WO1983003099A1 - 3-keto-delta 4,9-19-norsteroids - Google Patents

3-keto-delta 4,9-19-norsteroids Download PDF

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Publication number
WO1983003099A1
WO1983003099A1 PCT/FR1983/000034 FR8300034W WO8303099A1 WO 1983003099 A1 WO1983003099 A1 WO 1983003099A1 FR 8300034 W FR8300034 W FR 8300034W WO 8303099 A1 WO8303099 A1 WO 8303099A1
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radical
hydroxy
phenyl
products
methyl
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PCT/FR1983/000034
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English (en)
French (fr)
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Roussel-Uclaf
Daniel Philibert
Jean Georges Teutsch
Germain Costerousse
Roger Deraedt
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Roussel Uclaf
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Publication of WO1983003099A1 publication Critical patent/WO1983003099A1/en
Priority to OA58138A priority Critical patent/OA07567A/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/006—Ketals at position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/0025—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa substituted in position 16
    • C07J7/003—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/0075—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • the present invention relates to new products derived from the 3-keto ⁇ 4, 9 19-nor-steroid structure, their preparation process, their application as medicaments, the compositions containing them and the new intermediates obtained.
  • R 1 represents an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical having from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals chosen from hydroxy, halogen, trifluoromethyl, alkyl radicals , alkoxy, alkylthio optionally oxidized in the form of sulfoxide or sulfone, alkenyloxy having at most 6 carbon atoms and phenyloxy, either R 1 represents a naphthyl or phenyl-phenyl radical or an alkyl or alkenyl radical optionally bearing more than one unsaturation and having at most 6 carbon atoms;
  • R 2 represents a methyl or ethyl radical
  • R 3 represents a hydrogen atom, an alkyl, al kenyl or alkynyl radical optionally substituted, a hydroxy, acetyl, hydroxyacetyl, carboxyalkoxy radical having
  • R 4 represents a hydrogen atom, a hydroxy radical or an alkyl, alkenyl or alkynyl radical having at most 12 carbon chars optionally substituted by an a mino, alkylamino, dialkyl amino radical, or by a halogen, an aikylthio, alkoxy radical , trialkylsilyl or cyano;
  • R 5 represents a hydrogen atom or a radi cal methyl in the ⁇ or ⁇ position;
  • X represents an oxygen atom or a hydroxyimino or alkoxyimino radical having from 1 to 4 carbon atoms, in the syn or anti position;
  • a and B represent an ⁇ epoxy function or the presence of a second bond between carbons 9 and 10; as well as the salts of these products with the acids when R 4 represents a radical comprising an amino function; with the exception of products in which A and B represent a second bond between the carbons which carry them,
  • X represents an oxygen atom
  • R 5 represents a hydrogen atom and: a) R 2 represents a methyl radical and: ⁇ ) R 3 represents a hydroxy radical and: i) R 1 represents an ethyl or phenyl radical and R 4 represents a hydrogen atom, eu ii) R 1 represents an ethyl, propyl, isooropyle, vinyl, allyl, isopropenyl, phenyl, parafluorophenyl, methoxyphenyl or thienyl radical and R 4 represents an ethynyl radical, or: iii) R 1 represents a propyl, isopropyl, vinyl radical, allyl, isopropenyl, p-methoxyphenyl or thienyl and R 4 represents a methyl radical; ⁇ ) R 3 represents an acetyl radical and: i) R 1 represents an ethyl, vinyl or phenyl radical and R 4 represents a hydroxyl radical or:
  • R 1 represents a vinyl radical
  • R 3 represents a hydroxy radical
  • R 4 represents a hydrogen atom
  • halogen radicals such as fluoro, chloro, bromo, alkyl radicals such as rethyl, ethyl, halo alkyl radicals such as trifluoromethyl.
  • alkyl radicals such as rethyl, ethyl
  • halo alkyl radicals such as trifluoromethyl.
  • the cycloalkyl radicals can be the cyclopropyl, cyclobutyl, cyclo pentyl or cycl ⁇ hexyl radicals.
  • alkyl radicals such as methyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, oxyie, isopentyl, hexyl.
  • alkoxy and alkylthio radicals are derived from the previously mentioned alkyl radicals. The alkoxy and alkylthio radicals are preferred.
  • the alkenyloxy radicals are preferably vinyloxy or allyloxy radicals.
  • alkyl radicals which R 1 can represent mention may be made of the preceding alkyl radicals.
  • alkenyl radicals mention may be made of the vinyl and allyl radicals. Mention may also be made of radicals comprising several unsaturations such as the propa 1,2,2-dienyl radical.
  • the methyl value is preferred.
  • the tert-butoxycarbonylmethoxy, carboxy methoxy radicals optionally salified, for example in the form of alkali or alkaline-earth metal, magnesium, ammonium or organic base salts are preferred. Mention may be made, for example, of the sodium, potassium, lithium, calcium, magnesium or ammonium salts.
  • organic bases mention may be made of methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, the dicyclohexylamine, morphoiine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
  • the sodium salt is preferred.
