WO1998050415A1 - Pregnan 3,20 diol mono- et di-sulfates - Google Patents

Pregnan 3,20 diol mono- et di-sulfates Download PDF

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Publication number
WO1998050415A1
WO1998050415A1 PCT/US1998/008485 US9808485W WO9850415A1 WO 1998050415 A1 WO1998050415 A1 WO 1998050415A1 US 9808485 W US9808485 W US 9808485W WO 9850415 A1 WO9850415 A1 WO 9850415A1
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WO
WIPO (PCT)
Prior art keywords
pregnan
diol
sulfate ester
compound
salt
Prior art date
Application number
PCT/US1998/008485
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English (en)
Inventor
Reinhold Hans Wilhelm Bender
Horace Fletcher, Iii
Wenzhong James Huang
Michael Z. Kagan
Syed Muzafar Shah
Original Assignee
American Home Products Corporation
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 American Home Products Corporation filed Critical American Home Products Corporation
Priority to JP54816298A priority Critical patent/JP2001523268A/ja
Priority to BR9809380-0A priority patent/BR9809380A/pt
Priority to CA002289095A priority patent/CA2289095A1/fr
Priority to KR19997010101A priority patent/KR20010012156A/ko
Priority to AU71658/98A priority patent/AU7165898A/en
Priority to EP98918804A priority patent/EP0980384A1/fr
Publication of WO1998050415A1 publication Critical patent/WO1998050415A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • 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
    • C07J7/007—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 not substituted in position 17 alfa
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders.
  • the estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17- ⁇ -estradiol, dihydroequilenin and 17- ⁇ -dihydroequilenin (U.S. Patent 2,834,712).
  • the estrogenic compositions are usually buffered or stabilized with alkali metal salts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5.
  • Urea has also been used as a stabilizer (U.S. 3,608,077).
  • the incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. 4,154,820.
  • R and R 1 are each, independently, hydrogen or SO 3 " X ;
  • X + is alkali metal, alkaline earth metal, ammonium, alkylammonium containing 1-6 carbon atoms, dialkylammonium containing 1-6 carbon atoms in each alkyl group, trialkylammonium containing 1-6 carbon atoms in each alkyl group or tetraalkylammonium salts containing 1-6 carbon atoms in each alkyl group; with the proviso that R and R 1 are not both hydrogen.
  • Alkali metal salts include sodium and potassium salts, particularly preferred are sodium salts.
  • Alkaline earth metal salts include calcium and magnesium salts.
  • Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl, preferred alkyl groups being methyl and ethyl. Where more than one alkyl group is present the groups may be the same or different.
  • Preferred trialkylammonium salts are trimethyl- ammonium salts and triethylammonium salts.
  • the salts of the invention are preferably in greater than 1 percent purity.
  • this invention also provides 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol 3-sulfate ester sodium salt in greater than 1 percent purity, 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol 20-sulfate ester sodium salt in greater than 1 percent purity, and 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol 3,20-(bis)sulfate ester (bis)sodium salt in greater than one percent purity.
  • This invention also provides a compound consisting essentially of 5 -pregnan- 3 ⁇ ,20 ⁇ -diol 3-sulfate ester sodium salt, a compound consisting essentially of 5 - pregnan-3 ⁇ ,20 ⁇ -diol 20-sulfate ester sodium salt, and a compound consisting essentially of 5 -pregnan-3 ⁇ ,20 ⁇ -diol 3,20-(bis)sulfate ester (bis)sodium salt.
  • This invention further provides a composition of matter consisting essentially of a compound having the formula
  • R and R 1 are each, independently, hydrogen or SO 3 " X ;
