17Beta-Alkyl-17Alpha-oxy-estratrienes
The invention relates to 17β-alkyl-17α-oxy-oestratrienes of the formula (I), to processes for their preparation, to the use of the 17β-alkyl-17α-oxy-oestratrienes for preparing pharmaceuticals and to pharmaceutical preparations comprising these compounds.
1 . Compounds of the general formula (I)
in which
Hal represents fluorine or chlorine which is attached in the 11β-position to the oestratriene skeleton; and
R 1 , R 2 and R 4 independently of one another, represent hydrogen, fluorine, chlorine or bromine, and
R 3 represents hydrogen or a C 1 -C 4 -alkyl or C 1 -C 4 -alkanoyl radical, and
R 17′ represents hydrogen or a C 1 -C 4 -alkyl or C 1 -C 4 -alkanoyl radical,
R 17″ represents an optionally mono- or polyfluorinated C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl or C 2 -C 4 -alkynyl radical,
where R 17′ —O is attached in the 17α-position and R 17′ is attached in the 17β-position to the oestratriene skeleton; and
U represents a straight-chain or branched C 1 -c 13 -alkylene, C 2 -C 13 -alkenylene or C 2 -C 13 -alkynylene radical, or
represents the group A-B, where
A is attached to the oestratriene skeleton and is a benzylidene radical attached via —CH 2 — to the oestratriene skeleton, is a phenylene radical or is a C 1 -C 3 -alkylene-phenylene radical attached via the alkyl group to the oestratriene skeleton and B is a straight-chain or branched C 1 -C 13 -alkylene, C 2 -C 13 -alkenylene or C 2 -C 13 -alkynylene radical and
where A and B may also be attached to one another via an oxygen atom,
V represents a methylene or a —C(O)— group and
X represents a bond or a C 1 -C 3 -alkylene group and
R 5 represents hydrogen or a C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl or C 2 -C 4 -alkynyl radical
R 6 represents hydrogen or the group —CH 2 —R 7 or C(O)—R 7 , in which R 7 represents hydrogen or a straight-chain or branched nonfluorinated or at least partially fluorinated C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl radical which may be mono- or polysubstituted by hydroxyl, or
R 5 and R 6 together with X and the nitrogen atom of the side chain form a 4- to 6-membered heterocyclyl ring which, in addition to the nitrogen atom of the side chain, may have a further heteroatom and/or may contain a carbonyl group,
Y represents a C 5 -C 8 -alkylene group,
E represents a C 1 -C 4 -perfluoroalkyl radical or represents a phenyl radical which is mono- to pentasubstituted by halogen or —CF 3 ,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
2 . Compounds according to claim 1 in which
Hal represents fluorine and
R 1 , R 2 und R 4 independently of one another represent hydrogen, chlorine or bromine, and
R 3 represents hydrogen, a methyl or acetyl radical, and
R 5 represents hydrogen or a C 1 -C 3 -alkyl radical, and
R 6 represents hydrogen or —CH 2 —R 7 , in which R 7 represents hydrogen or a methyl or ethyl radical, or
R 5 und R 6 together with the nitrogen atom of the side chain form a 5-membered heterocyclyl ring which, in addition to the nitrogen atom of the side chain, may have a further heteroatom and/or may contain a carbonyl group, and
R 17′ represents hydrogen, a methyl radical or acetyl radical, and
R 17″ represents a methyl, ethynyl or trifluoromethyl radical, and
U represents a butylene, pentylene, hexylene or heptylene radical, and
V represents a methylene group, and
X represents a bond or a methylene group, and
Y represents a bond or a C 5 -C 7 -alkylene group, and
E represents —C 2 F 5 , —C 3 F 7 , —C 4 F 9 or represents a trifluoromethylphenyl radical,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
3 . Compounds according to claim 1 in which
R 1 represents hydrogen, and
R 2 represents hydrogen or chlorine, and
R 4 represents hydrogen, chlorine or bromine,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
4 . Compounds according to claim 1 in which
R 3 represents hydrogen,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
5 . Compounds according to claim 1 in which
Hal represents fluorine,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
6 . Compounds according to claim 1 in which represents hydrogen and R 6 represents a methyl group or
R 5 and R 6 together with the nitrogen atom of the side chain form a pyrrolidine ring,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
7 . Compounds according to claim 1 in which
R 17′ represents hydrogen and R 17″ represents a methyl radical,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
8 . Compounds according to claim 1 in which
U represents an n-butylene radical:
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
9 . Compounds according to claim 1 in which
V represents a methylene group,
and their enantiomers and their diastereomers, their salts, solvates and salts of the solvates.
10 . Compounds according to claim 1 in which
X represents a bond,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
11 . Compounds according to claim 1 in which
Y represents an n-pentylene or n-hexylene group,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
12 . Compounds according to claim 1 in which
E represents —C 2 F 5 ,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
13 . Compounds according to claim 1 in which
R 1 represents hydrogen, and
R 2 represents hydrogen or chlorine, and
R 4 represents hydrogen, chlorine or bromine, and
R 3 represents hydrogen, and
Hal represents fluorine, and
R 5 represents hydrogen and R 6 represents a methyl group or
R 5 and R 6 together with the nitrogen atom of the side chain form a pyrrolidine ring, and
R 17′ represents hydrogen, and
R 17″ represents a methyl radical, and
U represents an n-butylene radical, and
V represents a methylene group, and
X represents a bond, and
Y represents an n-pentylene or n-hexylene group, and
E represents —C 2 F 5 ,
and their enantiomers and diastereomers, their salts, solvates and salts of the solvates.
14 . Intermediates of the formula (IX)
in which R 1 , R 2 , R 3 , R 4 , Hal, R 17′ , R 17″ , U and V have the meanings according to claim 1 and LG represents a sulphonate group or halogen.
15 . (canceled)
16 . (canceled)
17 . Pharmaceutical formulation, comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
18 . A method of treating an oestrogen-dependent disorder comprising administering to a human in need thereof a therapeutically acceptable amount of a compound according to claim 1 .