U.S. patent application number 12/810860 was filed with the patent office on 2010-12-09 for 19-nor-steroid derivatives with a 15alpha, 16alpha-methylene group and a saturated 17, 17-spiro-lactone ring, use thereof, and medicaments containing said derivatives.
This patent application is currently assigned to BAYER SCHERING PHARMA AKTEINGESELLSCHAFT. Invention is credited to Rolf Bohlmann, Steffen Borden, Thomas Frenzel, Jan Hubner, Ulrich Klar, Joachim Kuhnke, Frederik Menges, Hans Peter Muhn, Katja Prelle, Sven Ring.
Application Number | 20100311702 12/810860 |
Document ID | / |
Family ID | 40548690 |
Filed Date | 2010-12-09 |
United States Patent
Application |
20100311702 |
Kind Code |
A1 |
Klar; Ulrich ; et
al. |
December 9, 2010 |
19-NOR-STEROID DERIVATIVES WITH A 15ALPHA, 16ALPHA-METHYLENE GROUP
AND A SATURATED 17, 17-SPIRO-LACTONE RING, USE THEREOF, AND
MEDICAMENTS CONTAINING SAID DERIVATIVES
Abstract
The
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one--
21-carboxylic acid .gamma.-lactone derivatives of the present
invention possess progestational efficacy. They have the general
chemical formula I, in which Z is selected from the group
comprising an oxygen atom, two hydrogen atoms, NOR and
NNHSO.sub.2R, where R is hydrogen, C.sub.1-C.sub.10-alkyl, aryl or
C.sub.7-C.sub.20-aralkyl, R.sup.4 is hydrogen or halogen, and
moreover either: R.sup.6a, R.sup.6b together form methylene or
1,2-ethanediyl or R.sup.6a is hydrogen and R.sup.6b is selected
from the group comprising hydrogen, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl or C.sub.2-C.sub.10-alkynyl, and R.sup.7
is selected from the group comprising hydrogen,
C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.2-C.sub.10-alkenyl or C.sub.2-C.sub.10-alkynyl, or: R.sup.6a
is hydrogen and R.sup.6b and R.sup.7, together, denote a bond, an
oxygen or form methylene, R.sup.18 represents hydrogen or
C.sub.1-C.sub.3-alkyl and in addition include their solvates,
hydrates, stereoisomers and salts. ##STR00001##
Inventors: |
Klar; Ulrich; (Berlin,
DE) ; Kuhnke; Joachim; (Potsdam, DE) ;
Bohlmann; Rolf; (Berlin, DE) ; Hubner; Jan;
(Berlin, DE) ; Ring; Sven; (Jena, DE) ;
Frenzel; Thomas; (Hofheim, DE) ; Menges;
Frederik; (Schriesheim, DE) ; Borden; Steffen;
(Berlin, DE) ; Muhn; Hans Peter; (Berlin, DE)
; Prelle; Katja; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
BAYER SCHERING PHARMA
AKTEINGESELLSCHAFT
BERLIN
DE
|
Family ID: |
40548690 |
Appl. No.: |
12/810860 |
Filed: |
December 23, 2008 |
PCT Filed: |
December 23, 2008 |
PCT NO: |
PCT/EP08/11165 |
371 Date: |
August 23, 2010 |
Current U.S.
Class: |
514/170 ;
514/173; 540/15; 540/8 |
Current CPC
Class: |
A61P 15/18 20180101;
A61P 15/12 20180101; A61P 43/00 20180101; C07J 53/008 20130101;
A61P 5/24 20180101; A61P 15/00 20180101; A61P 5/26 20180101; A61P
5/42 20180101; A61P 5/00 20180101; A61P 5/34 20180101; C07J 21/003
20130101; A61P 5/30 20180101 |
Class at
Publication: |
514/170 ; 540/15;
540/8; 514/173 |
International
Class: |
A61K 31/585 20060101
A61K031/585; C07J 21/00 20060101 C07J021/00; A61P 15/18 20060101
A61P015/18; A61P 5/24 20060101 A61P005/24; A61P 5/42 20060101
A61P005/42; A61P 5/26 20060101 A61P005/26 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 29, 2007 |
DE |
102007063495.3 |
Claims
1.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives of general formula I
##STR00049## in which Z denotes oxygen, two hydrogen atoms, a group
.dbd.NOR.sup.1 or .dbd.NNHSO.sub.2R.sup.1, R.sup.1 denotes
hydrogen, C.sub.1-C.sub.10-alkyl, aryl, C.sub.7-C.sub.20-aralkyl,
R.sup.4 denotes hydrogen or halogen, R.sup.6a, R.sup.6b which may
be identical or different, denote hydrogen, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl or together
denote methylene or 1,2-ethanediyl, R.sup.7 denotes hydrogen,
C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, R.sup.6a,
R.sup.7 together, denote a bond, an oxygen or a methylene group,
R.sup.18 denotes hydrogen, C.sub.1-C.sub.3-alkyl, and their
solvates, hydrates, stereoisomers and salts.
2.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that Z is selected from the group comprising
oxygen, NOR.sup.1 and NNHSO.sub.2R.sup.1.
3.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that Z stands for oxygen.
4.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.4 is hydrogen or chlorine.
5.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.6a, R.sup.6b together form
1,2-ethanediyl or are each hydrogen.
6.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.7 is hydrogen or methyl or ethyl or
vinyl.
7.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.6a and R.sup.7 together form a
methylene group.
8.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.6a and R.sup.7 together represent a
bond.
9.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-2-
1-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, characterized in that R.sup.18 is hydrogen or methyl.
10.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one--
21-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1, selected from the group
17.beta.-Hydroxy-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4--
en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.-
alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.beta.-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.a-
lpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-ethyl-15.alpha.,16.alpha.-methylene-19-nor-17.a-
lpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.beta.-ethyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-vinyl-15.alpha.,16.alpha.-methylene-19-nor-17.a-
lpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.beta.-vinyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-cyclopropyl-15.alpha.,16.alpha.-methylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.beta.-cyclopropyl-15.alpha.,16.alpha.-methylene-19-nor-
-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6-methylene-15.alpha.,16.alpha.-methylene-19-nor-17.alph-
a.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6.alpha.-hydroxymethyl-15.alpha.,16.alpha.-methylene-19--
nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6,6-hydroxymethyl-15.alpha.,16.alpha.-methylene-19-nor-1-
7.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
6,6-(1,2-Ethanediyl)-17.beta.-hydroxy-15.alpha.,16.alpha.-methylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6.alpha.,7.alpha.,15.alpha.,16.alpha.-bismethylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6.beta.,7.beta.,15.alpha.,16.alpha.-bismethylene-19-nor--
17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4,-
6-dien-3-one-21-carboxylic acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-15.alpha.,16.alpha.-methylene-19--
nor-17.alpha.-pregna-4-ene-21-carboxylic acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-methyl-15.alpha.,16.alph-
a.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-methyl-15.alpha.,16.alpha-
.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-ethyl-15.alpha.,16.alpha-
.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-ethyl-15.alpha.,16.alpha.-
-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-vinyl-15.alpha.,16.alpha-
.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-vinyl-15.alpha.,16.alpha.-
-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-cyclopropyl-15.alpha.,16-
.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-cyclopropyl-15.alpha.,16.-
alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6-methylene-15.alpha.,16.alpha.-m-
ethylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.alpha.-hydroxymethyl-15.alpha.,-
16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.beta.-hydroxymethyl-15.alpha.,1-
6.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17.beta.-hydroxy-15.alpha.,16-
.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.alpha.,7.alpha.,15.alpha.,16.al-
pha.-bismethylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.beta.,7.beta.,15.alpha.,16.alph-
a.-bismethylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-15.alpha.,16.alpha.-methylene-19--
nor-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-18-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-
-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-methyl-18-methyl-15.alpha.,16.alpha.-methylene--
19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-7.beta.-methyl-18-methyl-15.alpha.,16.alpha.-methylene-1-
9-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-7.alpha.-ethyl-18-methyl-15.alpha.,16.alpha.-methylene-1-
9-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-7.beta.-ethyl-18-methyl-15.alpha.,16.alpha.-methylene-19-
-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-vinyl-18-methyl-15.alpha.,16.alpha.-methylene-1-
9-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-7.beta.-vinyl-18-methyl-15.alpha.,16.alpha.-methylene-19-
-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-7.alpha.-cyclopropyl-18-methyl-15.alpha.,16.alpha.-methy-
lene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-7.beta.-cyclopropyl-18-methyl-15.alpha.,16.alpha.-methyl-
ene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-6-methylene-18-methyl-15.alpha.,16.alpha.-methylene-19-n-
or-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6.alpha.-hydroxymethyl-18-methyl-15.alpha.,16.alpha.-met-
hylene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-6.beta.-hydroxymethyl-18-methyl-15.alpha.,16.alpha.-meth-
ylene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
6,6-(1,2-Ethanediyl)-17.beta.-hydroxy-18-methyl-15.alpha.,16.alpha.-methy-
lene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
17.beta.-Hydroxy-6.alpha.,7.alpha.,15.alpha.,16.alpha.-bismethylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-6.beta.,7.beta.,15.alpha.,16.alpha.-bismethylene-19-nor--
17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
17.beta.-Hydroxy-18-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-
-pregna-4,6-dien-3-one-21-carboxylic acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-18-methyl-15.alpha.,16.alpha.-met-
hylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-methyl-18-methyl-15.alph-
a.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-methyl-18-methyl-15.alpha-
.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-ethyl-18-methyl-15.alpha-
.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-ethyl-18-methyl-15.alpha.-
,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-vinyl-18-methyl-15.alpha-
.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-vinyl-18-methyl-15.alpha.-
,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.alpha.-cyclopropyl-18-methyl-15-
.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-7.beta.-cyclopropyl-18-methyl-15.-
alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6-methylene-18-methyl-15.alpha.,1-
6.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.alpha.-hydroxymethyl-18-methyl--
15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.beta.-hydroxymethyl-18-methyl-1-
5.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17.beta.-hydroxy-18-methyl-15-
.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic
acid .gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.alpha.,7.alpha.,15.alpha.,16.al-
pha.-bismethylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-6.beta.,7.beta.,15.alpha.,16.alph-
a.-bismethylene-19-nor-17.alpha.-pregna-4-ene-21-carboxylic acid
.gamma.-lactone
(E/Z)-3-(Hydroxyimino)-17.beta.-hydroxy-18-methyl-15.alpha.,16.alpha.-met-
hylene-19-nor-17.alpha.-pregna-4,6-diene-21-carboxylic acid
.gamma.-lactone.
