Substituted urea neuropeptide Y Y5 Receptor antagonists
A novel class of compounds such as antagonists of the neuropeptide Y Y5 receptor, methods of making such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the neuropeptide Y Y5 receptor are disclosed.
1. A compound having the structural formula I:
R 1 is hydrogen or (C 1 -C 6 )alkyl;
R 2 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl;
j is 0, 1 or 2;
k is 1 or 2;
p is 1, 2 or 3;
r is 1, 2 or 3;
R 4 is a subsituent independently selected from hydrogen, —OH, halogen, haloalkyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, —CN, (C 1 -C 6 )alkylO—, (C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkylS—, (C 3 -C 7 )cycloalkylS—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylS—, —NR 9 R 10 , —NO 2 , —CONR 9 R 10 and —NR 2 COR 10 ;
R 5 is a substituent independently selected from hydrogen, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylO—, (C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylO—, —CONH 2 and —CONR 9 R 10 ;
R 6 is (C 1 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )haloalkylSO 2 —, hydroxy(C 2 -C 6 )alkyl)SO 2 ,—, (amino(C 2 -C 6 )alkyl)SO 2 —, alkoxy(C 2 -C 6 )alkyl)SO 2 —, alkylamino(C 2 -C 6 )alkyl)SO 2 —, dialkylamino(C 2 -C 6 )alkyl)SO 2 —, arylSO 2 —, heteroarylSO 2 —, aryl(C 2 -C 6 -alkylSO 2 —, R 9 R 10 NSO 2 —, (C 1 -C 6 )alkylC(O)—, (C 3 -C 7 )cycloalkylC(O)—, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylC(O)—, arylC(O)—, heteroarylC(O)—, R 9 R 10 NC(O)—, —(S)CNR 9 R 10 , aryl, heteroaryl, —(CH 2 ) n C(O)NR 9 R 10 , alkylS(NCN═)C—, R 9 R 10 N(NCN═)C—, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, or R 9 OC(O)—;
R 7 is hydrogen or alkyl;
R 8 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )haloalkylSO 2 — or arylSO 2 —;
R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl, acyl or heteroaryl; and,
R 10 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl or heteroaryl;
or R 9 and R 10 taken together with the nitrogen atom form a 4-7 membered ring containing 1 or 2 heteroatoms selected from N, O or S with proviso that two O or S atoms are not adjacent to one another;
n is 1 to 6;
or a pharmaceutically acceptable salt and/or hydrate thereof.
2. A compound of claim 1 wherein
3. A compound of claim 2 wherein R 5 is a substituent independently selected from hydrogen, halogen, haloalkyl, alkoxy and haloalkoxy and the sum of j and k is 1, 2 or 3.
4. A compound of claim 2 wherein R 6 is (C 1 -C 6 )alkyl SO 2 —, hydroxy(C 2 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, R 9 R 10 NSO 2 — or NH 2 SO 2 —.
5. A compound of claim 1 selected from
or a pharmaceutically acceptable salt and/or hydrate thereof.
6. A compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt and/or hydrate thereof.
7. A compound of claim 2 wherein R 6 is heterorarylC(O)—, (C 1 -C 6 )alkylC(O)— or (C 3 -C 7 )cycloalkyl C(O)—.
8. A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt and/or hydrate thereof.
9. A compound of claim 2 wherein R 6 is heteroaryl.
10. A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt and/or hydrate thereof.
11. A compound of claim 1 selected from the structural formulas set forth in the following table, and the pharmaceutically acceptable addition salts and/or hydrates thereof:
Y
R 1
R 2
R 3
R 4
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
2-F
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H.
12. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier.
13. A method of treating metabolic or eating disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 of said compound.
14. The method of claim 13 wherein said metabolic disorder is obesity.
15. The method of claim 13 wherein said eating disorder is hyperphagia.
16. A method of treating disorders associated with obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
17. The method of claim 16 wherein said disorders associated with obesity are Type II Diabetes, insulin resistance, hyperlipidemia and hypertension.