Novel steroidal antiestrogens and antiandrogens and uses thereof

Abstract

The present invention comprises the design, synthesis and development of a new class of chemotherapeutic agents for prophylactic and therapeutic treatments in a mammal, particularly a human, believed to be at risk of suffering from a hormone-responsive disorder. In an embodiment of the invention, such treatments include therapeutic compositions comprising novel steroidal antiestrogen and antiandrogen compounds. In a preferred embodiment, such a novel compound of the present invention has an address and a message component, which are made into a single composite entity for more aggressive intervention and effective treatment of hormone-responsive disorders, thereby prolonging the disease-free interval for the patient and reducing a number of side effects.

1 - 21 . (canceled)  
     
     
         22 . A therapeutic composition for prophylaxis or treatment of an estrogen or androgen mediated disorder, said composition comprising: 
 a compound having the structural formula, wherein said compound has a message unit at the 17α-position of an address unit, comprising either:    an address unit having the structure:                          wherein:    R 1  is H, CH 3 , CH 2 CH 3 , OH, OCH 3 , OCH 2 CH 3 , C 1 -C 6  alkyl, CH═CH 2 , CH═CHCH 3 , CH 2 -aryl;    R 2  is H, CH 3 , COCH 3 , CO(CH 2 ) n CH 3 , CO-aryl, alkyl, cycloalkyl (ether), ester; and    R 3  is H, CH 3 , CH 2 CH 3 , aryl, heteroaryl, C 1 -C 6  alkyl, alkyl (C 1 -C 6 ) amides, alkyl (C 1 -C 6 ) sulfide, alkyl (C 1 -C 6 ) sulfone, alkyl (C 1 -C 6 ) sulfoxide;    and    a message unit having the structure:                          wherein:    R 4  is H, C 1 -C 4  alkyl;    R 5  is substituted aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, amine-linked heteroaryls, aminoalkoxy arene hybrid, or peptidyl hybrid, wherein any substituted aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, amine-linked heteroaryls, aminoalkoxy arene hybrid and peptidyl hybrid, may optionally be substituted, independently, with H, CH 3 , OH, OCH 3 , OCF 3 , N(CH 3 ) 2 , NHCOCH 3 , aryl, CO 2 CH 3 , CONH 2 , C 1 -C 4  alkyl, (CF 2 ) n F wherein n=1-4, Cl, Br, I, F, O(CH 2 ) n H wherein n=1-4, NO 2 , NH 2 , NHCOR 4 , CO 2 H, CO 2 R 4 , CONHR 4 , amyl, thioether, SR 6 , S(O)R 6 , SO 2 R 6 , SO 2 NR 6 R 7 ; wherein R 4  has the definition given above; wherein R 6  is H, C 1 -C 4  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl, or alkenyl; wherein R 7  is H, C 1 -C 4  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, OR 8  or NHR 8 ; wherein R 8  is H, C 1 -C 6  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, SO 2 R 6  or S(O)R 6 , wherein R 6  has the definition given above,    wherein R 5  can be in either the E or Z configuration in relation to the 17α-position of said address unit; or    an address unit having one of the following different structures:                          wherein:    R 10  is H, CH 3 ;    R 11  is H, C 1 -C 4  alkyl;    R 12  is O, (H, OH);    R 13  is H, OH, Cl, Br, I, CH 3 ;    R 14  is H, C 1 -C 4  alkyl;    R is O, (H, OH);    R 16  is O, NH; and    R 17  through R 18  each independently is H, CH 3 ; and    a message unit having the structure:                          wherein:    R 4  is H, C 1 -C 4  alkyl;    R 5  is aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, or amine-linked heteroaryls, wherein any aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, and amine-linked heteroaryls may optionally be substituted, independently, with H, CH 3 , OH, OCH 3 , OCF 3 , N(CH 3 ) 2 , NHCOCH 3 , aryl, CO 2 CH 3 , CONH 2 , C 1 -C 4  alkyl, (CF 2 ) n F wherein n=1-4, Cl, Br, I, F, O(CH 2 ) n H wherein n=1-4, NO 2 , NH 2 , NHCOR 4 , CO 2 H, CO 2 R 4 , CONHR 4 , amyl, thioether, SR 6 , S(O)R 6 , SO 2 R 6 , SO 2 NR 6 R 7 ; wherein R 4  has the definition given above; wherein R 6  is H, C 1 -C 4  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl, or alkenyl; wherein R 7  is H, C 1 -C 4  alkyl or perf luoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, OR 8  or NHR 8 ; wherein R 8  is H, C 1 -C 6  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, SO 2 R 6  or S(O)R 6 , wherein R 6  has the definition given above,    wherein R 5  can be in either the E or Z configuration in relation to the 17α-position of the address unit;    said compound in a pharmaceutically acceptable inert carrier substance, wherein said compound is capable of binding to a hormone receptor.    
     
     
         23 . The composition of  claim 22 , wherein said hormone receptor is an estrogen receptor.  
     
     
         24 . The composition of  claim 22 , wherein said hormone receptor is an androgen receptor.  
     
