CA1329770C - 17-methylene- and 17-ethylidene-estratrienes - Google Patents

17-methylene- and 17-ethylidene-estratrienes

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Publication number
CA1329770C
CA1329770C CA000585132A CA585132A CA1329770C CA 1329770 C CA1329770 C CA 1329770C CA 000585132 A CA000585132 A CA 000585132A CA 585132 A CA585132 A CA 585132A CA 1329770 C CA1329770 C CA 1329770C
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CA
Canada
Prior art keywords
composition
methylene
compound
estratriene
ethylidene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA000585132A
Other languages
French (fr)
Inventor
Peter Jungblut
Rudolf Wiechert
Dieter Bittler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Application granted granted Critical
Publication of CA1329770C publication Critical patent/CA1329770C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system

Abstract

Abstract of the Disclosure A pharmaceutical preparation for treating menopausal symptoms, estrogen deficiency and hormone-dependent tumors, and for use as a contraceptive, comprises a compound of formula I

(I).

wherein R1 is hydrogen, methyl, a tetrahydropyranyl group or an acyl group and R2 is hydrogen or methyl.

Description

1 32~770 The invention relates to new pharmaceutical preparations and their use for treatment of menopausal complaints, estrogen deficiency and hormone-dependent tumors and for use as a contraceptive.
The phaxmaceutical preparation is characterized by the ccntent of one or more compounds of formula I
l~R2 RIO ~ (I) wherein R1 is hydrogen, methyl, a tetrahydropyranyl group of an acyl group and ; 15 R2 is hydrogen or methyl.
Suitable acyl groups are physiologically compatible groups derived from acids customarily used for the ~ esterification of hydroxy steroids~ The identity and ; structure of the acyl moiety are not critical. Suitable acyl groups include organic carboxylic acids of 1-12 carbon atoms, e.g., hydrocarbQn acids, pertaining to the aliphatic, cycloaliphatic, aromatic or aromatic-aliphatic series which can be saturated nr unsaturated, mono- or poly-basic and/or substituted. Examples that can be mentioned for the substituents are alkyl (e.g., of 1-4 C atoms), hydroxy, alkoxy (e.g., of 1-4 C atoms), oxo or amino groups (e.g., amino and mono- or dialkylamino (1-4 C-alkyl groups) and halogen atoms. Among these are also the usual inorganic acids.
Examples of such carboxylic acids of 1-12 carbon atoms include alkanoyl groups from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, .

pelargonic acid, capric acid, undecylic acid, lauric acid, trimethylacetic acid, tertbutylacetic acid, cyclopentylacetic acid, diethylaminoacetic acid, lactic acid, succinic acid, adipic acid; other preferred groups include benzoic acid, nicotinic acid, morpholinoacetic acid, etc.
Examples of inorganic acids include sulfuric and phosphoric acids.
The asters of succinic acid, adipic acid, sulfuric acid, and phosphoric acid can optionally be converted with an alkali into the water-soluble salts.
Hetero acyl groups can be derived from heterocyclic acids comprising 1-2 fused rings, wherein each ring contains 4-7 ring atoms and 1-2 hetero atoms, the hetero atoms comprising 0, N and/or S. Suitable acyl groups include that from pyrrolidino-, piperidino~, piperazino-, morpholinosulfonic acid, etc.
Suitable halogen atoms throughout the foregoing are fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
The compounds of formula I with Rl meaning hydrogen atom or acetyl are already known.
17-methylene-1,3,5(10)-estratrien-3-ol and the 3-acetate are descri~ed, for example, in J. Org. Chem. 1981, 46, 3326-3328, as intermediate products for production of D-homosteroids. 17-ethylidene-1,3,5(10)-estratrien-3-ol is an intermediate product for production of the corresponding 17-beta ethyl compound (U.S. Patent 3,946,052). It is reported of 17-methylene compounds (and specifically 3 OH and 3-methoxy 17-methylene estratxiene) in Jap. Patent 71034421 ~Chem. Abstracts Vol. 75 (1971) 151978z) that they are anticholesterol agents.
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1 32q770 It has been found that the estratrienes substituted in the 17-position by methylene or ethylidene are clearly different from estrones. In comparison with the estrones, from which they are produced, the compounds of formula I show a lower affînity to the estrogen receptors than estradiol and, as compared with estradiol, bring about increased cellular memhrane and blood/lymphatic vessel permeability.
In the estrogen receptor binding test for estrogenic activity with the use of cytosol from pig uterus homogenate and of 6,73H estradiol as the reference compound, the compounds of formula I show a lower affinity for the estrogen receptor~
The following table indicates the competition at the receptor in percent.

