Fluorinated 4-azasteroid derivatives as androgen receptor modulators

Abstract

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

1 . A compound of structural formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or an enantiomer thereof; wherein 
 n is 0, 1 or 2;  
 a-b represents CF═CH, CHFCH 2 , or CF 2 CH 2 ;  
 R 1  is hydrogen, hydroxymethyl, or C 1-3  alkyl, wherein alkyl is unsubstituted or substituted with one to seven fluorine atoms;  
 R 2  is hydrogen or C 1-4  alkyl;  
 R 3  is selected from 
 C 1-4  alkyl,  
 (CH 2 ) n -cycloheteroalkyl, and  
 (CH 2 ) n -aryl, wherein aryl is selected from 
 (1) phenyl,  
 (2) naphthyl,  
 (3) benzimidazolyl,  
 (4) benzofuranyl,  
 (5) benzothiophenyl,  
 (6) benzoxazolyl,  
 (7) benzothiazolyl,  
 (8) benzodihydrofuranyl,  
 (9) 1,3-benzodioxolyl,  
 (10) 2,3-dihydro-1,4-benzodioxinyl,  
 (11) indolyl,  
 (12) quinolyl,  
 (13) isoquinolyl,  
 (14) furanyl,  
 (15) thienyl,  
 (16) imidazolyl,  
 (17) oxazolyl,  
 (18) thiazolyl,  
 (19) isoxazolyl,  
 (20) isothiazolyl,  
 (21) pyrazolyl,  
 (22) pyrrolyl,  
 (23) pyridyl,  
 (24) pyrimidyl,  
 (25) pyrazinyl,  
 (26) thiadiazolyl,  
 (27) oxadiazolyl,  
 (28) triazolyl,  
 (29) tetrazolyl, and  
 (30) indanyl;  
 wherein the alkyl group or the cycloheteroalkyl group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and C 1-4  alkoxy; the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, C 1-8  alkyl, C 3-8  cycloalkyl, C 3-8  cycloheteroalkyl, phenyl-C 1-6  alkyl, amino-C 0-6  alkyl, C 1-6  alkylamino-C 0-6  alkyl, (C 1-6  alkyl) 2 amino-C 0-6  alkyl, phenyl-C 0-6  alkylamino-C 0-6  alkyl, (phenyl-C 0-6  alkyl) 2 amino-C 0-6  alkyl, C 1-6  alkylthio, phenyl-C 0-6  alkylthio, C 1-6  alkylsulfinyl, phenyl-C 0-6  alkylsulfinyl, C 1-6  alkylsulfonyl, phenyl-C 0-6  alkylsulfonyl, C 1-6  alkoxy-C 0-6  alkyl, phenyl-C 0-6  alkoxy-C 0-6  alkyl, hydroxycarbonyl-C 0-6  alkyl, C 1-6  alkoxycarbonyl-C 0-6  alkyl, phenyl-C 0-6  alkoxycarbonyl-C 0-6  alkyl, hydroxycarbonyl-C 1-6  alkyloxy, hydroxy-C 0-6  alkyl, cyano, nitro, perfluoro-C 1-4  alkyl, perfluoro-C 1-4  alkoxy, oxo, C 1-6  alkylcarbonyloxy, phenyl-C 0-6  alkylcarbonyloxy, C 1-6  alkylcarbonylamino, phenyl-C 0-6  alkylcarbonylamino, C 1-6  alkylsulfonylamino, phenyl-C 0-6  alkylsulfonylamino, C 1-6  alkoxycarbonylamino, phenyl-C 0-6  alkoxycarbonylamino, C 1-6  alkylaminocarbonylamino, phenyl-C 0-6  alkylaminocarbonylamino, (C 1-6  alkyl) 2  aminocarbonylamino, (phenyl-C 0-6  alkyl) 2  aminocarbonylamino, (C 1-6  alkyl) 2  aminocarbonyloxy, and (phenyl-C 0-6  alkyl) 2  aminocarbonyloxy; and wherein any methylene (CH 2 ) carbon atom in (CH 2 ) n  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 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;  
 or R 2  and R 3  together form a 5- or 6-membered saturated ring fused with a 5- or 6-membered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O, and S.  
 
