MCH antagonists for the treatment of obesity

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate of said compound, wherein:

X is a single bond, —C—, —CH—or alkylene, and when X is a single bond, R 6 is absent and the carbon atom marked 1 is directly attached to N of N—Y;

Y is a single bond, —C—, —CH—or alkylene, and when Y is a single bond, R 5 is absent and the carbon atom marked 7 is directly attached to N of N—X;

R 1 is aryl or heteroaryl, wherein each of said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of CN, CF 3 , halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 2 is H, alkyl, aryl or aralkyl wherein each of said aryl or aralkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 3 is H, alkyl, aryl or aralkyl wherein each of said aryl or aralkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of CF 3 , halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 4 is selected from the group consisting of

wherein each R 7 in said —N(R 7 ) 2 , can be the same or different and each R 7 is H, alkyl, cycloalkyl or aryl, wherein each of said alkyl, aryl or cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH; or each R 7 can be joined together and with the nitrogen to which they are attached to form a 3 to 7-membered heterocyclyl ring;

n is 0;

p is 0 to 5 and when p is >1, the number of p moieties can be the same or different;

R 5 is H or 1 or 2 substituents independently selected from alkyl or cycloalkyl;

R 6 is H or 1 or 2 substituents independently selected from alkyl or cycloalkyl; and

R 8 is H, OH, alkoxy, alkyl, cycloalkyl, aryl, —N(H)R 7 , —N(H)C(O)alkyl, —N(H)C(O)aryl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(H)aryl, —N(H)S(O 2 )alkyl or —N(H)S(O 2 )aryl;

with the proviso that the carbons shown marked 1 and 6 on the aromatic ring, along with X—R 6 , can optionally form a 4 to 8 membered ring system.

2. The compound of claim 1 of formula Ia:

or a pharmaceutically acceptable salt or solvate of said compound, wherein:

q is 0 to 5 and when q is >1, the number of q moieties can be the same or different;

X is —CH— or alkylene;

Y is a CH2;

R 2 is H, alkyl, aryl or aralkyl wherein each of said aryl or aralkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 3 is H, alkyl, aryl or aralkyl wherein each of said aryl or aralkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of CF 3 , halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH; R 4 is

R 5 and R 6 can be the same or different, and are independently H or alkyl;

R 8 is H, OH, alkoxy, alkyl, cycloalkyl, aryl, —N(H)R 7 , —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl or —N(H)S(O 2 )alkyl; and

R 9 is alkyl, F, Cl, Br, I, NO 2 , C(O)NH 2 , C(O)N(H)R or N(H)C(O)R, wherein R is alkyl, OCF 3 , CH 3 or CN.

3. The compound of claim 2 wherein R 9 is a 3 or 4-substituted aryl.

4. The compound of claim 2 wherein R 9 is a 3-cyano substituted aryl.

5. The compound of claim 1 of formula Ib:

or a pharmaceutically acceptable salt or solvate of said compound, wherein:

X is an alkylene group;

R 1 is 3-cyanophenyl;

R 2 is H;

R 3 is a phenyl, wherein said phenyl is substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of CF 3 , halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH; R 4 is

 and

R 8 is H, alkyl, cycloalkyl, aryl, —N(H)alkyl, —N(H)aryl, OH, alkoxy, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl or —N(H)S(O 2 )alkyl.

6. The compound of claim 1 of formula Ic:

methyl group is (S), (R) or racemic formula Ic or a pharmaceutically acceptable salt or solvate of said compound, wherein:

R 1 is 3-cyanophenyl;

R 2 is H;

R 3 is a phenyl, wherein said phenyl is substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of CF 3 , halogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

R 4 is

 and

R 8 is H, alkyl, cycloalkyl, aryl, —N(H)alkyl, —N(H)aryl, OH, alkoxy, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl or —N(H)S(O 2 )alkyl.

7. A compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate of said compound.

8. The compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or solvate of said compound.

9. The compound of claim 1 of the formula

or a pharmaceutically acceptable salt or solvate of said compound.

10. The compound of claim 1 of the formula

or a pharmaceutically acceptable salt or solvate of said compound.

11. The compound of claim 1 of the formula

or a pharmaceutically acceptable salt or solvate of said compound.

12. A method of treating a metabolic disorder, eating disorder or diabetes comprising administering an effective amount of a compound of claim 1 to a patient in need of such treatment.

13. The method of claim 12 wherein said eating disorder is hyperphagia.

14. The method of claim 12 wherein said metabolic disorder is obesity.

15. A method of treating disorders associated with obesity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.

16. The method of claim 15 wherein said disorders associated with obesity are type II diabetes, insulin resistance, hyperlipidemia and hypertension.

17. A method of treating an eating disorder which comprises administering to a patient in need of such treatment

an amount of a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

an amount of at least one more compound, said other compound (b) is selected from an antiobesity and/or anorectic agent such as a β 3 agonist, a thyromimetic agent, an anoretic agent, and an NPY antagonist;

wherein the amounts of the (a) and (b) compounds result in a therapeutic effect.

18. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising:

a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

an amount of at least one more compound, said other compound (b) is selected from an antiobesity and/or anorectic agent such as a β 3 agonist, a thyromimetic agent, an anoretic agent, and an NPY antagonist; and

a pharmaceutically acceptable carrier.

19. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising:

a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

at least one other compound, selected from being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide and chlorpropamide; and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in combination with at least one pharmaceutically acceptable carrier.

21. A process for making a pharmaceutical composition comprising combining at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.