  • R 3 When substituted, R 3 may be substituted by an alkylamino or dialkylamino radical, by a halogen, an alkylthio, an alkoxy or a trialkylsilyl.
  • R 4 there may be mentioned in particular the methyl, ethyl, ethynyl, prop-1-ynyl values. Mention may also be made of the 3-dimethylamino prop-1-ynyl values or the 3-amino prop-1-ynyl radical.
  • R 3 or R 4 the radicals having at most 4 carbon atoms and especially ethynyl or propynyl are preferred.
  • the methyloxime value is preferred.
  • salts with acids there may be mentioned the salts formed with hydrochloric, acetic, trifluoroacetic, tartaric maleic, methanesulfonic, benzene sulfonic, p-toluene sulfonic, phosphoric, sulfuric, hydrobromic acids.
  • a subject of the invention is in particular, the products of formula I as defined above, in which either the radical R 1 represents a cycloalkyl radical having from 3 to 6 carbon atoms or a substituted thienyl radical, or X represents a radical hydroxyimino or alkoxyimino having from 1 to 4 carbon atoms in syn or anti position, either the letters A and B represent an ⁇ epoxy function, or R 5 represents a methyl radical.
  • a more particular subject of the invention is the products of formula I as defined above, in which R 3 represents a hydroxy radical, R 4 represents a propynyl radical, R 2 represents a methyl radical and R 5 represents an atom of hydrogen and those in which R 3 represents an acetyl radical, R 4 represents a methyl radical or a hydrogen atom and R 1 represents an optionally substituted phenyl radical.
  • radical R 1 represents a cyclopropyl, a phenyl group optionally substituted by one of the radicals chosen from the group formed by the chloro radicals, fluoro, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy or a chlorothienyl group and R 4 represents a propynyl radical.
  • a class of preferred products is also constituted by the products of formula I in which the letters A and B represent an epoxy group.
  • the subject of the invention is also a process for preparing the products of formula I as defined above, characterized in that a product of general formula II is subjected:
  • K represents a blocked ketone group in the form of a ketal, a thioketal, an oxime or a methyloxime
  • R ′ 3 has the values of R 3 indicated above, with in addition the blocked acetyl value
  • R ′ 1 has the value of R 1 indicated above, with in addition the phenyl value substituted by a protected hydroxy radical, R 2 , R 4 and R 5 having the values indicated above, to the action of a dehydrating agent capable of release the protected function (s), to obtain a product of formula I:
  • product of formula I corresponding to a product of formula I in which X represents an oxygen atom and A and 3 together form a second bond between the carbons which carry them, product of formula I, which, if desired, is subjected, in any order , to one or more of the following reactions: a) oxidation so as to obtain the products in which A and B form an epoxide function and, when R 1 contains a sulfur atom, oxidation to sulfoxide or sulfone of this atom.
  • the dehydrating agent capable of releasing the protected function or functions which are ketone or hydroxy functions is a sulphonic resin (acid form), for example a commercial sulphonic resin with polystyrene support or with a styrene / divinylbenzene polymer support, but it is also possible to use a mineral acid such as hydrochloric acid or sulfuric acid in a lower alkanol, or perchlorigue acid in acetic acid, or a sulfonic acid such as paratoluenesulfonic acid.
  • the oxidizing agent is preferably a peracid such as metachloroperbenzoic acid, peracetic acid or perphthalic acid.
  • the action of the hydroxylamine or of an alkyl derivative of the hydroxylamine, preferably methylhydroxylaraine, is preferably carried out in an alcohol such as ethanol. It is also preferable to use a salt, in particular the hydrochloride.
  • R 3 comprises an alkoxyesterified carboxy radical
  • the hydrolysis can be carried out under reflux of an organic solvent such as benzene, in the presence of an acid such as paratoluenesulfonic acid.
  • Salification is carried out under usual conditions the. One can operate for example in the presence of ethanolic soda. It is also possible to use a sodium salt such as carbonate or sodium or potassium acid carbonate. Similarly salification with an acid is carried out under the usual conditions. It is preferably carried out with hydrochloric acid, for example in ethereal solution.
  • the above process is carried out using products of formula II in which R ' 3 represents a hydroxy radical, R 4 represents a propynyl radical, R 2 represents a methyl radical and R 5 represents an atom of hydrogen or those in which R ' 3 represents an acetyl radical, R 4 represents a methyl radical or a hydrogen atom and R' 1 represents an optionally substituted phenyl radical, finally those in which the radical R ' 1 represents a cyclopropyl , a phenyl group optionally substituted by one of the radicals chosen from the group formed by the chloro, fluoro, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy radicals, or a chlorothienyl group and R 4 represents a propynyl radical.
  • the study of the products on the hormonal receptors made it possible to highlight progestomimetics or antiprestomimetics, androgens or antiandrogens activities.
