2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations

Abstract

The present invention relates to new formulations containing one or more estrogens and 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, which have the general structures below:

What is claimed:  
     
         1 . A pharmaceutical composition comprising one or more estrogens and a compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from H, OH or the C 1 -C 12  esters (straight chain or branched) or C 1 -C 12  (straight chain or branched or cyclic) alkyl ethers thereof, or halogens; or C 1 -C 4  halogenated ethers including triflouromethyl ether and trichloromethyl ether.  
 R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from H, OH or the C 1 -C 12  esters (straight chain or branched) or C 1 -C 12  alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C 1 -C 4  halogenated ethers including triflouromethyl ether and trichloromethyl ether, cyano, C 1 -C 6  alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH.  
 X is selected from H, C 1 -C 6  alkyl, cyano, nitro, trifluoromethyl, halogen;  
 n is 2 or 3;  
 Y is selected from: 
 a) the moiety:  
                     
  wherein R 7  and R 8  are independently selected from the group of H, C 1 -C 6  alkyl, or phenyl optionally substituted by CN, C 1 -C 6  alkyl (straight chain or branched), C 1 -C 6  alkoxy (straight chain or branched), halogen, —OH, —CF 3 , or —OCF 3 ;  
 b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C 1 C 4  alkyl)—, —N═, and —S(O) m —, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H—, —CN—, —CONHR 1 —, —NH 2 —, C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1 —, —NHCOR 1 —, —NO 2 , and phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl;  
 c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C 1 C 4  alkyl)—, —N═, and —S(O) m —, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H—, —CN—, —CONHR 1 —, —NH 2 —, C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1 —, —NHCOR 1 —, —NO 2 , and phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl;  
 d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C 1 C 4  alkyl)—, —N═, and —S(O) m —, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H—, —CN—, —CONHR 1 —, —NH 2 —, C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1 —, —NHCOR 1 —, —NO 2 , and phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 e) a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C 1 C 4  alkyl)—, and —S(O) m —, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H—, —CN—, —CONHR 1 —, —NH 2 —, C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1 —, —NHCOR 1 —, —NO 2 , and phenyl optionally substituted with 1-3 (C 1 -C 4 ) alkyl;  
 or a pharmaceutically acceptable salt thereof, an a pharmaceutically acceptable carrier or excipient.  
 
 
     
     
         2 . A pharmaceutical composition of  claim 1  wherein: 
 R 1  is selected from H, OH or the C 1 -C 4  esters or alkyl ethers thereof, halogen;  
 R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from H, OH or the C 1 -C 4  esters or alkyl ethers thereof, halogen, cyano, C 1 -C 6  alkyl, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH;  
 X is selected from H, C 1 -C 6  alkyl, cyano, nitro, triflouromethyl, halogen;  
 Y is the moiety  
                     
 R 7  and R 8  are selected independently from H, C 1 -C 6  alkyl, or combined by —(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONH(C 1 -C 4 ), —NH 2 , C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 (C 1 -C 4 ), —NHCO(C 1 -C 4 ), and —NO 2 ;  
 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.  
 
     
     
         3 . A pharmaceutical composition of  claim 1  wherein: 
 R 1  is OH;  
 R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from H, OH or the C 1 -C 4  esters or alkyl ethers thereof, halogen, cyano, C 1 -C 6  alkyl, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH;  
 X is selected from the group of Cl, NO 2 , CN, CF 3 , or CH 3 ;  
 Y is the moiety  
                     
 R 7  and R 8  are concatenated together as —(CH 2 ) r —, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three subsituents selected from the group of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONH(C 1 -C 4 ), —NH 2 , C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 (C 1 -C 4 ), —NHCO(C 1 -C 4 ), and —NO 2 ;  
 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.  
 
     
     
         4 . A pharmaceutical composition of  claim 1  in which the compound is 5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof.  
     
     
         5 . A pharmaceutical composition of  claim 1  in which the compound is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         6 . A pharmaceutical composition of  claim 1  in which the compound is 4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole} or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A pharmaceutical composition of  claim 1  in which the compound is 4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A pharmaceutical composition of  claim 1  in which the compound is 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A pharmaceutical composition of  claim 1  in which the compound is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A pharmaceutical composition of  claim 1  in which the compound is 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A pharmaceutical composition of  claim 1  in which the compound is 2-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A pharmaceutical composition of  claim 1  in which the compound is 3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-phenyl)-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         13 . A pharmaceutical composition of  claim 1  in which the compound is 2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A pharmaceutical composition of  claim 1  in which the compound is 2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof.  
     
     
         15 . A pharmaceutical composition of  claim 1  wherein the one or more estrogens are selected from equilin, equilenin, estradiene, ethinyl estradiol, 17β-estradiol, 17alpha-dihydroequilenin, 17β-dihydroequilenin, menstranol, conjugated estrogens, estrone, 17alpha-estradiol sulfate, Delta8,9-dehydroestrone, equol or enterolactone; or a pharmaceutically acceptable salt or ester thereof.  
     
     
         16 . A pharmaceutical composition of  claim 15  wherein the pharmaceutically acceptable salt of the one or more estrogens is a sodium salt.  
     
     
         17 . A method of treating or preventing bone loss in a mammal, the method comprising administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         18 . A method of treating or preventing disease states or syndromes which are caused or associated with an estrogen deficiency in a mammal, the method comprising administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A method of treating or preventing cardiovascular disease in a mammal, the method comprising administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         20 . A method of treating or preventing disease in a mammal which result from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue, the method comprising administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         21 . A method of treatment of  claim 20  wherein the disease is endometriosis.