EP1631580A2 - Verfahren zur herstellung von dhea-derivaten - Google Patents

Verfahren zur herstellung von dhea-derivaten

Info

Publication number
EP1631580A2
EP1631580A2 EP04742438A EP04742438A EP1631580A2 EP 1631580 A2 EP1631580 A2 EP 1631580A2 EP 04742438 A EP04742438 A EP 04742438A EP 04742438 A EP04742438 A EP 04742438A EP 1631580 A2 EP1631580 A2 EP 1631580A2
Authority
EP
European Patent Office
Prior art keywords
group
formula
dhea
cyclic
saturated
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.)
Withdrawn
Application number
EP04742438A
Other languages
English (en)
French (fr)
Inventor
Marc Criton
Damien Gloux
Jean-Louis Montero
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.)
Laboratories Mayoly Spindler SAS
Original Assignee
Laboratories Mayoly Spindler SAS
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 Laboratories Mayoly Spindler SAS filed Critical Laboratories Mayoly Spindler SAS
Publication of EP1631580A2 publication Critical patent/EP1631580A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the invention relates to new processes for the preparation of DHEA derivatives from DHEA itself.
  • the invention relates in particular to new methods for preparing 7- ⁇ -hydroxy dehydroepiandrosterone (7- ⁇ -OH-DHEA), 7- ⁇ -hydroxy dehydroepiandrosterone (7- ⁇ -OH-DHEA) ), 7-oxo-dehydroepiandrosterone (7-oxo-DHEA).
  • DHEA is a natural steroid produced primarily by the adrenal cortex. DHEA administered topically or orally is known for its ability to promote keratinization of the epidemic (JP-07 196467).
  • hydroxylated derivatives 7 increase the proliferation of fibroblasts and the viability of keratinocytes and are endowed with anti-radical activity (WO 98/40074).
  • Document FR 2 771 105-A1 describes a process for the preparation of 7 ⁇ -OH-DHEA by bioconversion from Fusarium moniliforme.
  • the toxins secreted by it can be very dangerous for humans.
  • the document FR 2 793 491-A1 relates to the obtaining in two stages of 7 ⁇ -OH-DHEA.
  • the allylic oxidation of 3-O-acetyl-DHEA using copper catalysts and a perester (tert-butylperbenzoate) leads to the diester (3 ⁇ -acetate, 7 ⁇ -benzoate-dehydroxyandrost-5ene-17-one ) in the form of the stereospecifically pure ⁇ -isomer.
  • the latter after treatment with sodium methanolate leads to 7 ⁇ -OH-DHEA.
  • the document FR 2 820 745-A1 proposes synthesis methods in 3 and 5 stages.
  • the synthesis in 3 stages consists in carrying out an oxidation on the allylic position of 3-O-acetyl-DHEA to obtain the acetylated derivative 3 of 7-oxo DHEA.
  • FIG. 1 illustrates a process which makes it possible to obtain 7-oxo-DHEA in four stages from DHEA:
  • the ketone function in position 17 of the DHEA is optionally protected by an appropriate protective group.
  • step 1 When you simply want to obtain 7-oxo-DHEA, the protection of the ketone in position 17 (step 1), and its subsequent deprotection (step 1)
  • the process of the invention differs from the processes of the prior art, in particular in that a hemiester or a di-ester (III) of a diacid is used.
  • formula (II) and DHEA to prepare 7-oxo-DHEA, 7- ⁇ -hydroxy-DHEA and 7- ⁇ -hydroxy-DHEA.
  • esters (III) has several advantages over the compounds of the prior art: - better oxidation yields of the intermediate products which are easier to purify, these products generally being obtained by recrystallization.
  • the elongation of the chain in position 3 clogs the ⁇ side and makes it possible to increase the diasteroselectivity of the reduction of 7-oxo derivatives to 7 ⁇ hydroxy by NaBH 4 without necessarily adding ceric chloride (CeCl 3 ).
  • DHEA (1) is first of all optionally protected in position 17, preferably in the form of a cyclic acetal.
  • R h R 2 -O-CH 2 -CH 2 -O-
  • DHEA (1) is treated with ethylene glycol, at reflux of toluene, in the presence of paratoluene sulfonic acid using a Dean Stark device.
  • the protected product is obtained by recrystallization from an alcoholic solution (methanol or ethanol for example).
  • the acetalization in position 17 of the DHEA can be omitted.