 
 
   
   
       2 . The compound of  claim 1  wherein R 1  is hydrogen or methyl.  
   
   
       3 . A compound of structural formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or an enantiomer thereof; wherein 
 n is 0, 1 or 2;  
 a-b represents CF═CH, CHFCH 2 , or CF 2 CH 2 ;  
 R 1  is hydrogen, hydroxymethyl, or C 1-3  alkyl, wherein alkyl is unsubstituted or substituted with one to seven fluorine atoms;  
 R 2  is hydrogen or C 1-4  alkyl;  
 R 3  is selected from 
 C 1-4  alkyl, and  
 (CH 2 ) n -aryl, wherein aryl is selected from 
 (1) phenyl,  
 (2) naphthyl,  
 (3) benzimidazolyl,  
 (4) benzofuranyl,  
 (5) benzothiophenyl,  
 (6) benzoxazolyl,  
 (7) benzothiazolyl,  
 (8) benzodihydrofuranyl,  
 (9) 1,3-benzodioxolyl,  
 (10) 2,3-dihydro-1,4-benzodioxinyl,  
 (11) indolyl,  
 (12) quinolyl,  
 (13) isoquinolyl,  
 (14) furanyl,  
 (15) thienyl,  
 (16) imidazolyl,  
 (17) oxazolyl,  
 (18) thiazolyl,  
 (19) isoxazolyl,  
 (20) isothiazolyl,  
 (21) pyrazolyl,  
 (22) pyrrolyl,  
 (23) pyridyl,  
 (24) pyrimidyl,  
 (25) pyrazinyl,  
 (26) thiadiazolyl,  
 (27) oxadiazolyl,  
 (28) triazolyl,  
 (29) tetrazolyl, and  
 (30) indanyl;  
 wherein the alkyl group or the cycloheteroalkyl group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and C 1-4  alkoxy; the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, C 1-8  alkyl, C 3-8  cycloalkyl, C 3-8  cycloheteroalkyl, phenyl-C 1-6  alkyl, amino-C 0-6  alkyl, C 1-6  alkylamino-C 0-6  alkyl, (C 1-6  alkyl) 2 amino-C 0-6  alkyl, phenyl-C 0-6  alkylamino-C 0-6  alkyl, (phenyl-C 0-6  alkyl) 2 amino-C 0-6  alkyl, C 1-6  alkylthio, phenyl-C 0-6  alkylthio, C 1-6  alkylsulfinyl, phenyl-C 0-6  alkylsulfinyl, C 1-6  alkylsulfonyl, phenyl-C 0-6  alkylsulfonyl, C 1-6  alkoxy-C 0-6  alkyl, phenyl-C 0-6  alkoxy-C 0-6  alkyl, hydroxycarbonyl-C 0-6  alkyl, C 1-6  alkoxycarbonyl-C 0-6  alkyl, phenyl-C 0-6  alkoxycarbonyl-C 0-6  alkyl, hydroxycarbonyl-C 1-6  alkyloxy, hydroxy-C 0-6  alkyl, cyano, nitro, perfluoro-C 1-4  alkyl, perfluoro-C 1-4  alkoxy, oxo, C 1-6  alkylcarbonyloxy, phenyl-C 0-6  alkylcarbonyloxy, C 1-6  alkylcarbonylamino, phenyl-C 0-6  alkylcarbonylamino, C 1-6  alkylsulfonylamino, phenyl-C 0-6  alkylsulfonylamino, C 1-6  alkoxycarbonylamino, phenyl-C 0-6  alkoxycarbonylamino, C 1-6  alkylaminocarbonylamino, phenyl-C 0-6  alkylaminocarbonylamino, (C 1-6  alkyl) 2  aminocarbonylamino, (phenyl-C 0-6  alkyl) 2  aminocarbonylamino, (C 1-6  alkyl) 2  aminocarbonyloxy, and (phenyl-C 0-6  alkyl) 2  aminocarbonyloxy; and wherein any methylene (CH 2 ) carbon atom in (CH 2 ) n  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 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;  
 or R 2  and R 3  together form a 5- or 6-membered saturated ring fused with a 5- or 6-membered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O, and S.  
 
 
 
   
   
       4 . The compound of  claim 3 , wherein R 1  is hydrogen or methyl.  
   
