Structural modification of 19-norprogesterone i: 17-alpha-substituted-11-beta-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents

Abstract

Disclosed are compounds having the general formula: wherein R 1 -R 4 and X are as defined herein, pharmaceutical compositions including such compounds, and a method of treating a patient involving antagonizing the endogenous progesterone, such as in inducing menses and treating endometriosis, dysmenorrhea, endocrine hormone-dependent tumors, meningiomas, uterine leiomyomas, or uterine fibroids, inhibiting uterine endometrial proliferation, inducing cervical ripening, inducing labor, and in contraception.

1 - 60 . (canceled) 
     
     
         61 . A compound having the general formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a member selected from the group consisting of —OCH 3 , —SCH 3 , —N(CH 3 ) 2 , —NHCH 3 , —NC 4 H 8 , —NC 5 H 10 , —NC 4 H 8 O, —CHO, —CH(OH)CH 3 , —C(O)CH 3 , —O(CH 2 ) 2 N(CH 3 ) 2 , —O(CH 2 ) 2 NC 4 Hs, and —O(CH 2 ) 2 NC 5 H 10 ; 
         R 2  is a member selected from the group consisting of hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkylcarbonate, cypionyloxy, S-alkyl, —SCN, S-acyl, and —OC(O)R 6 , wherein R 6  is a member selected from the group consisting of alkyl, alkoxy ester and alkoxy; 
         R 3  is a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; 
         R 4  is a member selected from the group consisting of hydrogen and alkyl; and 
         X is a member selected from the group consisting of ═O and ═N—OR 5 , wherein R 5  is a member selected from the group consisting of hydrogen and alkyl. 
       
     
     
         62 . The compound in accordance with  claim 61 , wherein R 1  is a member selected from the group consisting of —N(CH 3 ) 2 , —NC 4 H 8 , —NC 4 H 8 O, —C(O)CH 3 , —O(CH 2 ) 2 N(CH 3 ) 2 , —O(CH 2 ) 2 NC 4 H 8 , and —O(CH 2 ) 2 NC 5 H 10 . 
     
     
         63 . The compound in accordance with  claim 61 , wherein R 2  is a member selected from the group consisting of hydrogen, alkyloxy, alkoxy, —SAc, —SCN, —OC(O)CH 2 N(CH 3 ) 2 , and —OC(O)R 6 , wherein R 6  is a member selected from the group consisting of alky, alkoxy ester and alkoxy. 
     
     
         64 . The compound in accordance with  claim 63 , wherein R 2  is —OC(O)R 6  and R 6  is a member selected from the group consisting of-CH 2 CH 3 , —CH 2 OCH 3 , and —OCH 3 . 
     
     
         65 . The compound in accordance with  claim 61 , wherein R 2  is an alkoxy selected from the group consisting of methoxy, ethoxy, vinyloxy, ethynyloxy and cyclopropyloxy. 
     
     
         66 . The compound in accordance with  claim 61 , wherein R 3  is a member selected from the group consisting of alkyl, alkoxy, acyloxy and hydroxy. 
     
     
         67 . The compound in accordance with  claim 61 , wherein R 4  is alkyl. 
     
     
         68 . The compound in accordance with  claim 61 , wherein X is ═O. 
     
     
         69 . The compound in accordance with  claim 61 , wherein X is ═N—OR 5 . 
     
     
         70 . The compound in accordance with  claim 61 , wherein R 3  is acyloxy selected from the group consisting of —OC(O)H, —OC(O)CH 2 CH 3  and —OC(O)C 6 H 13 . 
     
     
         71 . The compound in accordance with  claim 61 , wherein the compound is:
 R 1  is —N(CH 3 ) 2 ;   R 2  is hydrogen;   R 3  is methoxymethyl;   R 4  is methyl; and   X is ═O;   R 1  is —NC 4 H 8 ;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 4 H 8 O;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —C(O)CH 3 ;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —SCH 3 ;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is hydrogen;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is hydrogen;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is acetoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —C(O)CH 3 ;   R 2  is acetoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —C(O)CH 3 ;   R 2  is —SAc;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —C(O)CH 3 ;   R 2  is methoxy;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is methoxy;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is methoxy;   R 3  is ethoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 4 H 8 ;   R 2  is methoxy;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is methoxy;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —C(O)CH 3 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —O(CH 2 ) 2 N(CH 3 ) 2 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —O(CH 2 ) 2 NC 4 H 8 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —O(CH 2 ) 2 NC 5 H 10 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)CH 2 CH 3 ;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)CH 2 OCH 3 ;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)OCH 3 ;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OCH═CH 2 ;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OCH═CH 2 ;   R 3  is methoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OCH═CH 2 ;   R 3  is ethoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —SCN;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)H;   R 3  is —OC(O)H;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)H;   R 3  is hydroxy;   R 4  is methyl; and   X is ═O;   R 1  is —N(CH 3 ) 2 ;   R 2  is —OC(O)CH 2 N(CH 3 ) 2 ;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NC 5 H 10 ;   R 2  is hydrogen;   R 3  is acetoxy;   R 4  is methyl; and   X is ═N—OR 5 , wherein R 5  is hydrogen;   R 1  is —N(CH 3 ) 2 ;   R 2  is hydrogen;   R 3  is methoxy;   R 4  is methyl; and   X is ═N—OR 5 , wherein R 5  is hydrogen;   R 1  is —NC 5 H 10 ;   R 2  is hydrogen;   R 3  is methoxy;   R 4  is methyl; and   X is ═N—OR 5 , wherein R 5  is hydrogen;   R 1  is —N(CH 3 ) 2 ;   R 2  is methoxy;   R 3  is methoxy;   R 4  is methyl; and   X is ═N—OR 5 , wherein R 5  is hydrogen;   R 1  is —NHCH 3 ;   R 2  is methoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O;   R 1  is —NHCH 3 ;   R 2  is acetoxy;   R 3  is acetoxy;   R 4  is methyl; and   X is ═O; or   R 1  is —N(CH 3 ) 2 ;   R 2  is hydrogen;   R 3  is acyloxy;   R 4  is methyl; and   X is ═O.   
     
     
         72 . A pharmaceutical composition comprising a compound in accordance with  claim 61  and a pharmaceutically acceptable excipient. 
     
     
         73 . A method of producing an antiprogestational effect in a patient, a method of inducing menses in a patient, a method of treating endometriosis, a method of treating dysmenorrhea, a method of treating endocrine hormone-dependent tumors, a method of treating meningiomas, a method of treating uterine fibroids in a patient, a method of inhibiting uterine endometrial proliferation in a patient, a method of inducing labor, a method of providing contraception, or a method of providing postcoital contraception, said method comprising administering to a patient an effective amount of a compound in accordance with  claim 61 .