Cyclohexyl derivatives as selective estrogen receptor modulators

Abstract

The present invention is directed to novel cyclohexyl derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and diseases mediated by an estrogen receptor.

1 . A compound of the formula (I)  
     
       
         
         
             
             
         
       
       wherein  
          represents a single or a double bond;  
       R 1a  is selected from the group consisting of hydrogen and lower alkyl;  
       R 1  is selected from the group consisting of alkyl, hydroxy substituted alkyl, alkenyl, hydroxy substituted alkenyl, alkynyl, hydroxy substituted alkynyl, alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl, aryl-carbonyl, heteroaryl-carbonyl, heterocycloalkyl-carbonyl, alkyl-carbonyl-alkyl, NR A R B -carbonyl and NR A R B -alkoxy-alkyl;  
       R A  and R B  are each independently selected from the group consisting of hydrogen and alkyl; alternatively R A  and R B  are taken together with the N atom to which they are bound to form a heteroaryl or heterocycloalkyl group;  
       R 2  is selected from the group consisting of hydrogen, carboxy, alkyl, hydroxy substituted alkyl, alkenyl, hydroxy substituted alkenyl, alkynyl, hydroxy substituted alkynyl, alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl, aryl-carbonyl, heteroaryl-carbonyl, heterocycloalkyl-carbonyl, alkyl-carbonyl-alkyl, NR A R B -carbonyl and NR A R B -alkoxy-alkyl;  
       alternatively R 1  and R 2  are taken together with the atoms to which they are bound to form a five to eight membered saturated ring structure of the formula  
       
         
           
           
               
               
           
         
       
       wherein n is an integer from 1 to 4;  
       wherein R C  and R D  are independently selected from hydrogen, hydroxy, alkyl, alkenyl, alkynyl or alkoxy; alternatively R C  and R D  are taken together with the carbon atom to which they are bound to form an oxo group;  
       alternatively still, R 1  and R 2  are taken together with the atoms to which they are bound to form a heteroatom containing saturated ring structure of the formula  
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 1 to 3;  
       R 3  is selected from the group consisting of hydrogen and alkyl;  
       
         
           
           
               
               
           
         
       
        is selected from the group consisting of aryl, aralkyl and heteroaryl; wherein the heteroaryl group is bound to the core structure through a carbon atom; and wherein the aryl, aralkyl or heteroaryl group is optionally substituted with one or more substitutents independently selected from hydroxy, alkoxy, aralkyl, aralkyloxy or NR A R B -alkoxy;  
       
         
           
           
               
               
           
         
       
        is selected from the group consisting of aryl, aralkyl and heteroaryl; wherein the heteroaryl group is bound to the core structure through a carbon atom; and wherein the aryl, aralkyl or heteroaryl group is optionally substituted with one or more substitutents independently selected from hydroxy, alkoxy, aralkyl, aralkyloxy or NR A R B -alkoxy;  
       provided that when   is a double bond, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen, and  
       
         
           
           
               
               
           
         
       
        are the same and selected from the group consisting of phenyl or substituted phenyl, wherein the substituents on the phenyl are one to two selected from alkoxy, then R 1  is other than hydroxy substituted lower alkyl or alkoxycarbonyl;  
       provided further that when   is a double bond, R 1a  is hydrogen or lower alkyl,  
       
         
           
           
               
               
           
         
       
        is phenyl, then R 1  is selected from the group consisting of NR A R B -carbonyl and NR A R B -alkoxy-alkyl;  
       provided further that when   is a single bond, R 1a  is hydrogen, R 2  is hydrogen or lower alkyl, R 3  is hydrogen, and  
       
         
           
           
               
               
           
         
       
        are the same and are phenyl, then R 1  is other than lower alkyl, hydroxy substituted lower alkyl, alkylcarbonyl or alkoxycarbonyl;  
       provided further that when   is a single bond, R 1  is lower alkyl, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen and  
       
         
           
           
               
               
           
         
       
        is other than benzimidazolyl;  
       provided further that when   is a single or double bond, R 1a  is lower alkyl, R 3  is hydrogen, R 1  and R 2  are taken together with the atoms to which they are bound to form cyclohexyl or 3-hydroxyphenyl and  
       