  • Ri, R taken together represent O. This is particularly the case when the synthesis stops at the oxidation at position 7 of DHEA.
  • X represents a single bond or a group chosen from -
  • the third step of the process illustrated in Figure 1 is the oxidation in position 7 (allylic) of the DHEA cycle.
  • Allylic oxidation is a well-known reaction in organic chemistry. Some of the methods used suffer from low yields, delicate processing conditions (reaction conditions, temperature, treatment, etc.), the use of expensive and / or ecologically and physiologically undesirable reagents, such as chromium.
  • the present invention provides an oxidation process in a O 2004 0
  • organic solvent using oxygen, photons and a photochemical sensitizer using oxygen, photons and a photochemical sensitizer.
  • the compounds of formula (III) undergo an allylic oxidation by photo oxidation using a lamp and under bubbling oxygen (or compressed air) in the presence of Bengal rose.
  • a sodium lamp is used.
  • the corresponding 5-hydroperoxide is thus obtained, which is easily converted into 7-hydroperoxide and then into 7-oxo by treatment with CuCl 2 in pyridine or, advantageously, with acetic anhydride in pyridine, as illustrated in Figure 1 below.
  • X represents a single bond or a group chosen from - (CH 2 ) -, C 2 -C 20 alkyls, saturated or unsaturated, linear, branched or cyclic, C 6 -C 0 aryls, C 8 aralkyls -C 20 , are new products, and constitute another object of the invention.
  • the compound (IV) can then be deprotected in a conventional manner by treatment with sodium methanolate in methanol (deprotection of the protective group R of the alcohol in position 3) and optionally treatment with a solution of perchloric acid (deprotection of the ketone in position 17 when it has been protected).
  • the ketone of formula (IV) can be used to prepare 7- ⁇ -OH-DHEA (4) and 7- ⁇ -OH-DHEA (3).
  • the compounds of formula (IV) whose position 17 is protected by an acetal (Ri, R 2 represent -OWO-), can be reduced diastereoselectively with Lithium known under the trade name of L-Selectride®, at low temperature to lead to the corresponding 7 ⁇ OH derivatives which correspond to formula (VI) (step 6).
  • Position 17 can be subsequently unprotected in a known manner.
  • X represents a single bond or a group chosen from - (CH 2 ) -, C 2 -C 20 alkyls, saturated or unsaturated, linear, branched or cyclic, C 6 -C 20 aryls, C 8 aralkyls -C 20 , are new products, and constitute another object of the invention.
  • the compounds of formula (VI) are deprotected in position 3 by transesterification by treatment with sodium methanolate in methanol.
  • Deprotection of the acetal in position 17 is carried out by treatment with a solution of perchloric acid and makes it possible to obtain 7 ⁇ OH DHEA (4).
  • the compounds of formula (IV) and whose function 17 is protected (R], R 2 represent -OWO-) can be reduced diastereoselectively by treatment with NaBH in the presence of ceric chloride to lead to the hydroxylated 7 ⁇ derivatives of formula (V) (step 5).
  • Position 17 can be subsequently unprotected in a known manner.
  • the compounds of formula (V) can undergo a configuration inversion to lead to the 7 ⁇ hydroxy or ester derivatives of formula (VI) and vice versa.
  • the present invention proposes two ways:
  • the first way implements a configuration inversion of 7 ⁇ hydroxyl to 7 ⁇ hydroxyl, or vice versa, using the diethyl azodicarboxylate / triphenylphosphine and carboxylic acid system (and more particularly para nitro benzoic acid) or the N, N, N ', N'-tetramethylazodicarboxamide system and tributyl phosphine in the presence of para methoxy benzoic acid.
  • para methoxybenzoic acid can be replaced by a carboxylic acid chosen from those corresponding to the formula R 5 CO H where R 5 can be chosen from the compounds corresponding to the formula R 4 PI1, Ri being chosen from H-, NO 2 -, CH 3 O-, CN-, Cl-, Br-, F- and R 5 can also be chosen from the group consisting of: CH 3 -, C1CH 2 -, C1 2 CH-, C1 3 C-, CH 3 CH 2 -.
