U.S. patent number RE39,862 [Application Number 11/008,758] was granted by the patent office on 2007-09-25 for unsaturated 14, 15-cyclopropanoandrostanes, a method for their production and pharmaceutical compositions containing these compounds.
This patent grant is currently assigned to Schering AG. Invention is credited to Walter Elger, Guenter Kaufmann, Sven Ring.
United States Patent |
RE39,862 |
Ring , et al. |
September 25, 2007 |
Unsaturated 14, 15-cyclopropanoandrostanes, a method for their
production and pharmaceutical compositions containing these
compounds
Abstract
The invention relates to new unsaturated
14,15-cyclopropano-androstanes of the general formula (I)
##STR00001## to their synthesis and to pharmaceutical compositions,
containing these compounds. The compounds of formula (I) have
gestagenic and/or androgenic activity.
Inventors: |
Ring; Sven (Jena,
DE), Elger; Walter (Berlin, DE), Kaufmann;
Guenter (Jena, DE) |
Assignee: |
Schering AG (Berlin,
DE)
|
Family
ID: |
7932216 |
Appl.
No.: |
11/008,758 |
Filed: |
November 21, 2000 |
PCT
Filed: |
November 21, 2000 |
PCT No.: |
PCT/EP00/11557 |
371(c)(1),(2),(4) Date: |
May 24, 2002 |
PCT
Pub. No.: |
WO01/42275 |
PCT
Pub. Date: |
June 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
10148157 |
May 24, 2002 |
06710039 |
Mar 23, 2004 |
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Current U.S.
Class: |
514/178;
552/510 |
Current CPC
Class: |
A61P
35/00 (20180101); C07J 53/004 (20130101); A61P
5/24 (20180101); A61P 5/26 (20180101); A61P
5/34 (20180101); A61P 15/00 (20180101); A61P
15/08 (20180101) |
Current International
Class: |
A61K
31/56 (20060101); C07J 53/00 (20060101) |
Field of
Search: |
;514/178 ;552/510 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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376097 |
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Mar 1964 |
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CH |
|
31269 |
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Jan 1961 |
|
DE |
|
33136 |
|
Nov 1964 |
|
DE |
|
19827523 |
|
Dec 1999 |
|
DE |
|
0768316 |
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Apr 1997 |
|
EP |
|
839908 |
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Jun 1960 |
|
GB |
|
855800 |
|
Dec 1960 |
|
GB |
|
874572 |
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Aug 1961 |
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GB |
|
928714 |
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Jun 1963 |
|
GB |
|
WO-99/67275 |
|
Dec 1999 |
|
WO |
|
WO 99/67275 |
|
Dec 1999 |
|
WO |
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Other References
PS. Furth et al., J. Enzyme Inhibition, 1990, vol. 4, pp. 131-135.
cited by examiner .
X.S. Fei et al., J. Chem. Soc. Perkin Trans. 1, 1998, pp.
1139-1142. cited by examiner .
Blackmore Peter et al., Molecular Pharmacology, BD. 49, NR. 4,
1996, pp. 727-739. cited by examiner .
R. Ernst: "Dictionary of Engineering and Technology", Vol. 1, Fifth
Edition, P. 841. cited by other .
CRC Hand Book of Chemistry and Physics by D.R. Lide. Boca Raton,
Ann Arbor, London, Tokyo, pp. 2-23-2-24. cited by other.
|
Primary Examiner: Badio; Barbara P.
Attorney, Agent or Firm: Striker; Michael J.
Claims
What is claimed is:
1. Unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.of .[.the.]. formula
(I): ##STR00005## wherein R.sub.1 .[.is.]. .Iadd.represents
.Iaddend.a hydrogen atom, a hydroxy group, a C.sub.1-10-alkyl
.Iadd.group.Iaddend., a C.sub.1-10-alkyloxy .Iadd.group.Iaddend., a
C.sub.1-15 acyloxy .Iadd.group.Iaddend., a C.sub.4-15-aryloxy
.Iadd.group.Iaddend., a C.sub.7-15-aralkyloxy .Iadd.group.Iaddend.,
or a C.sub.7-15-alkylaryloxy group; R.sub.2 represents a hydrogen
atom, a hydroxy group, a C.sub.1-10 alkyl group, a C.sub.1-10 acyl
group, a C.sub.1-10 acyloxy group, a C.sub.6-15 aryl group, a
C.sub.7-15 aralkyl group, a C.sub.7-15 alkylaryl group, a
--(CH.sub.2).sub.nCH.sub.2Y group in which n=0, 1 or 2 and Y
represents a halogen atom.[.or a pseudohalogen.]. .Iadd., a cyano
group, an azido group, a cyanato group, or a thiocyanato
group.Iaddend.; .Iadd.a
--(CH.sub.2).sub.mCH.dbd.CH(CH.sub.2).sub.pR.sub.6 group
.Iaddend.in which m=0, 1, 2.Iadd., .Iaddend.or 3 and p=0, 1.Iadd.,
.Iaddend.or 2 and R.sub.6 represents a hydrogen atom, a
C.sub.1-10-alkyl group, a C.sub.6-15 aryl group, a C.sub.7-15
aralkyl group, a C.sub.7-15 alkylaryl group, a hydroxyl group, a
C.sub.1-10 alkyloxy group.Iadd., .Iaddend.or a C.sub.1-10 acyloxy
group; .Iadd.a --(CH.sub.2).sub.oC.ident.CR.sub.7 group .Iaddend.in
which o=0, 1.Iadd., .Iaddend.or 2 and R.sub.7 represents a hydrogen
atom, a halogen atom, a C.sub.1-10 alkyl group, a C.sub.6-15 aryl
group, a C.sub.7-15 aralkyl group, a C.sub.7-15 alkylaryl
group.Iadd., .Iaddend.or a C.sub.1-10 acyl group; or R.sub.1 and
R.sub.2 together represent a keto group, a methylene group, a
difluoromethylene group or, with inclusion of C-17, a spirooxirane