         
           
           
               
               
           
         
       
        is other than 4-(NR A R B -lower alkoxy)-phenyl, wherein R A  and R B  are each independently selected from hydrogen or lower alkyl or R A  and R B  are taken together with the N atom to which they are bound to form piperidinyl;  
       provided further than when   is a single or double bond, R 1a  is hydrogen, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form  
       
         
           
           
               
               
           
         
       
        then  
       
         
           
           
               
               
           
         
       
        are not the same and phenyl;  
       provided further that when   is a double bond, R 1a  is lower alkyl, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form a five membered saturated ring structure of the formula  
       
         
           
           
               
               
           
         
       
       wherein R C  is selected from hydroxy or alkoxy, then  
       
         
           
           
               
               
           
         
       
        are other than phenyl or substituted phenyl, wherein the substituents on the phenyl are one or more independently selected from hydroxy, alkoxy, aralkyl, aralkyloxy or NR A R B -alkoxy;  
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       2 . A compound as in  claim 1  wherein 
    represents a single or a double bond;    R 1a  is selected from the group consisting of hydrogen and lower alkyl;    R 1  is selected from the group consisting of lower alkyl, hydroxy substituted lower alkyl, lower alkenyl, hydroxy substituted lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, lower alkyl-carbonyl, phenyl-carbonyl, lower alkyl-carbonyl-lower alkyl, NR A R B -carbonyl and NR A R B -lower alkoxy-lower alkyl;    R A  and R B  are each independently selected from the group consisting of hydrogen and lower alkyl; alternatively R A  and R B  are taken together with the N atom to which they are bound to form a five to six membered heteroaryl or a five to six membered heterocycloalkyl group;    R 2  is selected from the group consisting of hydrogen, carboxy, lower alkyl, hydroxy substituted lower alkyl, lower alkenyl, hydroxy substituted lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, lower alkyl-carbonyl, phenyl-carbonyl, lower alkyl-carbonyl-lower alkyl, NR A R B -carbonyl and NR A R B -lower alkoxy-lower alkyl;    alternatively, R 1  and R 2  are taken together with the atom to which they are bound to form a saturated ring structure of the formula;                          wherein n is an integer from 1 to 4;    R C  and R D  are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkynyl and lower alkoxy; alternatively R C  and R D  are taken together with the carbon atom to which they are bound to form an oxo group;    alternatively still, R 1  and R 2  are taken together with the atom to which they are bound to form a heteroatom containing saturated ring structure of the formula                          wherein m is an integer from 1 to 2;    R 3  is selected from the group consisting of hydrogen and lower alkyl;                           is selected from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is bound to the core structure through a carbon atom; and wherein the aryl or heteroaryl group is optionally substituted with one to two substitutents independently selected from hydroxy, lower alkoxy, aralkyl, aralkyloxy or NR A R B -lower alkoxy;                           is selected from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is bound to the core structure through a carbon atom; and wherein the aryl or heteroaryl group is optionally substituted with one to two substitutents independently selected from hydroxy, lower alkoxy, aralkyl, aralkyloxy or NR A R B -lower alkoxy;    provided that when   is a double bond, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen, and                           are the same and selected from the group consisting of phenyl or substituted phenyl, wherein the substituents on the phenyl are one to two selected from lower alkoxy, then R 1  is other than hydroxy substituted lower alkyl or lower alkoxy-carbonyl;    provided further that when   is a double bond, R 1a  is hydrogen or lower alkyl,                           is phenyl, then R 1  is selected from the group consisting of NR A R B -carbonyl and NR A R B -lower alkoxy-lower alkyl;    provided further that when   is a single bond, R 1a  is hydrogen, R 2  is hydrogen or lower alkyl, R 3  is hydrogen, and                           are the same and are phenyl, then R 1  is other than lower alkyl, hydroxy substituted lower alkyl, lower alkyl-carbonyl or lower alkoxy-carbonyl;    provided further that when   is a single bond, R 1  is lower alkyl, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen and                           is other than benzimidazolyl;    provided further that when   is a single or double bond, R 1a  is lower alkyl, R 3  is hydrogen, R 1  and R 2  are taken together with the atoms to which they are bound to form cyclohexyl or 3-hydroxyphenyl and                           is other than 4-(NR A R B -lower alkoxy)-phenyl, wherein R A  and R B  are each independently selected from hydrogen or lower alkyl or R A  and R B  are taken together with the N atom to which they are bound to form piperidinyl;    provided further than when   is a single or double bond, R 1a  is hydrogen, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form                           then                           are not the same and phenyl;    provided further that when   is a double bond, R 1a  is lower alkyl, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form a five membered saturated ring structure of the formula                          wherein R C  is selected from hydroxy or lower alkoxy, then                           are other phenyl or substituted phenyl, wherein the substituents on the phenyl are one or more independently selected from hydroxy, lower alkoxy, aralkyl, aralkyloxy or NR A R B -lower alkoxy;    or a pharmaceutically acceptable salt thereof.    
   