  • the products of formula I as well as their addition salts with pharmaceutically acceptable acids can therefore be used as medicaments to fight mainly against the side effects of glucocorticcides, they also make it possible to fight against disorders due to a hypersecretion of glucocorticoids and in particular against aging in general and more particularly against hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as immunosuppression and insomnia.
  • the products of formula I as well as their addition salts with pharmaceutically acceptable acids which have anti progestomimetic properties can be used as contraceptives; they can be used against hormonal disturbances; they may also be of interest in the treatment of hormone-dependent cancers. Certain products of formula I as well as their addition salts with pharmaceutically acceptable acids may also have progestomimetic properties and can therefore be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiency. The products of formula I as well as their addition salts with pharmaceutically acceptable acids which have anti-androgenic properties can be used in the treatment of hypertrophies and cancer of the prostate, hyperandrogenism, anemia, hirsutism and acne.
  • a subject of the invention is therefore, as a medicament, the products of formula I which are pharmaceutically acceptable, that is to say non-toxic at the doses used, as well as their addition salts with pharmaceutically acceptable acids.
  • a more specific subject of the invention is, as medicaments, the following products:
  • the useful dosage varies depending on the condition to be treated and the route of administration; it can vary for example from 10 mg to 1 g per day in adults by the oral route.
  • the new products of formula I, and their salts, as defined above can be used to prepare pharmaceutical compositions containing, as active principle, at least one of said products.
  • the products of formula I and their salts are used digestively, parenterally or locally. They can be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels, which are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • a subject of the invention is therefore pharmaceutical compositions containing as active principle at least one product of formula (I), or at least one of their pharmaceutically acceptable salts.
  • the subject of the invention is also, as new industrial products and in particular as intermediate products necessary for the preparation of the products of formula I, as defined above, the products of general formula II a :
  • R ′ 1 represents either an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical having from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals chosen from halogen, optionally protected hydroxy radicals, trifluorcmethyl, alkyl, alkoxy, optionally alkylthio oxidized in the form of sulfoxide or sulfone, alkenyloxy having at most 6 carbon atoms and phenyloxy, or R ' 1 represents a naphthyl or phenyl-pher.yl radical or an alkyl or alkenyl radical optionally carrying several unsaturations and having at most 6 carbon atoms, R 2 represents a methyl or ethyl radical and or alternatively R '' 3 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxy, acetyl radical optionally protected in
  • R ' 4 represents a hydrogen atom, a hydroxy radical or an alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms, optionally substituted by an amino, alkylamino or dialkylamino radical. by a halogen, an alkylthio, alkoxy, trialkylsilyl or cyano radical; or else R " 3 represents a cyano radical and R ' 4 a CH group blocked in the form of an easily cleavable ether; R 5 represents a hydrogen atom or a methyl radical in the ⁇ or ⁇ position;
  • K represents a keto group blocked in the form of ketal, thioketal, oxime or methyloxime, with the exception of the products in which K represents a (1,2-ethanediyl) acetal radical, R 5 represents a hydrogen atom and a) R 2 represents a methyl radical and ⁇ ) R '' 3 represents a cyano radical, R ' 4 represents a trimethylsilyloxy radical and R 5 represents a phenyl, methyl, ethyl, propyl, isooropyle, tert-butyl, vinyl radical, allyl, isopropenyl, o- or p-methoxyphenyl, thienyl, methoxyvinyl cup-fluoro phenyl; ⁇ ) R '' 3 represents a hydroxy radical, R ' 4 represents an ethynyl radical and R' 1 represents an ethyl, propyl, isopropyl, vinyl, isoprop
  • R '' 3 represents a hydroxy radical
  • R ' 1 represents a vinyl radical
  • R' 4 represents a hydrogen atom.
  • the substituents of the thienyl radical can be those described above. The same is true for cycloalkyl radicals and values of R ' 1 identical to those of R 1 .
  • the hydroxy radical can be protected by a protective radical conventional in organic chemistry. Mention may be made, for example, of acyl radicals such as acetyl, chloroacetyl, trifluoroacetyl, phenoxyacetyl.
  • radicals such as the tetrahydropyrannyl, trityl, benzyl, benzhydryl or trimethylsilyl radicals.
  • the acyloxyalkyl radical which R '' 3 can represent is preferably the l-acetoxyethyl radical.
  • the easily cleavable ether which R ′ 4 can represent is preferably trimethylsilyl.
  • the ketone group is preferably blocked in the form of ethanediyl.
  • R '' 3 represents a hydroxyl radical
  • R ' 4 represents a propynyl radical
  • R 5 represents a hydrogen atom
  • R 2 represents a methyl radical
  • the cycloalkyl values especially cyclopentyl
  • the phenyl value optionally substituted by one of the radicals chosen from the group formed by the chloro, fluoro, methylthio, methylsulfonyl, hydroxy methoxy and allyloxy radicals finally the chlorothienyl value.