11.
15.alpha.,16.alpha.-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one--
21-carboxylic acid .gamma.-lactone derivatives as claimed in claim
1 for oral contraception and for the treatment of pre-, peri- and
postmenopausal complaints.
12. A method comprising using the
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivatives as claimed in claim 1
for the production of a medicinal product for oral contraception
and for the treatment of pre-, peri- and postmenopausal
complaints.
13. A method as in claim 12, characterized in that the medicinal
product has progestational, antimineralocorticoid and androgenic
action.
14. A medicinal product containing at least one
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivative as claimed in claim 1 and
at least one suitable pharmaceutically harmless additive.
15. The medicinal product as claimed in claim 14, additionally
containing at least one estrogen.
16. The medicinal product as claimed in claim 15, characterized in
that the estrogen is ethinylestradiol.
17. The medicinal product as claimed in claim 15, characterized in
that the estrogen is a natural estrogen.
18. The medicinal product as claimed in claim 17, characterized in
that the natural estrogen is estradiol.
19. The medicinal product as claimed in claim 17, characterized in
that the natural estrogen is estradiolvalerate.
20. The medicinal product as claimed in claim 17, characterized in
that the natural estrogen is a conjugated estrogen.
21. A method comprising using the
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivative as claimed in claim 1 for
the production of a medicinal product for intrauterine use.
22. A method as in claim 21 for the production of an intrauterine
system (IUS).
23. Medicinal containing at least one
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivative according to claim 1 and
at least one suitable pharmaceutically harmless additive,
characterized in that it is designed for intrauterine
administration.
24. The medicinal product as claimed in claim 23, characterized in
that it is an intrauterine system.
Description
[0001] The invention relates to
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivatives with progestational
action, use thereof and medicinal products containing the
derivatives, for example for the treatment of pre-, peri- and
postmenopausal and of premenstrual complaints.
[0002] Compounds with progestational, antimineralocorticoid,
antiandrogenic or antiestrogenic action based on a steroid
structure are known from the literature, derived for example from
19-nor-androst-4-en-3-one or a derivative thereof (the numbering of
the steroid structure is given for example in Fresenius/Grolitzer
3rd Ed. 1991 "Organic Chemical Nomenclature" p. 60 ff.).
[0003] Thus, WO 2006072467 A1 discloses the compound
6.beta.,7.beta.-15.beta.,16.beta.-dimethylene-3-oxo-17-pregn-4-ene-21,17.-
beta.-carbolactone (drospirenone), which has progestational action
and has been used for example in an oral contraceptive and in a
preparation for the treatment of postmenopausal complaints. Owing
to its comparatively low affinity for the progestogen receptor and
its comparatively high ovulation-inhibiting dose, however,
drospirenone is contained in the contraceptive at the relatively
high daily dose of 3 mg. Drospirenone is, moreover, also
characterized in that in addition to the progestational action it
also has aldosterone-antagonistic (antimineralocorticoid) and
antiandrogenic action. These two properties make drospirenone very
similar in its pharmacological profile to the natural progestogen,
progesterone, which however, unlike drospirenone, is not
sufficiently bioavailable orally. In order to lower the dose to be
administered, WO 2006072467 A1 further proposes an
18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and
pharmaceutical preparations containing this, which have a higher
progestational potency than drospirenone.
[0004] In addition, U.S. Pat. No. 3,705,179, for example, discloses
steroids that display antiandrogenic activity and are suitable for
the treatment of diseases that are linked to androgens.
[0005] The aim of the present invention is to make compounds
available that bind strongly, and preferably more strongly than
drospirenone, to the progestogen receptor. Moreover, the compounds
should preferably also have antimineralocorticoid action and, with
respect to the androgen receptor, a neutral to slightly androgenic
action. Another essential aim of the present invention consists of
achieving a balanced action profile with respect to the
progestational action to the antimineralocorticoid action, so that
the ratio of the progestational action to the antimineralocorticoid
action is less than with drospirenone.
[0006] This aim is achieved with the
15.alpha.,16.alpha.-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-c-
arboxylic acid .gamma.-lactone derivatives according to the
invention according to claim 1, the use of the derivatives
according to the invention according to claim 12 and a medicinal
product containing at least one derivative according to the
invention according to claim 14. Advantageous embodiments of the
invention are presented in the subclaims.
[0007] The present invention describes the novel
15,16-methylene-17-hydroxy-19-nor-17-pregna-4,20(Z)-dien-3-one-21-carboxy-
lic acid .gamma.-lactone derivatives of general formula I,
##STR00002##
in which Z denotes oxygen, two hydrogen atoms, a group
.dbd.NOR.sup.1 or .dbd.NNHSO.sub.2R.sup.1, R.sup.1 denotes
hydrogen, C.sub.1-C.sub.10-alkyl, aryl, C.sub.7-C.sub.20-aralkyl,
R.sup.4 denotes hydrogen or halogen, R.sup.6a, R.sup.6b which may
be identical or different, denote hydrogen, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl or together
denote methylene or 1,2-ethanediyl, R.sup.7 denotes hydrogen,
C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, R.sup.6a,
R.sup.7 together, denote a bond, an oxygen or a methylene group,
R.sup.18 denotes hydrogen, C.sub.1-C.sub.3-alkyl.
[0008] The residues R.sup.6a, R.sup.6b and R.sup.7 and the
three-membered ring can each be in the .alpha. or .beta.
position.