or a 2,2-dimethyl-1,3-dioxolane; .[.in which optionally a 1,2
double bond is present;.]. R.sub.3 represents a hydrogen
atom.Iadd., .Iaddend..[.or.]. a .alpha.-C.sub.1-10 alkyl
group.Iadd., .Iaddend.or a .beta.-C.sub.1-10 alkyl group; R.sub.4
represents a halogen atom, a .[.pseudohalogen.]. .Iadd.cyano
group.Iaddend., .Iadd.an azido group, a thiocyanato group, a
cyanato group, .Iaddend.a hydroxy group.Iadd., .Iaddend.or a
perfluoroalkyl group; R.sub.5 represents a C.sub.1-4 alkyl group;
.[.in which.]. an .alpha.-cyclopropane group or a
.beta.-cyclopropane group is .Iadd.present .Iaddend.between C-14
and C-15; .Iadd.in which optionally a 1,2-double bond is present
and .Iaddend.with the proviso that, if said 1,2-double bond is
present, then R.sub.4 can .[.be.]. .Iadd.represent .Iaddend.a
hydrogen atom in addition to said halogen atom, said
.[.pseudohalogen.]. .Iadd.cyano group, said azido group, said
thiocyanato group, .Iaddend.said hydroxy group.Iadd., .Iaddend.or
said perfluoroalkyl group; or pharmaceutically tolerated salts
thereof.
2. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein Y .[.is.]. .Iadd.denotes .Iaddend.a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom, a cyano group, an
.[.azide.]. .Iadd.azido .Iaddend.group.Iadd., .Iaddend.or a
.[.rhodanide.]. .Iadd.thiocyanato .Iaddend.group.
3. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.7 .[.is.]. .Iadd.denotes .Iaddend.a fluorine atom, a
chlorine atom, a bromine atom.Iadd., .Iaddend.or an iodine
atom.
4. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.4 .[.is.]. .Iadd.denotes .Iaddend.a fluorine atom, a
chlorine atom, a bromine atom, an .[.azide.]. .Iadd.azido
.Iaddend.group.Iadd., .Iaddend.or a .[.rhodanide.].
.Iadd.thiocyanato .Iaddend.group.
5. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.1 .[.is.]. .Iadd.denotes .Iaddend.a hydroxy group or
an acyloxy group.
6. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 5,
wherein said acyloxy group is a formyloxy, an acetyloxy, a
propionyloxy, a n-butyryloxy, an isobutyryloxy, a
heptanyloxy.Iadd., .Iaddend.or an undecanyloxy group.
7. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.2 is a hydrogen atom or an alkyl group.
8. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 7,
wherein said alkyl group is a methyl group or an ethyl group.
9. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.3 is a methyl group.
10. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.4 .[.is.]. .Iadd.denotes .Iaddend.a fluorine atom, a
chlorine atom, a bromine atom, a hydroxy group.Iadd., .Iaddend.or a
trifluoromethyl group.
11. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1,
wherein R.sub.5 .[.is.]. .Iadd.denotes .Iaddend.a methyl group or
an ethyl group.
12. The unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.selected from the
group consisting of
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne,
4-chloro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-en-
e-3-one,
4-chloro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4--
ene-3-one,
4-chloro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-on-
e,
4-bromo-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-
-one,
4-bromo-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-e-
ne-3-one,
4-bromo-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4--
ene-3-one,
4-bromo-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-one-
,
4-fluoro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-
-one,
4-fluoro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4--
ene-3-one,
4-fluoro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-one-
,
4-fluoro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3--
one,
4,17.beta.-dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne,
4,17.alpha.-dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne,
4,17.beta.-dihydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-one,
4,17.alpha.-dihydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-one,
4-trifluoromethyl-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst--
4-ene-3-one,
4-trifluoromethyl-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-
-4-ene-3-one,
4-trifluoromethyl-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4--
ene-3-one,
4-trifluoromethyl-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-
-ene-3-one,
17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3-one,
17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3-one,
17.beta.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene-3-one,
17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene-3-one,
4-chloro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-die-
ne-3-one,
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-
a-1,4-diene-3-one,
4-chloro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene--
3-one, and
4-chloro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene-
-3-one.