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- 4 ~ 1 32q7 70 T A B L E
Estrogen Receptor Bindinq Test Compound Mol_% Com~etition 2 x 10-849 Estradiol 2 x 10-788 2 ~ 10-8 8 17-methylene-1,3,5(10)- 2 x 10-725 lo estratrien-3-ol 2 x 10-~73 2 x 10 85 17-ethylidene-1,3,5(10)-estratrien-3-ol 2 x 10-711 2 x 10-648 In the uterus growth test with immature, 23-day-old Sprague-Dawley rats, for example, 17-methylene-1,3,5(10~-estratrien-3-ol exhibits only 1/70 of the uterotropic activity o~ estradiol. The value of 1/70 of ~ 20 the estradiol is found both if it is based on the uterus -~ wet weights including the intrauterine liquid, and if the DNA content is taken as measurement of the uterus cell content.
For performing the test, the immature female rats 2~ receive estradiol or 17-methylene-1,3,5(10)-estratrien-3-ol subcutaneously once a day for 3 days. On the 4th day, the animals are sacrificed and the uterus weight or DNA content per uterus is determined. ' A uterus weight of 50 mg or a DNA rontent of 302 micrograms is obtained with 0.07 microgram of estradiol . or with 5 micrograms of 17-methylene-1,3,5~10)- -estratrien-3-ol.
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5 ~ l 3 2 q 7 7 0 Upon local administration of estradiol or 17-methylene-1,3~5(10)-estratrien-3~ol into the uterine lumen of a female pig, a uterine edema is produced, the onset of which, using the 17-methylene compound, begins about 30 minutes later than with the estradiol but dccurs to the same extent as with estradiol. The extent of the edema can be determined by ascertaining t~e albumin and DNA content of the uterus.
I Intrauterine injection of 1 x 10~5-molar solutions~
(20-50 ml/uterus) of the compounds to be tested was performed. With estradiol, an increase o~ the albumin content to about 17 mg of albumin/1 mg of DNA resulted after 120 minutes. With the corresponding 17-methylene compound, an increase to the same value resulted after 150 minutesO
Introduction of the test compound into a uterine horn of a female pig brings about edema formation only at that location; the untreated horn is not affected.
Accordingly, the finding Xor the compounds of formula I is an activity disproportionation indicating a lower activity in the cell nuc]Leus by way of the estrogen receptor, with an edema for~ation that is unchanged as compared with eRtradiol.
The compounds of formula I are substrates for intracellular enzymes, the products of which lead to an increase in cellular membrane and blood/lymphatic vessel permeability, which can be demonstrated as so-called "water imbibition" in the form of a massive edema in the target organ, the uterus. These compounds are especially suitable for the treatment of climacteric c!omplaints, as well as generally for the treatment of symptoms occurring due to defunctionalization of the second activity segment of estradiol.
The active compounds are preferably administered orally, e.g. to mammals including humans, but they can also be administered locally and parenterally. For this ,:
. . . - , purpose, the active compounds are processed according to conventional methods for the customary forms of administration together with the additives, excipients and/or solubilizers customary in galenic pharmacy. For the ; 5 preferred oral ~dministration, especially suitable are tablets, dragees, capsules, pills, aqueous suspensions or alcoholic solutions, and for local and parenter21 administration, especially ointments and, respectively, oily solutions, such as, for example, sesame oil or castor oil solutions which can additionally contain, if desired, a solubilizer, e.g., benzyl benzoate.
The concentration of active compound in the pharmaceutical preparations depends on the type of ~ administration and the field of usage. Thus, for example, i 15 tablets, dragees, capsules or pills can contain 50-200 ~g ofactive compound per dosage unit, and oily solutions or ointments can contain 1-20 ~g of active compound per dosage unit, and oily solutions or ointments can contain 1-20 ~g of active compound per milliliter.
In a preferred embodiment, the oral form of administration contains ~0-150 ~g of active agent.
After treating thexapeutically castrated women, as well as menopausal women, all of who suffered from hot flashes and moodiness, with a daily dosage of 50-150 ~g of active compound according to formula 1, a marked decrease in discomfort occurred as early as after 2 days.
The systemic administration of compounds of formula I to Sprague-Dawley rats with mammary tumors induced by 7,12-` dimethylbenzanthracene leads to cessation of tumor growth without any marked effect on the estrous cycle. The compounds are thus likewise suitable for the treatment of ; hormone-dependent tumors as compared to the known compound Tamoxifen.

