IP Library › Granted Patent US 7,101,871

Granted Patent B2

US 7,101,871 · App. 10/501,059 · Granted Sep 5, 2006

Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

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Quick Facts

Patent No.: US 7,101,871
App. No.: 10/501,059
Granted: Sep 5, 2006
Kind: B2

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Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Claims (299)

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof; wherein each n is independently 0, 1, or 2;

Ar is phenyl substituted with one to five R 3 substituents;

R 1 is selected from the group consisting of

hydrogen,

C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 alkyloxycarbonyl, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, CN, hydroxy, R 2 , OR 2 , NHSO 2 R 2 , NR 2 SO 2 R 2 , SO 2 R 2 , CO 2 H, and C 1-6 alkyloxycarbonyl,

(CH 2 ) n -heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n -heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; and

wherein any methylene (CH 2 ) carbon atom in R 1 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens;

each R 3 is independently selected from the group consisting of

hydrogen,

halogen,

cyano,

hydroxy,

C 1-6 alkyl, unsubstituted or substituted with one to five halogens,

C 1-6 alkoxy, unsubstituted or substituted with one to five halogens,

carboxy,

alkoxycarbonyl,

amino,

NHR 2 ,

NR 2 R 2 ,

NHSO 2 R 2 ,

NR 2 SO 2 R 2 ,

NHCOR 2 ,

NR 2 COR 2 ,

NHCO 2 R 2 ,

NR 2 CO 2 R 2 ,

SO 2 R 2 ,

SO 2 NH 2 ,

SO 2 NHR 2 , and

SO 2 NR 2 R 2 ;

each R 2 is independently C 1-6 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, CO 2 H, and C 1-6 alkyloxycarbonyl;

R 4 and R 5 are independently selected from the group consisting of:

hydrogen,

cyano,

carboxy,

C 1-6 alkyloxycarbonyl,

C 1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 alkyloxycarbonyl, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,

(CH 2 ) n CONR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH 2 ) n -phenyl, (CH 2 ) n —C 3-6 cycloalkyl, and C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;

or wherein R 6 and R 7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine; and wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; and wherein any methylene (CH 2 ) carbon atom in R 4 or R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens; and

R 8 and R 9 are each independently hydrogen or C 1-6 alkyl.

2. The compound of claim 1 of the formula Ia:

wherein the carbon atom marked with an * has the R configuration and Ar, R 1 , R 4 , R 5 , R 8 , and R 9 are as defined in claim 1 .

3. The compound of claim 1 wherein R 3 is selected from the group consisting of

hydrogen,

halogen,

cyano,

hydroxy,

C 1-6 alkyl, unsubstituted or substituted with one to five halogens, and

C 1-6 alkoxy, unsubstituted or substituted with one to five halogens.

4. The compound of claim 3 wherein R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methyl.

5. The compound of claim 4 wherein R 3 is hydrogen, chloro, or fluoro.

6. The compound of claim 1 wherein R 1 is selected from the group consisting of:

hydrogen,

C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 alkyloxycarbonyl, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

7. The compound of claim 6 wherein R 1 is selected from the group consisting of

hydrogen,

C 1-4 alkyl,

2,2,2-trifluoroethyl,

methoxycarbonylmethyl,

carboxymethyl,

hydroxyethyl,

benzyloxymethyl,

benzyloxyethyl, and

cyclopropyl.

8. The compound of claim 7 wherein R 1 is selected from the group consisting of hydrogen, methyl, tert-butyl, and cyclopropyl.

9. The compound of claim 1 wherein R 4 and R 5 are independently selected from the group consisting of:

hydrogen,

wherein any methylene (CH 2 ) carbon atom in R 4 or R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens.

10. The compound of claim 9 wherein R 4 and R 5 are independently selected from the group consisting of:

hydrogen,

C 1-6 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 alkyloxycarbonyl, and phenyl-C 1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,

11. The compound of claim 10 wherein R 4 and R 5 are independently selected from the group consisting of:

hydrogen,

CH 3 ,

CH 2 CH 3 ,

CH 2 CH(CH 3 ) 2 ,

CH 2 -cyclopropyl,

CH 2 -cyclohexyl,

CH 2 OCH 2 Ph,

CH 2 OH

CH 2 Ph,

CH 2 (3-OCF 3 -Ph),

CH 2 (4-OCF 3 -Ph),

CH 2 (3-CF 3 ,5-CF 3 -Ph),

CH 2 (2-CF 3 -Ph),

CH 2 (2-Cl-Ph),

CH 2 (2-Me-Ph),

CH 2 (2-Me,5-Me-Ph),

CH 2 (2-Ph-Ph),

CH 2 (2-F,5-F-Ph),

CH 2 (2-F-Ph),

CH 2 (2-F,3-F-Ph),

CH 2 (2-pyridinyl),

CH 2 (3-pyridinyl),

CH 2 (4-pyridinyl),

CH 2 (1-oxidopyridin-2-yl),

CH 2 (1-oxidopyridin-3-yl),

CH 2 (1H-pyrazol-1-yl),

CH 2 (2-F,6-F-Ph), and

CH 2 CF 3 .