13. A method .[.for the.]. .Iadd.of .Iaddend.synthesis of the
.[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.defined in claim 1,
wherein, in compounds of formula (II): ##STR00006## in which
R.sub.1, R.sub.2, R.sub.3, R.sub.5 are as defined in claim 1.[.,
4,5 double.]. .Iadd.and in which a 4,5-double bond is present, the
4,5-double .Iaddend.bond is epoxidized with hydrogen peroxide under
alkaline conditions and the resulting epoxide mixture is treated in
a solvent with acids of .[.the.]. formula HR.sub.8, R.sub.8 being a
halogen atom.Iadd., a cyano group, an azido group, a cyanato,
.Iaddend.or a .[.pseudohalogen atom,.]. .Iadd.thiocyanato group,
.Iaddend.or reacted with catalytic amounts of a mineral acid.[.,.].
to obtain 4-bromo -compounds and, optionally, the obtained 4-bromo
compounds of the formula (I), as defined in claim 1, are reacted
with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate in
dimethylformamide in the presence of CuI.
14. The method as defined in claim 13, wherein said halogen atom
.[.is.]. .Iadd.denotes .Iaddend.a fluorine, chlorine.Iadd.,
.Iaddend.or bromine atom.
15. The method as defined in claim 13, wherein .[.said
pseudohalogen is an azide or a rhodanide.]. .Iadd.R.sub.8
represents said azido or said thiocyanato .Iaddend.group.
16. A pharmaceutical composition containing at least one of the
unsaturated .[.14,15-cyclo-pranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.defined in claim 1 and
at least one additional ingredient selected from the group
consisting of pharmaceutically tolerated inactive materials and
vehicles.
17. A method of hormone replacement therapy in a man or woman in
need of said therapy, said method comprising administering to said
man or said woman an effective amount of at least one of the
unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1
for said hormone replacement therapy.
18. A method of controlling fertility of a human being, said method
comprising administering to said human being an effective amount of
at least one of the unsaturated .[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1
for controlling said fertility.
19. A method of treating a hormone-induced disease suffered by a
man or a woman, said method comprising administering to said man or
said woman an effective amount of at least one of the unsaturated
.[.14,15-cyclopranoandrostanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.as defined in claim 1
for treating said hormone-induced disease.
20. The method as defined in claim 19, wherein said hormone-induced
disease is endometriosis, breast cancer.Iadd., .Iaddend.or
hypogonadism.
Description
.[.This application is a 371 of PCT/EP00/11557 filed Nov. 21,
2000..]. .Iadd.The invention described and claimed hereinbelow is
also described in PCT International Patent Application PCT/EP
00/11557, filed on Nov. 21, 2000, which provides the basis for a
claim of priority of invention for the claims appended hereinbelow
under 35 U.S.C. 365..Iaddend.
The invention relates to new unsaturated
.[.14,15-cyclopropane-androstanes.].
.Iadd.14,15-cyclopropanoandrostanes.Iaddend., a method for their
production and pharmaceutical compositions containing these
compounds. Unsaturated .[.14,15-cyclopropane-androstanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.of the following
formula.Iadd.:.Iaddend. ##STR00002## are described in the German
.[.application.]. .Iadd.Patent Application .Iaddend.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.sub.1 is a hydrogen atom, a hydroxy group, an
alkyloxy .Iadd.group.Iaddend., .Iadd.an .Iaddend.acyloxy
.Iadd.group.Iaddend., .[.alryloxy.]. .Iadd.an aryloxy group,
.Iaddend..[.or.]. .Iadd.an .Iaddend.alkylaryloxy group, an
--OCONHR.sub.9 .Iadd., .Iaddend.or --OCOOR.sub.9 group, in which
R.sub.9 represents a hydrogen atom, an alkyl .Iadd.group.Iaddend.,
.Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an
.Iaddend.aralkyl .Iadd.group, .Iaddend.or alkylaryl group with, in
each case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. R.sub.2
represents a hydrogen atom, a hydroxyl group, an alkyl
.Iadd.group.Iaddend., .Iadd.an .Iaddend.acyl .Iadd.group.Iaddend.,
.Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an
.Iaddend.aralkyl .Iadd.group.Iaddend., or .Iadd.an
.Iaddend.alkylaryl group with, in each case, 1 to 10 carbon
atoms.[.,.]. .Iadd.;.Iaddend. a --(CH.sub.2).sub.nCH.sub.2Y group,
with n=0, 1.Iadd., .Iaddend.or 2, in which Y represents a fluorine
.Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine .Iadd.atom.Iaddend.,
.Iadd.a .Iaddend.bromine .[.or.]. .Iadd.atom, an .Iaddend.iodine
atom, a cyano .Iadd.group.Iaddend., .[.azide or rhodanide.].