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With the use of the compounds in daily amounts of 0~15-15 ~g per kg, stimulation of growth o~ existing hormone-dependent tumors is prevented.
This antitumor activity can be demonstrated using any conventional protocol, e.g., as described in Science 137 (1962), 257-262.
The compounds of formula I, being substances with a selective estrogenic activity, can also be utilized in preparations for contraception, preferably in combination with a progestationally active hormone component, e.gO, ; levonorgestrel, gestodene, or desogestrel. Forms of administration that can be given orally contain preferably 50-200 ~g of a compound of formula I and 50-500 ~g of a strongly effective gestagen per dayO The compounds are administered analogously to the known compound Microgynon(R).
The compounds of formula I are either known or can be produced from known 3-hydroxy compounds according to methods known in the art by esterification or etherification.
The eskerification (acylation) preferably takes place with pyridine/acid anhydride or pyridine/acid chloride at room temperature.
Alkylating compounds, such as diazoalkanes or dialkylsulfates, can be used for the etherification.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

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' 1 ~29770 EXAMPIES

Directions ~or production of comps~unds of general ~ormula I
1~ 17-MPthylene-1,3,5~10~-estratrien-3-ol 74.6 ml of 15% butyllithium solution in hexane i5 instilled into a suspension of 44.0 g of methyltriphenylphosphonium bromide in 200 ml of dioxane under an argon stream and ice-bath cooling. It is then~
stirred for 1.5 hours more at room temperature. Then 6.0 g of 3-~tetrahydropyran-2'-yloxy)- 1,3,5(10)-estratrien-17-one is added, the hexane is distilled off up to boiling point of 100C and then the reaction mixture i5 refluxed for 19 hours: After ice water precipitation the substance is extracted with dichloromethane. After drying and concentration by evaporation the residue is chromatographed on silica gel, and 6.1 g of 17-methylene-~-ttetrahydropyran-2 9 -; yloxy)-1,3,5(10)-estratriene with a melting point of 73.5 C is obtained~
6 ml of 8% by volume of sulfuric acid is added to a solution of 6.0 g of 17-mathylene-3-~tetrahydropyran-2l-yloxy3-1,3,5(10)-estratriene in So ml of methanol and is allowed to stand for 4 hours at room temperature. Then rPaction solution is then diluted with ether, washed with water, dried and concentrated by evaporation. The !, xesidue is recrystallized from hexane and 4.1 g of 17-methylene-1,3,5(10j-estratrien 3-ol with a melting point ` of 133.5C is obtained.

2) 3-~ethoxy-17-methylene-1,3,5(10)-~s$ratriene 200 mg of 17-methylene-1,3,5~103-estratrien-3-ol is dissolved in 115 ml of 0.5 molar sodium hydroxide solution, is mixed with 2.5 ml of dimethyl sulfate and stirred overnight at room temperature. The reaction solution is extracted with dichloromethane, the organic ., , -. . . -: .

phase is washed with water, dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 170 mg of 3-methoxy-17-methylene-1,3,5(10)-estratriene is obtained.