   
       3 . A compound as in  claim 2  wherein 
    represents a single or a double bond;    R 1a  is selected from the group consisting of hydrogen and lower alkyl;    R 1  is selected from the group consisting of lower alkyl, hydroxy substituted lower alkyl, hydroxy substituted lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, lower alkyl-carbonyl-lower alkyl and NR A R B -lower alkoxy-lower alkyl and NR A R B -carbonyl;    wherein R A  and R B  are independently selected from hydrogen and lower alkyl; alternatively R A  and R B  are taken together with the nitrogen atom to which they are bound to form a five to six membered heteroaryl or a five to six membered heterocycloalkyl;    R 2  is selected from the group consisting of hydrogen, carboxy, lower alkyl, hydroxy substituted lower alkyl, lower alkyl-carbonyl, lower alkoxy-lower alkyl, lower alkyl-carbonyl-lower alkyl and NR A R B -lower alkoxy-lower alkyl;    R 3  is selected from the group consisting of hydrogen and lower alkyl;                           is selected from the group consisting of aryl; wherein the aryl group is optionally substituted with a substituent selected from hydroxy, lower alkoxy and aralkyloxy;                           is selected from the group consisting of aryl; wherein the aryl group is optionally substituted with one to two substituents independently selected from hydroxy, lower alkoxy, aralkyl and NR A R B -lower alkoxy;    provided that when   is a double bond, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen, and                           are the same and selected from the group consisting of phenyl or substituted phenyl, wherein the substituent on the phenyl is selected from lower alkoxy, then R 1  is other than hydroxy substituted lower alkyl or lower alkoxy-carbonyl;    provided further that when   is a double bond, R 1a  is hydrogen or lower alkyl,                           is phenyl, then R 1  is selected from the group consisting of NR A R B -carbonyl and NR A R B -lower alkoxy-lower alkyl;    provided further that when   is a single bond, R 1a  is hydrogen, R 2  is hydrogen or lower alkyl, R 3  is hydrogen, and                           are the same and are phenyl, then R 1  is other than lower alkyl, hydroxy substituted lower alkyl, lower alkyl-carbonyl or lower alkoxy-carbonyl;    or a pharmaceutically acceptable salt thereof.    
   
