Androgen receptor modulators and methods of use thereof

Abstract

Compounds of structural formula (I) as herein defined are disclosed as useful in a method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, as well as in a method of agonizing the androgen receptor in a patient, and in particular the method wherein the androgen receptor is antagonized in the prostate of a male patient or in the uterus of a female patient and agonized in bone and/or muscle tissue. These compounds are useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including: osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal symptoms in women, female sexual dysfunction, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, arthritis and joint repair, alone or in combination with other active agents. In addition, these compounds are useful as pharmaceutical composition ingredients alone and in combination with other active agents.

1 .- 13 . (canceled)  
     
     
         14 . A compound of structural formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         “b” is a single bond, and “a” is a double bond; 
 X is —C(O)—O—;  
 
         selected from:  
         R 1  is methyl;  
         R 2  is selected from:  
         (A) aryl, substituted by one substituents selected from: 
 (1) fluoro,  
 (2) chloro,  
 (3) bromo,  
 (4) methyl,  
 (5) methoxy,  
 (6) ethoxy,  
 (7) hydroxy,  
 (8) trifluoromethyl,  
 (9) trifluoromethoxy, and  
 (10) acetyl;  
 
         (B) C 1-6  alkyl, unsubstituted or substituted with one or two substituents independently selected from: 
 (1) fluoro,  
 (2) chloro,  
 (3) cyano,  
 (4) methoxy,  
 (5) hydroxy, and  
 (6) trifluoromethyl;  
 
         (C) trifluoromethyl;  
         (D) phenyl-C 1-6  alkyl-, wherein phenyl is unsubstituted or substituted with one or two substituents independently selected from: 
 (1) halogen,  
 (2) methyl,  
 (3) C 1-2  alkoxy,  
 (4) hydroxy,  
 (5) nitro,  
 (6) trifluoromethyl, and  
 (7) trifluoromethoxy;  
 
         (E) C 2-3  alkenyl;  
         (F) phenyl C 2 alkenyl, wherein phenyl is unsubstituted or substituted with a substituent selected from: 
 (1) halogen,  
 (2) methyl, and  
 (3) trifluoromethyl.  
 
         (G) cycloheteroalkyl, either unsubstituted or substituted with one or two substituents selected from: 
 (1) fluoro,  
 (2) phenyl,  
 (3) C 1-4  alkyl,  
 (4) C 1-3  alkoxy,  
 (5) hydroxy,  
 (6) trifluoromethyl,  
 (7) oxo, and  
 (8) spiro C 3-8  cycloalkyl;  
 
         provided that any heteroatom substituent is bonded to a carbon atom in the cycloheteroalkyl ring;  
         R 3  is hydrogen;  
         R 4  and R 5  are each hydrogen;  
         R 6  is hydrogen;  
         R 7  is hydrogen,  
         n is 2;  
         and pharmaceutically acceptable salts thereof.  
       
     
     
         15 . (canceled)  
     
     
         16 . A composition comprising a compound according to  claim 14  and a pharmaceutically acceptable carrier.  
     
     
         17 . The composition according to  claim 16  additionally comprising a bone-strengthening agent selected from: 
 (a) estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative,    (b) a bisphosphonate,    (c) an antiestrogen or a selective estrogen receptor modulator,    (d) an osteoclast integrin inhibitor,    (e) a cathepsin K inhibitor,    (f) an HMG-CoA reductase inhibitor,    (g) an osteoclast vacuolar ATPase inhibitor,    (h) an antagonist of VEGF binding to osteoclast receptors,    (i) a peroxisome proliferator-activated receptor γ,    (j) calcitonin,    (k) a calcium receptor antagonist,    (l) parathyroid hormone,    (m) a growth hormone secretagogue,    (n) human growth hormone,    (o) insulin-like growth factor,    (p) a P-38 protein kinase inhibitor,    (q) bone morphogenic protein,    (r) an inhibitor of BMP antagonism,    (s) a prostaglandin derivative,    (t) vitamin D or vitamin D derivative,    (u) vitamin K or vitamin K derivative,    (v) ipriflavone,    (w) fluoride salts, and    (x) dietary calcium supplement.    
     
     
         18 . The pharmaceutical composition according to  claim 16 , additionally comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt, trihydrate.  
     
