Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-09-24
2004-06-29
Qazi, Sabiha N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C206S112000, C206S116000, C206S126000, C514S179000, C514S182000, C552S525000, C552S539000, C552S576000, C552S621000, C552S632000, C552S639000, C552S641000
Reexamination Certificate
active
06756366
ABSTRACT:
The invention is in the field of androgenic hormones, more specifically derivatives of 19-nortestosterone.
Testosterone derivatives are known. As a medicine testosterone itself, the natural male hormone, has many known drawbacks as far as methods of administration are concerned. Thus, inter alia, it has a short-lasting activity 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.”
Several, mostly very old publications can be mentioned which form the 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 the 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.
In a more recent patent application, EP 869 132, 7&agr;-propyl-19-nortestosterone acetate is disclosed as an intermediate in the synthesis of certain estrogenic steroids. The disclosure does not bear any relevance to androgens, nor to any use of the above compound other than as a chemical intermediate.
The background art further includes A. J. Solo et al., in Steroids, 40 (6), 603-614 (1982) which relates to the androgenic and anabolic activities of certain 7&agr;-alkyl testosterones.
It is an object of the invention to provide orally active androgens. A further object of the invention is to provide androgens which in general have a desirable high potency. According to the invention, these and other objectives are achieved by compounds 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 (C
2-3
)alkyl, isopropyl, (C
2-3
)1-alkenyl, isopropenyl, 1,2-propadienyl, or (C
2-3
)1-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;
with the proviso that the compound is not (7&agr;,17&bgr;)-7-ethyl-17-hydroxyestr-4-en-3-one (7&agr;-ethyl-19-nortestosterone) or a carboxylic ester thereof, and is not (7&agr;,17&bgr;)-17-(acetyloxy)-7-propylestr-4-en-3-one (7&agr;-propyl-19-nortestosterone acetate).
The proviso is made in the recognition that the disclaimed compounds have been incidentally disclosed as intermediates in chemical synthesis, in DE 20 43 404 and EP 869 132, respectively. It is stressed that these compounds, as are the other compounds of the invention, are novel for use as a medicine in general, as an androgen, and more particularly as an orally active androgen. Hence, also the compounds disclaimed per se, form part of the present invention and the description hereinafter applies to these compounds as well.
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
1-2
)alkyl means an alkyl group having 1-2 carbon atoms and the term (C
2-3
)alkyl an alkyl group having 2-3 carbon atoms.
The term (C
2-3
)alkenyl means an alkenyl group having 2-3 carbon atoms. Preferred is ethenyl.
The term (C
2-3
)alkynyl means an alkynyl group having 2-3 carbon atoms. Preferred is ethynyl.
The term (C
1-6
)acyl means an acyl group derived from a carboxylic acid having from 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 from 1-15 carbon atoms. Also included within the definition of (C
1-15
)acyl are
[(C
3-6
)cycloalkyl]carbonyl,
[(C
5-6
)cycloalkenyl]carbonyl,
benzoyl,
[[(C
1-12
)alkyl](C
3-6
)cycloalkyl]carbonyl,
[[(C
2-12
)alkenyl](C
3-6
)cycloalkyl]carbonyl],
[[(C
2-12
)alkynyl](C
3-6
)cycloalkyl]carbonyl],
[[(C
1-10
)alkyl](C
5-6
)cycloalkenyl]carbonyl],
[[(C
2-10
)alkenyl](C
5-6
)cycloalkenyl]carbonyl],
[[(C
2-10
)alkynyl](C
5-6
)cycloalkenyl]carbonyl],
(C
1-9
)alkylbenzoyl,
(C
2-9
)alkenylbenzoyl,
(C
2-9
)alkynylbenzoyl.
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 nandrolone derivatives of the invention have the natural configurations 5&agr;, 8&bgr;, 9&agr;, 10&bgr;, 13&bgr;, 14&agr;, 17&bgr;.
The 7&agr;-substituted nandrolone derivatives of this invention have the natural configurations 5&agr;, 8&bgr;, 9&agr;, 10&bgr;, 13&bgr;, 14&agr; and 17&bgr;, and 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.
Unlike the known compound (MENT), which possesses a 7&agr;-methyl substituent, the compounds of formula I, which can be referred to as 7&agr;-substituted nandrolones, surprisingly have sufficient androgenic potency upon oral administration. None of the above, mostly very old references teaches orally active androgens, let alone that they provide the person skilled in the art with a clue to distinguish any other substituent a
Burma Bursi Roberta
Leysen Dirk
Louw Jaap van der
Akzo Nobel N.V.
Blackstone William M.
Milstead Mark W.
Qazi Sabiha N.
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