     
         25 . The composition of  claim 22 , wherein the composition is formulated for oral, topical, intravenous, intramuscular, subcutaneous, intra-vaginal, suppository or parenteral administration.  
     
     
         26 . A method of preventing or treating a patient suffering from or believed to be at risk of suffering from an estrogen or androgen mediated disorder, said method comprising the steps of: 
 providing said patient; and    administering to said patient an effective amount of the therapeutic composition of  claim 22 , wherein said amount of said composition is effective in preventing or treating said estrogen or androgen mediated disorder.    
     
     
         27 . The method of  claim 26 , wherein said estrogen or androgen mediated disorder is osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility.  
     
     
         28 . The method of  claim 26 , wherein said patient is human.  
     
     
         29 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 0.1 μg/kg/day to 10 μg/kg/day.  
     
     
         30 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 0.5 μg/kg/day to 5 μg/kg/day.  
     
     
         31 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 1 μg to 100 μg by local administration.  
     
     
         32 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 0.10 mg/kg/day to about 40 mg/kg/day.  
     
     
         33 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 0.50 mg/kg/day to about 20 mg/kg/day.  
     
     
         34 . The method of  claim 26 , wherein said composition is administered to said patient as a dosage unit from about 1.0 mg/kg/day to about 10 mg/kg/day.  
     
     
         35 . A kit comprising a therapeutic composition of  claim 22  and instructions for use thereof.  
     
     
         36 . A method for the prophylaxis or treatment of a prostate disorder in a patient, said method comprising the steps of: 
 providing a patient suffering from or believed to be at risk of developing a prostate disorder;    administering to said patient an effective amount of a compound having the structural formula:    an address unit having one of the following different structures:                          wherein    R 10  is H, CH 3 ;    R 11  is H, C 1 -C 4  alkyl;    R 12  is O, (H, OH);    R 13  is H, OH, Cl, Br, I, CH 3 ;    R 14  is H, C 1 -C 4  alkyl;    R 15  is O, (H, OH);    R 16  is O, NH; and    R 17  through R 18  each independently is H, CH 3 ; and    a message unit having the structure:                          wherein:    R 4  is H, C 1 -C 4  alkyl;    R 5  is aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, or amine-linked heteroaryls, wherein any aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linked aryls, and amine-linked heteroaryls may optionally be substituted, independently, with H, CH 3 , OH, OCH 3 , OCF 3 , N(CH 3 ) 2 , NHCOCH 3 , aryl, CO 2 CH 3 , CONH 2 , C 1 -C 4  alkyl, (CF 2 ) n F wherein n=1-4, Cl, Br, I, F, O(CH 2 ) n H wherein n=1-4, NO 2 , NH 2 , NHCOR 4 , CO 2 H, CO 2 R 4 , CONHR 4 , amyl, thioether, SR 6 , S(O)R 6 , SO 2 R 6 , SO 2 NR 6 R 7 ; wherein R 4  has the definition given above; wherein R 6  is H, C 1 -C 4  alkyl or perf luoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl, or alkenyl; wherein R 7  is H, C 1 -C 4  alkyl or perf luoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, OR 8  or NHR 8 ; wherein R 8  is H, C 1 -C 6  alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl, SO 2 R 6  or S(O)R 6 , wherein R 6  has the definition given above,    wherein R 5  can be in either the E or Z configuration in relation to the 17α-position of the address unit.    
     
     
         37 . The method of  claim 36 , wherein said compound binds to the androgen receptor.  
     
     
         38 . The method of  claim 36 , wherein said prostate disorder is prostate cancer, prostate carcinoma, or benign prostate hyperplasia.  
     
     
         39 . An article of manufacture comprising packaging material and a therapeutic composition contained within said packaging material; 
 wherein said therapeutic composition is therapeutically effective for prophylaxis or treatment of an estrogen or androgen mediated disorder;    wherein said packaging material comprises a label with instructions that indicates that the therapeutic composition can be used for prophylaxis or treatment an estrogen or androgen mediated disorder; and    wherein said therapeutic composition is the composition of  claim 22 .    
     
     
         40 . The article of manufacture of  claim 39 , wherein said estrogen or androgen mediated disorder is osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility.  
     
     
         41 . An article of manufacture comprising packaging material and a therapeutic composition contained within said packaging material; 
 wherein said therapeutic composition is therapeutically effective for treatment of osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility;    wherein said packaging material comprises a label with instructions that indicates that the therapeutic composition can be used for treatment of osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility; and    wherein said therapeutic composition is the composition of  claim 22 .    
     
     
         42 . A method of preventing or treating a patient suffering from or believed to be at risk of suffering from osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility, said method comprising the steps of: 
 providing said patient; and    administering to said patient an effective amount of the therapeutic composition of  claim 22 , wherein said amount of said composition is effective in preventing or treating osteoporosis, endometriosis, breast cancer, benign breast cancer, uterine cancer, ovarian cancer, polycystic ovarian disease, prostate cancer, benign prostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness, or infertility.