     
         19 .- 21 . (canceled)  
     
     
         22 . A compound of structural formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         X is —C(O)—O—,  
         R 1  is methyl;  
         R 2  is selected from:  
         (A) aryl, substituted by one substituents selected from: 
 (11) fluoro,  
 (12) chloro,  
 (13) bromo,  
 (14) methyl,  
 (15) methoxy,  
 (16) ethoxy,  
 (17) hydroxy,  
 (18) trifluoromethyl,  
 (19) trifluoromethoxy, and  
 (20) acetyl;  
 
         (B) C 1-6  alkyl, unsubstituted or substituted with one or two substituents independently selected from: 
 (7) fluoro,  
 (8) chloro,  
 (9) cyano,  
 (10) methoxy,  
 (11) hydroxy, and  
 (12) trifluoromethyl;  
 
         (C) trifluoromethyl;  
         (D) phenyl-C 1-6  alkyl-, wherein phenyl is unsubstituted or substituted with one or two substituents independently selected from: 
 (8) halogen,  
 (9) methyl,  
 (10) C 1-2  alkoxy,  
 (11) hydroxy,  
 (12) nitro,  
 (13) trifluoromethyl, and  
 (14) trifluoromethoxy;  
 
         (E) C 2-3  alkenyl;  
         (F) phenyl C 2 alkenyl, wherein phenyl is unsubstituted or substituted with a substituent selected from: 
 (4) halogen,  
 (5) methyl, and  
 (6) trifluoromethyl.  
 
         (G) cycloheteroalkyl, either unsubstituted or substituted with one or two substituents selected from: 
 (9) fluoro,  
 (10) phenyl,  
 (11) C 1-4 alkyl,  
 (12) C 1-3  alkoxy,  
 (13) hydroxy,  
 (14) trifluoromethyl,  
 (15) oxo, and  
 (16) spiro C 3-8  cycloalkyl;  
 
         provided that any heteroatom substituent is bonded to a carbon atom in the cycloheteroalkyl ring;  
         R 3  is hydrogen;  
         R 4  and R 5  are each hydrogen;  
         R 6  is hydrogen;  
         R 7  is hydrogen,  
         n is 2;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         23 . A compound according to  claim 22  selected from: 
 (1) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-bromoethyl ester;    (2) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-phenyl ester;    (3) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-chlorophenyl ester;    (4) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-nitrophenyl ester;    (5) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-methylphenyl ester;    (6) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-bromophenyl ester;    (7) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-fluorophenyl ester;    (8) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-methoxophenyl ester;    (9) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-nitrophenyl ester;    (10) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-naphthyl ester;    (11) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-trifluoromethylphenyl ester;    (12) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-ethyl ester;    (13) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-benzyl ester;    (14) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2,2,2-trifluoroethyl ester;    (15) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-methoxyethyl ester;    (16) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-(2,2-dimethylpropy) ester;    (17) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-fluoroethyl ester;    (18) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-allyl ester;    (19) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-methyl ester;    (20) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-propynoic ester;    (21) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-(2-methyl-2-butyl) ester;    (22) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-(trifluoromethyl)phenyl ester;    (23) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-(trifluoromethyl)phenyl ester;    (24) Carbamic acid, [(5α, 17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-fluorophenyl ester;    (25) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-fluorophenyl ester;    (26) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-(2-hydroxy-1-ethyl) ester;    (27) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-methoxyphenyl ester;    (28) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-methoxyphenyl ester;    (29) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-ethoxyphenyl ester;    (30) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-ethoxyphenyl ester;    (31) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-ethoxyphenyl ester;    (32) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-chlorophenyl ester;    (33) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-chlorophenyl ester;    (34) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-3-(trifluoromethoxy)phenyl ester;    (35) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-4-(trifluoromethoxy)phenyl ester;    (36) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2-propyl ester;    (37) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-propyl ester;    (38) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-butyl ester; and    (39) Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-1-hexyl ester.    
     
     
         24 . A compound which is 
 Carbamic acid, [(5α,17β)-3-oxo-4-methyl-azaandrost-1-ene-17-yl]-2,2,2-trifluoroethyl ester;    or a pharmaceutically acceptable salt thereof.    
     
     
         25 . A composition comprising a compound according to  claim 24  and a pharmaceutically acceptable carrier.