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

• US 20080182995A1
• Filed: 10/31/2007
• Published: 07/31/2008
• Est. Priority Date: 11/12/2003
• Status: Active Grant

• Current Assignee: Sino-Med International Alliance Inc.
• Original Assignee: Phenomix Corporation
• Inventors: Winn, David T., Betancort, Juan Manuel, Campbell, David A.
• Granted Patent: US 7,884,217 B2
• Time in Patent Office: Days
• US Class Current: 548/405
• 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 method of preparing a compound of formula I and the cyclic isomer thereof:

2. The method of claim 1 further comprising, when R² and R³ of the compound of formula I are independently or together groups that can be converted to hydroxyl, converting both R² and R³ to hydroxyl.

3. The method of claim 1 wherein R⁴ and R⁵ of the compound of formula IV are independently or together groups that can be converted to hydroxyl, comprising removing the Pr group of the compound of formula IV and converting R⁴ and R⁵ to hydroxyl.

4. The method of claim 1 wherein the compound of formula I is a mixture of stereoisomers.

5. The method of claim 1 wherein for the compound of formula I 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.

6. The method of claim 1 wherein C^a and C^b of the compound of formula I both have an R configuration and the C^a and C^b of the compound of formula IV both have an R configuration.

7. The method of claim 1 further comprising, prior to the step of removing the Pr group, resolving the intermediate of formula IV to produce a stereomeric mixture in which one or two stereoisomers at least predominate.

8. The method of claim 1 further comprising resolving the compound of formula I to produce at least a stereomeric mixture in which one or two stereoisomers predominate.

9. The method of claim 1, wherein R⁴ and R⁵ 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.

10. The method of claim 1 wherein Pr is Boc, Cbz, or Fmoc.

11. The method of claim 1 wherein Pr is Boc and the step of removing Pr comprises contacting the compound of formula IV with acid.

12. The method of claim 1 wherein Pr is Boc and R⁴ and R⁵ comprise pinanediol, and the step of removing Pr comprises contacting the compound of formula IV with hydrochloric acid and phenylboronic acid.