   
       4 . A compound as in  claim 3  wherein 
    represents a single or a double bond;    R 1a  is selected from the group consisting of hydrogen and methyl.    R 1  is selected from the group consisting of methyl, hydroxymethyl, 1-hydroxy-propyn-2-yl, 1-hydroxy-n-propyl, methoxymethyl, methoxycarbonyl, methylcarbonylmethyl, dimethylamino-ethoxy-methyl, morpholinyl-ethoxy-methyl, morpholinylcarbonyl and diethylaminocarbonyl;    R 2  is selected from the group consisting of hydrogen, carboxy, methyl, hydroxymethyl, methoxycarbonyl, methoxymethyl, methylcarbonylmethyl and dimethylamino-ethoxy-methyl;    R 3  is selected from the group consisting of hydrogen and ethyl;                           is selected from the group consisting of phenyl, 4-hydroxyphenyl, 4-methoxyphenyl and 4-benzyloxy-phenyl;                           is selected from the group consisting of phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-dimethylaminoethoxy-phenyl, 4-hydroxy-3-benzyl-phenyl and 4-(piperidinyl-ethoxy)-phenyl;    provided that when   is a double bond, R 1a  is hydrogen, R 2  is hydrogen, R 3  is hydrogen, and                           are the same and selected from the group consisting of phenyl and 4-methoxyphenyl, then R 1  is other than hydroxymethyl, 1-hydroxy-n-propyl or methoxycarbonyl;    provided further that when   is a double bond, R 1a  is hydrogen or methyl,                           is phenyl, then R 1  is selected from the group consisting of dimethylamino-ethoxy-methyl, morpholinyl-ethoxy-methyl, morpholinylcarbonyl and diethylaminocarbonyl;    provided further that when   is a single bond, R 1a  is hydrogen, R 2  is hydrogen or methyl, R 3  is hydrogen, and                           are the same and are phenyl, then R 1  is other than methyl, hydroxymethyl, 1-hydroxy-n-propyl or methoxycarbonyl;    or a pharmaceutically acceptable salt thereof.    
   
   
       5 . A compound as in  claim 2  wherein 
    represents a single or a double bond;    R 1a  is selected from the group consisting of hydrogen and lower alkyl;    R 1  and R 2  are taken together with the atoms to which they are bound to form a saturated ring structure of the formula                          wherein n is an integer from 1 to 4;    R C  and R D  are independently selected from the group consisting of hydrogen, hydroxy and lower alkynyl; alternatively R C  and R D  are taken together with the carbon atom to which they are bound to form an oxo group;    alternatively, R 1  and R 2  are taken together with the atoms to which they are bound to form a heteroatom containing saturated ring structure of the formula                          wherein m is an integer from 1 to 2;    R 3  is hydrogen;                           is aryl; wherein the aryl group is optionally substituted with a substituent selected from hydroxy or lower alkoxy;                           is aryl; wherein the aryl is optionally substituted with a substituent selected from lower alkoxy;    provided than when   is a single or double bond, R 1a  is hydrogen, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form                           then                           are not the same and phenyl;    provided further that when   is a double bond, R 1a  is lower alkyl, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form                           then                           is other than phenyl or substituted phenyl wherein the substituent selected from hydroxy or lower alkoxy and                           is other than phenyl or substituted phenyl, wherein the substituent on the phenyl is lower alkoxy;    or a pharmaceutically acceptable salt thereof.    
   
   
       6 . A compound as in  claim 5  wherein 
    represents a single or a double bond;    R 1a  is selected from the group consisting of hydrogen and methyl;    R 1  and R 2  are taken together with the atom to which they are bound to form a ring structure selected from the group consisting of 3-hydroxy-3-ethynyl-cyclopentyl, 3-hydroxy-cyclopentyl, 3-oxo-cyclopentyl, 3-hydroxy-cyclohexyl, 3-oxo-cyclohexyl, 3-oxo-cyclooctyl and dihydro-fur-4-yl;    R 3  is hydrogen;                           is selected from the group consisting of phenyl, 4-hydroxyphenyl and 4-methoxyphenyl;                           is selected from the group consisting of phenyl and 4-methoxyphenyl;    provided than when   is a single or double bond, R 1a  is hydrogen, R 3  is hydrogen and R 1  and R 2  are taken together with the atoms to which they are bound to form                           then                           are not the same and phenyl;    provided further that when   is a double bond, R 1a  is methyl and R 3  is hydrogen, then R 1  and R 2  are taken together with the atoms to which they are bound to form a ring structure other than                          or a pharmaceutically acceptable salt thereof.    
   