Compounds of formula I are preferred in which Z denotes oxygen, a
group .dbd.NOR.sup.1, R.sup.1 denotes hydrogen,
C.sub.1-C.sub.6-alkyl, aryl, C.sub.7-C.sub.12-aralkyl, R.sup.4
denotes hydrogen or halogen, R.sup.6a, R.sup.6b which may be
identical or different, denote hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl or together denote
methylene or 1,2-ethanediyl, R.sup.7 denotes hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, R.sup.6a, R.sup.7
together, denote a bond, or a methylene group, R.sup.18 denotes
hydrogen, C.sub.1-C.sub.2-alkyl,
[0009] Compounds of formula I are, especially preferred in
which
Z denotes oxygen, a group .dbd.NOR.sup.1, R.sup.1 denotes hydrogen,
C.sub.1-C.sub.3-alkyl, R.sup.4 denotes hydrogen, chlorine or
bromine, R.sup.6a, R.sup.6b which may be identical or different,
denote hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.2-C.sub.4-alkenyl, or
together denote methylene or together denote 1,2-ethanediyl,
R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.4-cycloalkyl, C.sub.2-C.sub.4-alkenyl, R.sup.6a,
R.sup.7 together, denote a bond, or a methylene group, R.sup.18
denotes hydrogen, methyl.
[0010] The numbering of the carbon backbone of the derivatives
according to the invention with the general chemical formula I
follows the numbering of a steroid structure in the usual way, as
described for example in Fresenius, loc. cit. The numbering of the
residues stated in the claims corresponds in a similar manner to
their bonding position on the carbon backbone of the derivative, as
far as this relates to R.sup.4, R.sup.6, R.sup.7 and R.sup.18. For
example, the residue R.sup.4 binds to the C.sup.4-position of the
derivative according to the invention.
[0011] With respect to the groups defined for Z, the groups NOR'
and NNHSO.sub.2R' each bind with a double bond via N to the carbon
backbone of the derivative according to .dbd.NOR' or
.dbd.NNH--SO.sub.2R'. OR' in NOR' and NHSO.sub.2R' in NNHSO.sub.2R'
can be in syn- or anti-position.
[0012] Alkyl groups R.sup.1, R.sup.6a, R.sup.6b, R.sup.7, R.sup.18,
R.sup.19, R.sup.20, R.sup.21a, R.sup.21b and R.sup.22 are to be
considered to be linear or branched alkyl groups with 1-10 carbon
atoms, for example methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl,
decyl.
[0013] The alkyl groups R.sup.1, R.sup.6a, R.sup.6b, R.sup.7,
R.sup.18, R.sup.19, R.sup.20, R.sup.21a, R.sup.21b and R.sup.22 can
be perfluorinated or can be substituted with 1-5 halogen atoms,
hydroxyl groups, C.sub.1-C.sub.4-alkoxy groups,
C.sub.6-C.sub.12-aryl groups (which can be substituted with 1-3
halogen atoms).
[0014] Alkenyl groups R.sup.6a and R.sup.6b are to be considered to
be linear or branched alkene groups with 2-10 carbon atoms, such as
for example vinyl, propenyl, butynyl, pentenyl, isobutenyl,
isopentenyl.
[0015] Alkynyl groups R.sup.6a and R.sup.6b are to be considered to
be linear or branched alkyne groups with 2-10 carbon atoms, such as
for example ethynyl, propynyl, butynyl, pentynyl, isobutynyl,
isopentynyl.
[0016] The alkenyl and alkynyl groups R.sup.6a and R.sup.6b can be
substituted with 1-5 halogen atoms, hydroxyl groups,
C.sub.1-C.sub.3-alkoxy groups, C.sub.6-C.sub.12-aryl groups (which
can be substituted with 1-3 halogen atoms).
[0017] As cycloalkyl groups R.sup.7, consideration may be given to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
[0018] The cycloalkyl groups R.sup.7 can be substituted with
halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2,
--NO.sub.2, --N.sub.3, --CN, C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-acyl, C.sub.1-C.sub.10-acyloxy groups.
[0019] As aryl residue R.sup.1, R.sup.6a, R.sup.6b and R.sup.7,
consideration may be given to substituted and unsubstituted
carbocyclic or heterocyclic residues with one or more heteroatoms,
e.g. phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl,
pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl,
which can be singly or multiply substituted with halogen, OH,
O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2, --NO.sub.2,
--N.sub.3, --CN, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-acyl,
C.sub.1-C.sub.10-acyloxy groups.
[0020] The aralkyl groups in R.sup.1 and R.sup.7 can contain up to
14, preferably 6 to 10, carbon atoms in the ring and 1 to 8,
preferably 1 to 4, atoms in the alkyl chain. As aralkyl residues,
consideration may be given for example to benzyl, phenylethyl,
naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl,
pyridylpropyl. The rings can be singly or multiply substituted with
halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NO.sub.2,
--N.sub.3, --CN, C.sub.1-C.sub.20-alkyl, C.sub.1-C.sub.20-acyl,
C.sub.1-C.sub.20-acyloxy groups.
[0021] Halogen means fluorine, chlorine or bromine.
[0022] The derivatives with the general chemical formula I include
all stereoisomers and mixtures thereof.
[0023] The derivatives according to the invention can also be in
the form of solvates, in particular of hydrates, and the compounds
according to the invention accordingly contain polar solvents, in
particular water, as structural element of the crystal lattice of
the compounds according to the invention. The polar solvent, in
particular water, can be present in stoichiometric proportions or
even in nonstoichiometric proportions. Stoichiometric solvates and
hydrates are also called hemi-, (semi-), mono-, sesqui-, di-, tri-,
tetra-, penta-, etc. solvates or hydrates.
[0024] It was found that the compounds or derivatives according to
the invention have good progestational action. Furthermore, some
interesting compounds according to the invention interact with the
mineralocorticoid receptor and are able to impart an antagonistic
action. Moreover, the compounds according to the invention have a
neutral to slightly androgenic action with respect to the androgen
receptor. Another property of the compounds is that the bonds of
these compounds to the progesterone receptor and to the
mineralocorticoid receptor are balanced relative to one another,
namely so that the ratio of their capacity for binding to the
progesterone receptor to the capacity for binding to the
mineralocorticoid receptor is less than in the case of
drospirenone. Therefore the antimineralocorticoid action of these
compounds at given progestational action is less than with
drospirenone. If the dosage of a given compound according to the
invention is based on its progestational action, the
antimineralocorticoid action of this compound at this dosage is
therefore less than with drospirenone.
[0025] The compounds listed below are preferred according to the
invention:
##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007##
##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
[0026] On the basis of their progestational efficacy, the novel
compounds with the general chemical formula I can be used alone or
in combination with estrogen in medicinal products for
contraception.
[0027] The derivatives according to the invention are therefore
suitable in particular for the production of a medicinal product
for oral contraception and for the treatment of pre-, peri- and
postmenopausal complaints, including use in preparations for
hormone replacement therapy (HRT).
[0028] Owing to their favorable action profile, the derivatives
according to the invention are moreover especially well suited to
the treatment of premenstrual complaints, such as headaches,
depressive moods, water retention and mastodynia.
[0029] The use of the derivatives according to the invention is
especially preferred for the production of a medicinal product with
progestational, and preferably also antimineralocorticoid and
neutral to slightly androgenic action.
[0030] Treatment with the derivatives according to the invention is
preferably applied to humans, but can also be carried out on
related mammalian species, for example dog and cat.
[0031] For use of the derivatives according to the invention as
medicinal products, they are combined with at least one suitable
pharmaceutically harmless additive, for example a carrier. The
additive is for example suitable for parenteral, preferably oral,
application. Relevant materials are pharmaceutically suitable
organic or inorganic inert additives, for example water, gelatin,
gum arabic, lactose, starch, magnesium stearate, talc, vegetable
oils, polyalkylene glycols etc. The medicinal products can be in
solid form, for example as tablets, coated tablets, suppositories,
capsules, or in liquid form, for example as solutions, suspensions
or emulsions. Optionally they also contain excipients, such as
preservatives, stabilizers, wetting agents or emulsifiers, salts
for altering the osmotic pressure or buffers. For parenteral
application, oily solutions are suitable in particular, for example
solutions in sesame oil, castor oil and cottonseed oil. To increase
the solubility, solubilizers can be added, for example benzyl
benzoate or benzyl alcohol. It is also possible to incorporate the
derivatives according to the invention in a transdermal system and
therefore apply them transdermally. For oral application,
consideration may be given in particular to tablets, coated
tablets, capsules, pills, suspensions or solutions.