.Iadd.an azido group, a thiocyanato .Iaddend.group, an --OR.sub.10
.Iadd.group .Iaddend.or .Iadd.a .Iaddend.--SR.sub.10 group.[.,.].
in which R.sub.10 represents a hydrogen atom, an alkyl
.Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend.,
.Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or .Iadd.an
.Iaddend.alkylaryl .[.groups.]. .Iadd.group .Iaddend.with, in each
case, 1 to 10 carbon atom.Iadd.s .Iaddend.or a COR.sub.9 acyl group
in which R.sub.9 represents an alkyl .Iadd.group.Iaddend., .Iadd.an
.Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl
.Iadd.group, .Iaddend.or .Iadd.an .Iaddend.alkylaryl group with, in
each case, 1 to 10 carbon atoms, .Iadd.or .Iaddend.a
--OR.sub.9.[.,.]. .Iadd.group .Iaddend.in which R.sub.9 represents
a hydrogen atom, an alkyl .Iadd.group.Iaddend., .Iadd.an
.Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl
.Iadd.group, .Iaddend.or .Iadd.an .Iaddend.alkylaryl group with, in
each case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. a
--(CH.sub.2).sub.m--CH.dbd.CH(CH.sub.2).sub.n--R.sub.8 group in
which m=0, 1, 2.Iadd., .Iaddend.or 3 and n=0, 1.Iadd., .Iaddend.or
2 and R.sub.8 represents a hydrogen atom.[.or.]. .Iadd.,
.Iaddend.an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl
.Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl .Iadd.group,
.Iaddend.or .Iadd.an alkylaryl .Iaddend.group with, in each case, 1
to 10 carbon atoms.[.or.]. .Iadd., .Iaddend.a hydroxyl group,
.Iadd.or .Iaddend.an alkoxy group or an acyloxy group with, in each
case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. .[.a
--(CH.sub.2).sub.oC.dbd.CR.sub.11 group.]. .Iadd.a
--(CH.sub.2).sub.oC.ident.CR.sub.11 group .Iaddend.in which o=0, 1,
or 2 and R.sub.11 represents a hydrogen atom, a fluorine
.Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine .Iadd.atom.Iaddend.,
.Iadd.a .Iaddend.bromine .[.or.]. .Iadd.atom, an .Iaddend.iodine
atom.Iadd., .Iaddend.or an alkyl .Iadd.group.Iaddend., .Iadd.an
.Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl
.Iadd.group, .Iaddend.or .Iadd.an alkylaryl .Iaddend.group with, in
each case, 1 to 10 carbon atoms.[.,.]. .Iadd.; or .Iaddend. R.sub.1
and R.sub.2 independently of one another represent a keto,
methylene, or difluoromethylene group.[.,.]. .Iadd.;.Iaddend.
.[.there possibly being.]. .Iadd.optionally .Iaddend.a double bond
.Iadd.is present .Iaddend.between C-6 and C-7, .[.if there is.]. an
.alpha. or .beta. cyclopropane group X .Iadd.is present
.Iaddend.between C-14 and C-15, .Iadd.with .Iaddend.X representing
a CZ.sub.2 in which Z represents a hydrogen, .Iadd.a
.Iaddend.fluorine .Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine
.Iadd.atom.Iaddend., .Iadd.a .Iaddend.bromine .Iadd.atom,
.Iaddend.or .Iadd.an .Iaddend.iodine atom, R.sub.3 and R.sub.4
independently of one another represent a hydrogen atom.[.,.].
.Iadd.or .Iaddend.an .alpha. or .beta. alkyl group with 1 to 10
carbon atoms.Iadd., .Iaddend.and R.sub.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.]. .Iadd.at 14,15-methylene .Iaddend.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.]. .Iadd.or
.Iaddend.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.
The objective was accomplished by unsaturated
14,15-cyclopropano-androstanes of the general formula
(I).Iadd.:.Iaddend. ##STR00003## in which R.sub.1 represents a
hydrogen atom, a hydroxy group, a C.sub.1-10 alkyl
.Iadd.group.Iaddend., a C.sub.1-10 alkyloxy .Iadd.group.Iaddend., a
C.sub.1-15 acyloxy .Iadd.group.Iaddend., a C.sub.4-15 aryloxy
.Iadd.group.Iaddend., a C.sub.7-15 aralkyloxy .Iadd.group.Iaddend.,
or a C.sub.7-15 alkylaryloxy group.[., in which.]. .Iadd.;.Iaddend.
R.sub.2 represents a hydrogen atom, a hydroxy group, a C.sub.1-10
alkyl .Iadd.group.Iaddend., a C.sub.1-10 acyl .Iadd.group.Iaddend.,
a C.sub.1-10 acyloxy .Iadd.group.Iaddend., a C.sub.6-15 aryl
.Iadd.group.Iaddend., a C.sub.7-15 aralkyl .Iadd.group, .Iaddend.or
a C.sub.7-15 alkylaryl group.Iadd.;.Iaddend. a
--(CH.sub.2).sub.nCH.sub.2Y group, in which n=0, 1.Iadd.,
.Iaddend.or 2 and Y represents a halogen atom, especially a
fluorine, chlorine, bromine.Iadd., .Iaddend.or iodine atom,
.Iadd.or .Iaddend.a pseudohalogen, especially a cyano, .[.azide or
rhodanide.]. .Iadd.an azido, or a thiocyanato .Iaddend.group.[.,.].