  • R ' 1 having the above meaning and Hal representing a halogen atom, where appropriate in the presence of a catalytic amount of cuprous halide, to obtain a product of formula II a , product which if desired is submitted, in order any one or more of the following reactions: a) action of a lithium acetylide-ethylene diamine complex on a product in which R '' 3 represents a cyano radical and R ' 4 an OH group blocked in the form of an easily cleavable ether, in order to obtain a product of formula IIa in which
  • R '' 3 represents a hydroxyl radical and R ' 4 represents an ethynyl radical; or b) action of a methyl magnesium halide on the same product in which R '' 3 represents a cyano radical and R ' 4 represents an OH group blocked in the form of easily cleavable ether to obtain a product in which R'' 3 represents an acetyl radical and R ′ 4 represents a hydroxyl radical; c) deprotection of the protected hydroxyl or acetyl groups.
  • Hal preferably represents a bromine or chlorine atom and the operation is carried out in the presence of a catalytic amount of cuprous chloride or bromide preferably at a temperature comprised between -40 ° C and 0 ° C.
  • the operation is carried out in the presence of a catalytic amount of cuprous chloride or bromide at a temperature between -40 ° C and 0oC.
  • the copper halide is optionally supplied in the form of a complex with a dialkyl sulfide.
  • the operation is preferably carried out within an organic solvent or a mixture of solvents such as, for example, ethyl ether, isopropyl ether or tetrahydrofuran.
  • R ′ 1 represents a radical different from the allyl radical
  • the compound of formula R ′ 1 MgBr is used to introduce the substituent 113 in the presence of a catalytic amount of cuprous chloride by operating at a temperature between - 40 ° C and -20 ° C in ethyl ether and / or tetrahydrofuran
  • R ' 1 represents the allyl radical
  • use is made to introduce the substituent in lia the compound of formula (R ' 4 ) 2 Culi, operating at a temperature between -90 ° C and -10 ° C.
  • Ri 3 and Ri 4 have the values previously indicated for R '' 3 and R ' 4 or Ri 3 and Ri 4 together form a keto radical.
  • cuprous chloride 0.82 g is introduced at -25 ° C. under nitrogen in 162 cm 3 of thienyl magnesium bromide in tetrahydrofuran (1.05 M / 1).
  • the mixture is left under nitrogen and stirred at -25 ° C for 17 hours then 2 hours at 0 ° C. Then poured into a frozen aqueous solution of ammonium chloride.
  • Preparation 2 3, 3-ethylene bis (oxy) 11 ⁇ - (p-fluorophenyl) 17 ⁇ - (prop- 1-ynyl) estr 9-en 5 ⁇ -17 ⁇ -diol: Act, under the same conditions as Preparation 1, p-fluorophenyl magnesium bromide on the same product 3,3-ethylene bis (oxy) 5 ⁇ , 10 ⁇ -epoxy 17 ⁇ (prop- 1 -ynyl) estra 9 (11) as 17 ⁇ ol in the presence of cuprous chloride in the tetrahydrofuran.
  • a mixture of 11.4 g of cuprous iodide in 120 cm3 of ether is cooled under nitrogen to 0 ° C. and 69 cm3 of methyl lithium 1.74 M in ether is added in 30 minutes. Stirred for another 10 minutes at 0 ° C. and then introduced dropwise over 30 minutes, 5.5 g of 3.3 bis-methoxy 5 ⁇ , 10 ⁇ -epoxy 17 ⁇ - (prop 1-ynyl) estra 9 (11) in 17 ⁇ - ol in 50 cm3 of tetrahydrofuran. The mixture is left stirring for 2 hours at 0 ° C. and then poured into a frozen aqueous solution of ammonium chloride. The mixture is stirred for one hour at room temperature. Extracted with ether, washed, dried, concentrated to dryness under reduced pressure and obtained 5.7 g of crude product.
  • Preparation 7 3,3-bis methoxy 11 ⁇ - (2-furyl) 17 ⁇ - (prop-1- ynyl) estr 9-en 5 ⁇ , 17 ⁇ -diol: The procedure is as in preparation 5, the cupolith difuryl is condensed on the same product 3,3-bis methoxy 5 ⁇ , 10 ⁇ -epoxy 17 ⁇ (prop-1-ynyl) estra 9 (11) as 17 ⁇ -ol.
  • Preparation 30 A 3, 3-ethylene bis (oxy) 5 ⁇ , 17 ⁇ -dihydroxy 11 ⁇ - (3-methoxy phenyl) 19-nor pregn-9-en 20-one:
  • the 3.20 bis ethylene ketal of 17 ⁇ -methyl 5 ⁇ , 10 ⁇ -epoxy 19-nor pregna-9 (11) in 3, 20 dione used at the start of preparation 31 was prepared as follows: a) 3.20 bis ethylene ketal of 17 ⁇ -methyl 19-nor pregna-5 (10) 9 (11) diene-3,20-dione:
  • Preparation 36 / (3,3-ethylene bis oxy 11 ⁇ - (3-methoxyphenyl) 17 ⁇ - (prop-1-ynyl) 17 ⁇ -estr-9-en 5 ⁇ -hydroxy 17-yl / oxy tert-butyl acetate:
  • Droduit After 1 hour 30 minutes, pour into an aqueous solution of ammonium chloride, extracted with ether, wash, dry, evaporate to dryness, and obtain the expected Droduit.
