IP Library › Granted Patent US 7,504,402

Granted Patent B2

US 7,504,402 · App. 11/011,889 · Granted Mar 17, 2009

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

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Quick Facts

Patent No.: US 7,504,402
App. No.: 11/011,889
Granted: Mar 17, 2009
Kind: B2

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Abstract

Triazole derivatives of structural formula I are selective inhibitors of the 11β-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.

Claims (254)

1. A method of treating a neurodegenerative disease wherein said neurodegenerative disease is selected from the group consisting of anxiety, or depression, in a mammalian patient comprising administering to the patient an effective amount of a compound of structural formula I:

or a pharmaceutically acceptable salt 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 is selected from the group consisting of

arylcarbonyl,

(CH 2 ) n -aryl, and

(CH 2 )n-heteroaryl;

in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 5 ;

R 2 is selected from the group consisting of

hydrogen,

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;

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 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 ,

OHC═CF 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; 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, 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 1-4 alkyl; and

each R 7 is hydrogen or R 6 .

2. A method of treating a neurodegenerative disease wherein said neurodegenerative disease is selected from the group consisting of anxiety, or depression, in a mammalian patient comprising administering to the patient an effective amount of a compound of structural formula II selected from the group consisting of:

(II)

R 3

R 2

R 1

CH 3

CH 2 CH 3

CH 3

CbzNH—

CH 3

NH 2

CH 3

and

CH 3