Anti-estrogen plus progestin containing oral contraceptives

Abstract

This invention provides a method of providing contraception which comprises administering to a female of child bearing age a combination of a non-uterotrophic anti-estrogen and a progestin for 28 days per 28-day menstrual cycle.

What is claimed is:  
     
         1 . A method of providing contraception which comprises administering to a female of childbearing age a contraceptive effective amount of a combination of an anti-estrogen of formulas I or II having the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen or mono- or poly-fluoroalkoxy of 1-12 carbon atoms;  
 R 2  is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, cyano, alkyl fo 1-6 carbon atoms, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH.  
 R 3  and R 4  are each, independently, H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, or cyano, with the proviso that, when R 1  is H, R 2  is not OH.  
 X is H, alkyl of 1-6 carbon atoms, cyano, nitro, triflouromethyl, or halogen,  
 n is 2 or 3;  
 Y is a saturated, partially saturated or unsaturated 5-7 membered heterocycle containing a nitrogen, which may optionally contain a second heteroatom selected from the group consisting of —O—, —NH—, alkylamine of 1-6 carbon atoms, —N═, and S(O) m ;  
 m is 0-2;  
 or a pharmaceutically acceptable salt thereof,  
 and a progestin for 28 consequetive days per 28-day menstrual cycle.  
 
     
     
         2 . The method according to  claim 1 , wherein 
 Y is                          
     
     
         3 . The method according to  claim 1 , wherein the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone.  
     
     
         4 . The method according to  claim 3 , wherein the progestin is levonorgestrel.  
     
     
         5 . The method according to  claim 4 , wherein the anti-estrogen is selected from the group consisting of 
 a) 5-benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    b) 5-benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    c) 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    d) 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    e) 5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    f) 5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    g) 5-benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;        h) 5-benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    i) 5-benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    j) 5-benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    k) 5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol or a pharmaceutically acceptable salt thereofe;    1) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof;    m) 5-benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    n) 5-benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;    o) 5-benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof;    p) 5-benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole or a pharmaceutically acceptable salt thereof;    q) 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylpiperazin-1-yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically acceptable salt thereof;    r) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxyphenyl)-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof;    s) 4-{3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole}hydrochloride;    t) 4-{3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol hydrochloride;    u) 3-methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    v) 4-{5-methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2-yl}-phenol or a pharmaceutically acceptable salt thereof;    w) 2-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    x) 5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole hydrochloride;    y) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl) -3-methyl-1H-indole hydrochloride;    z) 2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    aa) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    ab) 4-{5-fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl }-phenol hydrochloride;    ac) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol -5-ol hydrochloride;    ad) 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    ae) 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    af) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride;    ag) 2-(4-fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    ah) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    ai) 2-(3-methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    aj) 2-benzo[1,3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;        ak) 2-(4-isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    al) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride;    am) 2-(4-cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    an) 2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    ao) 2-(2,4-dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    ap) 2-(3-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    aq) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indole-5-ol or a pharmaceutically acceptable salt thereof;    ar) 2-(3-fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    as) 2-(3-fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    at) 2-(3-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-5-ol or a pharmaceutically acceptable salt thereof;    au) 3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole-5-ol or a pharmaceutically acceptable salt thereof;    av) 3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    aw) 3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    ax) 3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    ay) 3-chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    az) 2-(4-hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;    ba) 5-hydroxy-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-3-carbonitrile hydrochloride;    bb) 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl) -1H-indole-3-cabonitrile hydrochloride;    bc) di-propionate of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride;    bd) di-pivalate of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol hydrochloride;    be) di-pivalate ester of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;    
     
     
         6 . The method according to  claim 5 , wherein the anti-estrogen 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.  
     
     
         7 . The method according to  claim 6 , wherein the same dosage of the antiestrogen and progestin combination is administered in each of the 28 days.  
     
     
         8 . The method according to  claim 5 , wherein the antiestrogen is 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetate.  
     
     
         9 . The method according to  claim 8 , wherein the same dosage of the anti-estrogen and progestin combination is administered in each of the 28 days.  
     
     
         10 . A method of providing contraception which comprises administering to a female of child bearing age a combination of a daily dosage of 0.5-25 mg 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetate and 30-150 μg levonorgestrel for 28 consequetive days per 28 day menstrual cycle.  
     
     
         11 . The method according to  claim 10 , wherein the same dosage of the combination is administered in each of the 28 days.  
     
     
         12 . A method of providing contraception which comprises administering to a female of child bearing age a combination of a non-uterotrophic antiestrogen and a progestin for 28 days per 28-day menstrual cycle.  
     
     
         13 . The method according to  claim 12 , wherein the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone.  
     
     
         14 . The method according to  claim 13 , wherein the anti-estrogen is selected from the group consisting of raloxifene, droloxifene, idoxifine, nafoxidine, toremifene, TAT-59, levomeloxifene, LY-353381, CP-336156, MDL-103323, EM-800, and ICI-182,780.  
     
     
         15 . The method according to  claim 14 , wherein the same dosage of the antiestrogen and progestin combination is administered in each of the 28 days.  
     
     
         16 . A contraceptive kit adapted for daily oral administration which comprises 28 separate dosage units, each containing a combination of a non-uterotrophic anti-estrogen and a progestin.  
     
     
         17 . The kit according to  claim 16 , wherein the anti-estrogen is a compound of formulas I or II having the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen or mono- or poly-fluoroalkoxy of 1-12 carbon atoms;  
 R 2  is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, cyano, alkyl fo 1-6 carbon atoms, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH.  
 R 3  and R 4  are each, independently, H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, or cyano, with the proviso that, when R 1  is H, R 2  is not OH.  
 X is H, alkyl of 1-6 carbon atoms, cyano, nitro, triflouromethyl, or halogen;  
 n is 2 or 3;  
 Y is a saturated, partially saturated or unsaturated 5-7 membered heterocycle containing a nitrogen, which may optionally contain a second heteroatom selected from the group consisting of —O—, —NH—, alkylamine of 1-6 carbon atoms, —N═, and S(O) m ;  
 m is 0-2;  
 or a pharmaceutically acceptable salt thereof,  
 and the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone.  
 
     
     
         18 . The kit according to  claim 17 , wherein the anti-estrogen is 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetate and the progestin is levonorgestrel.