  • cuprous chloride 300 mg are added to 40 cm3 of 0.5 M thienyl magnesium bromide in tetrahydro furan. Cool to -20 ° C - 25 ° C and leave in contact
  • Preparation 48 20R-acetoxy 3,3-ethylene bis (oxy) 11 ⁇ - (3-methyloxyphenyl) 17 ⁇ -methyl 19-nor pregn-9-en 5 ⁇ -ol:
  • Preparation 55 / 1,2-ethanediyl acetal of 17 ⁇ - / 3- (dimethylamino prop-1-ynyl) 5 ⁇ , 17 ⁇ -dihydroxy 11 ⁇ - (3-methoxyphenyl) estr-9-en-3-one /: a) 3,3-ethylene bis oxy 11 ⁇ - (3-methoxy) phenyl 5a-hydroxy estr-9-en 17-one
  • cuprous chloride 350 mg are added, then 1.45 g of 3,3-ethylene bis oxy 5 ⁇ , 10 ⁇ -epoxy 17 ⁇ - (prop-1-ynyl) estr 9 (11) in 17 ⁇ -ol dissolved in 15 cm3 of tetrahydrofuran to 75 cm3 of the magnesium solution described above.
  • Example 36 // 11 ⁇ - (3-methoxyphenyl) 3-oxo 17 ⁇ - (prop-1-ynyl) (17 ⁇ ) estra-4,9-dièn-17-yl / oxy / tert-butyl acetate:
  • Example 37 Acid // 11 ⁇ - ( 3-methoxyphenyl) 3-oxo 17 ⁇ - (prop 1-ynyl) (17 ⁇ ) estra-4,9-dien-17-yl / oxy / acetic:
  • Example 38 Sodium salt of the acid // 11 ⁇ - (3-methoxyphenyl) 3-oxo 17 ⁇ (prop-1-ynyl) (17 ⁇ ) estra 4, 9-dièn-17-yl / oxy / acquitoue:
  • Example 45 9 ⁇ , 10 ⁇ -epoxy 17 ⁇ -hydroxy 11 ⁇ - (4-methylsulfonyl) phenyl 17 ⁇ - (prop-1-ynyl) estr 4-en 3-one:
  • the mixture is stirred for 1 hour 30 minutes at 0 ° C. under nitrogen then poured, with stirring, into 100 cm 3 of 0.5 M aqueous sodium thiosulfate solution and stirred for a few moments at room temperature.
  • Example 47 11 ⁇ - (3-fluorophenyl) 3-hydroxyimino 17 ⁇ - (prop1-ynyl) estra 4,9-dien 17 ⁇ -ol (syn (Z) and anti (E) isomers):
  • Example 50 11 ⁇ -tert-butyl 9 ⁇ , 10 ⁇ -epoxy 17 ⁇ -hvdroxy 17 ⁇ -
  • Example 44 The procedure is as in Example 44, starting from 1.5 g of 11 ⁇ cyclopentyl 17 ⁇ -hydroxy 17 ⁇ - (pro ⁇ -1-ynyl) estra 4,9-dien-3- one as obtained in Example 43 and 0.8 g of metachloro perbenzoic acid. 0.7 g of expected product is obtained after chromatography. Mp 170 ° C. Analysis: Calculated C%: .79.15, H%: 8.68
  • Example 53 11 ⁇ -phenyl 9 ⁇ -10 ⁇ -epoxy 17 ⁇ -hydroxy 17 ⁇ - (prop- 1-ynyl) estr-4-en 3-one: The procedure is as in Example 44 starting from 1.15 g of
  • Example 54 11 ⁇ - / 4 (3-methyl) butyl sulfonyl / phenyl / 9 ⁇ , 10 ⁇ epoxy 17 ⁇ -hydroxy 17 ⁇ (prop-1-ynyl) estr 4-en 3-one: The procedure is as in Example 45 a ' u starting from 11 ⁇ / 4 - / (3-methyl) butylthio / phenyl / 17 ⁇ -hydroxy 17 ⁇ - (pro ⁇ -1-ynyl) estra-4, 9-dièn-3-one as obtained in Example 49 .
  • Example 55 23-N, N-dimethylamino 17 ⁇ -hydroxy 11 ⁇ - (3-methoxy phenyl) 19, 21, 24-trinor 17 ⁇ -chola 4, 9-dièn-20-yn 3-one: Shake for 1 hour at temperature ambient 4.3 g of cyclic 1,2-ethanediylacetal of 17 ⁇ - / 3-dimethylaminb 1-propynyl / 5 ⁇ , 17 ⁇ -dihydroxy 11 ⁇ - / 3-methoxyphenyl / estr-9-en 3-one as obtained in the preparation 55 in 100 cm3 of methanol and 3 cm3 of 2N hydrochloric acid.
