3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
View Patent ↗The present invention is directed to 3-amino-4-phenylbutanoic acid derivatives of structural formula (I) 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.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
each n is independently 0, 1, or 2;
X, Y and Z are independently selected from the group consisting of:
(1) CR 1 ,
(2) NR 2 ,
(3) N,
(4) O, and
(5) S;
with the provisos that at least one of X, Y and Z is not CR 1 and two of X, Y, and Z cannot be O and/or S;
Ar is phenyl substituted with one to five R 3 substituents;
each R 1 is independently selected from the group consisting of
hydrogen,
halogen,
hydroxy,
cyano,
C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C 1-10 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C 1-10 alkylthio, wherein alkylthio is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C 2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, COOH, and COOC 1-6 alkyl,
(CH 2 ) n COOH,
(CH 2 ) n COOC 1-6 alkyl,
(CH 2 ) n CONR 4 R 5 , wherein R 4 and R 5 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 R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine 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;
(CH 2 ) n —NR 4 R 5 ,
(CH 2 ) n —OCONR 4 R 5 ,
(CH 2 ) n —SO 2 NR 4 R 5 ,
(CH 2 ) n —SO 2 R 6 ,
(CH 2 ) n —NR 7 SO 2 R 6 ,
(CH 2 ) n —NR 7 CONR 4 R 5 ,
(CH 2 ) n —NR 7 COR 7 ,
(CH 2 ) n —NR 7 CO 2 R 6 ,
(CH 2 ) n —COR 7 ,
(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,
(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, COOC 1-6 alkyl, 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 -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, and
(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,
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 2 is independently 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 or hydroxy,
C 2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
(CH 2 ) n COOH,
(CH 2 ) n COOC 1-6 alkyl,
(CH 2 ) n CONR 4 R 5 , wherein R 4 and R 5 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 R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, (CH 2 ) n COOC 1-6 alkyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens or one phenyl;
(CH 2 ) n —COR 7 ,
(CH 2 ) n —SO 2 NR 4 R 5 ,
(CH 2 ) n —SO 2 R 6 ,
(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,
(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, C 1-6 alkyloxycarbonyl, 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 -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, and
(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,
wherein any methylene (CH 2 ) carbon atom in R 2 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, and
C 1-6 alkoxy, unsubstituted or substituted with one to five halogens;
R 6 is independently selected from the group consisting of 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, and wherein any methylene (CH 2 ) carbon atom in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
each R 7 is hydrogen or R 6 ;
R 8 , R 9 and R 10 are each independently selected from the group consisting of
hydrogen,
cyano,
(CH 2 ) n COOH,
(CH 2 ) n COOC 1-6 alkyl,
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, and phenyl-C 13 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 -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
(CH 2 ) n CONR 4 R 5 , wherein R 4 and R 5 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 R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, (CH 2 ) n COOC 1-6 alkyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens or one phenyl; and
wherein any methylene (CH 2 ) carbon atom in R 8 , R 9 or R 10 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.
2. The compound of claim 1 of the structural formula Ia wherein the carbon atom marked with an * has the R stereochemical configuration
3. The compound of claim 1 of the structural formula Ib
4. The compound of claim 3 of the structural formula Ic wherein the carbon atom marked with an * has the R stereochemical configuration
5. The compound of claim 3 wherein R 9 and R 10 are hydrogen.
6. The compound of claim 1 of the structural formula Ie
7. The compound of claim 6 of the structural formula If wherein the carbon atom marked with an * has the R stereochemical configuration
8. The compound of claim 6 wherein R 9 and R 10 are hydrogen.
9. The compound of claim 1 of the structural formula Ih
10. The compound of claim 9 of the structural formula Ii wherein the carbon atom marked with an * has the R stereochemical configuration
11. The compound of claim 9 wherein R 9 and R 10 are hydrogen.
12. The compound of claim 1 of the structural formula Ik
13. The compound of claim 12 of the structural formula Il wherein the carbon atom marked with an * has the R stereochemical configuration
