Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV

• US 7,576,121 B2
• Filed: 05/01/2006
• Issued: 08/18/2009
• Est. Priority Date: 11/12/2003
• Status: Active Grant

• Current Assignee: Sino-Med International Alliance Inc.
• Original Assignee: Phenomix Corporation
• Inventors: Winn, David T., Campbell, David Alan, Betancort, Juan Manuel
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): NOLAN, JASON MICHAEL
• Application Number:
  US11/381,082
• Publication Number:
  US 20060258621A1
• Time in Patent Office: 1,205 Days
• Field of Search: 548/405, 514/422
• US Class Current: 514/422
• 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 (DPP-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. The pyrrolidine compound of claim 1, wherein R¹ is a substituted or unsubstituted (C_3-8)alkyl or (C_3-12)cycloalkyl group;

or is a (C_1-4 alkyl)phenyl or phenyl group, wherein the (C_1-4 alkyl)phenyl and phenyl, groups are optionally mono- or independently di-substituted with R⁴; and

wherein,

R⁴ is halogen, trifluoromethyl, cyano, nitro, (C_1-6)alkyl, (C_1-6)alkoxy, cycloalkyl, carboxy, acetamido, hydroxyl, hydroxy(C_1-6)alkyl, hydroxymethyl, trifluoromethoxy, amido, carbamyl, sulfonamide, alkylsulfonyl, phenylsulfonyl, aryl, heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more R⁵; and

R⁵ is halogen, (C_1-6)alkyl, (C_1-6)alkoxy, (C_1-6)alkylamino, (C_1-10) dialkylamino, benzyl, benzyloxy, hydroxyl(C_1-6)alkyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano, carboxy, acetamido, hydroxyl, sulfonamide, or carbamyl.

12. The pyrrolidine compound of claim 1, wherein R¹ is a substituted or unsubstituted (C_3-6)alkyl or (C_1-4 alkyl)phenyl group.

13. The pyrrolidine compound of claim 1, wherein R¹ is propyl, butyl, isopropyl, isobutyl, cyclopentyl, t-butyl or benzyl.

14. The pyrrolidine compound of claim 1, wherein R² and R³ are independently hydroxyl, methoxy, ethoxy, n-propoxy, i-propoxy, or n-butoxy;

or together are 1,2-dioxaethylene, 1,3-dioxapropylene, or pinanedioxy.

15. The pyrrolidine compound of claim 1, wherein R² and R³ are both hydroxyl.

16. The pyrrolidine compound of claim 1 selected from the group consisting of (2R)-1-{2-[(3S)-Pyrrolidin-3-propyl-3 -ylamino]-acetyl}-pyrrolidine-2-boronic acid, (2R)- 1- {2-[(3R)-Pyrrolidin-3-propyl-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid, (2R)- 1- {2-[(3S) -Pyrrolidin-3-benzyl-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid, (2R)-1-{2-[(3R) -Pyrrolidin-3-benzyl-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid.

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

18. A pyrrolidine compound of claim 17 having a stereomeric purity of at least about 90%.

19. A pyrrolidine compound of claim 17 having a stereomeric purity of at least about 98%.

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

21. A pyrrolidine compound of claim 20 having a stereomeric purity of at least about 90%.

22. A pyrrolidine compound of claim 20 having a stereomeric purity of at least about 98%.

54. 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-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol;

methanol;

ethanol;

isopropanol;

catechol;

or 1-butanol.

55. The pyrrolidine compound of claim 1, wherein R² and R³ are both hydroxyl.

56. The pyrrolidine compound of claim 1, wherein R¹ is a substituted or unsubstituted (C_3-8) alkyl, (C_2-8) alkenyl, (C₆-C₁₅) aralkyl, (C₃-C₁₂) cycloalkyl, (C₄-C₂₀) cycloalkylalkyl, (C₃-C₁₂) cycloalkenyl, (C₄-C₂₀) cycloalkenylalkyl, (C₃-C₂₀ with N, O and/or S) heterocyclyl, or (C₄-C₂₀ with N, O and/or S) heterocyclylalkyl group.

23. A pharmaceutical combination comprising:

a pyrrolidine compound represented by formula I;

24. A pharmaceutical combination of claim 23, wherein the second medicament is an antidiabetic agent.

25. A pharmaceutical combination of claim 24, wherein the weight ratio of the compound of formula I and the antidiabetic agent is from about 0.01:

1 to about 100;

1.

26. A pharmaceutical combination of claim 23, wherein the second medicament is glyburide, glipizide, nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone, acarbose, miglitol, exenatide, insulin, or any combination thereof.

27. A pharmaceutical combination of claim 23, wherein the second medicament is suitable for treatment of a diabetes-associated condition.

28. A pharmaceutical composition comprising:

a pyrrolidine compound represented by formula I;

29. A pharmaceutical composition of claim 28, 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.

30. A process for manufacture of a pharmaceutical composition of claim 28 comprising combining a pyrrolidine compound with a pharmaceutically acceptable carrier or diluent.

31. The process of claim 30, wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration or parenteral administration.

32. The process of claim 30, further comprising the step of formulating the composition into a tablet or capsule.

33. The process of claim 30, further comprising the step of lyophilizing the composition or the compound of formula I.

34. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with an effective amount of a pyrrolidine compound represented by formula I:

35. A method according to claim 34, wherein the dipeptidyl peptidase-IV is within a mammal in need of treatment for a malcondition selected from diabetes or errors in glucose metabolism, and the contacting step comprises administering to the mammal a therapeutically effective amount of a compound of formula I.

36. The method of claim 35, wherein the malcondition is impaired glycemic control.

37. The method of claim 35, wherein the malcondition is diabetes.

38. The method of claim 35, further comprising administering a therapeutically effective amount of 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.

39. The method of claim 34, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over at least one other dipeptidyl peptidase.

40. The method of claim 39, wherein the selective inhibition is by greater than 5-fold.

41. The method of claim 39, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII, dipeptidyl peptidase-VIII, dipeptidyl peptidase-IX or fibroblast activation protein.

42. The method of claim 39, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII by greater than 10-fold.

43. The method of claim 39, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII and fibroblast activation protein.

44. The method of claim 39, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII, dipeptidyl peptidase-VIII, and fibroblast activation protein.

45. A process for preparing an intermediate of formula IV:

46. The process of claim 45, wherein L is a halogen, mesylate, tosylate or triflate, and Pr is Boc, Cbz, Fmoc, or benzyl.

47. The process of claim 45, wherein the absolute configuration at C^a is R, and the absolute configuration at C^b is R or S.

48. A process for preparing a pyrrolidine compound represented by formula I and the cyclic isomer thereof:

49. A process of claim 48, further comprising converting R⁴ and R⁵ to hydroxyl such that R² and R³ are both hydroxyl.

50. The process of claim 49, wherein the pyrrolidine compound is a mixture of stereoisomers.

51. The process of claim 49 wherein one or two of the stereoisomers predominate and those stereoisomers have an R configuration at C^a and an R or S configuration C^b.

52. The process of claim 45, further comprising resolving the intermediate of formula IV to produce at least a stereomeric mixture in which one or two stereoisomers predominate.

53. The process of claim 48, further comprising resolving the pyrrolidine compound to produce at least a stereomeric mixture in which one or two stereoisomers predominate.