  • X is alkali metal, alkaline earth metal, ammonium, alkylammonium containing 1-6 carbon atoms, dialkylammonium containing 1-6 carbon atoms in each alkyl group, trialkylammonium containing 1-6 carbon atoms in each alkyl group or tetraalkylammonium salts containing 1-6 carbon atoms in each alkyl group; with the proviso that R and R 1 are not both hydrogen.
  • This invention additionally provides a method of using a compound having the formula
  • R and R 1 are each, independently, hydrogen, SO3H or SO3 " X + ;
  • X is alkali metal, alkaline earth metal, ammonium, alkylammonium containing 1-6 carbon atoms, dialkylammonium containing 1-6 carbon atoms in each alkyl group, trialkylammonium containing 1-6 carbon atoms in each alkyl group or tetraalkylammonium salts containing 1-6 carbon atoms in each alkyl group; as a progestational agent.
  • the present invention further provides compositions comprising a compound of formula I. In particular it provides compositions comprising at least 1 % of a compound of formula I.
  • One aspect of the present invention provides compositions wherein the only progestational agent is a compound of formula I.
  • Embodiments of the present invention include compositions wherein the only active compound is a compound of formula I. In these embodiments other excipients and carriers may be included but no further active materials are included.
  • the present invention also provides processes for the preparation of the compounds of formula I. It provides processes for the preparation of 5 ⁇ -pregnan-3,20-diol 3,20- (bis)sulfate ester (bis) salt (i.e. compounds wherein A and B are each independently a sulphate ester salt) which comprise:
  • 5oc-pregnan-3,20-diol-3,20-(bis)sulfate ester may be converted to pharmaceutically acceptable salts by neutralising the acid with an appropriate base, e.g. with an alkali metal carbonate, an alkaline earth metal carbonate or a primary, secondary, tertiary or quaternary amine carbonate.
  • Alkali metal or alkaline earth metal salts may be prepared by using the appropriate alkali metal hydride e.g. sodium hydride, potassium hydride or lithium hydride.
  • 3,20-(bis)sulfate ester may be converted to a different pharmaceutically acceptable salt by displacement, by using an ion exchange resin or by double decomposition (metastasis).
  • Displacement of a weak base with a stronger one may be utilised to convert, e.g. an amine salt to an alkali metal salt or an alkaline earth metal salt using an appropriate base, e.g. a hydroxide.
  • a trialkylamine salt such as a triethylamine salt may be converted to an alkali metal salt such as a sodium salt by treating it with an alkali metal hydroxide such as aqueous sodium hydroxide.
  • the displacement may be carried out using an ion exchange resin.
  • one salt may be converted to another by double decomposition, e.g. an alkaline earth metal salt such as the calcium salt may be replaced with an alkali metal salt.
  • an alkaline earth metal salt such as the calcium salt may be replaced with an alkali metal salt.
  • the calcium salt of the 5 ⁇ -pregnan-3,20-diol 3,20-(bis)sulfate ester may be dissolved in water followed by the addition of e.g. sodium carbonate. Insoluble calcium carbonate would then precipitate out to provide the sodium salt of the desired 5 -pregnan-3,20-diol 3,20- (bis)sulfate ester.
  • a pharmaceutically acceptable salt of the desired 5 ⁇ -pregnan-3,20-diol-3,20- (bis)sulfate ester may be prepared by directly converting the appropriate 5 ⁇ -pregnan- 3,20-diol. This may be performed by reacting it with the appropriate aminesulfur- trioxide complex, e.g. by reacting it with a trialkylaminesulfurtrioxide (such as triethyl- aminesulfurtrioxide complex) to provide the corresponding trialkylamine salt (such as the triethylamine salt). If desired the salt may then be converted to another salt of the invention as described above.
  • the invention also provides processes for the preparation of 5 ⁇ -pregnan-3,20- diol-3-sulfate ester salts or 5 ⁇ -pregnan-3,20-diol-20-sulfate ester salts (i.e., compounds wherein one of A and B is a sulphate ester salt and the other is hydrogen) which comprise:
  • the conversion of the appropriate 5 ⁇ -pregnan-3,20-diol-mono sulfate ester to a pharmaceutically acceptable salt and the conversion of a pharmaceutically acceptable salt of the appropriate 5 ⁇ -pregnan-3,20-diol-mono sulfate ester to a different pharmaceutically acceptable salt of the appropriate the appropriate 5 ⁇ -pregnan-3,20- diol-mono sulfate ester may be performed by analogy to the methods described above.
  • 5 -pregnan-3-ol,20-keto mono sulfate ester salt or 5 -pregnan-3-keto-20-ol mono sulfate ester salt may be converted to the desired 5 ⁇ -pregnan-3,20-diol-mono- sulfate ester salt by reduction with a suitable reducing agent, e.g. IJBH4. If desired one steroisomer may be converted another by inversion, e.g. by a MITSUNOBU inversion.
  • 5 -pregnan-3,20-diol may be converted directly to the desired pharmaceutically acceptable salt of the desired 5 ⁇ -pregnan-3,20-diol-monosulfate ester by analogy to the methods described above.
  • the invention also provides processes for the preparation of the free sulfate acids esters of formula I (i.e. compounds wherein at least one of A and B is a free sulphate acid) which comprises sulphonating the corresponding hydroxy compounds using, e.g. sulphuric acid, chloro-sulphuric acid or an amidosulfonic acid. Alternatively the pH of a salt of the corresponding mono or bis sulfate may be adjusted to provide the desired free acid.
  • the invention also provides processes for the preparation of 5 ⁇ -pregnan-3,20-diol (i.e. compounds wherein both A and B are hydroxy groups) which comprises the reduction of the corresponding 3,20-di-keto compound using a suitable reducing agent, e.g. IJBH4.
  • the present invention also provides a compound of formula I prepared by a chemical process, particularly those prepared according to the processes described above.
  • the invention also provides a compound of formula I obtainable by such processes.
  • the compounds of this invention can be prepared from readily available starting materials according to the processes in Scheme I-III.
  • Scheme I commercially available 5 ⁇ -pregnane-3 ⁇ , 20 ⁇ -diol (1) [D.M. Glick and H . Hirschmann, J. Org. Chem. 27, 3212 (1962)] is treated with two or more equivalents of triethylamine: sulfur trioxide reagent in a suitable solvent such as tetrahydrofuran at room temperature to afford 5 ⁇ -pregnan-3 ⁇ , 20 ⁇ -diol (bis)sulfate, (bis)triethylammo- nium salt (2a).
  • the triethylammonium salt (2a) is converted to the sodium salt (2b) by ion exchange chromotography (Dowex 50X8, Na+form).
  • 5 ⁇ -pregnane-3 ⁇ ,20b-diol-20-acetate (6) [prepared from 5 ⁇ -pregnan-3 ⁇ , 20 ⁇ -diol-diacetate according to the procedure of A. Butenandt and J. Schmidt, Chem. Ber. 67, 1893 (1934)] is treated with one or more equivalents of triethylamine: sulfur trioxide reagent to afford 5 ⁇ -pregnan-3 ⁇ , 20 ⁇ -diol-20-acetate-3- sulfate, triethylammonium salt (7).
  • the triethylammonium salt (7) is treated with methanol/aqueous sodium hydroxide to afford 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol-3-sulfate, sodium salt (8).
  • the results of these standard pharmacological test procedures demonstrate that the compounds of this invention are progestational.
  • the progestational activity of a compound is quantified based on its stimulation of alkaline phosphatase enzyme activity in T47D cells, a human breast cancer cell line which expresses high levels of progesterone receptors.
  • This is a well established test procedure in which both the progestin receptors and the response stimulated by activated progestin receptors are endogenous to the cells. Cells are pre-conditioned in low serum medium for one day and then treated with test compounds. Alkaline phosphatase activity is measured 24 hr after treatment.
  • progestins such as progesterone and medroxyprogesterone acetate, induce a 30 - 60 fold induction of alkaline phosphatase requiring only low nanomolar concentrations for activity.
  • the alkaline phosphatase activity induced by progestins is blocked or inhibited by progestin receptor antagonists such as RU486 indicating the specificity of the response.