[0032] Further examples of administration routes are intravaginal
or intrauterine administration. This is possible with
physiologically tolerated solutions such as, for example, an
aqueous or oily solution with or without suitable solubilizers,
dispersants or emulsifiers. Examples of suitable oils are peanut
oil, cottonseed oil, castor oil or sesame oil. The selection is by
no means restricted thereto.
[0033] For intravaginal or intrauterine administration it is
possible to use special systems such as an intravaginal system
(e.g. vaginal ring, VRS) or an intrauterine system (IUS) which
release an active substance of the present invention from a
reservoir over a prolonged period (e.g. 1, 2, 3, 4 or 5 years).
[0034] A representative example of an intrauterine system which may
be mentioned is MIRENA.RTM.. This is a T-shaped,
levonorgestrel-releasing intrauterine system from Bayer Schering
Pharma AG.
[0035] Administration is further possible via an implanted depot
system composed of an inert carrier material such as, for example,
a biodegradable polymer or a synthetic silicone polymer. These
depot systems release the active ingredient in a controlled manner
over a prolonged period (e.g. 3 months to 3 years) and are
implanted subcutaneously.
[0036] The dosage of the derivatives according to the invention in
contraceptive preparations should be 0.01 to 10 mg per day. The
daily dose in the treatment of premenstrual complaints is around
0.1 to 20 mg. The progestational derivatives according to the
invention are preferably administered orally in contraceptive
preparations and in medicinal products for the treatment of
premenstrual complaints. The daily dose is preferably administered
as a single dose. The aforementioned dosages relate to oral
administration forms.
[0037] On use of a depot formulation, the appropriate dosage,
equivalent to the aforementioned oral dosages, is released
continuously each day from the depot systems described above and
employed in the long term.
[0038] A depot formulation, for example an IUS, releases per day an
amount of 0.005 to 10 mg of a compound of general formula 1.
[0039] The progestational and estrogenic active components are
preferably applied together orally in contraceptive preparations.
The daily dose is preferably administered as a single dose.
[0040] As estrogens, consideration may be given to synthetic
estrogens, preferably ethinylestradiol, but also mestranol, and
natural estrogens, including phytoestrogens.
[0041] The estrogen is administered in a daily amount that
corresponds to the pharmacological action of 0.01 to 0.04 mg
ethinylestradiol. This amount relates to an oral administration
form. If a different administration route is chosen, an appropriate
dosage amount equivalent to the aforementioned oral dosage is to be
used.
[0042] As estrogens in medicinal products for the treatment of
pre-, peri- and postmenopausal complaints and for hormone
replacement therapy, natural estrogens are mainly used, in
particular estradiol, but also the esters of estradiol, for example
estradiol valerate, or also conjugated estrogens (CEEs=conjugated
equine estrogens).
[0043] The progestational, antimineralocorticoid and androgenic or
antiandrogenic action of the compounds according to the invention
was investigated by the following methods:
1. Progesterone Receptor Binding Test:
[0044] Using cytosol from progesterone receptor--expressing insect
cells (Hi5), competitive binding to the progesterone receptor was
determined from the ability to displace .sup.3H-progesterone as
reference substance from the receptor. If a compound has an
affinity corresponding to progesterone, this corresponds to a
competition factor (CF) of 1. CF values greater than 1 are
characterized by a lower affinity for the progesterone receptor,
and CF values of less than 1 are characterized by higher
affinity.
2. Mineralocorticoid Receptor Binding Test:
[0045] The test was carried out as in 1, with the following
modifications: cytosol from mineralocorticoid receptor-expressing
insect cells (Hi5) was used, and the reference substance was
.sup.3H-aldosterone.
3. Androgen Receptor Binding Test:
[0046] The test was carried out as in 1, with the following
modifications: cytosol from androgen receptor--expressing insect
cells (Hi5) was used, and the reference substance was
.sup.3H-testosterone.
[0047] The results of the binding tests and the ratio of the
competition factors CF(PR) and CR(MR) are shown in Table 1, which
for comparison also shows receptor binding values of drospirenone
as reference substance A.
4. Determination of Progestational Action by Means of
Transactivation Tests:
[0048] The culture medium used for culture of the cells used for
the assay was DMEM (Dulbecco's Modified Eagle Medium: 4500 mg/ml
glucose; PAA, #E15-009) with 10% FCS (Biochrom, S0115, batch
#6158), 4 mM L-glutamine, 1% penicillin/streptomycin, 1 mg/ml 6418
and 0.5 .mu.g/ml puromycin.
[0049] Reporter cell lines (CHO K1 cells stably transfected with a
fusion protein from the PR-ligand-binding domain and a
Gal4-transactivation domain and a reporter construct, which
contained luciferase under the control of a Gal-4-responsive
promoter) were seeded at a density of 4.times.10.sup.4 cells per
well in white, opaque tissue culture plates each with 96 wells
(PerkinElmer, #P12-106-017) and kept in culture medium with 3%
DCC-FCS (serum treated with activated charcoal to remove
interfering components contained in the serum). The test compounds
were added eight hours later, and the cells were incubated with the
compounds for 16 hours. The tests were carried out in triplicate.
At the end of incubation the medium containing the effector was
removed and replaced with lysis buffer. After luciferase assay
substrate (Promega, #E1501) had been added, the 96-well plates were
then put in a microplate luminometer (Pherastar, BMG labtech), and
the luminescence was measured. The IC.sub.50 values were evaluated
using software for calculating dose-effect relations. Table 1
presents the test results and, for comparison, corresponding
results for drospirenone as reference substance A.
[0050] If the production of the starting compounds is not described
here, these are known to a person skilled in the art or can be
prepared similarly to known compounds or methods described here.
The isomeric mixtures can be separated into the individual
compounds by the usual methods, for example crystallization,
chromatography or salt formation. The salts are prepared in the
usual way, by adding, to a solution of the compounds with the
general chemical formula I, the equivalent amount or an excess of a
base or acid, which is optionally in solution, if necessary
separating the precipitate or processing the solution in the usual
way.
[0051] The compounds of general formula I are prepared, starting
from compounds of general formula 1 (Scheme 2), according to the
methods shown in Scheme 1, in which R.sup.4, R.sup.6a, R.sup.6b,
[0052] R.sup.7, R.sup.18 and Z have the meanings stated previously
and [0053] R.sup.6, R.sup.7 in 5 and 6, together denote an oxygen
or a methylene group, [0054] U denotes an oxygen atom, two alkoxy
groups OR.sup.19, a
C.sub.2-C.sub.10-alkylene-.quadrature..quadrature.-dioxy group,
which can be linear or branched, and [0055] R.sup.19 stands for a
C.sub.1-C.sub.20-alkyl residue, [0056] R.sup.20 denotes a
C.sub.1-C.sub.20-alkyl residue, [0057] X denotes an
NR.sup.21aR.sup.21b group, an alkoxy group OR.sup.22 [0058]
R.sup.21a, R.sup.21b which may be identical or different, denote
hydrogen, C.sub.1-C.sub.10-alkyl or together a
C.sub.4-C.sub.10-.quadrature..quadrature.-alkylene group, which can
be linear or branched, [0059] R.sup.22 denotes a
C.sub.1-C.sub.20-alkyl residue.
[0060] Compounds 2 and 3 in Scheme 1 each have a double bond
between C5 and C6 or C5 and C10 and another double bond between C2
and C3 or C3 and C4.
[0061] Compounds 7 to 9 in Scheme 1 each have a double bond between
C4 and C5 or C5 and C6 or C5 and C10.
[0062] For a person skilled in the art it is obvious that in the
descriptions of the synthetic transformations it is always assumed
that if necessary other functional groups present on the steroid
structure are suitably protected.
[0063] The introduction of a 6,7-double bond with formation of
compounds with the general chemical formulae 4, 13 or 18 is carried
out by bromination of the respective 3,5-dienol ethers 3, 12 or 17
followed by elimination of hydrogen bromide (see for example J.
Fried, J. A. Edwards, Organic Reactions in Steroid Chemistry, Van
Nostrand Reinhold Company 1972, p. 265-374).
