19-nor-steroid derivatives with a 15alpha, 16alpha-methylene group and a saturated 17, 17-spiro-lactone ring, use thereof, and medicaments containing said derivatives

Abstract

The 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives of the present invention possess progestational efficacy. They have the general chemical formula I, in which Z is selected from the group comprising an oxygen atom, two hydrogen atoms, NOR and NNHSO 2 R, where R is hydrogen, C 1 -C 10 -alkyl, aryl or C 7 -C 20 -aralkyl, R 4 is hydrogen or halogen, and moreover either: R 6a , R 6b together form methylene or 1,2-ethanediyl or R 6a is hydrogen and R 6b is selected from the group comprising hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, and R 7 is selected from the group comprising hydrogen, C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, or: R 6a is hydrogen and R 6b and R 7 , together, denote a bond, an oxygen or form methylene, R 18 represents hydrogen or C 1 -C 3 -alkyl and in addition include their solvates, hydrates, stereoisomers and salts.

1 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives of general formula I 
       
         
           
           
               
               
           
         
         in which 
         Z denotes oxygen, two hydrogen atoms, a group ═NOR 1  or ═NNHSO 2 R 1 , 
         R 1  denotes hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl, 
         R 4  denotes hydrogen or halogen, 
         R 6a , R 6b  which may be identical or different, denote hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl or together denote methylene or 1,2-ethanediyl, 
         R 7  denotes hydrogen, C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, 
         R 6a , R 7  together, denote a bond, an oxygen or a methylene group, 
         R 18  denotes hydrogen, C 1 -C 3 -alkyl, 
         and their solvates, hydrates, stereoisomers and salts. 
       
     
     
         2 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that Z is selected from the group comprising oxygen, NOR 1  and NNHSO 2 R 1 . 
     
     
         3 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that Z stands for oxygen. 
     
     
         4 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 4  is hydrogen or chlorine. 
     
     
         5 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 6a , R 6b  together form 1,2-ethanediyl or are each hydrogen. 
     
     
         6 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 7  is hydrogen or methyl or ethyl or vinyl. 
     
     
         7 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 6a  and R 7  together form a methylene group. 
     
     
         8 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 6a  and R 7  together represent a bond. 
     
     
         9 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , characterized in that R 18  is hydrogen or methyl. 
     
     
         10 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1 , selected from the group
 17β-Hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6-methylene-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6α-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6,6-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   6,6-(1,2-Ethanediyl)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-15α,16α-methylene-19-nor-17α-pregna-4,6-dien-3-one-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6-methylene-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone   17β-Hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7α-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-7β-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6-methylene-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6α-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6β-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   6,6-(1,2-Ethanediyl)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone   17β-Hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4,6-dien-3-one-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6-methylene-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone   (E/Z)-3-(Hydroxyimino)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone.   
     
     
         11 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1  for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints. 
     
     
         12 . A method comprising using the 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in  claim 1  for the production of a medicinal product for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints. 
     
     
         13 . A method as in  claim 12 , characterized in that the medicinal product has progestational, antimineralocorticoid and androgenic action. 
     
     
         14 . A medicinal product containing at least one 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivative as claimed in  claim 1  and at least one suitable pharmaceutically harmless additive. 
     
     
         15 . The medicinal product as claimed in  claim 14 , additionally containing at least one estrogen. 
     
     
         16 . The medicinal product as claimed in  claim 15 , characterized in that the estrogen is ethinylestradiol. 
     
     
         17 . The medicinal product as claimed in  claim 15 , characterized in that the estrogen is a natural estrogen. 
     
     
         18 . The medicinal product as claimed in  claim 17 , characterized in that the natural estrogen is estradiol. 
     
     
         19 . The medicinal product as claimed in  claim 17 , characterized in that the natural estrogen is estradiolvalerate. 
     
     
         20 . The medicinal product as claimed in  claim 17 , characterized in that the natural estrogen is a conjugated estrogen. 
     
     
         21 . A method comprising using the 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivative as claimed in  claim 1  for the production of a medicinal product for intrauterine use. 
     
     
         22 . A method as in  claim 21  for the production of an intrauterine system (IUS). 
     
     
         23 . Medicinal containing at least one 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivative according to  claim 1  and at least one suitable pharmaceutically harmless additive, characterized in that it is designed for intrauterine administration. 
     
     
         24 . The medicinal product as claimed in  claim 23 , characterized in that it is an intrauterine system.