   
       5 . The compound of  claim 1  wherein a-b represents CF═CH.  
   
   
       6 . The compound of  claim 1  wherein a-b represents CHFCH 2 .  
   
   
       7 . The compound of  claim 1  wherein R 2  is hydrogen and R 3  is (CH 2 ) n -aryl.  
   
   
       8 . The compound of  claim 7  wherein n is 0 or 1.  
   
   
       9 . The compound of  claim 1  wherein R 1  is methyl, a-b represents CF═CH, R 2  is hydrogen, and R 3  is (CH 2 ) n -aryl.  
   
   
       10 . The compound of  claim 9  wherein n is 0 or 1.  
   
   
       11 . The compound of  claim 1  wherein R 1  is methyl, a-b represents CHFCH 2 , R 2  is hydrogen, and R 3  is (CH 2 ) n -aryl.  
   
   
       12 . The compound of  claim 11  wherein n is 0 or 1.  
   
   
       13 . The compound of  claim 1  wherein R 1  is methyl, a-b represents CF═CH, R 2  is hydrogen, and R 3  is (CH 2 ) n -cycloheteroalkyl.  
   
   
       14 . The compound of  claim 13 , wherein n is 0 or 1.  
   
   
       15 . The compound of  claim 1  wherein R 1  is methyl, a-b represents CHFCH 2 , R 2  is hydrogen, and R 3  is (CH 2 ) n -cycloheteroalkyl.  
   
   
       16 . The compound of  claim 15 , wherein n is 0 or 1.  
   
   
       17 . The compound of  claim 2  chosen from: 
 N-(2,2,2-trifluoroethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-chlorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(4-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamiide;    N-(4-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(4-chloro-2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,4-difluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(α-methylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(phenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(4-chloro-2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-methylpyridin-2-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(thiophen-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(thiophen-3-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-trifluoromethylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(1-methylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(1-methyl-5-trifluoromethylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(thiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(4-methylthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(thiazol-4-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(1-methylimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(2-trifluoromethylphenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(3-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(4-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(2-trifluoromethylphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(2-chlorophenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(benzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(1-methylbenzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide; and    N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.    
   
   
       18 . The compound of  claim 17  chosen from: 
 N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide; and    N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.    
   
   
       19 . The compound of  claim 18  chosen from: 
 N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.    
   
   
       20 . The compound of  claim 18  chosen from: 
 N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide; and    N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.    
   
   
       21 . A method for modulating a function mediated by the androgen receptor in a mammal in need of such modulation comprising administering a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       22 . A method of activating the function of the androgen receptor in a mammal in need of such activation comprising administering a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       23 . The method of  claim 21  wherein said function mediated by the androgen receptor is activated in at least one of bone and muscle tissue and blocked in the prostate or the uterus.  
   
   
       24 . A method of treating a condition in a mammal which is caused by androgen deficiency or which can be ameliorated by androgen replacement, or which can be increased by androgen replacement, which condition is selected from weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity,. aplastic anemia and other hematopoietic disorders, arthritic conditions, HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease, comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       25 . The method according to  claim 24  wherein said condition is osteoporosis.  
   
   
       26 . A method of treating osteoporosis in a-mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 11  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       27 . The method of  claim 26  further comprising the administration of an agent selected from: 
 (a) an 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 αvβ3 integrin receptor antagonist,    (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) an activator of peroxisome proliferator-activated receptor γ,    (j) calcitonin,    (k) a calcium receptor antagonist,    (l) parathyroid hormone or analog thereof,    (m) a growth hormone secretagogue,    (n) human growth hormone,    (o) insulin-like growth factor,    (p) a p38 protein kinase inhibitor,    (q) bone morphogenetic 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,    (x) dietary calcium supplement, and    (y) osteoprotegerin.    
   
