Open-chain prolyl urea-related modulators of androgen receptor function

Abstract

There are provided nuclear hormone receptor modulating compounds of formula I wherein R 1 , R 2 , R 3 , X, Y, n and G are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia, and also provided are pharmaceutical compositions containing such compounds. Other embodiments are also disclosed.

1 . A compound of the formula I  
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof wherein  
         R 1  is selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl and CH 2 OR 4 ;  
         R 2  is selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heterocyclo or substituted heterocyclo, heteroaryl or substituted heteroaryl and CH 2 OR 4 ;  
         R 3  is selected from the group consisting of hydrogen, alkyl or substituted alkyl, CH 2 OR 4 , OR 2 , SR 2 , halo, NHR 2 , NHCOR 4 , NHCO 2 R 4 , NHCONR 4 R 4 ′ and NHSO 2 R 4 ;  
         R 4  and R 4 ′ for each occurrence are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heterocyclo or substituted heterocyclo and heteroaryl or substituted heteroaryl;  
         G is a mono- or polycyclic ring system selected from the group consisting of aryl, heterocyclo and heteroaryl, wherein said ring system may optionally substituted with one or more substituents selected from the group consisting of hydrogen, halo, CN, CF 3 , OR 4 , CO 2 R 4 , NR 4 R 4 ′, CONR 4 R 4 ′, CH 2 OR 4 , SR 4 , SOR 4 , SO 2 R 4 , NO 2 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl and heteroaryl or substituted heteroaryl;  
         X is a linking group selected from the group consisting of NR 4  and CHR 4 ;  
         Y is selected from the group consisting of O, NR 4 , NOR 4 , S and CH 2 ;  
         z is —O— or NR 4 ; and  
         n is 2;  
         with the following provisos:  
         (a) when Y is NOR 4 , R 4  is not hydrogen;  
         (b) the following do not occur simultaneously: R 1  is methyl; X is NH; Y is O or S;  
         and Z is O; and  
         (c) the following do not occur simultaneously: 
 R 1  is methyl;  
 X is NH;  
 Z is O;  
 Y is NR 4 ;  
 R 4  is selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl and heteroaryl or substituted heteroaryl; and  
 G has the following structure:  
                     wherein    R 13  is selected from the group consisting of hydrogen, cyano (—CN), nitro (—NO 2 ), halo, heterocyclo, OR 14 , CO 2 R 15 , CONHR 15 , COR 15 , S(O) p R 15 , SO 2 NR 15 R 15 ′, NHCOR 15  and NHSO 2 R 15 ;    R 14  in each functional group is independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, CHF 2 , CF 3  and COR 15 ;    R 15  and R 15 ′ in each functional group are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl and —CN;    A and B are each independently selected from the group consisting of hydrogen, halo, cyano(—CN), nitro(—NO 2 ), alkyl or substituted alkyl and OR 14 ; and    p is an integer from 0 to 2.    
 
       
     
     
         2 . A compound or salt thereof as defined in  claim 1  wherein G is selected from:  
       
         
           
           
               
               
           
         
         wherein  
         R 8 , R 9 , R 10  and R 11  are each independently selected from the group consisting of hydrogen (H), NO 2 , CN, CF 3 , OR 4 , CO 2 R 4 , NR 4 ′, CONR 4 R 4 ′, CH 2 OR 4 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl and heteroaryl or substituted heteroaryl;  
         A to F is each independently selected from N or CR 1 ;  
         J, K, L, P and Q are each independently selected from NR 12 , O, S, SO, SO 2  or CR 12 R 12 ′;  
         R 12  and R 12 ′ in each functional group are each independently selected from a bond or R 1 ; and  
         m is an integer of 0 or 1.  
       
     
     
         3 . A compound or salt thereof as defined in  claim 2  wherein R 8  is CN.  
     
     
         4 . A pharmaceutical composition comprising the compound or salt as defined in  claim 1  and a pharmaceutically acceptable carrier therefore.  
     
     
         5 . A pharmaceutical composition as defined in  claim 4  further comprising a growth promoting agent.  
     
     
         6 . A pharmaceutical composition comprising a compound or salt as defined in  claim 1  and at least one additional therapeutic agent selected from the group consisting of parathyroid hormone, bisphosphonates, estrogen, testosterone, progesterone, selective estrogen receptor modulators, growth hormone secretagogues, growth hormone, progesterone receptor modulators, anti-diabetic agents, anti-hypertensive agents, anti-inflammatory agents, anti-osteoporosis agents, anti-obesity agents, cardiac glycosides, cholesterol lowering agents, anti-depressants, anti-anxiety agents, anabolic agents, and thyroid mimetics.  
     
     
         7 . A method for treating or delaying the progression or onset of muscular atrophy, lipodistrophy, long-term critical illness, sarcopenia, frailty or age-related functional decline, reduced muscle strength and function, reduced bone density or growth, the catabolic side effects of glucocorticoids, chronic fatigue syndrome, bone fracture repair, acute fatigue syndrome and muscle loss following elective surgery, cachexia, chronic catabolic state, eating disorders, side effects of chemotherapy, wasting, depression, nervousness, irritability, stress, growth retardation, reduced cognitive function, male contraception, hypogonadism, Syndrome X, diabetic complications or obesity, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound or salt as defined in  claim 1 .  
     
     
         8 . A method according to  claim 8  further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of other compounds or salts of formula I, parathyroid hormone, bisphosphonates, estrogen, testosterone, progesterone, selective estrogen receptor modulators, growth hormone secretagogues, growth hormone, progesterone receptor modulators, anti-diabetic agents, anti-hypertensive agents, anti-inflammatory agents, anti-osteoporosis agents, anti-obesity agents, cardiac glycosides, cholesterol lowering agents, anti-depressants, anti-anxiety agents, anabolic agents and thyroid mimetics.