Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-05-24
2004-04-20
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S179000, C552S510000
Reexamination Certificate
active
06723715
ABSTRACT:
The invention relates to new 14,15-cyclopropanosteroids of the 19-norandrostane series, their synthesis and pharmaceutical preparations containing these compounds.
14,15-Cyclopropanosteroids of the 19-norandrostane series of the following formula
are described in the German application No. 198 27 522.5 (PCT/DE99/01795), which claims a priority earlier than that of the present application, but was published after the latter was filed.
In the above formula, R
1
is a hydrogen atom or an alkyl group with 1 to 9 carbon atoms,
R
2
represents a hydrogen atoms or a methyl group,
R
3
and R
4
independently of one another represent a hydrogen atom, a hydroxy group, an acyloxy group —O—CO—R
5
, in which R
5
represents 1 to 10 carbon atoms, a carbamoyloxy group O—CO—NHR
6
, in which R
6
represents a hydrogen atom, an alkyl group or an acyl group in each case with 1 to 5 carbon atoms,
a sulfamoyloxy group —O—SO
2
—NR
7
R
8
, in which R
7
and R
8
independently of one another represent a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or, together with the nitrogen atom, represent a pyrrolidino, piperidino or morpholino group,
a —CH
2
R
9
group, in which R
9
represents hydroxy group, an alkoxy group, with 1 to 5 carbon atoms, a chlorine or bromine atom, an azide, nitrilo or thiocyano group or a —SR
10
group, in which R
10
represents an alkyl group with 1 to 5 carbon atoms,
or R
3
and R
4
together represent an oxo group
or R
3
and R
4
, with inclusion of the C-17, form a spirooxirane group or a 2,2-dimethyl-1,3-dioxolane and the 14,15-cyclopropane ring is either in the &agr; a or &bgr; position.
The EP 0 768 316 A1 discloses steroids with 14,15-methylene groups, which have progesterone activity and therefore, 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 or gestagen-dependent tumors.
With this state of the art as background, it is an object of the present invention to make available new, unsaturated, 14,15-cycloprano-androstanes.
This objective is accomplished by 14,15-cyclopranoandrostanes of the 19-norandrostane series of the general formula (I)
in which R
1
is a hydrogen atom, a hydroxy group, C
1-10
-alkyl, C
1-10
-alkyloxy, C
1-15
acyloxy, C
4-15
-aryloxy, C
7-15
-aralkyloxy or a C
7-15
-alkylaryloxy group
R
2
represents a hydrogen atom, a hydroxy group, a C
1-10
alkyl, C
1-10
acyl, C
1-10
acyloxy, C
6-15
aryl, C
7-15
aralkyl or C
7-15
alkylaryl group
a —(CH
2
)
n
CH
2
Y group
with 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,
—(CH
2
)
m
—CH═CH(CH
2
)
p
—R
6
group
with m=0, 1, 2 or 3 and p=0, 1 or 2 and R
5
represents a hydrogen atom, a C
1-10
alkyl, C
6-15
aryl, C
7-15
aralkyl or C
7-15
alkylaryl group or a hydroxyl group, a C
1-10
alkyloxy group or a C
1-10
acyloxy group,
a —(CH
2
)
o
C CR
7
group
with o=0, 1 or 2 and R
6
represents a hydrogen atom, a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, a C
1-10
alkyl, C
6-15
aryl, C
7-15
aralkyl, C
7-15
alkylaryl or C
1-10
acyl group
R
1
and R
2
together represent a keto, methylene, difluoromethylene group or, with inclusion of the C-17, a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
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 azide group, or a hydroxyl or perfluoroalkyl group and
R
5
represents a C
1-4
alkyl group, there being an &agr;- or &bgr;-cyclopropane group between C-14 and C-15,
and possibly double bonds in the 9,10 or 11,12 position,
with the proviso that, if there are 2 further double bonds in the 9,10 and 11,12 positions or one double bond in the 11,12 position, R
4
can be a hydrogen atom in addition to the meanings given above and with the further proviso that, when R
5
is a methyl group, R
4
can be a hydrogen atom in addition to the meanings given above, as well as their pharmaceutically tolerated salts.
Surprisingly, the compounds of formula (I) show an interesting mixed androgen/gestagen profile, the androgenic or gestagenic activity predominating depending on the substitution.
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 invention, 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 1 or 2 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 of 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 substituted by an aryl group, the two groups together having 7 to 15 carbon atoms. The aryl group may have further substituents, such as a halogen atom. Examples are a free or an aromatically substituted benzyl groups, such as a benzyl group or a halogenated benzyl group.
Within the sense of the present application, the concept of “C
7-15
aralkyloxy group” is understood to include “C
7-15
aralkyl groups”, which has been extended by an oxygen atom, such as a benzyloxy group.
Within the sense of the present application, the concept of “halogen” comprises a fluorine, bromine or iodine atom.
Within the sense of the present application, the concept of “pseudohalogen” comprises a cyanate, rhodanide, cyan or azide group.
Within the sense of the present applica
Elger Walter
Kaufmann Guenter
Ring Sven
Badio Barbara P.
Schering AG
Striker Michael J.
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