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
The 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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 2 R, where R is hydrogen, C 1 -C 10 -alkyl, aryl or C 7 -C 20 -aralkyl, R 4 is hydrogen or halogen, and moreover either: R 6a , R 6b together form methylene or 1,2-ethanediyl or R 6a is hydrogen and R 6b is selected from the group comprising hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, and R 7 is selected from the group comprising hydrogen, C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, or: R 6a is hydrogen and R 6b and R 7 , together, denote a bond, an oxygen or form methylene, R 18 represents hydrogen or C 1 -C 3 -alkyl and in addition include their solvates, hydrates, stereoisomers and salts.
1 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives of general formula I
in which
Z denotes oxygen, two hydrogen atoms, a group ═NOR 1 or ═NNHSO 2 R 1 ,
R 1 denotes hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl,
R 4 denotes hydrogen or halogen,
R 6a , R 6b which may be identical or different, denote hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl or together denote methylene or 1,2-ethanediyl,
R 7 denotes hydrogen, C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl,
R 6a , R 7 together, denote a bond, an oxygen or a methylene group,
R 18 denotes hydrogen, C 1 -C 3 -alkyl,
and their solvates, hydrates, stereoisomers and salts.
2 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that Z is selected from the group comprising oxygen, NOR 1 and NNHSO 2 R 1 .
3 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that Z stands for oxygen.
4 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 4 is hydrogen or chlorine.
5 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 6a , R 6b together form 1,2-ethanediyl or are each hydrogen.
6 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 7 is hydrogen or methyl or ethyl or vinyl.
7 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 6a and R 7 together form a methylene group.
8 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 6a and R 7 together represent a bond.
9 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , characterized in that R 18 is hydrogen or methyl.
10 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-lactone derivatives as claimed in claim 1 , selected from the group
17β-Hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6-methylene-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6α-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6,6-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
6,6-(1,2-Ethanediyl)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-15α,16α-methylene-19-nor-17α-pregna-4,6-dien-3-one-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-ethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-vinyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-cyclopropyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6-methylene-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β-hydroxymethyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-15α,16α-methylene-19-nor-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone
17β-Hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7α-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-7β-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6-methylene-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6α-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6β-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
6,6-(1,2-Ethanediyl)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-en-3-one-21-carboxylic acid γ-lactone
17β-Hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4,6-dien-3-one-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-methyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-ethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-vinyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7α-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-7β-cyclopropyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6-methylene-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β-hydroxymethyl-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-6,6-(1,2-ethanediyl)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6α,7α,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-6β,7β,15α,16α-bismethylene-19-nor-17α-pregna-4-ene-21-carboxylic acid γ-lactone
(E/Z)-3-(Hydroxyimino)-17β-hydroxy-18-methyl-15α,16α-methylene-19-nor-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone.
11 . 15α,16α-Methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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 15α,16α-methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid γ-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.