3) 3-Acetoxy-17-methylene-1,3,5(10)-estratriene 200 mg of 17-methylene-1,3,5(10)-estratrien-3-ol in 1 ml of pyridine and 0.5 ml of acetic anhydride is allowed to stand overnight at room temperature. It is then diluted with ice water, the precipitated precipitate is filtered off, taken up in dichloro-methane, dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 185 mg of 3-acetoxy 17-methylene-1,3~5(10)-estratriene is obtained.
4) 3-Butyryloxy-17-methylene-1,3,5(10~-estratriene 250 mg of 17-methylene-1,3,5(10)-estratrien-3-ol is reacted in 1.5 ml of pyridine with 0.75 ml of butyric acid anhydride and worked up as described in example 3.
After chromatography on silica gel, 245 mg of 3-butyryloxy-17-methylene-1,3,5(10)-estratriene is obtained.
5) 17-Ethylidene-1,3,5(10)-estratrien-3-ol 3.22 g of potassium tert-butylate in added by portions to a suspension of 10.6 g of ethyltriphenylphoshonium bromide in 50 ml of dimethyl sulfoxide and stirred for 1 more hour at room .J temperature. Then a solution of 4.0 g of tert-butyl-dimethylsilyloxy-1,3,5(10)-estratrien-17-one in 50 ml of dimethyl sulfoxide is instilled and stirred for 3 more ~ 30 hours at room temperature. The reaction solution is I diluted with ether, washed with water, dried and concentrated by evaporation. The residue is ~ ! . .

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~, ` 1 32~770 chromatographed on silica gel, and 450 mg of (syn) 17-ethylidene-1,3,5(10)-estratrien-3-ol is obtained.
6) 17-Ethylidene-1,3,5(10)-estratriene-3-methyl ether 100 mg of (syn) 17-ethylidene-1,3,5(10)-estratrien-3-one in 57.5 ml of 0.5 molar sodium hydroxide solution is reacted with 1.25 ml of dimethyl sulfate and worked up as described in example 2. After chromatography on silica gel, 75 mg of (syn) 17-ethylidene-1,3,5(10)-estratriene-3-methyl sther is obtained.

73 17-Ethylidene-3-propionyloxy-1,3,5(10)-estratriens ~ 100 mg of (syn) 17-ethylidene-1,3,5(10)-; estratrien-3-ol in 1 ml of pyridine is reacted with 0.5 ml of propionic acid anhydride and worked up as described in example 3. After chromatography on silica lS gel, 95 mg of (syn) 17-ethylidene-3-propionyloxy-1,3,5(10)-estratriene is obtained.

Example 1 Composition o~ a dragee . 0.050 mg 17-methylene-1,3,5(10)-estratrien-3-ol . 20 46.450 mg ~actose 26.800 mg Corn starch , 3.000 mg Poly(l-vinyl-2-pyrrolidone) average MW 25,000 :~ 3.700 mg Talc .
. 25 80.000 mg Total weight, supplemented to about 140 mg with the usual sugar mixture Example 2 Composition of an alcoholic solution 1 mg of 17 methylene-1,3,5(10)-estratrien-3-ol is dissolved in 10 ml of 46% ethyl alcohol.
, Ten drops tO.5 ml) contain 50 ug of active compound.
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Claims (15)

1. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I

(I) wherein R1 is hydrogen, methyl, tetrahydropyranyl or the acyl group of a C1-12 hydrocarbon carboxylic acid, optionally substituted by C1-4 alkyl, hydroxy, C1-4-alkoxy, oxo, amino or halogen, or of a mineral acid, and R2 is hydrogen or methyl, and a pharmaceutically acceptable excipient.
2. A composition of claim 1, wherein R1, is H.
3. A composition of claim 1, wherein R1, is methyl.
4. A composition of claim 1, wherein R1 is alkanoyl.
5. A composition of claim 1, wherein R1, is tetrahydropyranyl.
6. A composition of claim 1, wherein R2 is H.
7. A composition of claim 1, wherein R2 is CH3.
8. A composition of claim 1, wherein the amount of said compound is 50-200 µg.
9. A composition of claim 1, wherein the compound is 17-methylene-1,3,5(10)-estratrien-3-ol.
10. A composition of claim 1, wherein the compound is 17-ethylidene-1,3,5(10)-estratrien-3-ol.
11. A composition of claim 1, wherein the compound is 3-methoxy-17-methylene-1,3,5(10)-estratriene, 3-acetoxy-17-methylene-1,3,5(10)-estratriene, or 3-butyryloxy-17-methylene-1,3,5(10)-estratriene.
12. A composition of claim 1, wherein the compound is 17-ethylidene-1,3,5(10)-estratriene methyl ether or 17-ethylidene-3-propionyloxy-1,3,5(10)-estratriene.
13. Use of a composition according to any one of claims 1 to 12, for treating menopausal symptoms, estrogen deficiency or hormone-dependent tumors.
14. Use of a composition according to any one of claims 1 to 12, for preventing pregnancy in a female mammal.
15. The use of claim 14, wherein said composition is used in combination with a progestationally active compound.
CA000585132A 1987-12-07 1988-12-06 17-methylene- and 17-ethylidene-estratrienes Expired - Fee Related CA1329770C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3741801.7 1987-12-07
DE19873741801 DE3741801A1 (en) 1987-12-07 1987-12-07 17-Methylene-estratrienes

Publications (1)

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CA1329770C true CA1329770C (en) 1994-05-24

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US (1) US4977147A (en)
EP (1) EP0320437A3 (en)
JP (1) JPH01197438A (en)
AU (1) AU621844B2 (en)
CA (1) CA1329770C (en)
DE (1) DE3741801A1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028903A1 (en) * 1993-06-15 1994-12-22 Pherin Corporation Estrene steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods
CA2199044A1 (en) * 1994-09-29 1996-04-04 Pherin Corporation Novel estrenes for inducing hypothalamic effects
US5861431A (en) * 1995-06-07 1999-01-19 Iotek, Inc. Incontinence treatment
SE9502921D0 (en) * 1995-08-23 1995-08-23 Astra Ab New compounds
US6660726B2 (en) 2000-03-10 2003-12-09 Endeavor Pharmaceuticals Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same
US6855703B1 (en) 2000-03-10 2005-02-15 Endeavor Pharmaceuticals Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds
US7459445B2 (en) * 2000-03-10 2008-12-02 Duramed Pharmaceuticals, Inc. Estrogenic compounds and topical pharmaceutical formulations of the same
US7989436B2 (en) 2003-07-23 2011-08-02 Duramed Pharmaceuticals, Inc. Estrogenic compounds and pharmaceutical formulations comprising the same
US6992075B2 (en) * 2003-04-04 2006-01-31 Barr Laboratories, Inc. C(14) estrogenic compounds
WO2004091535A2 (en) * 2003-04-11 2004-10-28 Barr Laboratories, Inc. Methods of administering estrogens and progestins
CA2571440A1 (en) * 2004-06-29 2006-01-12 Jadolabs Gmbh Use of steroid-derived pharmaceutical compositions for treating disorders relating to pathological processes in lipid rafts

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3946052A (en) * 1975-06-16 1976-03-23 Stanford Research Institute 19-Norpregna- 1,3,5(10)-trien-3-ol and loweralkyl homologs thereof having postcoital antifertility activity
FR2332759A1 (en) * 1975-11-26 1977-06-24 Roussel Uclaf (17)-Hydroxymethyl gona-(1,3,5)-triene derivs. - with antioestrogen and hypophysis inhibiting activities

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US4977147A (en) 1990-12-11
EP0320437A3 (en) 1991-07-31
EP0320437A2 (en) 1989-06-14
JPH01197438A (en) 1989-08-09
AU2665388A (en) 1989-06-08
AU621844B2 (en) 1992-03-26
DE3741801A1 (en) 1989-06-15

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