  • Example 58 11 ⁇ - (3-hydroxyphenyl) 17 ⁇ -hydroxy 17 ⁇ (prop-1-ynyl) estra 4, 9-dien-3-one.
  • Stage A 3, 3-ethylene dioxy 11 ⁇ - / 3- (2-tetrahydropyrannyloxy) phenyl / 17 ⁇ - (prop-1-ynyl) estr-9-ene 5 ⁇ , 17 ⁇ -diol. a) Preparation of the magnesian.
  • the 11 ⁇ , 17 ⁇ - dihydroxy 21- methyl pregna 1,4,6-trien 20-yn 3-one steroid which binds only to the glucocorticoid receptor is added to the supernatant at the final concentration of 10 -6 M.
  • This supernatant is ultracentrifuged at 105,000 g for 60 minutes at 0 ° C. Aliquots of the supernatant thus obtained are incubated at 0 ° C with a constant concentration (T) of tritiated aldosterone in the presence of increasing concentrations (0-2500.
  • the concentration of bound tritiated aldosterone (B) is measured by the carbon-dextran adsorption technique.
  • Progestogenic receptor in the rabbit uterus Puberous rabbits of approximately 1 kg receive a skin application of 25 ⁇ g of estradiol. 5 days after this treatment, the animals are sacrificed, the uteruses are pre-lifted, weighed and homogenized at-0 ° C, using a Potter tefIon-glass in a TS buffered solution (Tris 10mM, sucrose 0.25 M, HCl pH 7.4) (1 g of tissue per 50 ml of TS). The homogenate is then ultracentrifuged (105,000 gx 90 min) at 0 ° C.
  • mice Male Sprague Dawley EOPS rats of 160-200 g are adrenalectomized. 4 to 8 days after this ablation, the animals are sacrificed, and the thymuses are removed and homogenized at 0 ° C. in a 10 mM Tris buffer, 0.25 M sucrose, 2 mM dithiothreitol, HCl pH 7.4, using a Potter polytetrafluoroethylene-glass (1 g of tissue for 10 ml of TS). The homogenate is then ultracentrifuged (105,000 gx 90 min) at 0 ° C.
  • Estrogen receptor for the mouse uterus 18 to 21-day-old female pubescent mice are sacrificed, the uteri are removed and then homogenized at 0 ° C using a Potter tefIon-glass in a TS buffered solution (Tris 10 mM, 0.25 M sucrose, HCl pH 7.4 (1 g of tissue for 25 ml of TS) The homogenate is then ultracentrifuged (105,000 g ⁇ 90 min) at 0 ° C. Aliquots of the supernatant thus obtained, are incubated at 0 ° C or 25 ° C for a time (t) with a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0 - 1000. 10 -9 M) or cold estradiol, either cold product to be tested.
  • T constant concentration
  • the concentration of bound tritiated estradiol (B) is then measured in each incubate by the carbon-dextran adsorption technique.
  • the products studied particularly the product of Example 23, have a very marked affinity for the glucocorticoid and progestogenic receptors, as well as a moderate affinity for the androgen receptor.
  • the products can exhibit agonist or antagonist activities of glucocorticoids, progestogens and androgens.
  • Antiglucocorticoid inactivities The technique used follows from the method described by Dausse et Coll in Molecular Pharmacology 13, 948 - 955 (1977) ("the relationship be between ⁇ lucocoftico ⁇ d structure and effects upon Thymoxytes"), for mouse thymocytes. Thymocytes of adrenalectomized rats are incubated at 37 ° C for 3 hours, in a nutritive medium containing 5.10 -8 M of dexamethasone in the presence or not of a product to be studied at different concentrations.
  • Tritiated uridine is added, and the incubation is continued for one hour.
  • the incubates are cooled, treated with a 5% trichloroacetic acid solution, filtered on Whatman GF / A paper, washed three times with a 5% trichloroacetic acid solution. The radioactivity retained by the filter is determined.
  • Glucocorticoids and in particular dexamethasone cause a decrease in the incorporation of tritiated uridine.
  • the products of Examples 10, 11, 12, 23, 26, 32, 34, 35,41,44,45 and 47 are opposed to this effect.
  • the products studied have a very marked anti-glucocorticoid activity while being devoid of glucocorticoid activity.

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PCT/FR1983/000034 1982-03-01 1983-02-25 3-keto-delta 4,9-19-norsteroids WO1983003099A1 (en)

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EP0384842A1 (fr) * 1989-02-24 1990-08-29 Roussel-Uclaf Nouveaux 19-nor stéroides ayant en position 11béta une chaîne carbonée comportant une fonction amide ou carbamate, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
FR2659233A1 (fr) * 1990-03-06 1991-09-13 Roussel Uclaf Nouvelle utilisation de composes anti-progestomimetiques chez les animaux d'elevage.