.Iadd.;.Iaddend. a
--(CH.sub.2).sub.m--CH.dbd.CH(CH.sub.2).sub.p--R.sub.6 group in
which m=0, 1, 2.Iadd., .Iaddend.or 3 and p=0, 1.Iadd., .Iaddend.or
2 and R.sub.6 represents a hydrogen atom, a C.sub.1-10 alkyl
.Iadd.group.Iaddend., a C.sub.6-15 aryl .Iadd.group.Iaddend., a
C.sub.7-15 aralkyl .[.or.]. .Iadd.group, .Iaddend.a C.sub.7-15
alkylaryl group.[.or.]. .Iadd., .Iaddend.a hydroxyl group, a
C.sub.1-10 alkyloxy group.Iadd., .Iaddend.or a C.sub.1-10 acyloxy
group.[.,.]. .Iadd.;.Iaddend. .Iadd.a
--(CH.sub.2).sub.oC.ident.CR.sub.7 group.Iaddend. in which o.[.-.].
.Iadd.=.Iaddend.0, 1 or 2 and .[.R7.]. .Iadd.R.sub.7
.Iaddend.represents a hydrogen atom, a halogen atom, especially a
fluorine, chlorine, bromine.Iadd., .Iaddend.or iodine atom, a
C.sub.1-10 alkyl .Iadd.group.Iaddend., a C.sub.6-15 aryl
.Iadd.group.Iaddend., a C.sub.7-15 aralkyl .Iadd.group.Iaddend., a
C.sub.7-15 alkylaryl .Iadd.group, .Iaddend.or a C.sub.1-10 acyl
group.[.,.]. .Iadd.; or.Iaddend. R.sub.1 and R.sub.2 together
represent a keto .Iadd.group.Iaddend., .Iadd.a .Iaddend.methylene
.[.or.]. .Iadd.group, a .Iaddend.difluoromethylene group.Iadd.,
.Iaddend.or, with inclusion of .Iadd.a .Iaddend.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 .alpha. or
.beta. cyclopropane group .Iadd.is present .Iaddend.between C-14
and C-15.[.,.]. .Iadd.;.Iaddend. R.sub.3 represents a hydrogen atom
or an .alpha. or .beta. C.sub.1-10 alkyl group.[.,.].
.Iadd.;.Iaddend. R.sub.4 represents .Iadd.a hydroxyl group, a
perfluoroalkyl group, a halogen atom, especially a fluorine atom, a
chlorine atom,.Iaddend. or .Iadd.a .Iaddend.bromine atom.Iadd.,
.Iaddend.or a pseudohalogen, especially .[.a rhodanide or an azide
group, or a hydroxyl or perfluoroalkyl group and.]. .Iadd.an azido
group or a thiocyanato group;.Iaddend. R.sub.5 represents a
C.sub.1-4 alkyl group.[.,.]. .Iadd.; and.Iaddend. .Iadd.optionally
a double bond is present between C-1 and C-2;.Iaddend. with the
proviso that, if .[.there is a.]. .Iadd.the .Iaddend.double bond
.Iadd.is present .Iaddend.in the 1,2 position, R.sub.4, in addition
to the meanings given above, may be a hydrogen atom.[., as well as
their pharmaceutically tolerated salts.]. .Iadd.; or.Iaddend.
.Iadd.pharmaceutically tolerated salts thereof.Iaddend..
Surprisingly, it was found that the inventive, unsaturated
.[.14,15-cyclopropane-androstanes.].
.Iadd.14,15-cyclopropanoandrostanes .Iaddend.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.sub.1-4 or
C.sub.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.sub.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.sub.1-10
or C.sub.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.sub.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.sub.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.sub.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.sub.7-15 alkylaryloxy group" is understood to be a "C.sub.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.sub.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 group, such as a benzyl group or a
halogenated benzyl group.
Within the sense of the present application, the concept of
"C.sub.7-15 aralkyloxy group" is understood to include "C.sub.7-15
aralkyl groups", which has been extended by an oxygen atom, such as
a benzyloxy group.
Within the sense of the present invention, the concept of "halogen"
comprises a fluorine, chlorine, bromine or iodine atom.
Within the sense of the present application, the concept of
"pseudohalogen" comprises a .[.cyanate, rhodanide,.].
.Iadd.cyanato, thiocyanato, .Iaddend.cyano.Iadd., .Iaddend.or
.[.azide.]. .Iadd.azido .Iaddend.group.
Within the sense of the present application, the concept of
"perfluoroalkyl group" comprises a branched or linear fluoroalkyl
group with 1 to 3 carbon atoms, such as a trifluoromethyl,
pentafluoroethyl, heptafluoro-n-propyl or heptafluoro-i-propyl
group.
R.sub.1 represents preferably a hydroxy or acyloxy group,
especially a hydroxy group, formyloxy group, acetyloxy group,
propionyloxy group, n-butyryloxy group, i-butyryloxy group,
heptanyloxy group or undecanyl group.