  • Another way of preparing 7 ⁇ OH DHEA by inversion of 7 ⁇ derivatives can be used in the process of the invention. It consists of introduce a good group leaving at position 7 of the 7 ⁇ OH, using methane sulfonyl chloride (MsCl), para toluene sulfonyl chloride (TsCl) or trifluoromethane sulfonyl chloride (TfCl) then carry out an inversion of Walden by a SN 2 nucleophilic substitution in basic medium (OH " ) (step 7).
  • MsCl methane sulfonyl chloride
  • TsCl para toluene sulfonyl chloride
  • TfCl trifluoromethane sulfonyl chloride
  • the leaving group can be displaced by the alkaline salt of a carboxylic acid (cesium, sodium or potassium) to lead to the corresponding diester.
  • the carboxylic acid will be chosen from compounds corresponding to the formula R 5 CO 2 H, where R 5 can be chosen from the compounds corresponding to the formula RiPh, in which R 4 can be chosen from, H-, NO 2 -, CH 3 O-, CN-, Cl-, Br-, F- and R 5 can also be chosen from the group consisting of: CH 3 -, C1CH -, CI2CH-, CI 3 C-, CH 3 CH2-.
  • reaction could be carried out conventionally or be accelerated by ultrasonic activation.
  • the intermediate compounds in the Mitsunobu reactions can be represented by the formulas Vbis and VIbis below:
  • the compounds of formula (VI) are deprotected by transesterification by treatment with sodium methanolate in methanol (step 8).
  • Deprotection of the carbonyl in position 17 protected by an acetal is carried out by treatment with a solution of perchloric acid and thus makes it possible to obtain 7 ⁇ OH DHEA.
  • R represents the hydrogen atom or a group of formula (II bis):
  • W represents a linear, branched or cyclic, saturated or unsaturated C 2 -C 8 alkyl group; preferably R], 2 represents -O-CH 2 -CH 2 -O-,
  • R represents a group of formula (II ter) HO-OC- (X) -CO- (II ter) in which X represents a single bond or a group chosen from - (CH 2 ) -, C 2 -C 20 alkyls , saturated or unsaturated, linear, branched or cyclic, C 6 -C 20 aryls, Cs-C 2 o aralkyls;
  • the compounds of formula (VII) have an acid function carboxylic acid which can be used for coupling to another molecule which can be chosen in particular from cosmetic active principles comprising at least one function capable of forming a covalent bond with the carboxylic acid function. This is the case for example with retinol, ⁇ hydroxy acids, ⁇ keto acids.
  • a molecule active in cosmetics or in dermatology comprising at least one alcohol function or one amino function is grafted onto the molecule (VII) via its carboxylic acid function, so as to form either an ester function or a function.
  • amide If the active molecule has other functionalities capable of reacting during coupling with the molecule (VII), these are advantageously protected using an appropriate protective group according to methods well known to those skilled in the art ( case of ⁇ hydroxy acids for example).
  • MA denotes a molecule active in cosmetics, such as retinol for its cosmetic properties (anti-wrinkle, anti-aging), ⁇ hydroxy acids or ⁇ keto acids for their exfoliating properties, -bisabolol for its anti-inflammatory properties, the whole trans farnesol for its bacteriostatic properties, ⁇ -tocopherol for its antioxidant properties, an amino acid such as especially natural amino acids.
  • a further subject of the invention is cosmetic and / or dermatological compositions comprising at least one compound of formula (VIII) in a support cosmetically and / or dermatologically acceptable.
  • compositions are intended in particular to prevent and / or delay and / or treat the appearance of the signs of skin aging.
  • Paratoluene sulfonic acid (0.29 g, 1.5) is added to a solution of DHEA (50 g, 0.173 mol) in toluene (170 ml) placed in a three-necked flask surmounted by a Dean Stark and a condenser. mmol) and ethylene glycol (65 ml, 1.17 mol) and the whole is brought to reflux. The reaction mixture is left stirring for 4 hours, the mixture is allowed to return to ambient temperature, then sodium bicarbonate (100 mg) is added. The residual ethylene glycol is removed by simple decantation and the organic phase is concentrated. The resulting oil is taken up in ethyl acetate (300 ml).
