Compositions and methods of treatment for conditions responsive to testosterone elevation

Abstract

This invention relates to methods and pharmaceutical compositions useful in the treatment of conditions that are responsive to the elevation of testosterone levels in the body and the use of estrogen agonists/antagonists for the manufacture of medicaments for the treatment of conditions that are responsive to the elevation of testosterone levels in the body. The compositions are comprised of an estrogen agonist/antagonist and a pharmaceutically acceptable vehicle, carrier or diluent. These compositions are effective in treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and are effective in increasing libido in female subjects including post-menopausal women. In the case of male subject sexual dysfunction, the compositions may also include a compound which is an elevator of cyclic guanosine 3′,5′-monophosphate (cGMP). Additionally, the compositions are effective in other conditions whose etiology is a result of testosterone deficiency or which can be ameliorated by increasing testosterone levels within the body. Methods of the invention include the treatment of conditions that are responsive to elevation of testosterone levels such as treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and the increase of libido of female subjects including post-menopausal women. The methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with testosterone administration.

What is claimed is:  
     
         1 . A method of treating timidity in post menopausal women, enhancing libido in postmenopausal women, or treating male sexual dysfunction, the method comprising the step of: 
 administering to a patient in need thereof an effective amount of an estrogen agonist/antagonist.    
     
     
         2 . A method as claimed in  claim 1  further comprising co-administering an effective amount of an elevator of cyclic guanosine 3′,5′-monophosphate.  
     
     
         3 . A method as claimed in  claim 1  wherein the estrogen agonist/antagonist is a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is selected from CH 2  and NR;  
 B, D and E are independently selected from CH and N;  
 Y is 
 (a) phenyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (c) C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (d) C 3 -C 8  cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n — optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  is 
 (a) —(CH 2 ) p  W(CH 2 ) q —;  
 (b) —O(CH 2 ) p  CR 5 R 6 —;  
 (c) —O(CH 2 ) p W(CH 2 ) q —;  
 (d) —OCHR 2 CHR 3 —; or  
 (e) —SCHR 2 CHR 3 —;  
 
 G is 
 (a) —NR 7 R 8 ;  
                     
  wherein n is 0, 1 or 2; m is 1, 2 or 3; Z 2  is —NH—, —O—, —S—, or —CH 2 —; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R 4 ; or  
 (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 
 Z 1  and G in combination may be  
                     
 W is 
 (a) —CH 2 —;  
 (b) —CH═CH—;  
 (c) —O—;  
 (d) —NR 2 —;  
 (e) —S(O) n —;  
                     
 (g) —CR 2 (OH)—;  
 (h) —CONR 2 —;  
 (i) —NR 2 CO—;  
                     
 (k) —C≡C—;  
 
 R is hydrogen or C 1 -C 6  alkyl;  
 R 2  and R 3  are independently 
 (a) hydrogen; or  
 (b) C 1 -C 4  alkyl;  
 
 R 4  is 
 (a) hydrogen;  
 (b) halogen;  
 (c) C 1 -C 6  alkyl;  
 (d) C 1 -C 4  alkoxy;  
 (e) C 1 -C 4  acyloxy;  
 (f) C 1 -C 4  alkylthio;  
 (g) C 1 -C 4  alkylsulfinyl;  
 (h) C 1 -C 4  alkylsulfonyl;  
 (i) hydroxy (C 1 -C 4 )alkyl;  
 (j) aryl (C 1 -C 4 )alkyl;  
 (k) —CO 2 H;  
 (l) —CN;  
 (m) —CONHOR;  
 (n) —SO 2 NHR;  
 (o) —NH 2 ;  
 (p) C 1 -C 4  alkylamino;  
 (q) C 1 -C 4  dialkylamino;  
 (r) —NHSO 2 R;  
 (s) —NO 2 ;  
 (t) -aryl; or  
 (u) —OH;  
 