[0064] The dienol ether bromination of compounds 3, 12 or 17 can
for example be carried out as for the specification from Steroids
1, 233 (1963). Hydrogen bromide elimination with formation of the
compounds with the general chemical formulae 4, 13 or 18 is
achieved by heating the 6-bromo compound with basic reagents, for
example with LiBr or Li.sub.2CO.sub.3, in aprotic solvents, such as
dimethylformamide, at temperatures of 50-120.degree. C. or
alternatively by heating the 6-bromo compounds in a solvent, such
as collidine or lutidine.
[0065] The introduction of a substituent R.sup.4 can be carried
out, for example, starting from a compound of formula 6, 11, 13,
14, 16 or 18, by epoxidation of the 4,5-double bond with hydrogen
peroxide under alkaline conditions and reaction of the resultant
epoxides in a suitable solvent with acids with the general formula
H--R.sup.4, where R.sup.4 can be a halogen atom, preferably
chlorine or bromine. Compounds in which R.sup.4 has the meaning
bromine can for example be reacted with methyl
2,2-difluoro-2-(fluorosulfonyl)acetate in dimethylformamide in the
presence of copper(I) iodide to compounds in which R.sup.4 has the
meaning fluorine. Alternatively, starting from a compound of
formula 6, 11, 13, 14, 16 or 18, halogen can be introduced directly
by reaction with sulfuryl chloride or sulfuryl bromide in the
presence of a suitable base, for example pyridine, with R.sup.4
having the meaning chlorine or bromine. Compound 4 is converted by
methenylation of the 6,7-double bond by known methods, for example
with dimethylsulfoxonium methylide (see for example DE-A 11 83 500,
DE-A 29 22 500, EP-A 0 019 690, U.S. Pat. No. 4,291,029; J. Am.
Chem. Soc. 84, 867 (1962)) to a compound 5 (R.sup.6, R.sup.7
together form a methylene group), obtaining a mixture of the
.alpha.- and .beta.-isomers, which can be separated into the
individual isomers for example by chromatography.
[0066] Compounds of type 5 can be obtained as described in the
examples or similarly to these specifications, using similar
reagents to those described there.
[0067] Synthesis of the spirocyclic compound 18 (R.sup.6a, R.sup.6b
together form 1,2-ethanediyl) starts from compounds 11 or 14, which
are first converted to a 3-amino-3,5-diene derivative 15
(X.dbd.NR.sup.21aR.sup.21b). By reaction with formalin in alcoholic
solution, the 6-hydroxymethylene derivative 16
(R.sup.6=hydroxymethylene) is obtained. After converting the
hydroxyl group into a leaving group, such as a mesylate, tosylate
or even benzoate, compound 18 can be prepared by reaction with
trimethylsulfoxonium iodide using bases, such as alkali hydroxides,
alkali alcoholates in suitable solvents such as dimethyl
sulfoxide.
[0068] For introduction of a 6-methylene group, compound 16
(R.sup.6=hydroxymethylene) can be dehydrated with for example
hydrochloric acid in dioxane/water. Compound 18 (R.sup.6a, R.sup.6b
together form methylene) can also be produced after converting the
hydroxyl group into a leaving group, such as a mesylate, tosylate
or even benzoate (see DE-A 34 02 3291, EP-A. 0 150 157, U.S. Pat.
No. 4,584,288; J. Med. Chem. 34, 2464 (1991)).
[0069] Another possibility for the production of 6-methylene
compounds 18 is the direct reaction of the 4(5)-unsaturated
3-ketones such as compound 16 (R.sup.6=hydrogen), with formaldehyde
acetals in the presence of sodium acetate with for example
phosphorus oxychloride or phosphorus pentachloride in suitable
solvents such as chloroform (see for example K. Annen, H.
Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).
[0070] The 6-methylene compounds can be used for the preparation of
compounds of general formula 18, in which R.sup.6a is methyl and
R.sup.6b and R.sup.7 together form an additional bond.
[0071] For this it is possible for example to use a method
described in Tetrahedron 21, 1619 (1965), in which isomerization of
the double bond is achieved by heating the 6-methylene compounds in
ethanol with 5% palladium/charcoal catalyst, which has been
pretreated either with hydrogen or by heating with a small amount
of cyclohexene. The isomerization can also be carried out with a
catalyst that has not been pretreated, if a small amount of
cyclohexene is added to the reaction mixture. The formation of
small proportions of hydrogenated products can be prevented by
adding an excess of sodium acetate.
[0072] Alternatively, compound 17 (X.dbd.OR.sup.22) can be used as
precursor. The direct preparation of 6-methyl-4,6-digin-3-one
derivatives has been described (see K. Annen, H. Hofmeister, H.
Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).
[0073] Compounds 18 in which R.sup.6b represents an .alpha.-methyl
function can be prepared in suitable conditions from the
6-methylene compounds (18: R.sup.6a, R.sup.6b together form
methylene) by hydrogenation under suitable conditions. The best
results (selective hydrogenation of the exo-methylene function) are
achieved by transfer-hydrogenation (J. Chem. Soc. 3578 (1954)). If
the 6-methylene derivatives 18 are heated in a suitable solvent,
for example ethanol, in the presence of a hydride donor, for
example cyclohexene, then 6.alpha.-methyl derivatives are obtained
at very good yields. Small proportions of 6.beta.-methyl compound
can be isomerized in acid conditions (Tetrahedron 1619 (1965)).
[0074] The selective preparation of 6.beta.-methyl compounds is
also possible. For this, the 4-en-3-ones such as compound 16 are
reacted for example with ethylene glycol, trimethyl orthoformate in
dichloromethane in the presence of catalytic amounts of an acid,
for example p-toluenesulfonic acid, to the corresponding 3-ketals.
During this ketalization there is isomerisation of the double bond
into position 5. Selective epoxidation of this 5-double bond is
achieved for example by using organic per-acids, for example
m-chloroperbenzoic acid, in suitable solvents such as
dichloromethane. As an alternative, the epoxidation can also be
carried out with hydrogen peroxide in the presence of for example
hexachloroacetone or 3-nitrotrifluoroacetophenone. The
5,6.alpha.-epoxides formed can then be opened axially using
appropriate alkylmagnesium halides or alkyllithium compounds. In
this way, 5.alpha.-hydroxy-6.beta.-alkyl compounds are obtained.
The 3-keto protecting group can be cleaved, obtaining the
5.alpha.-hydroxy function, by treatment in mild acidic conditions
(acetic acid or 4N hydrochloric acid at 0.degree. C.). Basic
elimination of the 5.alpha.-hydroxy function with for example
dilute aqueous sodium hydroxide solution yields the 3-keto-4-ene
compounds with a 6-alkyl group in the .beta. position.
Alternatively, cleavage of the ketal in harsher conditions (aqueous
hydrochloric acid or another strong acid) yields the corresponding
6.alpha.-alkyl compounds.
[0075] The introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group
to compounds of general formula 14 is effected by 1,6-addition of a
corresponding organometallic compound to the precursor of general
formula 13 under the action of copper salts. Divalent metals, such
as magnesium and zinc, are preferred; chlorine, bromine and iodine
are preferred as counter ion. Suitable copper salts are monovalent
or divalent copper compounds, for example copper chloride, copper
bromide or copper acetate. The reaction takes place in an inert
solvent, for example tetrahydrofuran, diethyl ether or
dichloromethane.
[0076] The compounds 6, 11, 13, 14, 16, 18 or 20 obtained, in which
Z stands for an oxygen atom, can be converted by reaction with
hydroxylamine hydrochloride, alkyloxyamine hydrochlorides or
sulfonyl hydrazines in the presence of a tertiary amine at
temperatures between -20 and +40.degree. C. to their corresponding
EIZ-configured oximes or sulfonyl hydrazones (general formula I
with Z denoting .dbd.NOR.sup.1, .dbd.NNHSO.sub.2R.sup.1)). Suitable
tertiary bases are for example trimethylamine, triethylamine,
pyridine, N,N-dimethylaminopyridine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), pyridine being preferred.
An analogous method is described for example in WO 98/24801 for the
production of corresponding 3-oxyimino derivatives of
drospirenone.
[0077] For the preparation of an end product with the general
chemical formula I with Z denoting two hydrogen atoms, the 3-oxo
group can be removed for example following the instructions given
in DE-A 28 05 490 by reductive cleavage of a thioketal of the
3-keto compound on a suitable precursor, for example compounds of
the general formulae 6, 11, 13, 14, 16, 18 or 20.