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EP0116974A1 (de) * 1983-02-18 1984-08-29 Schering Aktiengesellschaft 11-Beta-Aryl-Estradiene, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate
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FR2573657A1 (fr) * 1984-11-29 1986-05-30 Roussel Uclaf Produit comprenant une substance antiprogestomimetique et une substance uterotonique
EP0184471A1 (fr) * 1984-11-29 1986-06-11 Roussel-Uclaf Produit comprenant une substance antiprogestomimétique et une substance utérotonique
FR2576025A1 (fr) * 1985-01-14 1986-07-18 Roussel Uclaf Nouveaux steroides substitues en position 10, leur procede et les intermediaires de preparation, leur application comme medicaments, les compositions pharmaceutiques les contenant
EP0188396A3 (en) * 1985-01-14 1986-12-10 Roussel-Uclaf Steroids substituted in position 10, their preparation and intermediates obtained in their preparation, their use as medicaments and pharmaceutical compositions containing them
US4753932A (en) * 1985-01-14 1988-06-28 Roussel Uclaf Novel 10-substituted steroids
EP0190759A3 (en) * 1985-02-07 1986-11-20 Schering Aktiengesellschaft Berlin Und Bergkamen 11-beta phenyl gonanes, their preparation and pharmaceutical compositions containing them
FR2582654A1 (fr) * 1985-05-31 1986-12-05 Erba Farmitalia Steroides 11b-substitues utiles notamment dans le traitement des tumeurs hormono-dependantes et procede pour la fabrication
EP0245170A1 (fr) * 1986-05-06 1987-11-11 Roussel-Uclaf Nouveaux produits 19-nor ou 19-nor D-homo stéroides substitués en position 11 beta par un radical phényle portant un radical alkynile, leur procédé de préparation, leur application comme médicaments et les compositions les renfermant
FR2598421A1 (fr) * 1986-05-06 1987-11-13 Roussel Uclaf Nouveaux produits 19-nor ou 19-nor d-homo steroides substitues en position 11b par un radical phenyle portant un radical alkynyle, leur procede de preparation, leur application comme medicaments et les compositions les renfermant
EP0280618A1 (fr) * 1987-02-18 1988-08-31 Roussel-Uclaf Nouveaux 19-nor stéroîdes substitués en position 7, leur préparation, leur application comme médicaments, les compositions pharmaceutiques les renfermant
FR2610933A1 (fr) * 1987-02-18 1988-08-19 Roussel Uclaf Nouveaux 19-nor steroides substitues en position 7, leur preparation, leur application comme medicaments, les compositions pharmaceutiques les renfermant
CN1057770C (zh) * 1987-03-18 2000-10-25 先灵公司 19,11β－桥甾族化合物在制药中的应用
WO1988007051A1 (en) * 1987-03-18 1988-09-22 Schering Aktiengesellschaft Berlin Und Bergkamen 19, 11beta-BRIDGED STEROIDS, THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING SAME
US5446178A (en) * 1987-03-18 1995-08-29 Schering Aktiengesellschaft Process for preparing 19,11β-bridged steroids
EP0283428A1 (de) * 1987-03-18 1988-09-21 Schering Aktiengesellschaft 19,11beta-Überbrückte Steroide, deren Herstellung und diese enthaltende pharmazeutische Präparate
WO1989000578A1 (en) * 1987-07-16 1989-01-26 Schering Aktiengesellschaft Berlin Und Bergkamen 11beta-PHENYL-4,9,15-ESTRATRIENES, THEIR MANUFACTURE, AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US5132299A (en) * 1987-07-16 1992-07-21 Schering Aktiengesellschaft 11β-phenyl-4,9,15-estratrienes, their manufacture and pharmaceutical preparations containing same
EP0299913A1 (de) * 1987-07-16 1989-01-18 Schering Aktiengesellschaft 11Beta-Phenyl-4,9,15-Estratriene, deren Herstellung und diese enthaltende pharmazeutische Präparate
WO1990000174A1 (de) * 1988-07-01 1990-01-11 Schering Aktiengesellschaft Berlin Und Bergkamen 13-ALKYL-11β-PHENYLGONANE
EP0349481A1 (de) * 1988-07-01 1990-01-03 Schering Aktiengesellschaft 13-Alkyl-11Beta-phenylgonane
US5446036A (en) * 1988-07-01 1995-08-29 Schering Aktiengesellschaft 13-alkyl-11beta-phenylgonanes
US5273971A (en) * 1988-07-01 1993-12-28 Schering Aktiengesellschaft 13-alkyl-11β-phenylgonanes
EP0369881A1 (fr) * 1988-11-16 1990-05-23 Roussel-Uclaf Nouveaux produits dérivés de la structure 3-céto delta-4,9 19-nor stéroides et leur application comme médicaments
FR2643638A1 (fr) * 1989-02-24 1990-08-31 Roussel Uclaf Nouveaux 19-nor steroides ayant en position 11beta une chaine carbonee comportant une fonction amide ou carbamate, leur procede de preparation et les intermediaires de ce procede, leur application comme medicaments et les compositions pharmaceutiques les contenant
FR2665901A2 (fr) * 1989-02-24 1992-02-21 Roussel Uclaf Nouveaux 19-nor sterouides ayant en position 11beta une chaine carbonee comportant une fonction amide, leur preparation, leur application comme medicaments.