 R 5  and R 6  are independently C 1 -C 8  alkyl or together form a C 3 -C 10 carbocyclic ring;  
 R 7  and R 8  are independently 
 (a) phenyl;  
 (b) a C 3 -C 10  carbocyclic ring, saturated or unsaturated;  
 (c) a C 3 -C 10  heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;  
 (d) H;  
 (e) C 0 -C 6  alkyl; or  
 (f) form a 3 to 8 membered nitrogen containing ring with R 5  or R 6 ;  
 
 R 7  and R 8  in either linear or ring form may optionally be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, halogen, alkoxy, hydroxy and carboxy;  
 a ring formed by R 7  and R 8  may be optionally fused to a phenyl ring;  
 e is 0, 1 or 2;  
 m is 1, 2 or 3;  
 n is 0, 1 or 2;  
 p is 0, 1, 2 or 3;  
 q is 0, 1, 2 or 3;  
 or an optical or geometric isomer thereof; or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester or quaternary ammonium salt or prodrug thereof.  
 
     
     
         4 . A method as claimed in  claim 1  wherein the estrogen agonist/antagonist is a compound of formula (IA):  
       
         
           
           
               
               
           
         
       
       wherein G is  
       
         
           
           
               
               
           
         
         R 4  is H, OH, F, or Cl; and B and E are independently selected from CH and N.  
       
     
     
         5 . A method as claimed in  claim 1  wherein the estrogen agonist/antagonist is a member of the group consisting of 
 cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,  
 (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,  
 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,  
 cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene,  
 1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline,  
 cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, and  
 1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.  
 
     
     
         6 . A method as claimed in  claim 1  wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         7 . A method as claimed in  claim 1  wherein said estrogen agonist/antagonist is a compound of formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1A  and R 2A  may be the same or different provided that, when R 1A  and R 2A  are the same, each is a methyl or ethyl group, and, when R 1A  and R 2A  are different, one of them is a methyl or ethyl group and the other is hydrogen or a benzyl group; a compound of formulas III or IV:  
                     
 a compound of formulas V and VI:  
                     
 wherein:  
 R 1B  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 trifluoromethyl ether and trichloromethyl ether.  
 R 2B , R 3B , R 4B , R 5B , and R 6B  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 trifluoromethyl ether and trichloromethyl ether, cyano, C 1 -C 6  alkyl (straight chain or branched), or trifluoromethyl;  
 X A  is selected from H, C 1 -C 6  alkyl, cyano, nitro, trifluoromethyl, and halogen;  
 s is 2 or 3;  
 Y A  is selected from: 
 a) the moiety:  
                     
  wherein R 7B  and R 8B  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) u —, wherein u 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 1B , —NH 2 , C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1B , —NHCOR 1B , —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) u —, wherein u 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 1B , —N HCOR 1B , —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) u —, wherein u 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 1B , —NH 2 , C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1B , —NHCOR 1B , —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) u —, wherein u 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 1B —, —NH 2 , —N═, C 1 -C 4  alkylamino, di(C 1 -C 4 )alkylamino, —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , and phenyl optionally substituted with 1-3 (C 1 -C 4 ) alkyl;  
 or a componud of formula Va:  
                     
 or optical or geometric isomers thereof; nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts; or prodrugs thereof.  
 
 
     
     
         8 . A method as claimed in  claim 1  wherein said estrogen agonist/antagonist is a member selected from the group consisting of 4-hydroxy tamoxifen, raloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol and {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, GW 5638, GW 7604 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.  
     
     
         9 . A kit for treating timidity in post menopausal women, enhancing libido in postmenopausal women, or treating male sexual dysfunction, said kit comprising: 
 a) a pharmaceutical composition comprising an estrogen agonist/antagonist and a pharmaceutically acceptable vehicle, carrier or diluent; and    b) instructions describing a method of using the pharmaceutical composition to treat timidity in post menopausal women, enhance libido in postmenopausal women or treat male sexual dysfunction.    
     
     
         10 . A kit as claimed in  claim 9  wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         11 . A kit according to  claim 9  further comprising an elevator of cyclic guanosine 3′,5′-monophosphate.