   
       28 . The method according to  claim 27  wherein: 
 (a) the estrogen or estrogen derivative, alone or in combination with a progestin or progestin derivative, is selected from conjugated estrogen, equine estrogen, 17β-estradiol, estrone, 17β-ethynyl estradiol, 17β-ethynyl estradiol with at least one agent selected from norethindrone and medroxyprogesterone acetate;    (b) the bisphosphonate is selected from alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate, and zoledronate;    (c) the antiestrogen or selective estrogen receptor modulator is selected from raloxifene, clomiphene, zuclomiphene, enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11,555A, U-100A, tamoxifen, lasofoxifene, toremifene, azorxifene, EM-800, EM-652, TSE 424, droloxifene, idoxifene, and levormeloxifene;    (d) the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, dihydroxy-open acid simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, and nisvastatin;    (e) calcitonin is salmon calcitonin administered as a nasal spray;    (f) bone morphogenetic protein is selected from BMP 2, BMP 3, BMP 5, BMP 6, BMP 7, TGF beta, and GDF5;    (g) insulin-like growth factor is selected from IGF I and IGF II alone or in combination with IGF binding protein 3;    (h) the prostaglandin derivative is selected from agonists of prostaglandin receptors EP1, EP2, EP4, FP, and IP;    (i) the fibroblast growth factor is selected from aFGF and bFGF;    (j) parathyroid hormone (PTH) or PTH analog is selected from PTH subcutaneous injection, human PTH (1-84), human PTH (1-34), and other partial sequences, native or with substitutions;    (k) vitamin D or vitamin D derivative is selected from natural vitamin D, 25-OH-vitamin D3, 1α,25(OH) 2  vitamin D3, 1α-OH-vitamin D3, 1α-OH-vitamin D2, dihydrotachysterol, 26,27-F6-1α,25(OH) 2  vitamin D3, 19-nor-1α,25(OH) 2  vitamin D3, 22-oxacalcitriol, calcipotriol, 1α,25(OH) 2 -16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089, 20-epi-1α,25(OH) 2  vitamin D3, KH1060, ED71, 1α,24(S)-(OH) 2  vitamin D3, and 1α,24(R)-(OH) 2  vitamin D3;    (l) the dietary calcium supplement is selected from calcium carbonate, calcium citrate, and natural calcium salts; and    (m) the fluoride salts are selected from sodium fluoride and monosodium fluorophosphate (MFP);    and pharmaceutically acceptable salts thereof.    
   
   
       29 . The method according to  claim 28 , wherein the bisphosphonate is alendronate monosodium trihydrate or alendronate monosodium monohydrate.  
   
   
       30 . The method of  claim 20 , wherein said agent is selected from: 
 (a) an 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 αvβ3 integrin receptor antagonist,    (e) a cathepsin K inhibitor,    (f) an osteoclast vacuolar ATPase inhibitor,    (g) an antagonist of VEGF binding to osteoclast receptors,    (h) calcitonin,    (i) ostoprotegrin, and    (j) parathyroid hormone or analog thereof.    
   
   
       31 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       32 . The composition of  claim 31  which further comprises an active ingredient selected from: 
 (a) an 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 αvβ3 integrin receptor antagonist,    (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) an activator of peroxisome proliferator-activated receptor γ,    (j) calcitonin,    (k) a calcium receptor antagonist,    (l) parathyroid hormone or analog thereof,    (m) a growth hormone secretagogue,    (n) human growth hormone,    (o) insulin-like growth factor,    (p) a p38 protein kinase inhibitor,    (q) bone morphogenetic 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,    (x) dietary calcium supplement, and    (y) osteoprotegerin    
   
   
       33 . The composition of  claim 32  wherein said active ingredient is selected from: 
 (a) an 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 αvβ3 integrin receptor antagonist,    (e) a cathepsin K inhibitor,    (f) an osteoclast vacuolar ATPase inhibitor,    (g) calcitonin,    (h) osteoprotegrin, and    (i) parathyroid hormone or analog thereof.    
   
   
       34 . The composition of  claim 33 , wherein said bisphosphonate is alendronate.  
   
   
       35 . A method of increasing bone mineral density in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       36 . A method of reducing the risk of vertebral or non-vertebral fractures in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       37 . A method of effecting a bone turnover marker in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       38 . A pharmaceutical composition made by combining a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       39 . A process for making a pharmaceutical composition comprising combining a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       40 . A method of treating or preventing an arthritic condition in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt or an enantiomer thereof.  
   
   
       41 . A method of  claim 40 , wherein the arthritic condition is selected from rheumatoid arthritis and osteoarthritis.