EP0384842A1 (fr) * 1989-02-24 1990-08-29 Roussel-Uclaf Nouveaux 19-nor stéroides ayant en position 11béta une chaîne carbonée comportant une fonction amide ou carbamate, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
EP0411733A3 (en) * 1989-08-04 1992-01-22 Schering Aktiengesellschaft Berlin Und Bergkamen 11-beta-aryle-gona-4,9-dien-3-ones
WO1991001958A3 (de) * 1989-08-04 1991-12-12 Schering Ag 11β-ARYL-GONA-4,9-DIEN-3-ONE
FR2659233A1 (fr) * 1990-03-06 1991-09-13 Roussel Uclaf Nouvelle utilisation de composes anti-progestomimetiques chez les animaux d'elevage.
EP0447014A3 (en) * 1990-03-15 1992-04-15 Schering Aktiengesellschaft Berlin Und Bergkamen Process for the preparation of intermediates used in the synthesis of progesterone antagonists (synthesis of onapristone)
US5739125A (en) * 1990-08-15 1998-04-14 Schering Aktiengesellschaft 11 Beta-aryl-gona-4, 9-dien-3-ones
US5407928A (en) * 1990-08-15 1995-04-18 Schering Aktiengesellschaft 11β-aryl-gona-4,9-dien-3-ones
WO1996008505A1 (de) * 1994-09-14 1996-03-21 Schering Aktiengesellschaft Steroidester und -amide, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung
US6596713B1 (en) 1994-09-14 2003-07-22 Schering Aktiengesellschaft Steroid esters and amides, process for their production and their pharmaceutical use
EP0763541A1 (en) * 1995-08-17 1997-03-19 Akzo Nobel N.V. 11-(Substituted phenyl)-estra-4,9-diene derivatives
US6011025A (en) * 1995-08-17 2000-01-04 Akzo Nobel, N.V. 11-(substituted phenyl)-estra-4,9-diene derivatives
CN1129602C (zh) * 1995-08-17 2003-12-03 阿克佐诺贝尔公司 11－(取代的苯基)－雌－4,9－二烯衍生物
US8426394B2 (en) 2008-04-28 2013-04-23 Repros Therapeutics Inc. Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc
US8735381B2 (en) 2008-04-28 2014-05-27 Repros Therapeutics Inc. Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc
WO2011119194A1 (en) * 2010-03-22 2011-09-29 Repros Therapeutics Inc. Compositions and methods for non-toxic delivery of antiprogestins
US10328022B2 (en) 2012-05-31 2019-06-25 Repros Therapeutics Inc. Formulations and methods for vaginal delivery of antiprogestins
US9545411B2 (en) 2012-11-02 2017-01-17 Repros Therapeutics Inc. Methods and compositions for treating progesterone-dependent conditions

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FI80049C (fi) 1990-04-10
GB8305558D0 (en) 1983-03-30
KR840003649A (ko) 1984-09-15
CH657368A5 (fr) 1986-08-29
JPS58201800A (ja) 1983-11-24
ES8401495A1 (es) 1983-12-01
FR2522328A1 (fr) 1983-09-02
JPH0443920B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1992-07-20
LU84667A1 (fr) 1983-09-08
IT8347820A0 (it) 1983-02-28
ZA83982B (en) 1984-03-28
FI830652A0 (fi) 1983-02-28
SU1340593A3 (ru) 1987-09-23
MX7199E (es) 1987-12-23
US4477445A (en) 1984-10-16
JPH054397B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1993-01-19
KR880001870B1 (ko) 1988-09-23
SE8300308D0 (sv) 1983-01-21
GB2118186A (en) 1983-10-26
AT396109B (de) 1993-06-25
DK89783D0 (da) 1983-02-25
US4540686A (en) 1985-09-10
DE3307143A1 (de) 1983-09-08
PH21308A (en) 1987-09-28
GR78465B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1984-09-27
PT76307B (fr) 1986-01-27
YU47883A (en) 1986-04-30
FI80049B (fi) 1989-12-29
FI830652L (fi) 1983-09-02
EG15881A (en) 1991-06-30
HU193269B (en) 1987-09-28
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AU1191383A (en) 1983-09-08
IL67920A0 (en) 1983-06-15
BE896042A (fr) 1983-08-29
MA19716A1 (fr) 1983-10-01
CA1206471A (fr) 1986-06-24
NL8300738A (nl) 1983-10-03
IE830429L (en) 1983-09-01
PT76307A (fr) 1983-03-01
AR241187A1 (es) 1992-01-31
AU562739B2 (en) 1987-06-18
ES520195A0 (es) 1983-12-01
FR2522328B1 (fr) 1986-02-14
ATA71183A (de) 1992-10-15
IE54748B1 (en) 1990-01-31
GB2118186B (en) 1986-04-23
DK89783A (da) 1983-09-02
JPH02275895A (ja) 1990-11-09
IT1197592B (it) 1988-12-06

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