[0078] The formation of spirolactones to compounds of the general
formulae 6 or 11 is carried out starting from the corresponding
17-hydroxypropenyl compounds 5 or 10, by oxidation. Oxidation
processes that may be mentioned are for example the Jones
oxidation, oxidation with potassium permanganate for example in an
aqueous system of tert.-butanol and sodium dihydrogen phosphate,
oxidation with sodium chlorite in aqueous tert.-butanol, optionally
in the presence of a chlorine trap, for example 2-methyl-2-butene,
or by oxidation with manganese dioxide.
[0079] Alternatively the spirolactone can be introduced directly
from the ketones of general formulae 1 or 7 optionally also after
cleavage of the enol ethers in 1 or ketals in 7 according to the
method described by Georges Sturtz et al. in Tetrahedron Letters 47
(1976).
##STR00014## ##STR00015## ##STR00016##
[0080] Compound 1 in Scheme 2 in each case has a double bond
between C5 and Ce or C5 and C10 and another double bond between C2
and C3 or C3 and C4.
##STR00017##
[0081] The following examples offer a more detailed explanation of
the invention without limiting it to these examples:
EXAMPLE 1
17-spirolactonization with manganese dioxide
17.beta.-Hydroxy-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4-e-
n-3-one-21-carboxylic acid .gamma.-lactone
##STR00018##
[0083] 1.14 g manganese dioxide is added to a solution of 150 mg of
the compound prepared according to Example 1a in 7 ml
dichloromethane and it is stirred for approx. 16 hours at
23.degree. C. It is filtered on Celite and after concentration by
evaporation and chromatography, 125 mg of the title compound is
isolated.
[0084] .sup.1H-NMR (CDCl.sub.3): .delta.=0.52 (1H), 0.57 (1H), 0.75
(1H), 1.03 (1H), 1.15 (1H), 1.22 (3H), 1.23-134(3H), 1.43-1.65
(3H), 1.76-1.86 (2H), 1.97-2.56 (11H), 5.84 (1H) ppm.
EXAMPLE 1a
Cleavage of 3-Ketal
17.alpha.(Z)-(3'-Hydroxyprop-1'-yl)-15.alpha.,16.alpha.-methylene-17.beta.-
-hydroxyestra-4-en-3-one
##STR00019##
[0086] 1.8 .mu.l of 4N hydrochloric acid is added to a solution of
880 mg of the compounds prepared according to Example 1b in 35 ml
acetone and it is stirred for 1 hour at 23.degree. C. It is poured
into saturated sodium hydrogencarbonate solution, extracted several
times with ethyl acetate, the combined organic extracts are washed
with saturated sodium chloride solution and dried over sodium
sulfate. The residue obtained after filtration and evaporation of
the solvent is purified by chromatography. 580 mg of the title
compound is isolated.
EXAMPLE 1b
Hydroboration
17.alpha.(Z)-(3'-Hydroxyprop-1'-yl)-15.alpha.,16.alpha.-methylene-17.beta.-
-hydroxyestra-5-en-3-one-3-ethylene ketal and
17.alpha.(Z)-(3'-hydroxyprop-1'-yl)-15.alpha.,16.alpha.-methylene-17.beta-
.-hydroxyestra-5(10)-en-3-one-3-ethylene ketal
##STR00020##
[0088] 10.5 ml of a 0.5-molar solution of 9-borabicyclononane in
tetrahydrofuran is added to a solution of 643 mg of the compound
prepared according to Example 1c in 7.5 ml tetrahydrofuran and it
is stirred for 4 hours at 23.degree. C. It is cooled to 4.degree.
C., 4.6 ml of 5% sodium hydroxide solution and 1.2 ml of 30%
hydrogen peroxide solution are added and it is stirred for a
further 15 hours at 23.degree. C. It is extracted with ethyl
acetate, the combined organic extracts are washed with water,
saturated sodium thiosulfate solution, and saturated sodium
chloride solution and dried over sodium sulfate. After filtration
and removal of the solvent, 880 mg of the title compound is
isolated, and is reacted further without purification.
EXAMPLE 1c
17-allyl Addition
17.alpha.-(2'-Propen-1'-yl)-15.alpha.,16.alpha.-methylene-17.beta.-hydrox-
yestra-5-en-3-one-3-ethylene ketal and
17.alpha.-(2'-propen-1'-yl)-15.alpha.,16.alpha.-methylene-17.beta.-hydrox-
yestra-5(10)-en-3-one-3-ethylene ketal
##STR00021##
[0090] 4.38 ml of a 1-molar solution of allylmagnesium bromide in
diethyl ether is added at 4.degree. C. to a solution of 600 mg of
the compound prepared according to Example 1d in 10 ml
dichloromethane, stirred for 1 minute and poured into saturated
ammonium chloride solution. It is extracted with ethyl acetate, the
combined organic extracts are washed with saturated sodium chloride
solution and dried over sodium sulfate. After filtration and
removal of the solvent, 690 mg of the title compound is isolated,
and is reacted further without purification.
EXAMPLE 1d
Oxidation of 17-OH
15.alpha.,16.alpha.-Methylene-estra-5-ene-3,17-dione-3-ethylene
ketal and
15.alpha.,16.alpha.-methylene-estra-5(10)-ene-3,17-dione-3-ethylene
ketal
##STR00022##
[0092] A spatula tip of molecular sieve 4 .ANG., 700 mg
N-methylmorpholino-N-oxide, and 90 mg tetrabutylammonium
perruthenate are added to a solution of 1.06 g of the compound
prepared according to Example 1s in 32 ml dichloromethane and it is
stirred at 23.degree. C. for approx. 16 hours. It is concentrated
by evaporation and the residue is purified by chromatography. 878
mg of the title compounds is isolated.
EXAMPLE 1e
3-enol ether to ethylene ketal
15.alpha.,16.alpha.-Methylene-17.alpha.-hydroxyestra-5-en-3-one-3-ethylene
ketal and
15.alpha.,16.alpha.-methylene-17.alpha.-hydroxyestra-5(10)-en-3-
-one-3-ethylene ketal
##STR00023##
[0094] 10 ml ethylene glycol and 4.4 mg p-toluenesulfonic acid
hydrate are added to a solution of 500 mg of the compound prepared
according to Example 1f in 10 ml tetrahydrofuran and it is stirred
at 23.degree. C. for 2 hours. It is poured into saturated sodium
hydrogencarbonate solution, extracted several times with ethyl
acetate, the combined organic extracts are washed with saturated
sodium chloride solution and dried over sodium sulfate. The residue
obtained after filtration and evaporation of the solvent is
purified by chromatography. 359 mg of the title compound is
isolated.
EXAMPLE 1f
(Birch)
3-Methoxy-15.alpha.,16.alpha.-methylene-17.alpha.-hydroxyestra-2,5-
(10)-diene
##STR00024##
[0096] 9.91 g lithium is added to 597 ml ammonia at -75.degree. C.
and within 1 hour a solution of 24.6 g of the compound prepared
according to Example 1 g in 1.2 l tetrahydrofuran is added
dropwise. 720 ml ethanol is added, after 1 hour it is allowed to
warm up to -50.degree. C. and it is stirred for a further 2 hours.
Then 600 ml water is added, it is allowed to warm up to 23.degree.
C., it is extracted several times with ethyl acetate, the combined
organic extracts are washed with saturated sodium chloride solution
and dried over sodium sulfate. After filtration and removal of the
solvent, 27.1 g of the title compound is isolated, and is reacted
further without purification.
EXAMPLE 1g
Simmons Smith
3-Methoxy-15.alpha.,16.alpha.-methylene-17.alpha.-hydroxyestra-1,3,5(10)-t-
riene
##STR00025##
[0098] 86.6 g zinc dust is added to a suspension of 1.5 g
copper(II) acetate in 900 ml diethyl ether and it is heated under
reflux for 10 minutes. Then 11.7 ml diiodomethane is added, and it
is heated under reflux for a further 30 minutes. A solution of 37.6
g of the compound prepared according to Example 1h in 100 ml
tetrahydrofuran is added and, spread over a total of 40 hours, a
further 35 ml of diiodomethane is added. The cooled mixture is
filtered on Celite, the filtrate is washed with saturated sodium
chloride solution and dried over sodium sulfate. The residue
obtained after filtration and evaporation of the solvent is
purified by recrystallization. 24.6 g of the title compound is
isolated.
