at least about 90%.

13. A pyrrolidine compound of claim 11 having a stereomeric purity of at least about 98%.

14. A pyrrolidine compound of claim 1 having the structure:

15. A pyrrolidine compound of claim 14 having a stereomeric purity of at least about 90%.

16. A pyrrolidine compound of claim 14 having a stereomeric purity of at least about 98%.

17. A pyrrolidine compound of claim 1 wherein the cyclic isomer form is represented by formula V:

29. A pyrrolidine compound of claim 1, wherein R² and R³ independently or together are the boronic acid protecting group formed from (+)-pinanediol;

pinacol;

1,2-dicyclohexyl-ethanediol;

1,2-ethanediol;

2,2-diethanolamine;

1,3-propanediol;

2,3-butanediol, diisopropyl tartrate;

1,4-butanediol;

diisopropylethanediol;

(S,S,)-5,6-decanediol;

1,1,2-triphenyl-1,2-ethanediol;

(2R,3R)-1,4-dimethoxy-1,1,4,4-tetraphenyl-2,3-butanediol;

methanol;

ethanol;

isopropanol;

catechol;

or 1-butanol.

30. The pyrrolidine compound of claim 1, wherein R¹ is methyl.

31. The pyrrolidine compound of claim 30, wherein R² and R³ are both hydroxyl.

18. A pharmaceutical combination comprising:

(a) a pyrrolidine compound represented by formula I;

19. A pharmaceutical combination of claim 18, wherein the second medicament is the antidiabetic agent.

20. A pharmaceutical combination of claim 19, wherein the weight ratio of the compound of formula I and the antidiabetic agent is from about 0.01:

1 to about 100;

1.

21. A pharmaceutical combination of claim 18, wherein the second medicament is glyburide, glipizide, nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone, acarbose, miglitol, exenatide insulin, or any combination thereof.

22. A pharmaceutical combination of claim 18, wherein the second medicament is suitable for treatment of a diabetes-associated condition.

23. A pharmaceutical composition comprising

(a) a pyrrolidine compound represented by formula I:

24. A pharmaceutical composition of claim 23, further comprising (c) a second medicament selected from the group consisting of a known second medicament that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal track, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides, proteins that affect glycemic control, or any combination thereof.

25. A process for manufacture of a pharmaceutical composition of claim 23 comprising combining a pyrrolidine compound with a pharmaceutically acceptable carrier or diluent.

26. A process of claim 25, wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration or parenteral administration.

27. A process of claim 25, further comprising the step of formulating the composition into a tablet or capsule.

28. A process of claim 25, further comprising the step of lyophilizing the composition or the compound of formula I.