Antigestagenically active steroids with a flourinated 17...

Details Antigestagenically active steroids with a flourinated 17... Antigestagenically active steroids with a flourinated 17...

2000-03-01

2001-11-13

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S181000, C514S182000, C552S510000, C552S598000

Reexamination Certificate

active

06316432

ABSTRACT:

This invention relates to antigestagenically active steroids with a fluorinated 17&agr;-alkyl chain, process for their production, pharmaceutical preparations that contain the latter and their use for the production of pharmaceutical agents.
The invention relates to 17&agr;-fluoroalkyl steroids of general formula I
in which
R
1
stands for a methyl or ethyl group,
R
2
stands for a radical of formula C
n
F
m
H
o
, whereby n is 2, 3, 4, 5 or 6, m>1 and m+o=2n+1,
R
3
stands for a free, etherified or esterified hydroxy group,
R
4
and R
5
each stand for a hydrogen atom, or together for an additional bond or a methylene group,
St stands for a steroidal ABC-ring system of partial formula A, B or C
in which
R
6
means a hydrogen atom, a straight-chain C
1
-C
4
alkyl group or branched C
3
-C
4
alkyl group or a halogen atom,
R
7
means a hydrogen atom, a straight-chain C
1
-C
4
alkyl group or a branched C
3
-C
4
alkyl group, or
if St stands for a steroidal ABC-ring system A or B, in addition
R
6
and R
7
together can mean an additional bond,
X means an oxygen atom, a hydroxyimino grouping ═N—OH or two hydrogen atoms,
R
8
means a radical Y or an aryl radical that is optionally substituted with Y, whereby Y is a hydrogen atom, a halogen atom, an —OH, —NO
2
, —N
3
, —CN, —NR
9a
R
9b
, —NHSO
2
R
9
, —CO
2
R
9
, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
alkanoyloxy, benzoyloxy, C
1
-C
10
alkanoyl, C
1
-C
10
hydroxyalkyl or benzoyl group, and R
9a
and R
9b
are the same or different and represent a hydrogen atom or a C
1
-C
10
alkyl group, R
9
is a hydrogen atom or C
1
-C
10
alkyl,
 and for —NR
9a
R
9b
radicals, as well as their physiologically compatible salts with acids and for —CO
2
R
9
radicals with R
9
meaning hydrogen, as well as their physiologically compatible salts with bases.
The wavy lines mean that the substituent in question can be in &agr;- or &bgr;-position.
In the alkyl groups that are mentioned within the scope of this invention, these are the methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl groups, for example.
The other C
1
-C
10
alkyl groups, Y, R
9
, R
9a
, R
9b
, have the higher homologues in addition, such as, for example, the pentyl, neopentyl, hexyl to decyl groups, for example.
C
1
-C
10
alkyl groups are to be understood to encompass, however, carbocyclic or alkylcycloalkyl groups as well with up to 10 carbon atoms, for example the cyclopropyl, cyclopentyl, cycloheptyl, methylcyclopropyl, methylcyclopentyl or methylcyclohexyl radical. A methyl or ethyl group is preferred for all cases above.
C
1
-C
10
alkoxy groups are the radicals that are lengthened by one oxygen atom and derived from the alkyl groups that are mentioned above, thus, e.g., the methoxy, ethoxy, n- or iso-propoxy, n-, iso- or tert-butoxy radical.
C
1
-C
10
alkanoyl is defined as the acyl radicals of straight-chain and branched C
1
-C
10
alkanecarboxylic acids, thus, for example, the formyl, acetyl, propionyl, butyryl or iso-butyryl radical, etc.
C
1
-C
10
Alkanoyloxy radicals are the radicals of the above alkanoyl radicals that are lengthened by one oxygen atom, thus, e.g., the acetyloxy, propionyloxy, and butyryloxy radical.
If a halogen atom is mentioned as a substituent, this can be a fluorine, chlorine or bromine atom. Fluorine is preferred.
For radicals R
2
, perfluorinated side chains of length n=2-4 are to be preferred and among the latter, in turn the pentafluoroethyl unit is especially to be preferred.
R
3
stands primarily for a free hydroxy group.
In the case of an etherified or esterified hydroxy group as a 17&bgr;-substituent, the latter is preferably etherified with a C
1
-C
10
alkyl group or esterified with a C
1
-C
10
alkanoyl group. For this alkyl or alkanoyl group, the same meanings as above hold true. The etherification or esterification of the hydroxy group is carried out according to the methods that are familiar to one skilled in the art.
R
4
and R
5
preferably each stand for a hydrogen atom or together for an additional bond.
If R
8
is a group Y, this is preferably a C
1
-C
10
alkanoyl or (1-hydroxy)—C
1
-C
10
alkyl group, whereby among these radicals, the acetyl and the propionyl group are especially to be preferred.
Preferred carbocyclic or heterocyclic aryl radicals are phenyl, 1- or 2-naphthalinyl, 2- or 3-furanyl, 2- or 3-benzofuranyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl. As substituted aryl radical R
8
(e.g., substituted one or up to several (e.g., 2-3) times with Y), primarily 4-cyanophenyl and a 4-halophenyl radical, especially the 4-fluorophenyl radical, can be cited.
Among all the radicals that are mentioned as preferred for R
8
, R
8
in the meaning of Y and Y in turn equal to acetyl is especially to be preferred.
The compounds that are mentioned below are especially preferred according to the invention:
11&bgr;-(4-Acetylphenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
4′-[17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)estr-4-en-11&bgr;-yl][1,1′-biphenyl]-4-carbonitrile;
11&bgr;-(4′-fluoro[1,1′-biphenyl]-4-yl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-11&bgr;-[4-(3-pyridinyl)phenyl]estr-4-en-3-one;
11&bgr;-(4-acetylphenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-3-one;
4′-[17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-11&bgr;-yl][1,1′-biphenyl]-4-carbonitrile;
11&bgr;-(4′-fluoro[1,1′-biphenyl]-4-yl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-3-one;
17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-11&bgr;-[4-(3-pyridinyl)phenyl]estra-4,15-dien-3-one;
11&bgr;-(4-acetylphenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
4′-[17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-11&bgr;-yl][1,1′-biphenyl]-4-carbonitrile;
11&bgr;-(4′-fluoro[1,1′-biphenyl]-4-yl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-11&bgr;-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one;
11&bgr;-(4-acetylphenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,9,15-trien-3-one;
4′-[17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)estra-4,9,15-trien-11&bgr;-yl][1,1′-biphenyl]-4-carbonitrile;
11&bgr;-(4′-fluoro[1,1′-biphenyl]-4-yl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl))estra-4,9,15-trien-3-one;
17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-11&bgr;-[4-(3-pyridinyl)phenyl]estra-4,9,15-trien-3-one;
6′-acetyl-9,11&agr;-dihydro-17-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estr-4-en-3-one;
4-[9,11&agr;-dihydro-17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estr-4-en-6′-yl]benzonitrile;
9,11&agr;-dihydro-6′-(4-fluorophenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estr-4-en-3-one;
9,11&agr;-dihydro-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-6′-(3-pyridinyl)-4′H-naphth[3′,2′,1′:10,9,11]estr-4-en-3-one;
6′-acetyl-9,11&agr;-dihydro-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estra-4,15-dien-3-one;
4-[9,11&agr;-dihydro-17&bgr;-hydroxy-3-oxo-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estra-4,15-dien-6′-yl]benzonitrile; 9,11&agr;-dihydro-6′-(4-fluorophenyl)-17&bgr;-hydroxy-17&agr;-(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1′:10,9,11]estra

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