  • progestin receptor antagonists such as RU486 indicating the specificity of the response.
  • 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol had an IC 5Q of 5 xlO "5 demonstrating progestational activity.
  • the neuroprotective and cognition enhancing effects of the compounds of this invention were evaluated in an in vitro standard pharmacological test procedure which measured the effects of 5 ⁇ -pregnan-3 ⁇ ,20 ⁇ -diol, as a representative compound of this invention, on calcium and potassium channel currents. Briefly, the following procedure was used.
  • the compounds of this invention are progestational agents. Based on the results obained in the standard pharmacological test procedures, the compounds of the invention are useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis luteal phase defects, benign breast and prostatic diseases and prostatic and endometrial cancers.
  • the compounds of this invention are also useful in protecting against epileptic seizures, in cognition enhancement, in treating Alzheimer's disease, dementias, vasomotor symtpoms related to menopause, and other central nervous system disorders
  • the compounds of this invention are futher useful in stimulating erythropoises.
  • the compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or and androgens.
  • the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
  • the pharmaceutical carrier may be solid or liquid.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. - I l ⁇
  • liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds of this invention can also be administered orally either in liquid or solid composition form.
  • the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermiable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 ⁇ g kg - 750 ⁇ g/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the crude triethylammonium salt (4) was dissolved in 300 ml of methanol and 100 ml of IN sodium hydroxide was added. The mixture was stirred 72 hours and the crude product was filtered on a Buchner funnel and dried in vacuo for 20 hours. The material was stirred in 100 ml of methanol and filtered. The filtrate was diluted with 400 ml of ether, stirred 18 hours and filtered on a Buchner funnel to provide the title compound as a white solid (3.6g, 48%).
  • 5 ⁇ -Pregnan-3 ⁇ , 20- ⁇ -diol-20-acetate (6) prepared from commercially available 5 ⁇ - Pregnan-3 ⁇ , 20 ⁇ -diol diacetate according to A. Butenandt, J. Schmidt, Chem. Ber. 67. 1893 (1934) (.75g, 21mmol) was dissolved in 10 ml of tetrahydrofuran and triethylamine sulfur trioxide complex (0.45g, 25 mmol) was added. The mixture was stirred at room temperature for 20 hours.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un composé de la formule: dans laquelle R et R1 sont chacun, indépendamment, hydrogène ou SO¿3??-X+; X+¿ est un métal alcalin, un métal alcalino-terreux, un ammonium, un alkylammonium renfermant de 1 à 6 atomes de carbone, ou un dialkylammonium renfermant de 1 à 6 atomes de carbone dans chaque groupe alkyle, ou un trialkylammonium renfermant de 1 à 6 atomes de carbone dans chaque groupe alkyle; à condition que R et R1 ne soient pas tous deux hydrogène, ledit composé étant utilisé comme progestatif.
PCT/US1998/008485 1997-05-02 1998-04-28 Pregnan 3,20 diol mono- et di-sulfates WO1998050415A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP54816298A JP2001523268A (ja) 1997-05-02 1998-04-28 プレグナン−３，２０−ジオールのモノおよびジ硫酸エステル
BR9809380-0A BR9809380A (pt) 1997-05-02 1998-04-28 Mono e dissulfatos de 3,20 diol pregnano
CA002289095A CA2289095A1 (fr) 1997-05-02 1998-04-28 Pregnan 3,20 diol mono- et di-sulfates
KR19997010101A KR20010012156A (ko) 1997-05-02 1998-04-28 프레그난-3,20-디올 모노- 및 디-설페이트
AU71658/98A AU7165898A (en) 1997-05-02 1998-04-28 Pregnane 3,2o diol mono- and di-sulphates
EP98918804A EP0980384A1 (fr) 1997-05-02 1998-04-28 Pregnan 3,20 diol mono- et di-sulfates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85087697A 1997-05-02 1997-05-02
US08/850,876 1997-05-02

