EP1150993A1 - Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose - Google Patents

Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose

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Publication number
EP1150993A1
EP1150993A1 EP00910664A EP00910664A EP1150993A1 EP 1150993 A1 EP1150993 A1 EP 1150993A1 EP 00910664 A EP00910664 A EP 00910664A EP 00910664 A EP00910664 A EP 00910664A EP 1150993 A1 EP1150993 A1 EP 1150993A1
Authority
EP
European Patent Office
Prior art keywords
cholesta
dimethyl
dien
designates
group
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Withdrawn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
EP00910664A
Other languages
German (de)
English (en)
Inventor
Thorsten Blume
Peter Esperling
Joachim Kuhnke
Christa Hegele-Hartung
Monika Lessl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to EP00910664A priority Critical patent/EP1150993A1/fr
Publication of EP1150993A1 publication Critical patent/EP1150993A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • 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
    • 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 present invention relates to pharmaceutically active unsaturated cholestane derivatives, to pharmaceutical compositions comprising them as active substances and to the use of these novel compounds for the preparation of medicaments. More particularly it has been found that the unsaturated cholestane derivatives of the invention can be used for regulating meiosis.
  • Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1 n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1 c DNA.
  • the meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly.
  • All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty.
  • the female has a stock of oocytes which is drawn upon until the stock is exhausted.
  • Meiosis in females is not completed until after fertilization, and results in only one ovum and two abortive polar bodies per germ cell.
  • only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.
  • MAS meiosis-activating substance
  • MPS meiosis preventing substance
  • novel, stable compounds with interesting pharmacological properties are provided.
  • the compounds described here are useful for the regulation of meiosis in oocytes and in male germ cells.
  • novel compounds which are suitable substrates for the introduction of fluorescense markers are designed and synthesized for bioimaging purposes.
  • the present invention relates to unsaturated cholestane derivatives of the general formula I
  • R ⁇ designates a hydrogen atom, a C2-Cg-alkyl group, an optionally substituted phenyl group, a cyano group, a CH2-NH-COR 1 group (with R 1 being a C-
  • R 2 designates a hydrogen atom, a C-j-Cs-alkyl group, a Cs-C ⁇ -alkenyl group, a C-i-C -hydroxyalkyl group, together with R 2' an optionally substituted benzylidene group, together with R 2 ' a hydroxymethylene group or together with R ⁇ an additional bond,
  • R 2' designates a hydrogen atom, together with R 2 an optionally substituted benzylidene group or together with R 2 a hydroxymethylen group
  • R3 designates a hydrogen atom or together with R ' an additional bond
  • R3' designates a hydrogen atom or together with R3 an additional bond
  • R4 designates a hydrogen atom or a methyl group
  • R4' designates a hydrogen atom or a methyl group
  • R8 designates together with R or with R14 an additional bond
  • R9 designates a hydrogen atom or together with R ⁇ an additional bond
  • R " l4 designates an ⁇ -hydrogen atom or together with R ⁇ an additional bond or together with R15 an additional bond
  • R15 designates a hydrogen atom or together with R ⁇ an additional bond
  • R ⁇ designates a hydrogen atom or together with R 2 ⁇ an additional bond
  • R ⁇ designates a hydrogen atom or together with R 2 ⁇ an additional bond
  • Preferred compounds of formula I are such wherein R ⁇ designates a hydrogen atom, a phenyl group or together with R 2 an additional bond.
  • Other preferred compounds are such wherein R 2 designates a C-j-Cs-alkyl group, an allyl group or an additional bond with R ⁇ .
  • Compounds wherein R 2 and R 2' designate an optionally substituted benzylidene group are also preferred.
  • esters of compounds of the general formula I are formally derived by estehfication of one or more hydroxylic groups of a compound of formula I with an acid which can for example be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.
  • an acid which can for example be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.
  • an alkyl group - when used alone or in combinations - may be a straight or branched alkyl group.
  • the expression C2-C5 alkyl designates an alkyl group having from two to six carbon atoms: preferred examples are ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and cyclohexyl more preferred ethyl.
  • C ⁇ -Cg alkyl designates an alkyl group having from one to eight carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and octyl more preferred methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, still more preferred methyl and ethyl.
  • Especially preferred compounds of formula I of the present invention are the following: 2 ⁇ -allyl-4,4-dimethyl-5 ⁇ -cholesta-8,14-dien-3 ⁇ -ol,
  • the compounds of the general formula I according to the invention can be synthesized analogously with the preparation of known compounds. Hence, synthesis of the compounds of formula I can follow the well established synthetic pathways described in the comprehensive sterol and steroid literature.
  • the following books can be used as the key source in the synthesis: L.F. Fieser & M. Fieser: Steroids: Reinhold Publishing Corporation, NY 1959; Rood ' s Chemistry of Carbon Compounds (editor: S. Coffrey): Elsevier Publishing Company, 1971 ; and especially Dictionary of Steroids (editors: R.A. Hill; D.N. Kirk; H.L.J. Makin and CM. Murphy): Chapman & Hall. The last one contains an extensive list of citations to the original papers covering the period up to 1990. All these books including the last mentioned citations are incorporated by reference.
