Non-aromatic estrogenic steroids with a hydrocarbon...

Details Non-aromatic estrogenic steroids with a hydrocarbon... Non-aromatic estrogenic steroids with a hydrocarbon...

2002-05-29

2004-01-13

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S642000, C552S644000, C552S645000, C552S649000

Reexamination Certificate

active

06677329

ABSTRACT:

This application is a 371 of PCT/EP00/08406 filed Aug. 28, 2000.
FIELD OF THE INVENTION
The invention is in the field of estrogenic compounds with a steroid skeleton having a non-aromatic A-ring and a free or capped hydroxyl group at carbon atom No. 3. Estrogenic compounds have a generally recognised utility in contraception and in the treatment of estrogen-deficiency related disorders, such as menopausal complaints, and osteoporosis.
BACKGROUND OF THE INVENTION
Many estrogenic compounds are known. For example, an instructive publication on estrogenic compounds with a non-aromatic A-ring and a free or capped hydroxyl group at carbon atom 3 is U.S. Pat. No. 3,413,287. Other documents describing estrogenic or hormonal effects of non-aromatic streroids with 3-hydroxyl substitution and a 4-5 double bond are WO 94 18224, U.S. Pat. No. 3,465,010, FR 2099385, U.S. Pat. No. 3,652,606 and EP 145 493. A document in which non-aromatic steroids with 3-keto substitution and a 5-10 double bond are disclosed is Baran et al (U.S. Pat. No. 3,377,366. Such compounds are described in general terms as agents with, among other, estrogenic or anti-estrogenic effects. Recently, in the field of drugs for estrogen receptors (ER) attention is focussed on the discovery of two distinct types of estrogen receptors, denoted ER&agr; and ERP (Mosselanan et al.,
FEBS Letters
392 (1996) 49-53 as well as EP-A-0 798 378). Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective affinity for either of the two is an important technical progress, making it possible to provide a more selective treatment of estrogen-deficiency related disorders, with a lower burden of estrogen-related side-effects.
BRIEF SUMMARY OF THE INVENTION
This invention provides estrogens satisfying the general formula
in which
R
1
is H, (C
1
-C
3
)alkyl or (C
2
-C
3
)acyl;
R
2
is H, &agr;-(C
1
-C
4
)alkyl, &agr;-(C
2
-C
4
)alkenyl or &agr;-(C
2
-C
4
)alkynyl;
R
3
is H or (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl or (C
2
-C
4
)alkynyl, each at location 15 or 16 of the steroid skeleton;
R
4
is H or (C
1
-C
5
)alkyl, (C
2
-C
5
)alkenyl or (C
2
-C
5
)alknyl, each optionally substituted with halogen; preferred is ethynyl;
R
5
is H, (C
1
-C
3
)alkyl or (C
2
-C
3
)acyl;
R
6
is (C
1
-C
5
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C
5
)alkynyl or (C
1
-C
5
)alkylidene, each optionally substituted with halogen or (C
1
-C
3
)alkyloxy; allyl is preferred; preferred halogens in R
6
are fluorine and chlorine.
Dotted bonds represent optional double bonds. When R
6
is alkylidene, the dotted line to R
6
represents the additional bond present in an alkylidene moiety, and when R
6
is alkyl or alkenyl, the bond from atom 11 to R
6
is a single bond.
It has been found that these non-aromatic estradiol derivatives with a substituent at the 11 position of the steroid skeleton possess selective affinity for the ER&agr;-receptor.
The compounds according to the present invention are suitable as improved estrogens, in the sense that they can be used in estrogen-related disorders, such as menopausal complaints and osteoporosis. Utility they also find in contraception, and they further may be suitable in the treatment or prevention of Alzheimer's desease, breast tumor, benign prostate hypertrophy, and cardiovascular disorders. The compounds of the invention are particularly suitable in the treatment and prevention of estrogen-deficiency related disorders under diminished estrogen-related side-effects.
DETAILED DESCRIPTION OF THE INVENTION
In this description terms have the following meaning:
(C
1
-C
5
)alkyl is a branched, unbranched or cyclized alkyl group having 1-5 carbon atoms, for example methyl, ethyl, isopropyl, 2-methylcyclopropyl, butyl, sec-butyl, tert-butyl etc.;
(C
2
-C
5
