Lonidamine analogues for fertility management

Abstract

Fertility management can include: administering to the subject one or more doses of a compound according to Formula I so as to reduce fertility in the subject. Fertility management can also include administering an effective amount of the compound to: impair Sertoli cell function in a male subject; inhibit spermatogenesis in the subject; reduce testis weight in the subject; reduce ovary weight in a female subject; reduce serum progesterone in the female subject; impair ovarian follicle function in the female subject; causing reversible fertility in the subject. In order to return fertility, the method can include ceasing administration of the compound to the subject so as to return fertility in the subject. The compound can be administered for irreversibly sterilizing the subject.

1 .- 24 . (canceled) 
     
     
         25 . A method for reducing fertility in a female subject, the method comprising:
 administering to the female subject one or more doses of a compound according to Formula I so as to reduce fertility in the subject:   
       
         
           
           
               
               
           
         
         wherein R 1  is carboxyl, acryl, or carboxylic acid hydrazide; 
         wherein R 2  is hydrogen, halogen, alcohol, alkyl, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl; 
         wherein X and Y are the same or different from each other and are halogen or lower alkyl; 
         wherein Z 1 , Z 2 , Z 3 , and Z 4  are carbon; and 
         pharmaceutically acceptable salts and esters thereof. 
       
     
     
         26 . A method as in  claim 25 , wherein
 wherein R 1  is carboxyl, acryl, or carboxylic acid hydrazide; and   wherein R 2  is halogen, alcohol, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl.   
     
     
         27 . A method as in  claim 25 , wherein
 R 1  includes one or more of a carboxylic acid, carboxylic acid ester, propionic acid, 2-methyl propionic acid, oxirane-carboxylic acid, cyclopropane carboxylic acid, propionic acid methyl ester, 2-methyl propionic acid methyl ester, oxirane-carboxylic acid methyl ester, or cyclopropane carboxylic acid methyl ester; and/or   R 2  includes a halogen, haloalkyl, or haloalkoxy.   
     
     
         28 . A method as in  claim 25 , wherein the, compound is selected from the group consisting of:
 3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-acrylic acid;   6-chloro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;   1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazole-3-carboxylic acid methyl ester;   6-fluoro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;   3-[1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazol-3-yl]-acrylic acid;   3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethoxy-1H-indazol-3-yl]acrylic acid; 3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-propionic acid;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid; and pharmaceutically acceptable salts and esters thereof.   
     
     
         29 . A method as in  claim 25 , wherein the compound is selected from the group consisting of:
 gamendazole;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid (JVVS-2-72 or H2-gamendazole);   3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid (JWS 1-190);   1-(2-chloro-4-fluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 2-22);   1-(2,4-difluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 1-282);   and   pharmaceutically acceptable salts and esters thereof.   
     
     
         30 . A method as in  claim 25 , wherein the compound is administered in an effective amount in accordance with at least one of the following:
 maintain bodyweight of the female subject;   inhibiting production of inhibin B in the female subject;   inhibiting production of estradiol in the female subject;   reducing ovary weight in the female subject;   reducing serum progesterone in the female subject;   inhibiting progesterone production in the female subject;   inducing atretic ovarian follicles in the female subject;   reducing number of viable ovarian follicles in the female subject;   reducing amount of germ cells in the female subject; or   inhibiting ovulation in the female subject.   
     
     
         31 . A method as in  claim 30 , wherein the compound is administered in an effective amount to reduce number of viable ovarian follicles in the subject. 
     
     
         32 . A method as in  claim 30 , wherein the compound is administered in an effective amount to reduce ovary weight in the subject. 
     
     
         33 . A method as in  claim 25 , wherein the compound is administered in a therapeutically effective amount for causing reversible infertility in the female subject, the method further comprising:
 ceasing administration of the compound to the female subject so as to return fertility in the subject.   
     
     
         34 . A method as in  claim 25 , wherein the compound is administered in an effective amount for irreversibly sterilizing the female subject. 
     
     
         35 . A method as in  claim 34 , wherein the compound is administered in an effective amount to induce irreversible sterility in the female subject in a single dose. 
     
     
         36 . A method as in  claim 34 , wherein the compound is administered in a multi-dose regimen to induce irreversible sterility in the subject. 
     
     
         37 . A method for inhibiting oogenesis in a female subject, the method comprising:
 administering to the female subject one or more doses of a composition having a pharmaceutically acceptable carrier and a compound according to Formula I so as to inhibit oogenesis:   
       
         
           
           
               
               
           
         
         wherein R 1  is carboxyl, acryl, or carboxylic acid hydrazide; 
         wherein R 2  is hydrogen, halogen, alcohol, alkyl, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl; 
         wherein X and Y are the same or different from each other and are halogen or lower alkyl; 
         wherein Z 1 , Z 2 , Z 3 , and Z 4  are carbon; and 
         pharmaceutically acceptable salts and esters thereof. 
       
     
     
         38 . A method as in  claim 36 , wherein
 wherein R 1  is carboxyl, acryl, or carboxylic acid hydrazide; and   wherein R 2  is halogen, alcohol, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl.   
     
     
         39 . A method as in  claim 36 , wherein
 R 1  includes one or more of a carboxylic acid, carboxylic acid ester, propionic acid, 2-methyl propionic acid, oxirane-carboxylic acid, cyclopropane carboxylic acid, propionic acid methyl ester, 2-methyl propionic acid methyl ester, oxirane-carboxylic acid methyl ester, or cyclopropane carboxylic acid methyl ester; and/or   R 2  includes a halogen, haloalkyl, or haloalkoxy.   
     
     
         40 . A method as in  claim 36 , wherein the, compound is selected from the group consisting of:
 3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-acrylic acid;   6-chloro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;   1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazole-3-carboxylic acid methyl ester;   6-fluoro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;   3-[1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazol-3-yl]-acrylic acid;   3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethoxy-1H-indazol-3-yl]acrylic acid; 3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-propionic acid;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid; and pharmaceutically acceptable salts and esters thereof.   
     
     
         41 . A method as in  claim 36 , wherein the compound is selected from the group consisting of:
 gamendazole;   3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid (JVVS-2-72 or H2-gamendazole);   3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid (JWS 1-190);   1-(2-chloro-4-fluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 2-22);   1-(2,4-difluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 1-282);   and   pharmaceutically acceptable salts and esters thereof.   
     
     
         42 . A method as in  claim 36 , wherein the compound is administered in an effective amount in accordance with at least one of the following:
 maintain bodyweight of the female subject;   inhibiting production of inhibin B in the female subject;   inhibiting production of estradiol in the female subject;   reducing ovary weight in the female subject;   reducing serum progesterone in the female subject;   inhibiting progesterone production in the female subject;   inducing atretic ovarian follicles in the female subject;   reducing number of viable ovarian follicles in the female subject;   reducing amount of germ cells in the female subject; or   inhibiting ovulation in the female subject.   
     
     
         43 . A method as in  claim 36 , wherein the compound is administered in a therapeutically effective amount for causing reversible infertility in the female subject, the method further comprising:
 ceasing administration of the compound to the female subject so as to return fertility in the subject.   
     
     
         44 . A method as in  claim 25 , wherein the compound is administered in an effective amount for irreversibly sterilizing the female subject. 
     
     
         45 . A method as in  claim 44 , wherein the compound is administered in an effective amount to induce irreversible sterility in the female subject in a single dose. 
     
     
         46 . A method as in  claim 44 , wherein the compound is administered in a multi-dose regimen to induce irreversible sterility in the subject.