Nonsteroidal gestagens

Abstract

This invention describes the new, nonsteroidal gestagens of general formula I in which A, B, Ar, R 1 , R 2 and R 3 have the meanings that are, indicated in more detail in the description. The new compounds show a very great affinity to the gestagen receptor. They can be used alone or in combination with estrogens in contraceptive preparations. In addition, they can be used for treating endometriosis. Together with estrogens, they can also be used in preparations for treating gynecological disorders, for treating premenstrual symptoms and for substitution therapy. Based on the androgenic action, they can also be used for male birth control, male HRT and hormone therapy and for treating andrological disease agents.

1 . Compounds of general formula I  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  and R 2  are the same or different and stand for a hydrogen atom, a C 1 -C 5  or a halogen atom, and also together with the C-atom of the chain stand for a ring with a total of 3-7 links,  
 R 3  stands for a C 1 -C 5  alkyl group or a partially or completely fluorinated C 1 -C 5  alkyl group,  
 A stands for a monocyclic or bicyclic aromatic ring that is optionally substituted by one or more radicals, selected from halogen atoms, C 1 -C 5  alkyl groups, C 2 -C 5  alkenyl groups —CR 5 ═CR 6 R 7 , whereby R 5 , R 6  and R 7  are the same or different and, independently of one another, mean hydrogen atoms or C 1 -C 5  alkyl groups; hydroxy groups, hydroxy groups that carry a C 1 -C 10  acyl group, a C 3 -C 10  carbalkoxyalkyl group, a C 2 -C 5  cyanalkyl group, a C 3 -C 10  unsubstituted or substituted allyl group, a C 3 -C 10  unsubstituted or substituted propargyl group, a C 2 -C 5  alkoxyalkyl group, a C 1 -C 5  alkyl group that is partially or completely substituted by fluorine atoms, the cyano or nitro group, C 1 -C 5  alklxy groups, C 1 -C 5  alkylthio groups, mono- or disubstituted C 1 -C 10  amino groups or partially or completely fluorinated C 1 -C 5  alkyl groups, 
 for an ester group —COOR 4 , whereby R 4  means a C 1 -C 5  alkyl group,  
 for a C 2 -C 5  alkenyl group —CR 5 ═CR 6 R 7 , whereby R 5 , R 6  and R 7  are the same or different, and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or C 1 -C 5  alkyl groups,  
 for an alkinyl group —C═CR 5 , whereby R 5  means a hydrogen atom or a C 1 -C 5  alkyl group,  
 for a partially or completely fluorinated C 1 -C 5  alkyl group,  
 
 B stands for a carbonyl group or a CH 2  group,  
 and  
 Ar stands for a ring system, selected from the group of general partial formulas 2-11,  
                                       
 in which  
 radicals X 3a , X 4 , X 6 , X 7  (in partial formula 2), X 4 , X 6 , X 7  (in partial formulas 3 and 4), X 3a , X 3b , X 4 , X 6 , X 7  (in partial formulas 5, 6 and 7) or Y 4 , Y 5 , Y 7 , Y 8  (in partial formulas 8, 9, 10 and 11) are the same or different and are selected from hydrogen atoms, C 1 -C 5  alkyl groups, which in addition can contain a hydroxy group that is optionally etherified with a C 1 -C 5  alkyl group or esterified with a C 1 -C 5  alkanoyl group, partially or completely fluorinated C 1 -C 5  alkyl groups, C 2 -C 5  alkenyl groups  
 —CR 5 ═CR 6 R 7 , whereby R 5 , R 6 , and R 7  have the above-mentioned meaning, alkinyl groups —C═CR 5 , whereby R 5  has the above-mentioned meaning,  
 radicals X 3a  and X 3b  also together with the C-atom of benzocondensed ring system 5, 6 or 7 can form a ring with a total of 3-7 links,  
 and moreover, radicals X 4 , X 6 , X 7  (in partial formulas 2, 3, 4, 5, 6 and 7) or Y 4 , Y 5 , Y 7 , Y 8  (in partial formulas 8, 9, 10 and 11) are selected from halogen atoms, hydroxy groups, C 1 -C 5  alkoxy groups or C 1 -C 5  alkanoyloxy groups, also if B in general formula I stands for a CH 2  group, Ar in addition stands for a phenyl radical of general partial formula 12,  
                     
 in which R 9  and R 10  are the same or different and mean a cyano group, a nitro group, a halogen atom, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, a partially or completely fluorinated C 1 -C 5  alkyl group, a C 1 -C 5  alkylthio group, a C 1 -C 5  alkylsulfinyl group or a C 1 -C 5  alkylsulfonyl group, and if B stands for a CH 2  group, the physiologically, compatible salts of the compounds of general formula I with acids.  
 