If R.sub.2 represents a --(CH.sub.2).sub.nCH.sub.2Y group, n
preferably is 1 and Y preferably represents a fluorine atom, a
cyano or rhodanide group. If R.sub.2 is a
--(CH.sub.2).sub.m--CH.dbd.CH(CH.sub.2).sub.p--R.sub.6 group, m
preferably is 1 and R.sub.6 preferably represents a methyl or ethyl
group or a methoxy or ethoxy group.
.Iadd.If R.sub.2 represents a --(CH.sub.2).sub.oC.ident.CR.sub.7
group, o preferably is 1 and R.sub.7 preferably represents a
fluorine atom, a methyl group, or an ethyl group..Iaddend.
It is particularly preferred if R.sub.2 represents a hydrogen atom
or a C.sub.1-6 alkyl group, especially a methyl or ethyl group.
R.sub.3 preferably represents a C.sub.1-4 alkyl group, especially a
methyl group.
R.sub.4 preferably represents a fluorine, chlorine or bromine atom
or a trifluormethyl or hydroxy group.
R.sub.5 preferably represents a methyl or ethyl group.
The most preferred compounds are the following: 1)
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne 2)
4-chloro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-e-
ne-3-one 3)
4-chloro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-one
4)
4-chloro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-
-one 5)
4-bromo-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-e-
ne-3-one 6)
4-bromo-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne 7)
4-bromo-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-
-one 8)
4-bromo-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-en-
e-3-one 9)
4-fluoro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-
-4-ene-3-one 10)
4-fluoro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3--
one 11)
4-fluoro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4-en-
e-3-one 12)
4-fluoro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3-on-
e 13)
4,17.beta.-dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne 14)
4,17.alpha.-dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-
-one 15)
4,17.beta.-dihydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3--
one 16)
4,17.alpha.-dihydroxy-14.beta.,15.beta.-methylene-androst-4-ene-3--
one 17)
4-trifluoromethyl-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-a-
ndrost-4-ene-3-one 18)
4-trifluoromethyl-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-
-4-ene-3-one 19)
4-trifluoromethyl-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androst-4--
ene-3-one 20)
4-trifluoromethyl-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androst-4-
-ene-3-one 21)
17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3-one
22)
17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3--
one 23)
17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene--
3-one 24)
17.beta.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene--
3-one 25)
17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene-
-3-one 26)
4-chloro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-andros-
ta-1,4-diene-3-one 27)
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-dien-
e-3-one 28)
4-chloro-17.beta.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene--
3-one and 29)
4-chloro-17.alpha.-hydroxy-14.beta.,15.beta.-methylene-androsta-1,4-diene-
-3-one
The inventive compounds and their pharmaceutically acceptable salts
can be synthesized in that, in compounds of the general formula
(II) ##STR00004## in which R.sub.1, R.sub.2, R.sub.3, and R.sub.5,
which have the meanings given above, and there is an .alpha. or
.beta. cyclopropane group between C-14 and C-15, the 4,5 double
bond is epoxidized under alkaline conditions with hydrogen peroxide
and the resulting epoxide mixture is treated in a suitable solvent
with acids of the general formula HR.sub.8, in which R.sub.8 may be
a halogen atom or a pseudohalogen. Moreover, the corresponding
4-bromo compounds can also be synthesized by the addition of
bromine by means of bromine, N-bromosuccinimide or N-bromoacetamide
to compounds of the general formula (II) in a mixture of acetic
acid and ether in the presence of a proton acceptor, such as
collidine, (X. S. Fei et. al., J. Chem. Soc. Perkin Trans. 1, 1998,
1139-1142).
4-Hydroxy compounds are obtained by reacting the epoxide mixture
above with catalytic amounts of mineral acid, such as sulfuric acid
(P. S. Furth et. al. J. Enzyme Inhibition, 1990, Vol. 4,
131-135).
Compounds of the general formula (I) with an additional double bond
in the 1,2 position can be obtained easily by methods known to
those skilled in the art, such as the dehydrogenation of the
4-ene-3-one system by means of 2,3-dichloro-5,6-dicyanobenzoquinone
in a suitable solvent, such as dioxane, toluene or t-butanol.
4-Trifluormethyl compound of the general formula (I) can be
obtained by the reaction of the 4-bromo compounds of the general
formula (I), which are mentioned above, with methyl
2,2-difluoro-2-(fluorosulfonyl)acetate in dimethylformamide the
presence of CuI (X. S. Fei et. al., J. Chem. Soc., Perkin Trans. 1,
1998, 1139-1142). The starting compounds of formula (II) can be
synthesized by known methods or by the method described in the
German application with the application No. 198 27 523.4
(PCT/DE99/01794). The introduction of the groups, which are
analogous to the groups R.sub.1, R.sub.2, R.sub.3 and R.sub.5
occurring there and are claimed here, is described in the
protective right mentioned.
Pharmaceutical compositions for the oral, rectal, subcutaneous,
intravenous or intramuscular applications, which contain at least
one compound of the general formula (I) and/or their acid addition
salts as active ingredient, together with the conventional vehicles
and diluents are also an object of the present invention.