)alkenyl is a branched, unbranched or cyclized alkenyl group having 2 to 5 carbon atoms, such as ethenyl, 2-butenyl, etc.
(C
2
-C
5
)alkynyl is a branched or unbranched alkynyl group having 2-5 carbon atoms, such as ethynyl and propynyl.
(C
2
-C
3
)acyl is a group having 2-3 carbon atoms and derived from an alkylcarboxylic acid, the alkyl moiety having the meaning as defined previously.
(C
1
-C
5
)alkylidene is a branched, unbranched or cyclized alkylidene group having 1-5 carbon atoms, such as methylene and ethylene.
Within the general formula given above, the compounds of the invention preferably are those satisfying the general formula II,
in which
R
1
is H, (C
1
-C
3
)alkyl, (C
2
-C
3
)acyl;
R
2
is H, &agr;-(C
1
-C
4
)alkyl, &agr;-(C
2
-C
4
)alkenyl, &agr;-(C
2
-C
4
)alkynyl;
R
3
is H or (C
1
-C
4
)alkyl at location 16 of the steroid skeleton;
R
4
is ethynyl
R
5
is H or (C
1
-C
3
)alkyl, (C
2
-C
3
)acyl;
R
6
is (C
1
-C
5
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C
5
)alkynyl; each can be substituted with chlorine or fluorine. When R
6
is (C
1
-C
2
)alkyl, ethenyl or ethynyl, each optionally substituted with chlorine or fluorine, it is preferred that R
3
is methyl at location 16 of the steroid skeleton.
More preferred are the steroids of the invention in which, in the above general formula II,
R
1
is H;
R
2
is H;
R
3
is H or 16 &agr;-methyl;
R
4
is ethynyl;
R
5
is H;
R
6
is propenyl, allyl or butenyl.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids. See for example: Fried, J. and Edwards, J. A., “
Organic Reactions in Steroid Chemistry
”, Volumes I and II, Van Nostrand Reinhold Company, N.Y., 1972; and C. Djerassi “Steroid Reactions”, Holden-Day, Inc., San Francisco, 1963.
Synthesis of steroids with particular substituents at the C7 position are e.g. available via conjugate additions of organometallic species to appropriate 4,6-diene-3-one steroids, generally producing the 7&agr; derived steroids (along with minor amounts of 7&bgr; steroids which can easily removed via crystallisation or chromatography. Many examples of which are known from literature. Introduction of substituents at the C11 position of the steroid skeleton can be performed in several ways. Conjugate addition of organometallic species to a suitably protected 5&agr;,10&agr;-epoxy, 9(11)-olefin as described by Teutsch et al, Steroids 37, 361 (1981) is such an approach, but other methods, using the 11-oxo functionality of an adequately protected 19-norandrost-5-ene as a reactive functionality for functional group interconversion to e.g. a C11-aldehyde according to well known chemical methodology (see a.o. E. Ottow et al., Tetr. Lett., 5253 (1993)) may be used as well to end up with claimed compounds. Of course a combination of both approaches outlined serves similarly well to achieve the goals. Introduction of a double bond at the 5(10) position is accomplished either by application of the so-called Birch reduction of the A ring of aromatic counterparts of suitably functionalized steroids, by dissolving metal reduction of &Dgr;-4,5-9,11-dienones, or by ketalization of 3-keto-&Dgr;-4,5-steroids. This latter procedure leads either directly to the desired selective &Dgr;-5(10)-isomers or leads to mixtures of ketals which can be separated via chromatography or crystallization at appropriate stages of the synthesis. Careful hydrolysis of the ketal at C3 generally affords the desired 3-oxo-&Dgr;-5(10)-isomers, which can be converted into the 3-OH compounds by hydride reductions. Saturated steroids (i.e. 5&agr;H-derivatives ) are easily available under reductive conditions like dissolving alkali metals in amines or ammonia. Introduction of double bonds at C14,15 is generally performed by firstly introducing a double bond at the C15,C16 position, followed by isomerization of this bond to the C14,C15 position according to well known procedures. The double bond introduced at C15,C16 may alternatively be used to perform a conjugate addition with e.g. cyanide, to allow the further construction of substituents at C15. The introduction of C16 substitution is easily performed by alkylation with appropriate bases and electrophiles.
The present in

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