EXAMPLE 1h
Benzoate Saponification
3-Methoxy-17.alpha.-hydroxyestra-1,3,5(10),15-tetraene
##STR00026##
[0100] 75.5 g potassium carbonate is added to a solution of 96.3 g
of the compound prepared according to Example 1i in 1.1 l methanol
and it is stirred at 50.degree. C. for 2 hours. It is concentrated
by evaporation, water is added, it is extracted several times with
ethyl acetate, the combined organic extracts are washed with water
and dried over sodium sulfate. The residue obtained after
filtration and evaporation of the solvent is purified by
recrystallization. 46 g of the title compound is isolated.
EXAMPLE 1i
Mitsunobu
4-Nitro-benzoic acid 3-methoxy-estra-1,3,5(10),15-tetraen-17-yl
ester
##STR00027##
[0102] 121 g triphenylphosphine, 27.1 g 4-nitrobenzoic acid, and
30.9 ml azodicarboxylic acid diisopropyl ester are added to a
solution of 43.9 g of
3-methoxy-17.beta.-hydroxyestra-1,3,5(10),15-tetraene in 1.6 l
tetrahydrofuran and it is stirred for 23.degree. C. for 2 hours.
Saturated sodium chloride solution is added, it is extracted with
ethyl acetate, the combined organic extracts are washed with
saturated sodium chloride solution and dried over sodium
sulfate.
[0103] The residue obtained after filtration and evaporation of the
solvent is taken up in 1.2 l acetone, 80 ml of 30% hydrogen
peroxide solution is added while cooling, and after 20 minutes it
is poured, while cooling, into 600 ml of semiconcentrated sodium
thiosulfate solution. It is extracted with ethyl acetate, the
combined organic extracts are washed with saturated sodium chloride
solution and dried over sodium sulfate. The residue obtained after
filtration and evaporation of the solvent is purified by
recrystallization. 52.5 g of the title compound is isolated.
EXAMPLE 2
Dienone Formation from Dienol Ether
17.beta.-Hydroxy-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.-pregna-4,6-
-dien-3-one-21-carboxylic acid .gamma.-lactone
##STR00028##
[0105] 119 mg sodium acetate, 1.2 ml water and, in portions, a
total of 460 g dibromohydantoin are added at -10.degree. C. to a
solution of 1.14 g of the compound prepared according to Example 2a
in 2.1 ml N-methylpyrrolidone. After 30 minutes, 447 mg lithium
bromide and 392 mg lithium carbonate are added and it is heated for
2.5 hours at a bath temperature of 100.degree. C. It is poured into
a mixture of ice and sodium chloride solution and the precipitated
product is filtered off with suction. 910 mg of the title compound
is isolated as a crystalline raw product, which can be reacted
further directly.
[0106] .sup.1H-NMR (CDCl.sub.3): .delta.=0.59 (1H), 0.72 (1H), 1.00
(1H), 1.10 (1H), 1.19-1.59 (5H), 1.24 (3H), 1.79 (1H), 1.87 (1H),
1.99-2.59 (9H), 5.80 (1H), 6.24 (1H), 6.38 (1H) ppm.
EXAMPLE 2a
Dienol Ether Formation
17.beta.-Hydroxy-3-methoxy-15.alpha.,16.alpha.-methylene-19-nor-17.alpha.--
pregna-3,5-diene-21-carboxylic acid .gamma.-lactone
##STR00029##
[0108] 221 mg of pyridinium p-toluenesulfonate is added to a
solution of 2 g of the compound prepared according to Example 1 in
29 ml 2,2-dimethoxypropane and it is heated under reflux for 4
hours. It is poured into saturated sodium hydrogencarbonate
solution, extracted several times with ethyl acetate, the combined
organic extracts are washed with saturated sodium chloride solution
and dried over sodium sulfate. The residue obtained after
filtration and evaporation of the solvent is purified by
crystallization. 1.15 g of the title compound is isolated.
EXAMPLE 3
1,6-addition (methyl)
17.beta.-Hydroxy-7.alpha.-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.a-
lpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (A) and
17.alpha.-hydroxy-7.beta.-methyl-15.alpha.,16.alpha.-methylene-19-nor-17.-
alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (B)
##STR00030##
[0110] 250 .mu.l of a 3-molar solution of methylmagnesium chloride
in tetrahydrofuran is added dropwise to a suspension of 7 mg
copper(I) chloride in 1.2 ml tetrahydrofuran cooled to -30.degree.
C., and it is stirred for a further 10 minutes. It is cooled to
-25.degree. C. and the solution is added dropwise to 100 mg of the
compound prepared according to Example 2 in 5 ml tetrahydrofuran.
After 2 minutes it is poured into 1N hydrochloric acid, extracted
several times with ethyl acetate, the combined organic extracts are
washed with saturated sodium chloride solution and dried over
sodium sulfate. The residue obtained after filtration and
evaporation of the solvent is purified by chromatography. 23 mg of
the title compound A is isolated along with a still contaminated
mixture, which contains proportions of the title compound B.
[0111] .sup.1H-NMR (CDCl.sub.3) of A: .delta.=0.51 (1H), 0.66 (1H),
0.81 (3H), 0.94-1.10 (2H), 1.22 (3H), 1.18-1.60 (6H), 1.74-1.91
(3H), 2.00-2.58 (10H), 5.85 (1H) ppm.
EXAMPLE 4
17.beta.-Hydroxy-7.alpha.-ethyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (A) and
17.beta.-hydroxy-7.beta.-ethyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (B)
##STR00031##
[0113] Similarly to Example 3, 200 mg of the compound prepared
according to Example 2 using ethylmagnesium chloride is reacted
and, after processing and purification, 81 mg of the title compound
A is isolated along with a still contaminated mixture, which
contains proportions of the title compound B.
[0114] .sup.1H-NMR (CDCl.sub.3) of A: .delta. 0.51 (1H), 0.75 (1H),
0.90 (3H), 0.95-1.10 (3H), 1.18-1.38 (4H), 1.22 (3H), 1.44 (1H),
1.50 (1H), 1.77-1.96 (4H), 2.01-2.10 (2H), 2.15 (1H), 2.22-2.54
(6H), 2.60 (1H), 5.86 (1H) ppm.
EXAMPLE 5
17.beta.-Hydroxy-7.alpha.-vinyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (A) and
17.beta.-hydroxy-7.beta.-vinyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (B)
##STR00032##
[0116] Similarly to Example 3, 210 mg of the compound prepared
according to Example 2 using vinylmagnesium chloride is reacted
and, after processing and purification, 16 mg of the title compound
A is isolated along with a still contaminated mixture, which
contains proportions of the title compound B.
[0117] .sup.1H-NMR (CDCl.sub.3) of A: .delta.=0.45 (1H), 0.63 (1H),
0.97-1.10 (2H), 1.16-1.36 (4H), 1.23 (3H), 1.40-1.57 (2H),
1.78-2.17 (5H), 2.22-2.54 (6H), 2.60 (1H), 2.79 (1H), 5.10 (1H),
5.18 (1H), 5.69 (1H), 5.88 (1H) ppm.
EXAMPLE 6
17.beta.-Hydroxy-7.alpha.-cyclopropyl-15.alpha.,16.alpha.-methylene-19-nor-
-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (A)
and
17.beta.-hydroxy-7.beta.-cyclopropyl-15.alpha.,16.alpha.-methylene-19-nor-
-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
(B)
##STR00033##
[0119] Similarly to Example 3, 200 mg of the compound prepared
according to Example 2 using cyclopropylmagnesium bromide is
reacted and, after processing and purification, 71 mg of the title
compound A is isolated along with a still contaminated mixture,
which contains proportions of the title compound B.