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JP (1) JP2001523268A (fr)
KR (1) KR20010012156A (fr)
CN (1) CN1254343A (fr)
AR (1) AR012636A1 (fr)
AU (1) AU7165898A (fr)
BR (1) BR9809380A (fr)
CA (1) CA2289095A1 (fr)
TW (1) TW434017B (fr)
WO (1) WO1998050415A1 (fr)
ZA (1) ZA983702B (fr)

Cited By (1)

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Publication number Priority date Publication date Assignee Title
EP1594510A2 (fr) * 2003-01-21 2005-11-16 Dimera Inc. Procede et kit pour reduire les symptomes des troubles du systeme vasculaire peripherique

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US3895103A (en) * 1971-11-22 1975-07-15 Alza Corp Intrauterine contraceptive device containing certain pharmaceutically acceptable steroids
WO1993005786A1 (fr) * 1991-09-13 1993-04-01 Cocensys, Inc. Nouveau recepteur a gabaa presentant des sites de liaison de steroides

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Publication number Priority date Publication date Assignee Title
US3895103A (en) * 1971-11-22 1975-07-15 Alza Corp Intrauterine contraceptive device containing certain pharmaceutically acceptable steroids
WO1993005786A1 (fr) * 1991-09-13 1993-04-01 Cocensys, Inc. Nouveau recepteur a gabaa presentant des sites de liaison de steroides

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CHEMICAL ABSTRACTS, vol. 125, no. 25, 16 December 1996, Columbus, Ohio, US; abstract no. 317832, SCHUTZER W E ET AL: "Differential effect of trilostane on the progestin milieu in the pregnant mare" page 230; column 2; XP002072245 *
CHEMICAL ABSTRACTS, vol. 88, no. 1, 2 January 1978, Columbus, Ohio, US; abstract no. 3403, S. TESHIMA ET AL: "Studies on Steroid Metabolism in the Echinoderm Asterias rubens" page 314; column 2; XP002072246 *
H. HIRSCHMANN ET AL: "The Isolation of 5.alpha.-Pregnane-3.beta.,20.beta.-diol 20-Sulfate and its Hydrolysis to Urandiol", JOURNAL OF BIOLOGICAL CHEMISTRY., vol. 238, 1963, MD US, pages 2305 - 2308, XP002072241 *
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NATO CONF. SER. [SER.] 4, 1977, 1 (MAR. NAT. PROD. CHEM.), 1977, pages 133 - 136 *
SEELEY D H ET AL: "Molecular interactions of progesterone analogs with rabbit uterine cytoplasmic receptor", JOURNAL OF BIOLOGICAL CHEMISTRY., vol. 257, no. 22, 25 November 1982 (1982-11-25), MD US, pages 13359 - 13366, XP002072244 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1594510A2 (fr) * 2003-01-21 2005-11-16 Dimera Inc. Procede et kit pour reduire les symptomes des troubles du systeme vasculaire peripherique
EP1594510A4 (fr) * 2003-01-21 2008-07-23 Dimera Inc Procede et kit pour reduire les symptomes des troubles du systeme vasculaire peripherique
US7572780B2 (en) 2003-01-21 2009-08-11 Dimera, Incorporated Method and kit for reducing the symptoms of peripheral vascular disease
US8182833B2 (en) 2003-01-21 2012-05-22 Dimera Incorporated Method and kit for reducing the symptoms of peripheral vascular disease with topical progesterone
US8420111B2 (en) 2003-01-21 2013-04-16 Dimera Incorporated Method and kit for reducing the symptoms of peripheral vascular disease

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JP2001523268A (ja) 2001-11-20
TW434017B (en) 2001-05-16
ZA983702B (en) 1999-11-01
AR012636A1 (es) 2000-11-08
BR9809380A (pt) 2000-07-04
CA2289095A1 (fr) 1998-11-12
EP0980384A1 (fr) 2000-02-23
CN1254343A (zh) 2000-05-24
KR20010012156A (ko) 2001-02-15
AU7165898A (en) 1998-11-27

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