  • the compounds of the present invention are synthesized according to the following general procedures:
  • sterols that are used as starting materials can be synthesized according to literature procedures:
  • the ⁇ -1 double bond can be introduced in an oxidation reaction with phenyl selenic anhydride as an oxidant in chlorobenzene [J. Chem Soc. Chem. Commun. 1978, 952] to give 4,4-dimethyl-5 ⁇ -cholesta-1 ,8,14-trien-3-one 3.
  • This reaction also works in the case of compounds without the 4,4-dimethyl group.
  • the new double bond can be selectively introduced as a ⁇ 1 -double bond.
  • the 3-keto group can then be reduced with sodium borohydride in the presence of cerium chloride [Luche reduction, for example: J. Am. Chem. Soc. 100 (1978), 2226] to give 4,4-dimethyl-5 ⁇ -cholesta-1 ,8,14-trien- 3 ⁇ -ol 4.
  • scheme 2 :
  • This amine can be used for further modification.
  • Substituents in position 2 can for example be introduced via aldol reactions and alkylations. If ketone 2 is treated with aromatic aldehydes in the presence of a base 2-benzylidene-substituted steroids of formula 10 are obtained. The aromatic ring can be substituted. Subsequent reduction with sodium borohydride in the presence of cerium chloride gives selectively the corresponding allylic 3 ⁇ - alcohols 11.
  • amine 12 is treated with hydroxysuccinimidyl ester derivatives of different carboxylic acids.
  • esters that contain fluorescence markers can be used (see example 11 in the experimental part).
  • Amides of formula 13 that contain the fluorescence markers can be used as molecular probes for bioimaging purposes.
  • Alkyl- and alkenyl substituents can be introduced in position 2 via deprotonation of ketone 2 and subsequent reaction of the enolate with alkyl- and alkenyl halides.
  • the 3-ketones of formula 14 can then be reduced with sodium borohydride to give two diastereomeric alcohols of formulae 15 and 16, which can be easily separated by column chromatography.
  • hydroxymethylsubstituents in position 2 can for example be introduced via a condensation reaction of a deprotonated 3-ketone with alkylformiates to give enol 17. This can be reduced with different reducing agents like sodium borohydride to give two diastereomeric alcohols 18 and 19.
  • scheme 7 :
  • compositions comprising one or more compounds of the general formula I as active substances.
  • the compositions may further comprise pharmaceutically acceptable excipients well known in the art like carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art.
  • solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes and cacao butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions.
  • liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilization.
  • the liquid compositions may contain other ingredients which are conventionally used in the art, some of which are men- tioned in the list above.
  • a composition for transdermal administration of a compound of this invention may be provided in the form of a patch and a composition for nasal administraton may be provided in the form of a nasal spray in liquid or powder form.
  • compositions of the invention are prepared by intimately bringing into association the active compound with the liquid or solid auxiliary ingredients and then, if necessary, shaping the product into the desired formulation.
  • the present invention relates to the use of the compounds of the general formula I for the preparation of a meiosis-regulating medicament.
  • the compounds of the present invention influence the meiosis in oocytes as well as in male germ cells.
  • the prospects of being able to influence the meiosis are several.
  • a compound of the general formula I can be used to stimulate the meiosis.
  • a compound of the general formula I can be used to stimulate the meiosis in humans.
  • the compounds of the general formula I are promising as new fertility-regulating agents without the usual side effects on the somatic cells which are known from the hitherto used hormonal contraceptives which are based on estrogens and/or gestagens.
  • the present invention concerns the use of the compounds of the general formula I for relieving infertility in females and males, particularly in mammals, more particularly in humans.
  • Meiosis-inducing substances of the general formula I can be used in the treatment of certain cases of infertility in females, including women, by administration thereof to females who, due to an insufficient own production of meiosis-activating substance, are unable to produce mature oocytes.
  • the compounds of the general formula I can also be used in artificial insemination procedures e.g. in in vitro fertilization or intracytoplasmic sperm injection.
  • in vitro fertilization is performed, better results can be achieved, when a compound of the invention is added to the medium in which the oocytes are cultured.
  • infertility in males, including men is caused by an insufficient own production of the meiosis-activating substance and thus a lack of mature sperm cells exists, administration of a compound of the invention may relieve the problem.
  • the compounds of the general formula I are useful as contraceptives in females and males, particularly in mammals, more particularly in humans.
  • a meiosis inducing substance can be administered so as to prematurely induce resumption of meiosis in oocytes while they are still in the growing follicle, before the ovulatory peak of gonadotropins occurs.
  • the resumption of the meiosis can, for example, be induced a week after the preceding menstruation has ceased.
  • the resulting overmature oocytes are then most likely not to be fertilized. The normal menstrual cycle is not likely to be affected.
