Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-05-24
2004-03-23
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S510000
Reexamination Certificate
active
06710039
ABSTRACT:
This application is a 371 of PCT/EP00/11557 filed Nov. 21, 2000.
The invention relates to new unsaturated 14,15-cyclopropane-androstanes, a method for their production and pharmaceutical compositions containing these compounds. Unsaturated 14,15-cyclopropane-androstanes of the following formula
are described in the German application No. 198 27 523.4 (PCT/DE99/01794), which claims a priority earlier than that of the present application, but was published after the latter was filed.
In the formula, R
1
is a hydrogen atom, a hydroxy group, an alkyloxy, acyloxy, alryloxy or alkylaryloxy group, an —OCONHR
9
or —OCOOR
9
group, in which R
9
represents a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms,
R
2
represents a hydrogen atom, a hydroxyl group, an alkyl, acyl, aryl, aralkyl, or alkyaryl group with, in each case, 1 to 10 carbon atoms,
a —(CH
2
)
n
CH
2
Y group with n=0, 1 or 2, in which Y represents a fluorine, chlorine, bromine or iodine atom, a cyano, azide or rhodanide group, an —OR
10
or —SR
10
group, in which R
10
represents a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms or a COR
9
acyl group in which R
9
represents an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms, a —OR
9
, in which R
9
represents a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms,
a —(CH
2
)
m
—CH═CH(CH
2
)
n
—R
8
group, in which m=0, 1, 2 or 3 and n=0, 1 or 2 and R
8
represents a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms or a hydroxl group, an alkoxy group or an acyloxy group with, in each case, 1 to 10 carbon atoms,
a —(CH
2
)
o
C═CR
11
group in which o=0, 1, or 2 and R
11
represents a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or an alkyl, aryl, aralkyl or alkylaryl group with, in each case, 1 to 10 carbon atoms,
R
1
and R
2
independently of one another represent a keto, methylene, or difluoromethylene group,
there possibly being a double bond between C-6 and C-7,
if there is an &agr; or &bgr; cyclopropane group X between C-14 and C-15, X representing a CZ
2
in which Z represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
R
3
and R
4
independently of one another represent a hydrogen atom, an &agr; or &bgr; alkyl group with 1 to 10 carbon atoms and
R
5
represents an alkyl group with 1 to 3 carbon atoms.
From the EP 0 768 316 A1, steroids are known with at 14,15 methylene group, which have progesterone activity and, with that, in combination with at least one suitable estrogen, are suitable for hormonal contraception and menopausal hormone replacement therapy (HRT) as well as for the treatment of endometriosis and gestagen-dependent tumors.
With this state of the art as background, it is an object of the present invention to prepare new, unsaturated, 14,15-cyclopropano-androstanes.
This objective was accomplished by unsaturated 14,15-cyclopropano-androstanes of the general formula (I)
in which R
1
represents a hydrogen atom, a hydroxy group, a C
1-10
alkyl, a C
1-10
alkyloxy, a C
1-15
acyloxy, a C
4-15
aryloxy, C
7-15
aralkyloxy, or a C
7-15
alkylaryloxy group, in which
R
2
represents a hydrogen atom, a hydroxy group, a C
1-10
alkyl, a C
1-10
acyl, a C
1-10
acyloxy, a C
6-15
aryl, a C
7-15
aralkyl or a C
7-15
alkylaryl group
a —(CH
2
)
n
CH
2
Y group,
in which n=0, 1 or 2 and Y represents a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, a pseudohalogen, especially a cyano, azide or rhodanide group,
a —(CH
2
)
m
—CH═CH(CH
2
)
p
—R
6
group
in which m=0, 1, 2 or 3 and p=0, 1 or 2 and R
6
represents a hydrogen atom, a C
1-10
alkyl, a C
6-15
aryl, a C
7-15
aralkyl or a C
7-15
alkylaryl group or a hydroxyl group, a C
1-10
alkyloxy group or a C
1-10
acyloxy group,
in which o−0, 1 or 2 and R7 represents a hydrogen atom, a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, a C
1-10
alkyl, a C
6-15
aryl, a C
7-15
aralkyl, a C
7-15
alkylaryl or a C
1-10
acyl group,
R
1
and R
2
together represent a keto, methylene or difluoromethylene group or, with inclusion of the C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane, there being a double bond between C-1 and C-2, there being an &agr; or &bgr; cyclopropane group between C-14 and C-15,
R
3
represents a hydrogen atom or an &agr; or &bgr; C
1-10
alkyl group,
R
4
represents a halogen atom, especially a fluorine, chlorine or bromine atom or a pseudohalogen, especially a rhodanide or an azide group, or a hydroxyl or perfluoroalkyl group and
R
5
represents a C
1-4
alkyl group,
with the proviso that, if there is a double bond in the 1,2 position, R
4
, in addition to the meanings given above, may be a hydrogen atom, as well as their pharmaceutically tolerated salts.
