PYRROLIDINE COMPOUNDS AND METHODS FOR SELECTIVE INHIBITION OF DIPEPTIDYL PEPTIDASE-IV

• US 20060264400A1
• Filed: 05/01/2006
• Published: 11/23/2006
• 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
• Granted Patent: US 7,317,109 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 having 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 1 wherein the cyclic isomer form is represented by formula V:

47. 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.

16. A pharmaceutical combination comprising:

(a) a pyrrolidine compound represented by formula I;

 

a cyclic isomer thereof, any pharmaceutically acceptable salt thereof, any prodrug thereof, or any solvate thereof;

wherein R² and R³ independently or together are —

OH, —

O⁻

M⁺ wherein M⁺ is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids, and the wavy lines at asymmetric carbons C^a and C^b independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and all stereomeric mixtures are included; and

(b) 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, provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.

17. A pharmaceutical combination of claim 16 wherein the second medicament is the antidiabetic agent.

18. A pharmaceutical combination of claim 17, wherein the weight ratio of the compound of formula I and the antidiabetic agent is from about 0.01:

1 to about 100;

1.

19. A pharmaceutical combination of claim 16, wherein the second medicament is glyburide, glipizide, nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone, acarbose, miglitol, exenatide, insulin, or any combination thereof.

20. A pharmaceutical combination of claim 16 wherein the second medicament is suitable for treatment of a diabetes-associated condition.

21. A pharmaceutical composition comprising:

(a) a pyrrolidine compound represented by formula I;

 

or a cyclic isomer thereof, or any pharmaceutically acceptable salt thereof, any prodrug thereof, or any solvate thereof;

wherein R² and R³ independently or together are —

OH, —

O⁻

M⁺ wherein M⁺ is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids, and the wavy lines at asymmetric carbons C^a and C^b independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and stereomeric mixtures are included; and

(b) a pharmaceutically acceptable carrier.

22. A pharmaceutical composition of claim 21, 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.

23. A process for manufacture of a pharmaceutical composition of claim 21 comprising combining a pyrrolidine compound with a pharmaceutically acceptable carrier or diluent.

24. A process of claim 23, wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration or parenteral administration.

25. A process of claim 23, further comprising the step of formulating the composition into a tablet or capsule.

26. A process of claim 23, further comprising the step of lyophilizing the composition or the compound of formula I.

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

28. A method of claim 27 wherein the dipeptidyl peptidase-IV is within a mammal in need of treatment for a malcondition that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV and the contacting step comprises administering to the mammal a therapeutically effective amount of a compound of formula I.

29. A method of claim 28, wherein the malcondition is impaired glycemic control.

30. A method of claim 28, wherein the malcondition is diabetes.

31. A method of claim 28, 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.

32. A method of claim 27, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over at least one other dipeptidyl peptidase.

33. A method of claim 32, wherein the selective inhibition is by greater than 5-fold.

34. A method of claim 33, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII, dipeptidyl peptidase-VIII, dipeptidyl peptidase-IX or fibroblast activation protein.

35. A method of claim 33, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII by greater than 10-fold.

36. A method of claim 33, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII and fibroblast activation protein.

37. A method of claim 33, wherein the pyrrolidine compound selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII, dipeptidyl peptidase-VIII, and fibroblast activation protein.

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

39. A process of claim 38, wherein L is a halogen, mesylate, tosylate or triflate, and Pr is Boc, Cbz, Fmoc, or benzyl.

40. A process of claim 38 wherein the absolute configuration at C^a is R and the absolute configuration at C^b is R or S.

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

42. A process of claim 41 further comprising converting R⁴ and R⁵ to hydroxyl such that R² and R³ are both hydroxyl.

43. A process of claim 42, wherein the pyrrolidine compound is a mixture of stereoisomers.

44. A process of claim 42, wherein one or two of the stereoisomers predominate and those stereoisomers have an R configuration at C^a and an R or S configuration at C^b.

45. A process of claim 38 further comprising resolving the intermediate of formula IV to produce at least a stereomeric mixture in which one or two stereoisomers predominate.

46. A process of claim 41 further comprising resolving the pyrrolidine compound to produce at least a stereomeric mixture in which one or two stereoisomers predominate.