Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2003-05-05
2004-11-30
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S648000
Reexamination Certificate
active
06825182
ABSTRACT:
DESCRIPTION
This invention relates to new 17&agr;-fluoroalkyl-11&bgr;-benzaldoxime steroids, a process for their production, pharmaceutical preparations that contain these active ingredients as well as their use for the production of pharmaceutical agents, especially for postmenopausal substitution therapy of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
Antigestagenically active steroids are already known from EP 0 057 115 A2. In this connection, this can be 3-oxo-estra-4,9-dienes substituted in 11-position.
11&bgr;-Benzaldoximes of the steroid series that have special antigestagenic properties are known from DE 43 32 283 A1, DE 43 32 284 A1, and DE 198 09 845 A1 (WO 9945023 A1).
Described in DE 43 32 283 A1 and DE 43 32 284 A1 are 11&bgr;-benzaldoxime-3-oxo-estra-4,9-diene derivatives, which can be substituted according to DE 43 32 283 A1 in 17&bgr;-position with hydroxy, alkoxy, acyloxy or aryloxy and in 17&agr;-position with &ohgr;-fluoroalkyl.
In DE 198 09 845 A1, substituted 11&bgr;-benzaldoxime-3-oxo-estra-4,9-dienes are described. In this case, these are S-substituted carboxylic acid thiol esters of these compounds. The compounds can also be substituted in 17&bgr;-position with hydroxy, alkoxy, acyloxy or aryloxy and in 17&agr;-position with &ohgr;-fluoroalkyl.
By contrast, steroids with 17&agr;-fluoroalkyl chains are disclosed in DE 197 06 061 A1. These compounds, especially ZK 230211 (11&bgr;-(4-acetylphenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one): U. Fuhrmann; H. Hess-Stumpp, A. Cleve, G. Neef, W. Schwede, J. Hoffmann, K.-H. Fritzemeier and K. Chwalisz:
J. Med. Chem.,
2000, 43, 5010-5016), show an almost purely antagonistic activity, high receptor selectivity and, i.a., antiproliferative activity in the tumor models.
The object on which this invention is based consists in finding active ingredients with antigestagenic action that have significantly reduced antiglucocorticoidal action compared to the known compounds and that are suitable for postmenopausal substitution therapy or for treatment of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
Another object on which this invention is based consists in finding a process for the production of active ingredients.
In addition, an object exists in finding pharmaceutical preparations that contain the active ingredients.
The compounds according to the invention have general formula I:
in which
R
1
stands for hydrogen, C
1
- to C
6
-alkyl, COR
4
, COOR
4
, COSR
4
or CONHR
5
, in which R
4
is C
1
- to C
6
-alkyl or unsubstituted or substituted aryl, and in which R
5
is hydrogen, C
1
- to C
6
-alkyl or unsubstituted or substituted aryl,
R
2
stands for hydrogen, C
1
- to C
6
-alkyl or C
1
- to C
6
-acyl, and
R
3
stands for a C
n
F
2n+1
group, in which n=1, 2 or 3, or for a CH
2
O(CH
2
)
m
C
n
F
2n+1
group, in which m=0 or 1 and n=1, 2 or 3.
In all other positions of the steroid skeleton as well as on the phenylene radical in 11&bgr;-position, any other substituents, especially alkyl and aryl groups, can be bonded instead of hydrogen. In addition, this invention relates to pharmaceutically compatible salts of these compounds. Such acid addition salts can be salts of inorganic and organic acids, for example salts of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other usable acids are described in, for example:
Fortschritte der Arzneimittelforschung [Progress in Pharmaceutical Agent Research]
, Vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966 as well as in:
Journal of Pharmaceutical Sciences
, Vol. 66, pages 1-5 (1977).
Radicals R
1
that are mentioned in this invention are especially a hydrogen atom or a methyl group or acyl groups, such as, for example, formyl, acetyl, propionyl and benzoyl radicals, or carboxylic acid ester groups, for example methoxycarbonyl radicals or ethoxycarbonyl radicals, or carboxylic acid thiol ester groups, such as methylthiocarbonyl radicals or ethylthiocarbonyl radicals, or urethane groups, such as ethylaminocarbonyl radicals or unsubstituted or substituted phenylaminocarbonyl radicals. The substituted phenylaminocarbonyl radical is preferably substituted with a C
1
- to C
6
-perfluoroalkyl radical.
R
2
preferably stands for a hydrogen atom, a methyl group or an acetyl group.
R
3
stands in particular for a perfluoroalkyl with n=1, 2 or 3. R
3
can thus stand for 1,1,1-trifluoromethyl, 1,1,2,2,2-pentafluoroethyl or 1,1,2,2,3,3,3-heptafluoropropyl. In addition, R
3
can stand for 1,1,1-trifluoroethyloxymethyl, if R
3
is provided by general formula CH
2
O(CH
2
)
m
C
n
F
2n+1
, and in this case, m=1 and n=1.
The compounds according to the invention are especially the following 17&agr;-fluoroalkyl-11&bgr;-benzaldoxime steroids:
1) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
2) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(Z)-oxime
3) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
4) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
5) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-O-acetyloxime
6) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
7) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylthio)carbonyl]oxime
8) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethoxy)carbonyl]oxime
9) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(methoxy)carbonyl]oxime
10) 4-[17&bgr;-Hydroxy-17&agr;-(1,1,2,2,3,3,3-heptafluoropropyl)-3-oxoestra-
4,9-
dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
11) 4-[17&bgr;-Methoxy-17&agr;-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
12) 4-[17&bgr;-Methoxy-17&agr;-(1,1,1-trifluoromethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
13) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
14) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-O-acetyloxime
15) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
16) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-{O-[(4′-trifluoromethyloxy)phenylamino]carbonyl}oxime
17) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethoxy)carbonyl]oxime
18) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(methoxy)carbonyl]oxime
19) 4-[17&bgr;-Methoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylthio)carbonyl]oxime
20) 4-[17&bgr;-Acetoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-[O-(ethylamino)carbonyl]oxime
21) 4-[17&bgr;-Acetoxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-3-oxoestra-4,9-dien-11&bgr;-yl]benzaldehyde-1(E)-oxime
22) 4-[17&bgr;-Hydroxy-17&agr;-[
Elger Walter
Kaufmann Guenter
Ring Sven
Schneider Birgitt
Schubert Gerd
Badio Barbara P.
Millen White Zelano & Branigan P.C.
Schering AG
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