14. The compound of claim 12 wherein R 9 and R 10 are hydrogen.
15. The compound of claim 1 of the structural formula In
16. The compound of claim 15 of the structural formula Io wherein the carbon atom marked with an * has the R stereochemical configuration
17. The compound of claim 15 wherein R 9 and R 10 are hydrogen.
18. The compound of claim 1 of structural formula Iq
19. The compound of claim 18 of the structural formula Ir wherein the carbon atom marked with an * has the R stereochemical configuration
20. The compound of claim 18 wherein R 9 and R 10 are hydrogen.
21. The compound of claim 1 of the structural formula It
22. The compound of claim 21 of the structural formula Iu wherein the carbon atom marked with an * has the R stereochemical configuration
23. The compound of claim 21 wherein R 9 and R 10 are hydrogen.
24. The compound of claim 1 of the structural formula Iw
25. The compound of claim 24 of the structural formula Ix wherein the carbon atom marked with an * has the R stereochemical configuration
26. The compound of claim 24 wherein R 9 and R 10 are hydrogen.
27. The compound of claim 1 of the structural formula Iz
28. The compound of claim 27 of the structural formula Iaa wherein the carbon atom marked with an * has the R stereochemical configuration
29. The compound of claim 27 wherein R 9 and R 10 are hydrogen.
30. The compound of claim 1 of the structural formula Iac
31. The compound of claim 30 of the structural formula Iad wherein the carbon atom marked with an * has the R stereochemical configuration
32. The compound of claim 30 wherein R 9 and R 10 are hydrogen.
33. The compound of claim 1 of the structural formula Iaf
34. The compound of claim 33 of the structural formula Ig wherein the carbon atom marked with an * has the R stereochemical configuration
35. The compound of claim 33 wherein R 9 and R 10 are hydrogen.
36. The compound of claim 1 of the structural formula Iai
37. The compound of claim 36 of the structural formula Iaj wherein the carbon atom marked with an * has the R stereochemical configuration
38. The compound of claim 36 wherein R 9 and R 10 are hydrogen.
39. The compound of claim 1 of the structural formula Ial
40. The compound of claim 39 of the structural formula Iam wherein the carbon atom marked with an * has the R stereochemical configuration
41. The compound of claim 39 wherein R 9 and R 10 are hydrogen.
42. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methyl.
43. The compound of claim 1 wherein R 1 is selected from the group consisting of:
hydrogen,
halogen,
hydroxy,
C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C 2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, COOH, and COOC 1-6 alkyl,
(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
(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, COOC 1-6 alkyl, 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.
44. The compound of claim 43 wherein R 1 is selected from the group consisting of
hydrogen,
methyl,
ethyl,
trifluoromethyl,
CH 2 CF 3 ,
CF 2 CF 3 ,
phenyl,
4-(methoxycarbonyl)phenyl,
4-fluorophenyl,
4-(trifluoromethyl)phenyl,
4-(methylsulfonyl)phenyl,
cyclopropyl,
fluoro,
chloro,
bromo, and
2-(methoxycarbonyl)vinyl.
45. The compound of claim 1 wherein R 2 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 or hydroxy,
(CH 2 ) n -aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, CN, hydroxy, NR 7 SO 2 R 6 , SO 2 R 6 , CO 2 H, COOC 1-6 alkyl, 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 2 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.
46. The compound of claim 45 wherein R 2 is selected from the group consisting of:
hydrogen,
methyl,
CH 2 CF 3 ,
isobutyl,
4-(trifluoromethyl)benzyl, and
4-fluorobenzyl.
47. The compound of claim 1 wherein R 8 , R 9 , and R 10 are independently selected from the group consisting of:
hydrogen,
C 1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkoxy,
and phenyl-C 13 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 —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 (CR 2 ) carbon atom in R 8 , R 9 or R 10 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.
48. The compound of claim 47 wherein R 8 , R 9 , and R 10 are each independently selected from the group consisting of
hydrogen,
trifluoromethyl,
methyl,
ethyl,
cyclopropyl,
CR 2 -Ph, and
CR 2 (4-F-Ph).
49. The compound of claim 48 wherein R 9 and R 10 are hydrogen.
50. The compound of claim 49 which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
51. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
52. 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 .