12. The compound of claim 11 wherein R 5 is hydrogen.

13. The compound of claim 1 wherein R 8 and R 9 are independently selected from hydrogen and methyl.

14. The compound of claim 13 wherein R 8 and R 9 are hydrogen.

15. The compound of claim 1 wherein R 1 is selected from the group consisting of

hydrogen,

C 1-4 alkyl,

2,2,2-trifluoroethyl,

methoxycarbonylmethyl,

carboxymethyl,

hydroxyethyl,

benzyloxymethyl,

benzyloxyethyl, and

cyclopropyl;

R 3 is hydrogen, chloro, or fluoro;

R 4 is selected from the group consisting of:

hydrogen,

CH 3 ,

CH 2 CH 3 ,

CH 2 CH(CH 3 ) 2 ,

CH 2 -cyclopropyl,

CH 2 -cyclohexyl,

CH 2 OCH 2 Ph,

CH 2 OH

CH 2 Ph,

CH 2 (3-OCF 3 -Ph),

CH 2 (4-OCF 3 -Ph), and

CH 2 (3-CF 3 ,5-CF 3 -Ph)

CH 2 (2-CF 3 -Ph),

CH 2 (2-Cl-Ph),

CH 2 (2-Me-Ph),

CH 2 (2-Me,5-Me-Ph),

CH 2 (2-Ph-Ph),

CH 2 (2-F,5-F-Ph),

CH 2 (2-F-Ph),

CH 2 (2-F,3-F-Ph),

CH 2 (2-pyridinyl),

CH 2 (3-pyridinyl),

CH 2 (4-pyridinyl),

CH 2 (1-oxidopyridin-2-yl),

CH 2 (1-oxidopyridin-3-yl),

CH 2 (1H-pyrazol-1-yl),

CH 2 (2-F,6-F-Ph), and

CH 2 CF 3 ; and

R 8 and R 9 are hydrogen.

16. The compound of claim 15 wherein R 5 is hydrogen.

17. The compound of claim 15 which is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 15 of structural formula Ib selected from the group consisting of

R 3

R 4

R 1

2-F, 5-F

2-F, 4-F, 5-F

CH 2 -cPr

2-F, 4-F, 5-F

2-F, 5-F

2-F, 4-F, 5-F

cPr

2-F, 5-F

CH 2 CO 2 Me

2-F, 4-F, 5-F

CH 2 CH 2 OH

2-F, 4-F, 5-F

CH 2 CH 2 OCH 2 C 6 H 5

2-F, 4-F, 5-F

2-F, 5-F

2-F, 4-F, 5-F

CH 2 OH

2-F

CH 2 Ph

3-F, 4-F

CH 2 Ph

2-F, 4-F, 5-F

CH 2 OCH 2 Ph

2-F, 4-F, 5-F

CH 2 Ph

3-F, 4-F

CH 2 Ph

2-F, 5-F

CH 2 (4-OCF 3 —Ph)

2-F, 4-F, 5-F

CH 2 (3-OCF 3 —Ph)

2-F, 4-F, 5-F

CH 2 CH(CH 3 ) 2

2-F, 4-F, 5-F

CH 2 (3-CF 3 , 5-CF 3 —Ph)

2-F, 5-F

2-F, 4-F, 5-F

CH 2 (2-CF 3 —Ph)

2-F, 4-F, 5-F

CH 2 (2-Cl—Ph)

2-F, 4-F, 5-F

CH 2 (2-CH 3 —Ph)

2-F, 4-F, 5-F

CH 2 (2-CH 3 , 5-CH 3 —Ph)

2-F, 4-F, 5-F

CHMe 2

2-F, 4-F, 5-F

CH 2 (2-Ph—Ph)

2-F, 4-F, 5-F

CH 2 (2-F, 5-F—Ph)

2-F, 4-F, 5-F

CH 2 (2-F—Ph)

2-F, 4-F, 5-F

CH 2 CF 3

2-F, 4-F, 5-F

CH 2 (2-F, 3-F—Ph)

2-F, 4-F, 5-F

CH 2 (3-pyridyl)

2-F, 4-F, 5-F

CH 2 (2-F—Ph)

CH 2 CH 2 CH 3

2-F, 4-F, 5-F

CH 2 (4-pyridyl)

2-F, 4-F, 5-F

CH 2 (2-F—Ph)

2-F, 4-F, 5-F

CH 2 (2-pyridyl)

2-F, 4-F, 5-F

CH 2 (2-F, 6-F—Ph)

2-F, 4-F, 5-F

CH 2 CF 3

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.

20. A method for treating diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

21. A method for treating non-insulin dependent (Type 2) diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim 1 .

22. A compound which is:

or a pharmaceutically acceptable salt thereof.

23. A compound which is:

or a pharmaceutically acceptable salt thereof.

24. A compound which is:

or a pharmaceutically acceptable salt thereof.

25. A compound which is:

or a pharmaceutically acceptable salt thereof.

Assignments (2)

CHANGE OF NAME Recorded Aug 29, 2012

From: SCHERING CORPORATION

To: MERCK SHARP & DOHME CORP.

Reel/Frame 028866/0511 →

MERGER Recorded Aug 27, 2012

From: MERCK SHARP & DOHME CORP.

To: SCHERING CORPORATION

Reel/Frame 028850/0515 →