   
       7 - 10 . (canceled)  
   
   
       11 . A compound of formula (III)  
     
       
         
         
             
             
         
       
       wherein  
          represents a single or a double bond;  
       X is selected from the group consisting of C(O) and CH 2 ;  
       R 4  is selected from the group consisting of hydrogen and lower alkyl;  
       R 5  is selected from the group consisting of alkyl;  
       R 6  is selected from the group consisting of -(aralkyl)-Q-(alkyl)-NR A R B ;  
       Q is selected from the group consisting of O and S;  
       R A  and R B  are each independently selected from the group consisting of hydrogen and alkyl; alternatively R A  and R B  are taken together with the N atom to which they are bound to form a heteroaryl or heterocycloalkyl group;  
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       12 . A compound as in  claim 11  wherein 
    represents a single or a double bond;    X is selected from the group consisting of C(O) and CH 2 ;    R 4  is selected from the group consisting of hydrogen and lower alkyl;    R 5  is selected from the group consisting of lower alkyl;    R 6  is selected from the group consisting of -(benzyl)-Q-(lower alkyl)-NR A R B ;    Q is selected from the group consisting of O and S;    R A  and R B  are each independently selected from the group consisting of hydrogen and lower alkyl; alternatively R A  and R B  are taken together with the N atom to which they are bound to form a five to six membered heteroaryl or a five to six membered heterocycloalkyl group;    or a pharmaceutically acceptable salt thereof.    
   
   
       13 . A compound as in  claim 12  wherein 
    represents a single or a double bond;    X is C(O);    R 4  is selected from the group consisting of lower alkyl;    R 5  is selected from the group consisting of lower alkyl;    R 6  is selected from the group consisting of -(benzyl)-O-(lower alkyl)-NR A R B      wherein R A  and R B  are each independently selected from lower alkyl;    alternatively R A  and R B  are taken together with the N atom to which they are bound to form a five to six membered heteroaryl or five to six membered heterocycloalkyl group;    or a pharmaceutically acceptable salt thereof.    
   
   
       14 . A compound as in  claim 13  wherein 
    represents a single or a double bond;    X is C(O);    R 4  is ethyl;    R 5  is methyl;    R 6  is selected from the group consisting of 4-(dimethylamino-ethoxy)-benzyl, 4-(morpholinyl-ethoxy)-benzyl, 4-(piperidinyl-ethoxy)-benzyl and 4-(pyrrolidinyl-ethoxy)-benzyl;    or a pharmaceutically acceptable salt thereof.    
   
   
       15 . A compound selected from the group consisting of 
 3-(4-benzyloxy-benzyl)-2-methyl-4-oxo-cyclohex-2-enecarboxylic acid ethyl ester;    4-{4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-1-enyl}-phenol; 
 or a pharmaceutically acceptable salt thereof.  
   
   
   
       16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
   
   
       17 . A pharmaceutical composition made by mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       18 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       19 . A method of treating a disorder mediated by an estrogen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 .  
   
   
       20 . The method of  claim 19 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, cancer of the breast tissue, hyperplasia of the breast tissue, cancer of the endometrium, hyperplasia of the endometrium, cancer of the cervix, hyperplasia of the cervix, cancer of the prostate, hyperplasia of the prostate, endometriosis, uterine fibroids, osteoarthritis and contraception.  
   
   
       21 . The method of  claim 19 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.  
   
   
       22 . A method of treating a disorder mediated by an estrogen receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of  claim 16 .  
   
   
       23 . A method of contraception comprising co-therapy with a therapeutically effective amount of a compound as in  claim 1  and a progestogen or a progestogen antagonist.  
   
   
       24 - 31 . (canceled)  
   
   
       32 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 11 .  
   
   
       33 . A pharmaceutical composition made by mixing a compound of  claim 11  and a pharmaceutically acceptable carrier.  
   
   
       34 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 11  and a pharmaceutically acceptable carrier.  
   
   
       35 . A method of treating a disorder mediated by an estrogen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 11 .  
   
   
       36 . The method of  claim 35 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, cancer of the breast tissue, hyperplasia of the breast tissue, cancer of the endometrium, hyperplasia of the endometrium, cancer of the cervix, hyperplasia of the cervix, cancer of the prostate, hyperplasia of the prostate, endometriosis, uterine fibroids, osteoarthritis and contraception.  
   
   
       37 . The method of  claim 35 , wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.  
   
   
       38 . A method of treating a disorder mediated by an estrogen receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of  claim 32 .  
   
   
       39 . A method of contraception comprising co-therapy with a therapeutically effective amount of a compound as in  claim 11  and a progestogen or a progestogen antagonist.