Triazole derivatives as inhibitors of 11-β hydroxysteroid dehydrogenase-1

1. A compound of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein

each p is independently 0, 1, or 2;

each n is independently 0, 1, or 2;

X is selected from the group consisting of a single bond, O, S(O) p , NR 6 ,

R 1 and R 2 are each independently selected from the group consisting of C 1-8 alkyl, C 2-6 alkenyl, and (CH 2 ) n —C 3-6 cycloalkyl, in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 8 and oxo; or R 1 and R 2 together with the atoms to which they are attached form a fused 7- to 11-membered non-aromatic heterocyclic ring optionally fused with a benzo ring system and optionally containing an additional heteroatom selected from oxygen, sulfur, and nitrogen; or R 1 and R 2 together with the atoms to which they are attached form a fused 4-azatricyclo[4.3.1.1 3,8 ]undecane ring; said fused ring systems being unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy;

each R 4 is independently selected from the group consisting of: hydrogen, halogen, hydroxy, oxo, C 1-3 alkyl, and C 1-3 alkoxy;

R 3 is selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, (CH 2 ) n —C 3-6 cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, and (CH 2 ) n -heterocyclyl; in which aryl, heteroaryl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from R 5 ; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R 8 and oxo;

R 5 and R 8 are each independently selected from the group consisting of: hydrogen, formyl, C 1-6 alkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocyclyl, (CH 2 ) n C 3-7 cycloalkyl, halogen, OR 7 , (CH 2 ) n N(R 7 ) 2 , cyano, (CH 2 ) n CO 2 R 7 , NO 2 , (CH 2 ) n NR 7 SO 2 R 6 , (CH 2 ) n SO 2 N(R 7 ) 2 , (CH 2 ) n S(O) p R 6 , (CH 2 ) n SO 2 OR 7 , (CH 2 ) n NR 7 C(O)N(R 7 ) 2 , (CH 2 ) n C(O)N(R 7 ) 2 , (CH 2 ) n NR 6 C(O)R 6 , (CH 2 ) n NR 6 CO 2 R 7 , O(CH 2 ) n C(O)N(R 7 ) 2 , CF 3 , CH 2 CF 3 , OCF 3 , OCHCF 2 , and OCH 2 CF 3 ;

wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; or two R 5 substituents together with the atoms to which they are attached form a 5- to 8-membered ring optionally containing 1-2 heteroatoms independently selected from oxygen, sulfur, and nitrogen; and wherein any methylene (CH 2 ) carbon atom in R 5 and R 8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

each R 6 is independently selected from the group consisting of: C 1-8 alkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, and (CH 2 ) n C 3-7 cycloalkyl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, and amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

or two R 6 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 0-4 alkyl; and

each R 7 is hydrogen or R 6 .

2. A compound of claim 1 wherein R1 and R2 together with the atoms to which they are attached form a fused 7- to 9-membered non-aromatic heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-3 alkyl, and C1-3 alkoxy.

3. A compound of claim 2 wherein R 4 is hydrogen.

4. A compound of claim 1 wherein R 1 and R 2 together with the atoms to which they are attached form a fused 8-membered non-aromatic heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy.

5. A compound of claim 4 wherein R 4 is hydrogen.

6. A compound of claim 1 wherein R 1 is C 2-5 alkyl or (CH 2 ) n cyclopropyl wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituents independently selected from fluorine, C 1-3 alkyl, trifluoromethyl, C 1-3 alkoxy, and C 1-3 alkylthio.

7. The compound of claim 6 wherein R 2 is cyclopropyl, C 1-3 alkyl, or C 2-3 alkenyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituents independently selected from fluorine, C 1-3 alkyl, trifluoromethyl, C 1-3 alkoxy, and C 1-3 alkylthio.

8. The compound of claim 7 wherein R 4 is hydrogen.

9. The compound of claim 1 of structural formula II selected from the group consisting of:

(II)

R 3

R 3

—CH 3

—CF 2 H

H

—CO 2 Me

A compound in accordance with claim 1 of structural formula III selected from the group consisting of:

(III)

R 3

R 2

R 1

—CF 2 H

—CH 3

—CH 3

10. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

12. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with claim 1 .

13. A method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat obesity.

14. A method of treating Syndrome X in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat Syndrome X.

15. A method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount effective to treat atherosclerosis.