11β-benzaldoxime derivatives of D-homooestra-4,9-dien-3-ones
View Patent ↗The present patent application relates to 11β-benzaldoxime derivatives of D-homooestra-4,9-dien-3-ones of formula I: wherein R 1 is a hydrogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -acyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylthiocarbonyl, C 1 -C 6 -alkylaminocarbonyl or arylaminocarbonyl group; and R 2 is a hydrogen atom or a C 1 -C 6 -alkyl or C 1 -C 6 -acyl group. Compounds of formula I bind more strongly to the glucocorticoid receptor than to the progesterone receptor and are effective antiglucocorticoids. According to the invention, they are suitable for the treatment and/or prevention of symptoms and/or diseases that are attributable to an androgen deficiency induced by glucocorticoids, especially cortisol.
1. A 11β-Benzaldoxime compound of formula I:
wherein
R 1 is a hydrogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -acyl,benzoyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylthiocarbonyl, C 1 -C 6 -alkylaminocarbonyl or arylaminocarbonyl group; and
R 2 is a hydrogen atom or a C 1 -C 6 -alkyl or C 1 -C 6 -acyl group, or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , wherein
R 1 is a hydrogen atom or a C 1 -C 4 -alkyl, C 2 -C 4 -acyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylthiocarbonyl, C 1 -C 4 -alkylaminocarbonyl, phenylaminocarbonyl or (4-trifluoromethoxyphenyl)aminocarbonyl group; and
R 2 is a hydrogen atom or a methyl, ethyl, acetyl or benzoyl group.
3. The compound according to claim 1 , which is
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-oxime;
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1Z)-oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-oxime;
4-[17aβ-acetoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-oxime;
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-(O-acetyl)oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-(O-acetyl)oxime;
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(methoxy)carbonyl]oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(methoxy)carbonyl]oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(ethoxy)carbonyl]oxime;
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(ethoxy)carbonyl]oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(ethylthio)carbonyl]oxime;
4-[17aβ-methoxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(ethylamino)carbonyl]oxime;
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-[O-(ethylamino)carbonyl]oxime; or
4-[17aβ-hydroxy-17aα-(methoxymethyl)-17a-homo-3-oxooestra-4,9-dien-11β-yl]benzaldehyde (1E)-{O-[4′-trifuoromethoxy)phenylamino]-carbonyl}oxime.
4. A process for the preparation of compound according to claim 1 comprising
a) reacting a compound of formula II
with hydroxylamine in a solvent, in the presence of an organic or inorganic base, to give a compound of formula Ia:
and optionally
b) reacting a compound of formula Ia with a reagent selected from the group consisting of C 1 -C 6 -alkyl halides, C 1 -C 6 -acyl halides, C 1 -C 6 -carboxylic anhydrides, benzoyl halides, C 1 -C4-alkoxycarbonyl halides, C 1 -C 4 -alkythiocarbonyl halides, C 1 -C 6 -alkylaminocarbonyl halides, C 1 -C 6 -alkyl isocyantes, arylaminocarbonyl halides and aryl isocyanates.
5. A pharmaceutical composition comprising one or more compounds according to claim 1 , and pharmacologically acceptable carrier.
6. A method for the treatment of a glucocorticoid-induced androgen deficiency, comprising administering, to a host in need thereof, an effective amount of a compound according to claim 1 .
7. A method for the treatment of sexual dysfunction or infertility in men comprising administering, to a host in need thereof, an effective amount of a compound according to claim 1 .