Orally active androgens

Details Orally active androgens Orally active androgens

2000-07-11

2001-11-06

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S178000, C514S179000, C552S525000, C552S539000, C552S575000, C552S632000, C552S639000, C552S641000

Reexamination Certificate

active

06313108

ABSTRACT:

The invention is in the field of orally active androgenic hormones, more specifically &Dgr;
14
derivatives of 19-nortestosterone.
Testosterone denryatiyes are known. As a medicine testosterone itself, the natural male hormone, has many known drawbacks as far as methods of administration are concerned. It has a short-lasting activity, is insoluble in the usual pharmaceutically acceptable media, and is not very potent. The more potent dihydrotestosterone (5&agr;-reduced form of testosterone) is considered a health-risk, notably for the prostate.
A more potent androgen is 7&agr;-methyl-19-nortestosterone (MENT) disclosed in FR 4,521 M and U.S. Pat. No. 5,342,834. An important drawback of MENT, however, is its unfavourable kinetics which limits its use as an orally active androgen.
In the field of pharmaceutical preparations in general it is a common desire for a medicinal agent to be orally active. Oral dosage forms, e.g. solid dosage forms such as tablets and capsules, are among the most widely accepted forms of administration. In the field of androgens, a particular desire exists for the oral administration in connection with a utility such as male contraception. Since in the area of female contraception the word “pill” has almost become a synonym for reliable birth-control, it is evident that also in the case of male contraception oral activity is desired, so as to enable providing a male “pill.”
An androgen having a special position in the field, is the so-called “Segaloff steroid” which is a 19-nortestosterone derivative having, as in MENT, a 7&agr;-methyl group, and which has a double bond between carbon atoms 14 and 15 (&Dgr;
14
). This special position is due to the fact that it has long been recognized as the most potent oral androgen known. See, int.al. Avery et al,
Steroids
, 55, 59 (1990). The compound, together with its 7&agr;-H analogue, is also known from GB 1,341,601.
Despite having a special position in the field, the “Segaloff steroid” has not found practical use, which may be due to several drawbacks it has for clinical utility. E.g. with 19-nortestosterones metabolic stability is an issue. Thus it is known from GB 1,341,601 that these compounds are prone to metabolic inactivation by hepatic 17&bgr;-hydroxysteroid dehydrogenase. The classic solution to this problem, the introduction of an alkyl group in the 17&agr; position is believed to be responsible for unsatisfactory results such as a limited activity.
Several, mostly very old publications can be mentioned which form the further background-art relating to groups of steroid compounds which include 19-nortestosterone derivatives. None of these references teaches orally active androgens.
Thus, in FR 1,432,561, published in 1966, 19-nortestosterones like MENT having an alkyl substituent at C-7 are employed as a starting material for hormonal agents having a double bond between carbon atoms 5 and 6. Alkyl groups other than methyl are not disclosed.
BE 861 224 concerns all possible esters of a wide variety of 17-hydroxysteroids. The disclosure, which dates from 1976, specifically teaches that certain esters are desired for prolonged activity of the steroids. Among the large group of steroids disclosed are oestrogens, anti-oestrogens, androgens and anabolics. A great many possible substituents at various positions is given, among which are methyl and ethyl at C-7.
Chemical Abstracts 110: 95601y (1989) refers to a 17-hydroxy acetate of 7-allyl-19-nortestosterone as an intermediate in the synthesis of 7-allyloestradiol.
EP 159 739 teaches immunomodulating agents of the oestrane series, including particularly &Dgr;
4
- and &Dgr;
5(10)
-oestrene derivatives having an alkyl substituent in position 6 or 7. Said alkyl substituent typically is methyl.