[0120] .sup.1H-NMR (CDCl.sub.3) of A: .delta.=-0.05 (1H), 0.41-0.53
(4H), 0.56 (1H), 0.99 (1H), 1.12 (1H), 1.16-1.32 (5H), 1.23 (3H),
1.43-1.57 (2H), 1.81-1.93 (3H), 2.02-2.21 (3H), 2.24-2.34 (2H),
2.38-2.57 (5H), 5.90 (1H) ppm.
EXAMPLE 7
6-hydroxymethyl
17.beta.-Hydroxy-6.beta.-hydroxymethyl-15.alpha.,16.alpha.-methylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
##STR00034##
[0122] 400 .mu.l of 37% aqueous formaldehyde solution is added to a
solution of 400 mg of the compound prepared according to Example 7a
in a mixture of 4 ml toluene and 8 ml ethanol and it is stirred for
3 hours at 23.degree. C. It is concentrated by evaporation and the
residue is purified by chromatography. 180 mg of the title compound
is isolated.
[0123] .sup.1H-NMR (CDCl.sub.3): .delta.=0.52 (2H), 0.75 (1H), 1.03
(1H), 1.21 (3H), 1.17-1.86 (10H), 1.97-2.56 (9H), 2.68 (1H), 3.73
(2H), 5.93 (1H) ppm.
EXAMPLE 7a
Dienamine for 6-Alkylation
17.beta.-Hydroxy-3-pyrrolidinyl-15.alpha.,16.alpha.-methylene-19-nor-17.al-
pha.-pregna-3,5-diene-21-carboxylic acid .gamma.-lactone
##STR00035##
[0125] 280 .mu.l pyrrolidine is added to a solution of 500 mg of
the compound prepared according to Example 1 in 5.3 ml methanol and
it is heated under reflux for 2 hours. It is cooled, the
precipitate is filtered off with suction, it is washed with a
little cold methanol and 406 mg of the title compound is obtained,
and this is reacted further without additional purification.
EXAMPLE 8
6-spirocyclopropanation (Corey)
6,6-(1,2-Ethanediyl)-17.beta.-hydroxy-15.alpha.,16.alpha.-methylene-19-nor-
-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
##STR00036##
[0127] 100 mg trimethylsulfoxonium iodide is dissolved in 1.0 ml
dimethylsulfoxide, 18.5 mg of 60% sodium hydride dispersion is
added and it is stirred for 2 hours at 23.degree. C. Then a
solution of 58 mg of the compound prepared according to Example 8a
in 2.5 ml dimethylsulfoxide is added dropwise and it is stirred for
a further 3.5 hours at 23.degree. C. It is poured into water,
extracted several times with ethyl acetate, the combined organic
extracts are washed with water and saturated sodium chloride
solution and dried over sodium sulfate. The residue obtained after
filtration and evaporation of the solvent is purified by
chromatography. 20 mg of the title compound is isolated.
[0128] .sup.1H-NMR (CDCl.sub.3): .delta.=0.43 (1H), 0.50 (1H),
0.53-0.62 (2H), 0.74 (1H), 0.85 (1H), 1.00 (1H), 1.17-1.37 (5H),
1.24 (3H), 1.42-1.53 (2H), 1.66 (1H), 1.78-1.88 (3H), 2.02 (1H),
2.09-2.32 (4H), 2.37-2.54 (3H), 5.70 (1H) ppm.
EXAMPLE 8a
6-tosyloxymethyl
17.beta.-Hydroxy-6.beta.-(p-tolylsulfonyloxymethyl)-15.alpha.,16.alpha.-me-
thylene-19-nor-17.alpha.-pregna-4-en-3-one-21-carboxylic acid
.gamma.-lactone
##STR00037##
[0130] 665 .mu.l triethylamine and 190 mg p-toluenesulfonic acid
chloride are added to a solution of 150 mg of the compound prepared
according to Example 7 in 7.5 ml dichloromethane and it is stirred
for 37 hours at 23.degree. C. It is poured into saturated sodium
carbonate solution, extracted several times with ethyl acetate, the
combined organic extracts are washed with water and saturated
sodium chloride solution and dried over sodium sulfate. The residue
obtained after filtration and evaporation of the solvent is
purified by chromatography. 131 mg of the title compound is
isolated.
EXAMPLE 9
17.beta.-Hydroxy-6.beta.,7.beta.-15.alpha.,16.alpha.-bismethylene-19-nor-1-
7.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone (A)
and
17.beta.-hydroxy-6.alpha.,7.alpha.-15.alpha.,16.alpha.-bismethylene-19-no-
r-17.alpha.-pregna-4-en-3-one-21-carboxylic acid .gamma.-lactone
(B)
##STR00038##
[0132] Similarly to Example 8, 1.13 g of the compound prepared
according to Example 2 is reacted and, after processing and
purification, 46 mg of the title compound A and 222 mg of the title
compound B are isolated.
[0133] .sup.1H-NMR (CDCl.sub.3) of A: .delta.=0.58-0.68 (2H),
0.80-0.97 (2H), 1.09-1.37 (4H), 1.24 (3H), 1.43-1.96 (8H),
2.05-2.60 (8H), 6.15 (1H) ppm.
[0134] .sup.1H-NMR (CDCl.sub.3) of B: .delta.=0.60 (1H), 0.64-0.74
(2H), 0.95 (1H), 1.08 (1H), 1.14-1.51 (5H), 1.25 (3H), 1.66 (1H),
1.73-1.90 (3H), 1.98-2.58 (10H), 6.04 (1H) ppm.
EXAMPLE 10
[0135] Inert depot systems amenable to intrauterine implantation
and composed of a biodegradable polymer or a synthetic silicone
polymer consisting of an active ingredient-containing core in the
appropriate polymer-active ingredient mixing ratio, surrounded by a
polymer membrane ensuring the desired daily release rate, are
introduced into the lumen of the rat uterus. The female animals are
castrated beforehand and pretreated with estradiol for three days.
The implants of different length (5-20 mm) and a restricted
diameter (1.1 to 2 mm) remain for between 4 and 14 days in the rat
uterus in order to investigate the local and systemic
progestational effect of the released active ingredient on the
basis of various parameters in different tissues. The following
parameters are measured: 1) local progestational effect on the
uterus, on the basis of the weight of the uterus, the
histologically detectable epithelial height and the expression of
progestogen-regulated marker genes (e.g. IGFBP-1); 2) systemic
progestational effect on the mammary gland on the basis of the
expression of progestogen-regulated marker genes (e.g. RankL), 3)
systemic progestational effect on the pituitary on the basis of the
LH level (reduction in the estrogen-induced elevation of the LH
level).
[0136] The compounds of the present invention show a significant
progestational effect in the uterus which is comparable to a
corresponding treatment with a levonorgestrel-containing depot
system such as MIRENA.RTM..
TABLE-US-00001 TABLE 1 Receptor binding In vitro Transactivation
mineralo- progesterone corticoid CF- receptor receptor androgen
receptor progesterone receptor PR/ Agonism Agonism IC50 Competition
Competition IC50 Competition EC50 Efficacy CF- Ex. structure [nM]
factor factor [nM] factor [nM] [%] MR A ##STR00039## 43.3 2.7 0.5
630 37 88 72.2 5.40 1 ##STR00040## 15 0.74 1.8 6 110.0 0.1 55.9
0.41 3 ##STR00041## 12.1 0.60 1.3 61 2.8 0.6 87.0 0.46 4
##STR00042## 33 1.74 1.2 74 5.6 0.7 56.7 1.45 5 ##STR00043## 15
1.16 1.4 55 3.0 3.4 66.1 0.83 6 ##STR00044## 51 2.65 1.6 78 6.3 1.0
48.6 1.66 7 ##STR00045## 1100 49.90 2.1 10000 1000.0 910.0 22.8
23.76 8 ##STR00046## 8.9 0.71 0.9 26 1.4 0.1 69.7 0.79 9
##STR00047## 16 0.86 0.7 420 38.5 1 77.4 1.16 9 ##STR00048## 24
1.28 0.5 330 30.3 23 107.4 2.46
[0137] The compounds in Examples 1, 3-6 and 8-9 possess improved
selectivity on the progesterone receptor (PR) compared with the
mineralocorticoid receptor (MR) expressed by the ratio of the
competition factors CF-PR/CF-MR. The ratios are in a range from
0.41 to 2.46 and are therefore well below that of DRSP (5.4
* * * * *