Surprisingly, it was found that the inventive, unsaturated 14,15-cyclopropane-androstanes of the general formula (I) are compounds with gestagenic and/or androgenic activity.
Within the sense of the invention, pharmaceutically tolerated salts are alkali or alkaline earth salts, especially sodium, potassium or ammonium salts. These salts can be synthesized by standard techniques and methods, which are well known in the art.
Within the sense of the present invention, a “C
1-4
or C
1-10
alkyl group” is understood to be a branched or linear alkyl group with 1 to 4 or 1 to 10 carbon atoms. As examples, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, n-pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group are mentioned.
Within the sense of the present application, the concept of “C
1-10
alkoxy group” is understood to include cyclic or acyclic groups, the alkyl portion of which contains 1 to 10 carbon atoms. “Cyclic groups” are understood to include also heterocyclic groups, which may have one or two hetero atoms in the ring, which may be selected from a nitrogen atom, an oxygen atom and a sulfur atom. A methoxy group, an ethoxy group or an n- or iso-propoxy group or an iso- or t-butoxy, a 1′-methoxy-cyclopentoxy or a tetrahydropyranyloxy group are examples.
In the sense of the present application, the concept of C
1-10
or C
1-15
acyl or acyloxy group” is understood to be a group with 1 to 10 or 1 to 15 carbon atoms of the linear or branched alkane carboxylic acids, such as formic acid, acetic acid, propionic acid, butyric acid, iso-butyric acid, heptanoic acid or undecanoic acid.
Within the sense of the present application, the concept of a “C
6-15
aryl group” is understood to include a substituted or unsubstituted aryl group with 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as a halogenated phenyl group or a nitrophenyl group, or a naphthyl group.
Within the sense of the present application, the concept of a “C
4-15
aryloxy group” is understood to include a carbocyclic or heterocyclic group with 4 to 15 carbon atoms. Examples are a benzoyloxy group, a 1- or 2-naphthinyloxy group, a 2- or 3-furanyloxy group, a 2- or 3-thienyl group and a 2-, 3- or 4-pyridinyloxy group.
Within the sense of the present application, the concept of a “C
7-15
alkylaryl group” is understood to include an aryl group, which is substituted by an alkyl group, the two group together having 7 to 15 carbon atoms. The aryl group may have additional substituents, such as a halogen atom. Examples are a toluenyl group (methylphenyl group), a halogenated toluenyl group, an ethylphenyl group, a dimethylphenyl group or a trimethylphenyl group.
Within the sense of the present application, the concept of a “C
7-15
alkylaryloxy group” is understood to be a “C
7-15
aralkyl group”, such as a 3- or a 4-methylphenyloxy group, which is extended by an oxygen atom.
Within the sense of the present application, the concept of a “C
7-15
aralkyl group” is understood to include an alkyl group, which is
Elger Walter
Kaufmann Guenter
Ring Sven
Badio Barbara P.
Schering AG
Striker Michael J.
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