     
     
         2 . Compounds of general formula I according to  claim 1  in the form of the racemate or diastereomer mixture.  
     
     
         3 . Compounds of general formula I according to  claim 1  in the form of separate optical isomers.  
     
     
         4 . Compounds of general formula I according to  claim 1 , characterized in that R 1  and R 2  are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring.  
     
     
         5 . Compounds of general formula I according to  claim 1 , wherein R 3  stands for a C 1 -C 5  perfluoroalkyl group.  
     
     
         6 . Compounds of general formula I according to  claim 1 , wherein A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, (CH 2 ) n  group (n=3,4,5), which with 2 adjacent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, and ethoxy groups.  
     
     
         7 . Compounds of general formula I according to  claim 1 , wherein X 3a  stands for a hydrogen atom or a C 1 -C 5  alkyl group.  
     
     
         8 . Compounds of general formula I according to  claim 1 , wherein X 3a  and X 3b  are the same or different and stand for a hydrogen atom or a C 1 -C 5  alkyl group.  
     
     
         9 . Compounds of general formula I according to  claim 1 , wherein X 4 , X 6  and X 7  are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom.  
     
     
         10 . Compounds of general formula I according to  claim 1 , wherein Y 4  stands for a C 1 -C 5  alkyl group or a C 1 -C 5  perfluoroalkyl group.  
     
     
         11 . Compounds of general formula I according to  claim 1 , wherein Y 5 , Y 7  and Y 8  are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom.  
     
     
         12 . Compounds of general formula I according to  claim 1 , wherein R 1  and R 2  are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring, and R 1  stands for a C 1 -C 5  perfluoroalkyl group, A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, (CH 2 ) n  group (n=3,4,5), which with 2 adjacent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, and ethoxy groups, and either X 3a  stands for a hydrogen atom or a C 1 -C 5  alkyl group, or X 3a  and X 3b  are the same or different and stand for a hydrogen atom or a C 1 -C 5  alkyl group and X 4 , X 6  and X 7  are the same or different, and stand for, independently of one another, a hydrogen atom or a halogen atom, or Y 4  stands for a C 1 -C 5  alkyl group or a C 1 -C 5  perfluoroalkyl group, and Y 5 , Y 7  and Y 8  are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom, and the other substituents all have the meanings that are indicated in Formula 1.  
     
     
         13 . Compounds of general formula I according to  claim 1 , in which Ar stands for a ring system of partial formula 6.  
     
     
         14 . Compounds of general formula I according to  claim 1 , in which Ar stands for a ring system of partial formula 7.  
     
     
         15 . Compounds of general formula I according to  claim 1 , in which Ar stands for a ring system of partial formula 10.  
     
     
         16 . Compounds of general formula I according to  claim 1 , in which Ar stands for a ring system of partial formula 11.  
     