Pharmaceutical preparations of the invention are prepared with the
usual solid or liquid vehicles and/or diluents and the inactive
ingredients, the use of which is generally customary in accordance
with the desired type of application, in a suitable dosage and by a
known procedure. In the case of a preferred oral form of
administration, preferably tablets, film-coated tablets, coated
tablets, capsules, pills, powders, solutions or suspensions are
prepared also in sustained release form. In addition, parenteral
forms of medicinal drugs, such as injection solutions or
suspensions, can also be considered.
Medicinal drug forms as tablets can be obtained for example by
mixing the active ingredient with the known inert materials, such
as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone,
disintegrants such as corn starch or alginic acid, binders such as
starch or gelatin, lubricants such as magnesium stearate or talc
and/or agents, which can achieve a sustained release effect, such
as carboxypolymethylene, carboxymethylcellulose, cellulose acetate
phthalate or polyvinyl acetate. The tablets may also consist of
several layers.
Similarly, coated tablets can be prepared by coating cores,
prepared similarly to the tablets, with agents used in conventional
tablet coatings, such as polyvinylpyrrolidone or shellac, gum
arabic, talc, titanium dioxide or sugar. The tablet coating may
consist of several layers, the inert materials, named above, for
example being used.
To improve the taste, the solutions or suspensions with the
inventive active ingredient can be mixed with materials such as
saccharin, cyclamate or sugar and/or with aromatic and flavoring
materials such as vanillin or orange extract. Moreover, they may be
mixed with suspending agents, such as sodium
carboxymethylcellulose, or preservatives, such as p-hydroxybenzoic
acid.
Capsules can be prepared by mixing medicinal drugs with vehicles,
such as lactose or sorbitol, which are then brought into the
capsules.
Suppositories are prepared preferably by mixing active ingredients
with suitable vehicles, such as neutral fats or polyethylene
glycols or their derivatives.
The pharmaceutical forms of preparations furthermore can be
percutaneous forms, such as transdermal therapeutic systems (TTS)
or gels, sprays or ointments or intranasal forms, such as nose
sprays or oral nose drops.
The inventive 14,15-cyclopropanoandrostanes of the general formula
(I) are compounds with hormonal (gestagenic and/or androgenic)
activity.
For example, the compound of the general formula (I), in which
R.sub.1 is a hydroxyl group, R.sub.2 and R.sub.3 are hydrogen
atoms, R.sub.5 is a methyl group and X is a CH.sub.2 group and the
14,15 cyclopropane ring is in the .alpha. position, namely
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne is an androgen.
The
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-
-3-one binds to the extent of 42%.+-.3% to the androgen receptor of
the rat prostate (reference substance.
17.beta.-hydroxy-17.alpha.-methyl-estra-4,9,11-triene-3-one; R
1881). On the other hand, there is practically no binding to the
progesterone receptor of the rabbit uterus (reference substance:
progesterone). It was possible to demonstrate distinct androgenic
activity in the Hershberger test. On the other hand, there is
hardly any gestagenic activity in the pregnancy maintenance
test.
These test results open up various possibilities for the inventive
compounds of the general formula (I) for fertility control in men,
hormone replacement therapy (HRT) in men and women or the treatment
of hormonally induced diseases in men and women, such as
endometriosis, breast cancer or hypogonadism.
The following examples are intended to explain the invention in
greater detail without limit it.
EXAMPLES
Example 1
17.beta.-Hydroxy-4,5-epoxy-14.alpha.,15.alpha.-methylene-androstan-3-one
Synthesis of 4,5-Epoxides
17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
(2 g) is dissolved in 80 mL of methanol and treated at 0.degree. C.
with 26 mL of a hydrogen peroxide solution (35%). While stirring,
5.2 mL of a 10% sodium hydroxide solution are added, the stirring
being continued at 0.degree. C. for 30 hours. The reaction solution
is mixed with 50 mL of dichloromethane and 25 mL of water and the
organic phase is removed, washed with semi-concentrated thiosulfate
solution, dried and evaporated to dryness. The residue obtained
consists of a mixture of 4.alpha.,5.alpha.- or
4.beta.,5.beta.-epoxides and is used in the subsequent step without
further purification.
Example 2
17.alpha.-Hydroxy-4,5-epoxy-14.alpha.,15.alpha.-methylene-androstan-3-one
The compound, named above, can be obtained from
17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
by a method, similar to that of Example 1.
Example 3
4-Chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-on-
e
17.beta.-hydroxy-4,5-epoxy-14.alpha.,15.alpha.-methylene-androstan-3-one
(1.5 g) is dissolved in 150 mL of acetone and treated at 0.degree.
C. with 5.5 mL of concentrated hydrochloric acid. After 24 hours at
0.degree. C., the reaction mixture is neutralized with sodium
carbonate solution and the acetone is evaporated. The residue is
extracted with dichloromethane. The organic extracts are dried and
concentrated. After crystallization from ethanol,
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne is obtained.
