Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
View Patent ↗The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme 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
V is selected from the group consisting of:
Ar is phenyl unsubstituted or substituted with one to five halogen atoms;
R 1 and R 2 are each independently selected from the group consisting of:
C 1 -C 6 alkyl;
cycloalkyl;
heterocyclyl; and
heteroaryl;
R 3 is selected from the group consisting of:
C 1 -C 6 alkyl;
cycloalkyl;
heterocyclyl;
cyano;
heteroaryl;
—C(O)O C 1 -C 6 alkyl; and
—C(O)NH 2 ;
wherein each C 1-6 alkyl, cycloalkyl, heteroaryl, and heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of:
cyano;
—OH;
—C(O)NH 2 ;
—CO 2 H;
—C(O)OC 1-6 alkyl;
halogen;
oxo; and
—C(O)heterocyclyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar is substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine and bromine.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is selected from the group consisting of:
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each C 1 -C 6 alkyl wherein alkyl is substituted with —OH.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6 alkyl, cycloalkyl, heteroaryl and heterocyclyl is substituted with 1-4 substituents independently selected from the group consisting of —OH; cyano; —C(O)NH 2 ; and —CO 2 H.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is
Ar is phenyl substituted with two to three fluorine atoms;
R 1 is C 1 -C 6 alkyl;
wherein C 1 -C 6 alkyl is substituted with 1-4 substituents independently selected from the group consisting of:
—OH;
—C(O)NH 2 ;
—CO 2 H;
—C(O)OC 1-6 alkyl;
halogen;
oxo; and
—C(O)heterocyclyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is
Ar is phenyl substituted with two to three fluorine atoms;
R 2 is C 1 -C 6 alkyl;
wherein C 1 -C 6 alkyl is substituted with 1-4 substituents independently selected from the group consisting of:
—OH;
—C(O)NH 2 ;
—CO 2 H;
—C(O)OC 1-6 alkyl;
halogen;
oxo; and
—C(O)heterocyclyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein when R 2 is C 1-6 alkyl and said C 1-6 alkyl is substituted with —C(O)heterocyclyl, said heterocyclyl is morpholine.
10. The compound of claim 1 of structural formula Ia or Ib having the indicated stereochemical configuration at the two stereogenic carbon atoms marked with an *:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 of structural formula Ia having the indicated absolute stereochemical configuration at the two stereogenic carbon atoms marked with an *:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 10 of structural formulae Ic and Id having the indicated stereochemical configuration at the three stereogenic carbon atoms marked with an *:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 of structural formula Ic having the indicated absolute stereochemical configuration at the three stereogenic carbon atoms marked with an *:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 wherein V is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 is independently selected from the group consisting of C 1 -C 6 alkyl and
cycloalkyl;
wherein each C 1-6 alkyl and cycloalkyl is substituted with 1-4 substituents independently selected from the group consisting of:
cyano;
—OH;
—C(O)NH 2 ;
—CO 2 H;
—C(O)OC 1-6 alkyl;
halogen;
oxo; and
—C(O)heterocyclyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of cyano, C 1 -C 6 alkyl, and —C(O)NH 2 .
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein when R 3 is C 1-6 alkyl, said C 1-6 alkyl is substituted with 1-4 substituents independently selected from the group consisting of —OH, —C(O)NH 2 , —CO 2 H, —C(O)OC 1-6 alkyl, and halogen.
18. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 additionally comprising metformin or pioglitazone.
21. A method of treating a condition selected from the group consisting of insulin resistance, hyperglycemia, Type 2 diabetes in a mammal comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.