17-Methylene steroids, process for their production and pharmaceutical compositions that contain these compounds
The invention relates to 17-methylene steroids, process for their production and pharmaceutical compositions that contain these compounds. The compounds according to the invention have a hybrid-type profile of action in the sense that they act as inhibitors of 5α-reductase and simultaneously as gestagens. They are therefore suitable for treating diseases that are the result of elevated androgen levels in certain organs and tissues in men and women. Together with other hormonal substances, such as an estrogen, testosterone or a strong androgen, the compounds according to the invention are suitable as contraceptive agents for women and for men.
1. A 17-Methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 and R 20a are, independently of one another, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen.
2. A 17-Methylene steroids according to claim 1 , wherein R 4 is a chlorine or bromine atom or a cyano group.
3. A 17-Methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
one of radicals R 20 and R 20a is a hydrogen atom or a methyl group, and the other radical is a fluorine, chlorine or bromine atom, an azido, cyano or rhodano group or hydroxymethyl.
4. A 17-Methylene steroids according to claim 1 , wherein R 10 is a hydrogen atom or a methyl group.
5. A 17-Methylene steroid selected from the group consisting of
1) E-17-Chloromethylene-4-chloro-estr-4-en-3-one,
2) E-17-Cyanomethylene-4-chloro-estr-4-en-3-one,
3) Z-17-Cyanomethylene-4-chloro-estr-4-en-3-one,
4) Z-17-(1′)-Cyanoethylidene-4-chloro-estr-4-en-3one,
5) Z-17-Ethylidene-4-chloro-estr-4-en-3-one,
6) E-17-Ethylidene-4-chloro-estr-4-en-3-one,
7) E-17-Bromomethylene-4-chloro-estr-4-en-3-one,
8) Z-17-Chloroethylidene-4-chloro-estr-4-en-3-one,
9) Z-17-Bromoethylidene-4-chloro-estr-4-en-3-one,
10) E-17-Chloromethylene-4-cyano-androst-4-en-3-one,
11) E-17-Chloromethylene-4-chloro-androst-4-en-3-one,
12) E-17-(2′)-Hydroxyethylidene-4-chloro-estr-4-en-3-one, and
13) Z-17-(2′)-Hydroxyethylidene-4-chloro-estr-4-en-3-one.
6. A process for preparing a 17-methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or a halogen atom or a pseudohalogen, and
R 20a is a hydrogen atom, comprising reacting a compound of formula II,
in an aprotic solvent with an acid chloride to form a 17-methylene steroid of formula III,
the 4,5-epoxide is generated with H 2 O 2 /NaOH, the 4,5-epoxide is then opened with a nucleophilic reagent, which is derived from a halogen atom or pseudohalogen, in a dipolar aprotic solvent to a halogen- or pseudohalogen hydrin, and optionally reacted with mineral acid, carboxylic acid or sulfonic acid in a protic or aprotic solvent with dehydration to a compound of formula IV,
wherein R 4 is a halogen atom or pseudohalogen, R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
and R 20 is a C 1-4 alkyl or hydroxy-C 1-4 alkyl group, a halogen atom or a pseudohalogen.
7. A process for preparing a 17-methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 and R 20a are, independently of one another, a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen, comprising reacting a compound of formula V,
with an acid chloride in an aprotic solvent to form a methylene steroid of formula VI,
the 4,5-epoxide is generated with H 2 O 2 /NaOH, the 4,5-epoxide is then opened with a nucleophilic reagent, which is derived from a halogen atom or pseudohalogen, in a dipolar aprotic solvent to a halogen- or pseudohalogen hydrin, and optionally reacted with mineral acid, carboxylic acid or sulfonic acid in a protic or aprotic solvent with dehydration to a compound of formula VII,
in which R 4 is a halogen atom or pseudohalogen, R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
and R 20 is a C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and R 20a is a hydrogen atom, a halogen atom or a pseudohalogen.
8. A 17-methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or an ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group,
R 20 and R 20a are, independently of one another, a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen,
and a pharmaceutically compatible adjuvant or vehicle.
9. A 17-Methylene steroid of formula I
in which
R 4 is a fluorine, bromine, or iodine atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 and R 20a are, independently of one another, a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen.
10. A 17-Methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group,
R 20a is a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen.
11. A 17-Methylene steroid of formula I
in which
R 4 is a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 and R 20a are, independently of one another, a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen.
12. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 8 and a pharmaceutically compatible adjuvant or vehicle.
13. A 17-Methylene steroid of formula I
in which
R 4 is an azido, rhodano or cyano group,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
R 20 and R 20a are, independently of one another, a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, or
one of radicals R 20 and R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other radical is a halogen atom or a pseudohalogen.
14. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 1 and a pharmaceutically compatible adjuvant or vehicle.
15. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 9 and a pharmaceutically compatible adjuvant or vehicle.
16. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 10 and a pharmaceutically compatible adjuvant or vehicle.
17. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 11 and a pharmaceutically compatible adjuvant or vehicle.
18. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 5 and a pharmaceutically compatible adjuvant or vehicle.
19. A method of treating a prostate disease comprising administering to a patient in need thereof an effective amount of a compound according to claim 5 or a pharmaceutical composition comprising said effective amount of said compound and a pharmaceutical compatible adjuvant or vehicle.
20. A method of effecting contraception in a man or in a woman comprising administering to a patient in need thereof an effective amount of a compound according to claim 5 or a pharmaceutical composition comprising said effective amount of said compound and a pharmaceutical compatible adjuvant or vehicle.
21. A method inhibiting 5α-reductase comprising administering to a patient in need thereof an effective amount of a compound according to claim 5 .
22. A 17-Methylene steroid according to claim 1 , wherein R 4 is a halogen atom.
23. A 17-Methylene steroid according to claim 1 , wherein R 4 is an azido, rhodano or cyano group.
24. A 17-Methylene steroid according to claim 1 , wherein R 4 is a cyano group.
25. A 17-Methylene steroid of formula I
in which
R 4 is a halogen atom or a pseudohalogen,
R 10 is a hydrogen atom or a straight-chain or branched C 1 -C 4 alkyl group,
one of R 20 or R 20a is a hydrogen atom, a straight-chain or branched C 1-4 alkyl or hydroxy-C 1-4 alkyl group, and the other of
R 20 or R 20a is a straight-chain or branched C 1-4 alkyl, a hydroxy-C 1-4 alkyl group, a halogen atom or a pseudohalogen.