.sup.1H-NMR: 0.12 (1H, dd, I=5.5, 3.3 Hz, CH.sub.2-bridge), 0.22
(1H, dd, J=8.2, 5.5 Hz, CH.sub.2-bridge), 0.99 (3H, s, H-18), 1.30
(3H, s, H-19), 3.49 (1H, dd, J=9.3, 7.1 Hz, H-17).
Example 4
4-Chloro-17.alpha.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne
17.alpha.-Hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
is reacted by a method, similar to that of Example 3.
.sup.1H-NMR: 0.32 (1H, dd, J=7.7, 4.9 Hz, CH.sub.2-bridge), 0.72
(1H, dd, J=4.4, 3.3 Hz, CH.sub.2-bridge), 0.99 (3H, s, H-18), 1.29
(3H, s, H-19), 3.80 (1H, d, J=6.0 Hz, H-17).
Example 5
4,17.beta.-Dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
An epoxide mixture (3.5 g),
17.beta.-hydroxy-4,5-epoxy-14.alpha.,15.alpha.-methylene-androstan-3-one,
(step 1) is dissolved in 50 mL of acetic acid, which contains 2% by
volume of concentrated sulfuric acid. The solution is allowed to
stand for 3 days at 10.degree. C. After that, it is treated with
200 mL ethyl acetate and neutralized with sodium carbonate
solution. The organic phase is dried and concentrated. The residue
is dissolved in 100 mL of methanol, treated with 4 g of potassium
hydroxide, refluxed for 1 hour and then cooled. After
neutralization with 50% acetic acid, it is poured into 1 L of water
and the crystals are filtered off with suction,
4,17.beta.-Dihydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
being obtained.
.sup.1H-NMR: 0.13 (1H, dd, J=5.6, 3.2 Hz, CH.sub.2-bridge), 0.24
(1H, dd, J=8.3, 5.6 Hz, CH.sub.2-bridge), 0.99 (3H, s, H-18), 1.30
(3H, s, H-19), 3.50 (1H, dd, J=9.4, 6.8 Hz, H-17), 6.10 (1H, s,
4-OH).
Example 6
4-Bromo-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
The target compound is synthesized in a manner similar to the
synthesis of
4-Chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene--
3-one, 48% hydrobromic acid being used instead of hydrochloric
acid.
.sup.1H-NMR: 0.12 (1H, dd, J=5.5, 3.3 Hz, CH.sub.2-bridge), 0.21
(1H, dd, J=8.4, 5.4 Hz, CH.sub.2-bridge), 1.00 (3H, s, H-18), 1.33
(3H, s, H-19), 3.49 (1H, dd, J=9.3, 7.1 Hz, H-17).
Example 7
4-Trifluoromethyl-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-
-ene-3-one
4-Bromo-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-on-
e (1.5 g) is dissolved in 180 mL of dimethylformamide and stirred
at 75.degree. C. for 12 hours with 1 g of CuI as well as 2.8 mL of
methyl 2,2-difluoro-2-(fluorosulfonyl) acetate. After working up
and chromatographic purification,
4-Trifluoromethyl-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst--
4-ene-3-one is obtained.
.sup.1H-NMR: 0.14 (1H, dd, J=5.5, 3.0 Hz, CH.sub.2-bridge), 0.25
(1H, dd, J=8.2, 5.8 Hz, CH.sub.2-bridge), 1.00 (3H, s, H-18), 1.32
(3H, s, H-19), 3.51 (1H, m, H-17). .sup.19F-NMR: -55.3 (3F, s,
4-F.sub.3C).
Example 8
17.beta.-Hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3-one
17.beta.-Hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-one
(4 g) in 160 mL of toluene is stirred for 6 days at 85.degree. C.
with 3.2 g of 2,3-dichloro-5-6-dicyanobenzoquinone. The precipitate
is filtered off, washed with a little toluene and the filtrates and
washings are evaporated to dryness. The residue is purified by
chromatography,
17.beta.-Hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-3-one
being obtained.
.sup.1H-NMR: 0.13 (1H, dd, J=5.6, 3.2 Hz, CH.sub.2-bridge), 0.24
(1H, dd, J=8.3, 5.6 Hz, CH.sub.2-bridge), 0.98 (3H, s, H-18), 1.35
(3H, s, H-19), 3.50 (1H, m, H-17), 6.06 (1H, m, H-4); 6.22 (1H, dd,
J=12.09; 1.65 Hz, H{2}), 7.04 (1H, d, J=9.9 Hz, H-1).
Example 9
4-Chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androsta-1,4-diene-
-3-one
This compound is prepared from
4-chloro-17.beta.-hydroxy-14.alpha.,15.alpha.-methylene-androst-4-ene-3-o-
ne by a method to that of Example 6.
.sup.1H-NMR: 0.13 (1d, dd, j=5.6, 3.2 Hz, CH.sub.2-bridge), 0.24
(1H, dd, J=8.3, 5.6 Hz, CH.sub.2-bridge), 0.98 (3H, s, H-18), 1.35
(3H, s, H-19), 3.50 (1H, m, H-17), 6.22 (1H, dd, j=12.09, 1.65 Hz,
H{2}), 7.04 (1H, d, J=9.9 Hz, H-1).
* * * * *