  • Adipic acid (5 g - 1 eq - 34.21 mmol) dissolved in 50 ml of pyridine is treated with para toluene sulfonyl chloride (11.91 g - 0.9 eq - 31.2 mmol). The whole is left under stirring at 0 ° C for 30 minutes. To the resulting reaction mixture is added dropwise DHEA (2.81 g - 0.28 eq - 9.77 mmol) dissolved in 60 ml of pyridine. After 4 hours of stirring at room temperature, 250 ml of water are added to the reaction mixture and the whole is extracted three times with ethyl acetate.
  • DHEA hemi succinate (1 g - 1 eq - 2.57 mmol) and N, N'- carbonyldiimidazole (0.83 g - 2 eq - 5.14 mmol) are dissolved in 60 ml of anhydrous THF and the whole is left at room temperature and with stirring for 12 hours.
  • DHEA (3.7 g - 5 eq - 12.85 mmol) is then added and the whole is brought to reflux for eight hours.
  • the reaction mixture is then cooled, diluted with 200 ml of water and then extracted with chloroform.
  • the organic phase is washed with water, dried with sodium sulfate and then concentrated in vacuo.
  • the resulting crude product is purified by chromatography on a column of silica gel (hexane / AcOEt 97.5 / 2.5) then recrystallized from methanol to yield the corresponding diester with a yield of 24%
  • the dimer can be obtained by treating the hemi ester of DHEA with thionyl chloride and DHEA.
  • the reaction medium is poured into a 5% aqueous solution of sodium bicarbonate.
  • the two phases are separated, the aqueous phase is washed with 100 ml of dichloromethane.
  • the organic phases are combined, washed with water, dried over sodium sulfate and then concentrated in vacuo.
  • the resulting crude product is purified by chromatography on a column of silica gel (hexane / AcOEt 97.5 / 2.5) then recrystallized from methanol to yield the corresponding diester with a yield of 32%
  • the precipitate of N-hydroxyphthalimide is filtered and the filtrate is washed with a saturated sodium bicarbonate solution, with a sodium chloride solution and finally with water.
  • the organic phase is dried over magnesium sulfate and then concentrated in vacuo.
  • the resulting crude product is taken up with pyridine (150 ml) and is then added dropwise to acetic anhydride (75 ml). The reaction is left under stirring and at room temperature for 15 hours.
  • the pyridine is concentrated under vacuum, the resulting crude product is taken up with ethyl acetate (100 ml), the organic phase is washed twice with water, twice with a saturated solution in sodium chloride, it is dried over magnesium sulfate, then concentrated in vacuo. Recrystallization from a minimum of methanol makes it possible to obtain the desired product with a yield of 44%
  • the compounds of formula (IV) are first deprotected by treatment with sodium methanolate in methanol to yield the derivative 3 ⁇ hydroxy 7-oxo 17 dioxolane DHEA
  • the derivative 3 ⁇ -hydroxy-17, 17-ethylenedioxy-DHEA (1.5 g - 0.43 mmol) is dissolved in 38 ml of acetone, is then added 67.5 ml of water and 21.5 ml of an aqueous solution at 0.1% in perchloric acid.
  • the reaction mixture is left stirring for 20 hours at room temperature.
  • a 5% sodium bicarbonate solution is added (100 ml).
  • the acetone is removed under vacuum and the aqueous phase and extracted with dichloromethane (3 x 10 ml).
  • the sentence organic is concentrated under vacuum and the resulting crude product is recrystallized from methanol to yield the desired product with a yield of 65%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
EP04742438A 2003-04-07 2004-04-06 Verfahren zur herstellung von dhea-derivaten Withdrawn EP1631580A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0304282A FR2853318A1 (fr) 2003-04-07 2003-04-07 Nouveaux procedes de preparation de derives de la dhea
PCT/FR2004/000847 WO2004091474A2 (fr) 2003-04-07 2004-04-06 Procedes de preparation de derives de la dhea

