Treating diabetes with dipeptidyl peptidase-IV inhibitors
View Patent ↗The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-N 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
R 1 , R 9 , R 10 and R 11 are selected from the group consisting of halogen and hydrogen;
X is selected from the group consisting of —NR 4 — and —CHR 4 —;
Y is selected from the group consisting of —N— and —CHR 2 —;
Z is selected from the group consisting of —N— and —CH—;
R 2 is selected from the group consisting of hydrogen or taken with R 8 forms (CH 2 )n;
R 3 is selected from the group consisting of hydrogen, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl),
SO 2 N(C 1-6 alkyl) 2 , SO 2 NHC 3-6 cycloalkyl, SOC 1-6 alkylNP, SO 2 NHP, SO 2 C 1-6 alkyl and
SO 2 C 3-6 cycloalkyl, wherein Q is a amine protecting group;
R 4 is hydrogen or C 1-6 alkyl or taken together with R 6 forms a six-membered ring;
R 5 is hydrogen or C 1-6 alkyl or taken together with R 7 forms —(CH 2 )n-;
R 6 is hydrogen or C 1-6 alkyl or taken together with R 4 forms a six-membered ring;
R 7 is hydrogen or C 1-6 alkyl or taken together with R 5 forms —(CH 2 )n-;
R 8 is hydrogen or C 1-6 alkyl or taken together with R 2 forms —(CH 2 )n-, wherein when
Y and X are CH 2 and R 3 is SO 2 C 1-6 alkyl or SO 2 C 3-6 cycloalkyl then R 5 , R 6 , R 7 and R 8 cannot be simultaneously hydrogen; and
n is 1 or 2.
2. The compound of claim 1 wherein R 1 and R 10 are fluorine.
3. The compound of claim 1 wherein R 9 and R 11 are fluorine.
4. The compound of claim 1 wherein Y is —N—.
5. The compound of claim 1 wherein Y is —CHR 2 —.
6. The compound of claim 5 wherein Y is —CH 2 —.
7. The compound of claim 1 wherein R 5 taken together with R 7 form (CH 2 ) 2 .
8. The compound of claim 1 wherein R 2 taken together with R 8 form (CH 2 ) 2 .
9. The compound of claim 1 wherein Z is —N—.
10. The compound of claim 1 wherein Z is —CH—.
11. The compound of claim 1 wherein X is —NH—.
12. The compound of claim 1 wherein X is —CHR 4 —.
13. The compound of claim 1 wherein Z is —N—, X is —CNR 4 — and R 4 and R 6 taken together form a pyrimidine.
14. The compound of claim 1 wherein R 3 is SO 2 NH 2 , SO 2 NH(C 1-6 alkyl), SO 2 N(C 1-6 alkyl) 2 or SO 2 NHC 3-6 cycloalkyl.
15. The compound of claim 1 having structural Formula Ia or Ib having the indicated stereochemical configuration at the two stereogenic carbon atoms marked with an *:
wherein W is
16. The compound of claim 1 having structural Formulae Ic or Id:
wherein W is
17. The compound of claim 1 , wherein R 5 , R 6 , R 7 and R 8 are not simultaneously hydrogen.
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. A method of treating a condition selected from the group consisting of insulin resistance, hyperglycemia, and Type 2 diabetes comprising administering a compound of claim 1 to a mammal in need thereof.