DE 20 43 404 concerns 7&bgr;-steroids which have anti-hormonal activities. The alkyl substituent mostly is methyl, but ethyl and propyl are disclosed as well. In the synthesis of 7&bgr;-ethyl-19-nortestosterone, which is a compound according to the teaching of DE 20 43 404, the 7&agr;-isomer is formed as well. It is not taught to use this isomer for anything, and the teaching of this document does not distinguish the ethyl or propyl substituents from the methyl moiety.
As background art reference is further made to Solo et al,
Steroids
, 40, 603-614 (1990). Disclosed herein are various 7&agr;-alkyl derivatives of testosterone.
It is an object of the invention to provide orally active androgens which are an improvement as compared to the Segaloff steroid in that they are better suitable for clinical use, and particularly possess sufficient oral activity and metabolic stability.
According to the invention, compounds are provided satisfying the general formula I given below.
wherein
R
1
is O, (H,H), (H,OR), NOR, with R being hydrogen, (C
1-6
) alkyl, or (C
1-6
) acyl;
R
2
is selected from the group consisting of (C
2-4
) alkyl, (C
2-4
) alkenyl, or (C
2-4
) alkynyl, each optionally substituted by halogen; or
R
2
is cyclopropyl, or cyclopropenyl, each optionally substituted by (C
1-2
) alkyl, or halogen;
R
3
is hydrogen, (C
1-2
) alkyl, or ethenyl;
R
4
is (C
1-2
) alkyl;
R
5
is hydrogen, or (C
1-15
) acyl;
and the dotted lines indicate optional bonds.
The invention includes pharmaceutically acceptable salts or esters, prodrugs and precursors of the above steroids.
The term (C
1-6
) alkyl as used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms, like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Likewise, the term (C
2-4
) alkyl means a branched or unbranched alkyl group having 2-4 carbon atoms and the term (C
1-2
) alkyl means an alkyl group having 1-2 carbon atoms.
The term (C
2-4
) alkenyl means a branched or unbranched alkenyl group having at least one double bond and 2-4 carbon atoms. Preferred alkenyl groups have 2-3 carbon atoms, such as vinyl and propenyl.
The term (C
2-4
) alkynyl means a branched or unbranched alkynyl group having at least one triple bond and 2-4 carbon atoms. Preferred alkynyl groups have 2-3 carbon atoms, such as ethynyl and propynyl.
The term (C
1-6
) acyl means an acyl group derived from a carboxylic acid having 1-6 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, and hexanoyl, Likewise, the term (C
1-15
) acyl means an acyl group derived from a carboxylic acid having 1-15 carbon atoms. Also included within the definition of (C
1-6
) acyl or (C
1-15
) acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on. Preferred is hemi-succinoyl.
The term halogen means fluorine, chlorine, bromine, or iodine. When halogen is a substituent at an alkyl group, Cl and F are preferred, F being most preferred.
It is understood that the 7&agr;-substituted &Dgr;
14
-nandrolone derivatives of the invention have the natural configurations 5&agr;, 8&bgr;, 9&agr;, 10&bgr;, 13&bgr;, and 17&bgr;.
The 7&agr;-substituted &Dgr;
14
-nandrolone derivatives of this invention have the natural configurations 5&agr;, 8&bgr;, 9&agr;, 10&bgr;, 13&bgr; and 17&bgr;, and may possess also one or more additional chiral carbon atoms. The compounds may therefore be obtained as a pure diastereomer, or as a mixture of diastereomers. Methods for obtaining the pure diastereomers are well known in the art, e.g. crystallization or chromatography.
The compounds of the invention, which are distinguished from the aforementioned known “Segaloff steroid” by the length of the 7&agr; substituent, surprisingly are an improvement over said known steroid and have unexpected advantages for clinical utility. This is exhibited by, inter alia, a surprisingly better oral activity. Preferred compounds of the invention further display a much better metabolic stability than the Segaloff steroid.
Preferred compounds of the invention have R
2
selected from the group consisting of ethyl, ethenyl, ethynyl, propyl, 1-propenyl, 2-propenyl, 1-propynyl, 1,2-propadienyl, and cyclopropyl. Even more preferred are compounds i

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