Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-09-11
2004-03-16
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S182000, C552S510000
Reexamination Certificate
active
06706700
ABSTRACT:
This application is a 371 of PCT/EP00/12009 filed Nov. 29, 2000.
The present invention is in the field of steroid compounds having a cyclopropane ring, which ring includes carbon atoms 14 and 15 of the steroid skeleton. More particularly, the invention pertains to such steroid compounds as possess an androgenic activity.
Steroids having the above-indicated cyclopropane ring have been disclosed in EP 768 316, which is in the field of female contraception and hormone-therapy against endometriosis or climacteric complaints. The steroids are described as having progestagenic activity, examples being 14&agr;,15&agr;-methylene estra-4,9-diene-3-one-17&agr;-ol and 3-oxo 14&bgr;,15&bgr;-methylene estra-4,9-diene-17&bgr;-yl (N-phenyl)carbamate. Neither potency, nor any other receptor activities, of these progestagens can be derived from this disclosure.
In a non-prepublished patent application PCT/DE99/01795 (published on Dec. 29, 1999 as WO 99/67276) a group of 14,15-cyclopropyl steroids has been described, among which are 17&bgr;-hydroxy substituted ones.
Another non-prepublished patent application is WO 00/53619 wherein a group of androgenic steroids is described which have a 14&bgr;,17&agr; configuration, viz. (14&bgr;,17&agr;)-17-(hydroxymethyl) steroids.
The present invention now provides a novel group of steroids of the general type as indicated above, which possess an unexpected androgenic activity. Distinct from the progestagens disclosed in the art, the androgens of the present invention—including very potent ones—int.al. satisfy the requirements that the cyclopropane ring is &bgr;-oriented and that on carbon atom no. 17 a hydroxymethyl group is present which is &agr;-oriented. As a consequence, the steroids of the invention have the 14&bgr;-configuration, contrary to natural steroid hormones, such as testosterone and estradiol, which have a configuration 14&agr;, 17&bgr;.
The steroids according to the invention satisfy the structural formula I:
wherein
R
1
is O, (H,H), (H,OR), NOR, with R being hydrogen, (C
1-6
) alkyl, (C
1-6
) acyl;
R
2
is hydrogen, or (C
1-6
) alkyl;
R
3
is hydrogen; or R
3
is (C
1-6
) alkyl, (C
2-6
) alkenyl, or (C
2-6
) alkynyl, each optionally substituted by halogen;
R
4
is hydrogen, (C
1-6
) alkyl, or (C
2-6
) alkenyl;
R
5
is (C
1-6
) alkyl;
R
6
is hydrogen, halogen, or (C
1-4
) alkyl;
R
7
is hydrogen, or (C
1-6
) alkyl;
R
8
is hydrogen, hydroxy, (C
1-6
) alkoxy, halogen, or (C
1-6
) alkyl;
R
9
and R
10
are independently hydrogen; or R
9
and R
10
are independently (C
1-6
)alkyl, (C
2-6
) alkenyl, (C
3-6
) cycloalkyl, (C
5-6
) cycloalkenyl, or (C
2-6
) alkynyl, each optionally substituted by (C
1-4
) alkoxy, or halogen;
R
11
is hydrogen, SO
3
H, (C
1-15
) acyl; and the dotted lines indicate optional bonds, selected from a &Dgr;
4
, &Dgr;
5(10)
, or &Dgr;
11
double bond, or a &Dgr;
4.9
or &Dgr;
4.11
diene system.
The invention not only pertains to steroids which satisfy structural formula I, but also to pharmaceutically acceptable salts or esters, prodrugs and precursors thereof.
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
1-4
) alkyl means an alkyl group having 1-4 carbon atoms. Preferred alkyl groups have 1-4 carbon atoms, and most preferred alkyl groups are methyl and ethyl.
The term (C
2-6
) alkenyl means a branched or unbranched alkenyl group having at least one double bond and 2-6-carbon atoms. Preferred alkenyl groups have 2-4 carbon atoms, such as vinyl and propenyl.
The term (C
2-6
) alkynyl means a branched or unbranched alkynyl group having at least one triple bond and 2-6 carbon atoms. Preferred alkynyl groups have 2-4 carbon atoms, such as ethynyl and propynyl.
The term (C
3-6
) cycloalkyl means a cycloalkane ring having 3-6 carbon atoms, like cyclopropane, cyclobutane, cyclopentane and cyclohexane.
The term (C
5-6
) cycloalkenyl means a cycloalkene ring having at least one double bond and 5 or 6 carbon atoms.
The term (C
1-6
) alkoxy means a branched or unbranched alkyloxy group having 1-6 carbon atoms, like methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tertiary butyloxy, pentyloxy, and hexyloxy. Likewise, the term (C
1-4
) alkoxy means a branched or unbranched alkyloxy group having 1-4 carbon atoms. Preferred alkyloxy groups have 1-4 carbon atoms, and most preferred is methyloxy.
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.
The term halogen means fluorine, chlorine, bromine, or iodine. When halogen is a substituent at an alkyl group, like in the definition R
3
, R
6
, R
8
, R
9
and R
10
, Cl and F are preferred, F being most preferred.
The 14&bgr;,15&bgr;-methylene-17&agr;-methanol steroid derivatives of this invention have the natural configurations 5&agr;, 8&bgr;, 9&agr;, 10&bgr;, and 13&bgr;. The configuration at C-17 is 17&agr;. The compounds of the invention may possess also one or more additional chiral carbon atoms. They 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.
For therapeutic use, salts of the compounds of formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of the acids according to formula I may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention. Examples of salts of acids according to the invention are mineral salts such as sodium salt, potassium salt, and salts derived from organic bases like ammonia, imidazole, ethylenediamine, triethylamine and the like.
The compounds of the invention as described hereinbefore in general possess an unexpected androgenic activity. Androgenic activity can be measured in various ways. Thus, the potency of androgens can be determined in vitro using the cytoplasmic androgen receptor from human breast tumor cells (MCF-7 cell line); see Bergink, E. W. et al,
Comparison of the receptor binding properties of nandrolone and testosterone under in vitro and in vivo conditions
, J. Steroid Biochem. 22, 831-836 (1985). It is also possible to use Chinese hamster ovary (CHO) cells transfected with the human androgen receptor (incubation time 16 h, temperature 4° C.) and compared with the affinity of 5&agr;-dihydrotestosterone [according to the procedure described by Bergink, E. W. et al, J. Steroid Biochem. 19, 1563-1570 (1983)]. The transactivative androgen activity of the compounds of the invention can be measured, e.g. in Chinese hamster ovary cells (CHO) transfected with the human androgen receptor (hAR), in combination with a mouse mammary tumor virus (MMTV), and luciferase receptor gene (incubation time 16 h, temperature 37° C.) and compared with the activity of 5&agr;-dihydrotestosterone [according to the procedure described by Schoonen, W. G. E. J. et al, Analyt. Biochem. 261, 222-224 (1998)]. For the in vivo potency determination of androgens the classical Hershberger test can be used. In this test the androgenic (increase in prostate weight) and anabolic activities [increase of the musculus levator ani (MLA)] of a compound are tested in immature castrated rats after daily administration for 7 days; see Hershberger, L. G. et al,
Myotrophic activity of
19-
Nortestosterone and other steroids determined by modified levator ani muscle method
, Proce
Buma Bursi Roberta
De Gooyer Marcel Evert
Leysen Dirk
Van der Louw Jaap
Akzo-Nobel, N.V.
Badio Barbara P.
Blackstone William M.
Minstead Mark W.
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