     
         17 . Compounds of general formula I according to  claim 1 , namely 
 4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,    6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,    5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino)-phthalide,    5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-(hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-hydroxy-4-methyl-4-(4-tolyl)-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(3-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-(2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,    5-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide,    5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide,    5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide,    5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide,    6-acetyl-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,    5-[4-(3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    5-[4-(3-flucrophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,    6-(3-hydroxy-3-methyl-1-butinyl)-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide,    6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,    6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-4-trifluoromethyl-2,3-benzoxazin-1-one,    4-ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-2,3-benzoxazin-1-one,    4-ethyl-6-[2-hydroxy-4-(2-methyloxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,    6-(2-hydroxy-4-2-methoxyphenyl)-4-methyl-2-triflucrometyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,    4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,    6-(4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-1-one,    4-ethyl-6-(4-(5-fluoro-2- merhoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one,    6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromelhyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,    1-(4-nitro-3-trifluoromethylanilino)-4-phenyl-2-trifluoromethyl-2-pentanol,    1-(4-nitro-3trifluoromethylanilino)-4-phenyl-2-trifluoromethyl-2-pentanol,    5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino)-phthalide,    5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl-propionylamino]-phthalide,    5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl-propionylamino]-phthalide,    5-[2-hydroxy-3-(1-phenyl-cyclohexyl)-2-trifluoromethyl-propionylaminc]-phthalide,    2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid,    4-(4-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    4-(4-acer-yl-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    b  4 -(4-carbamoylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    4-(4-cyano-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    4-(3-bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid,    2-Hydroxy-4-methyl-4-(3-nitro-4-mrethoxyphenyl)-2-trifluoromethyl-valeric acid,    4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid,    4-(3-chlorophenyl)-4-methyl-2-oxo-valeric acid,    4-(3-bromophenyl)-4-methyl-2-oxo-valeric acid,    4-(2-iodophenyl)-4-methyl-2-oxo-valeric acid,    4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid,    4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid,    4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid,    4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid,    3-(1-phenylcyclopentyl)-pyruvic acid,    6-[3-(1-phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,    6-[3-(1-phenyl-cyclobutyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,    6-[3-(1-phenyl-cyclohexyl)-2-oxo-propionylamino]-4-methyl-2,3-benzoxazin-1-one,    5-[4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,    5-[4-(4-iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,    5-[4-(3-iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,    5-[4-(4-bromo-2-methoxyphenyl)-2-oxo-valeroylamino)-phthalide,    5-[3-(1-phenyl-cyclopentyl)-2-oxo-propionylamino]-phthalide,    6-[4-(5-fluoro-2-methoxophenyl)-4-methyl-2-oxo-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,    6-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-4-ethyl-2,3-benzoxazin-1-one,    6-(2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one,    5-[4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino)-phthalide,    5-(4-(3-chloro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide.    
     
     
         18 . Pharmaceutical preparations that contain at least one compound of general formula I according to  claim 1  as well as a pharmaceutically compatible vehicle.  
     
     
         19 . Use of the compounds of general formula I according to  claim 1  for the production of pharmaceutical preparations.  
     
     
         20 . Process for the production of compounds of general formula I  
       
         
           
           
               
               
           
         
       
       in which A, B, Ar, R 1 , R 2  and R 3  have the meaning that is indicated in  claim 1 , wherein a carbonyl compound of general formula II  
       
         
           
           
               
               
           
         
       
       in which A, B, Ar, R 1  and R 2  have the meaning that is indicated in formula I, is reacted with a compound of general formula C n F 2n+1 —SiR 3 , in which R 3  has the meaning that is indicated in general formula 1, in the presence of a catalyst to a compound of general formula I.  
     
     
         21 . Process according to  claim 20 , wherein the catalyst is a fluoride salt or an alkali carbonate.  
     
     
         22 . Process for the production of compounds of general formula I  
       
         
           
           
               
               
           
         
       
       in which 
 A, B, Ar, R 1 , R 2  and R 3  have the meaning that is indicated in  claim 1 , wherein a compound of general formula III  
                     
 in which A, B, R 1 , R 2  and R 3  have the meaning that is indicated in general formula 1 and FG means a leaving group, is reacted with a compound Ar—NH—R 11 , whereby R 11  means a hydrogen atom or a C 1 -C 5  alkanoyl group, and Ar has the meaning that is indicated in general formula I, and optionally then radical R 11  is cleaved off.  
 
     
     
         23 . Process according to  claim 22 , wherein leaving group FG in connection with general formula III is a chlorine, bromine or iodine atom, a tosylate or mesylate radical or a C 1 -C 4  perfluoroalkylsulfonyloxy radical.  
     
     
         24 . Process according to  claim 23 , wherein the compound of general formula III is an acid chloride that is formed as an intermediate product from the corresponding carboxylic acid.  
     
     
         25 . Process for the production of compounds of general formula I  
       
         
           
           
               
               
           
         
       
       in which 
 A, Ar, R 1 , R 2  and R 3  have the meaning that is indicated in  claim 1 , and B means a —CH 2  group, wherein a compound of general formula IV  
                     
 in which A, R 1 , R 2  and R 3  have the meaning that is indicated in formula I, is reacted with a compound of formula Ar—NH—R 11 , whereby R 11  and Ar have the meanings that are indicated in  claim 23 , and optionally then radical R 11  is cleaved off.