Publications (1)

Publication Number Publication Date
EP1631580A2 true EP1631580A2 (de) 2006-03-08

Family

ID=32982279

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04742438A Withdrawn EP1631580A2 (de) 2003-04-07 2004-04-06 Verfahren zur herstellung von dhea-derivaten

Country Status (5)

Country Link
US (1) US20070032462A1 (de)
EP (1) EP1631580A2 (de)
JP (1) JP2006522078A (de)
FR (1) FR2853318A1 (de)
WO (1) WO2004091474A2 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2986634B1 (de) 2013-04-19 2019-11-20 University of Houston System Cokristalline dhea-formulierungen
CN106632220A (zh) * 2016-12-12 2017-05-10 荆楚理工学院 一种伏立诺他中间体辛二酸酐的制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2746041B2 (ja) * 1992-02-14 1998-04-28 三菱化学株式会社 新規なステロイド誘導体
US5736537A (en) * 1995-09-12 1998-04-07 Estee Lauder, Inc. Dehydroep:androsterone sailcylate useful against skin atrophy
FR2806725B1 (fr) * 2000-03-27 2005-06-17 Oreal Derives de dehydroepiandrosterone, leur procede de preparation et leurs utilisations, notamment cosmetiques
FR2820745A1 (fr) * 2001-02-14 2002-08-16 Oreal Procedes de preparation de la 7alpha-hydroxy- dehydroepiandrosterone
CN1135983C (zh) * 2001-06-28 2004-01-28 中山大学 二酸（5－雄甾烯－17－酮－3β－羟基）二酯用于制备药物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004091474A2 *

Also Published As

Publication number Publication date
JP2006522078A (ja) 2006-09-28
WO2004091474A3 (fr) 2004-12-16
FR2853318A1 (fr) 2004-10-08
WO2004091474A2 (fr) 2004-10-28
US20070032462A1 (en) 2007-02-08

Similar Documents

Publication Publication Date Title
FR2529888A1 (fr) Composes 1a-hydroxyles
FR2540869A1 (fr) Procede pour la preparation de derives hydroxyles de la vitamine d2 et produits intermediaires utilises dans ce procede
WO1991013066A2 (fr) PROCEDE DE PREPARATION DE L'ACIDE CIS-β-PHENYLGLYCIDIQUE-(2R,3R)
CH653668A5 (fr) Derives du cyclopropane, leur procede de preparation, agents parfumants constitues par lesdits composes et compositions parfumantes les renfermant.
EP0004493B1 (de) Äther deren organische Reste asymmetrische Atome enthalten, Verfahren zu ihrer Herstellung und ihre Anwendung zur Spaltung von Alkoholen, Phenolen oder gewissen Verbindungen mit Laktonstruktur
EP0508842A1 (de) Acylaminophenolderivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP2903697B1 (de) Verfahren zur synthese von cyclohexenonen und verwendung davon in der parfümindustrie
JP2550391B2 (ja) １β−ヒドロキシビタミンＤ▲下２▼およびＤ▲下３▼の製造方法
WO1993002064A1 (fr) Nouveau derive de la 7-desacetoxy baccatine iv, sa preparation et son emploi
EP1631580A2 (de) Verfahren zur herstellung von dhea-derivaten
CA1140110A (fr) Procede de preparation de nouveaux derives de l'androst-4-ene
FR2571369A1 (fr) Derives de la vitamine d et precurseurs de ceux-ci et compositions pharmaceutiques en contenant
EP0101383B1 (de) 14-Aminosteroidderivate, ihre therapeutische Anwendung und Verfahren zu ihrer Herstellung
CA1094569A (fr) Procede de preparation de nouvelles lactones derivees du cyclopentanol
NL7905040A (nl) Werkwijze voor de bereiding van 1alpha-gehydroxyleerde vitamine d verbindingen.
EP3063166B1 (de) Verfahren zur herstellung von 6-alkylierten steroidderivaten und von den entsprechenden alkylierten 5,6,7,8-tetrahydronaphthalen-2(4 alpha.h)-onen
EP0012072B1 (de) Von 2-Hydroxycyclopentancarbonsäure abgeleitete beta-Lactone, Verfahren zu ihrer Herstellung und pharmazeutische Zusammensetzungen, die sie enthalten
CH641814A5 (fr) Derives acetyleniques de l'androst-4-ene, leurs procedes de preparation et medicaments les renfermant.
EP0801639B1 (de) Verfahren zur herstellung von substituierten anthrachinonen und deren verwendung zur herstellung von rheinen
FR2474037A1 (fr) Nouveaux acides 16,17-dihydropregnene-21-carboxyliques et leurs derives utiles notamment comme anti-inflammatoires
CA1087201A (fr) Procede de preparation de nouveaux derives cyclopentaniques
FR2826004A1 (fr) Procede de preparation de derives estrogenes
EP2956449B1 (de) Verfahren zur herstellung 4-(heterocycloalkyl)benzol-1,3-diol-verbindungen
CH646983A5 (fr) Derives acetyleniques chlores de l'androst-4-ene, leur preparation et medicaments les renfermant.
BE853470A (fr) Nouveaux d-homosteroides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20051107

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080206