  • contraception in females can also be achieved by administration of a compound of the invention which inhibits the meiosis, so that no mature oocytes are produced.
  • contraception in males can be achieved by administration of a compound of the invention which inhibits the meiosis, so that no mature sperm cells are produced.
  • the present invention relates to the use of the compounds of the general formula I as tool substances or as starting materials for the synthesis of tool substances for bioimaging purposes in order to clarify the mode of action of such substances.
  • meiosis-activating sterols that contain a fluorescence marker can be used to visualize the compartments of the germ cell where the active substances exert their biological function. This information may be helpful to clarify the mode of action of such substances.
  • the present invention relates to a method of regulating meiosis comprising administering to a subject in need of such a regulation an effective amount of one or more compounds of the general formula I.
  • the present invention relates to a method of regulating meiosis in a mammalian germ cell comprising administering ex vivo or in vitro to a germ cell in need of such a regulation an effective amount of one or more compounds of the general formula I.
  • the germ cell may be an oocyte or a male germ cell.
  • compositions containing a compound of the invention may be any route which effectively transports the active compound to its site of action.
  • compositions which comprises at least one compound of the invention in connection with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for oral use, such compositions are preferably in the form of capsules or tablets.
  • the compounds of the invention When used as a contraceptive, the compounds of the invention will either have to be administered continuously or cyclically. When used as a contraceptive by females and not taken continuously, the timing of the administration relative to the ovulation will be important.
  • Example 4 1 ⁇ -cyano-4,4-dimethyl-5 ⁇ -cholesta-8,14-dien-3-one: 1.47 ml of a diethylaluminum cyanide solution (1 M in toluene) are added to a solution of 4,4-dimethyl-5 ⁇ -cholesta-1 ,8,14-trien-3-one in 5 ml tetrahydrofuran at 0 °C. The reaction mixture is allowed to warm to room temperature and stirred for one hour. After addition of 2.45 ml of a sodium hydroxide solution (1 M) at 0 °C the resulting mixture is diluted with water and extracted with diethylether.
  • a suspension of 64 mg 4-cyanobenzaldehyde and 27 mg potassium hydroxide in 2 ml ethanol is added dropwise to a suspension of 4,4-dimethyl-cholesta-8,14- dien-3-one in 4ml ethanol at room temperature.
  • the reaction mixture is stirred for 20 hours, diluted with water and extracted with dichloromethane. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered.
  • Example 8 (E)-N-[[4-[(3 ⁇ -hydroxy-4,4-dimethyl-5 ⁇ -cholesta-8, 14-dien-2- yliden)methyl]phenyl]methyl]octanamide: a) (E)-2-(4-aminomethyl-phenyl)-methylidene-4,4-dimethyl-5 ⁇ -cholesta-8,14- dien-3 ⁇ -ol:
  • a solution of 200 mg 4,4-dimethyl-cholesta-8,14-dien-3-one in 3 ml THF is added dropwise to a freshly prepared lithium diisopropylamide solution (5.8 ml, 1 M) at - 70 °C.
  • the solution is stirred for one hour before 0.07 ml 3-iodo-propene are added.
  • the reaction mixture is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered.
  • 160 mg 2 ⁇ -allyl-4,4-dimethyl-5 ⁇ -cholesta-8,14-dien-3-one are treated with 55 mg sodium borohydride as described in example 5 to give 15 mg 2 ⁇ -allyl-4,4- dimethyl-5 ⁇ -cholesta-8,14-dien-3 ⁇ -ol and 80 mg 2 ⁇ -allyl-4,4-dimethyl-5 ⁇ - cholesta-8, 14-dien-3 ⁇ -ol.
  • Example 11 Testing of meiosis-activating substances in the oocyte test
  • mice were obtained from immature female mice (C57BI/6J x DBA/2J F1- hybrids, Bomholtgaard, Denmark) weighing 13 - 16 grams, that were kept under controlled lighting and temperature.
  • the mice received an intra-peritoneal injection of 0.2 ml gonadotropins (Gonal F, Serono, Solna, Sweden , containing 20 IU FSH, alternatively, Puregon, Organon, Swords, Ireland containing 20 IU FSH) and 48 hours later the animals were killed by cervical dislocation.
  • gonadotropins Gonal F, Serono, Solna, Sweden , containing 20 IU FSH, alternatively, Puregon, Organon, Swords, Ireland containing 20 IU FSH
  • the ovaries were dissected out and the oocytes were isolated in Hx-medium (see below) under a stereo microscope by manual rupture of the follicles using a pair of 27 gauge needles.
  • Spherical, naked oocytes (NO) displaying an intact germinal vesicle (GV) were placed in ⁇ -minimum essential medium ( ⁇ -MEM without ribonucleosides, Gibco BRL, Cat. No. 22561) supplemented with 3 mM hypoxanthine (Sigma Cat. No. H-9377), 8 mg/ml Human Serum Albumin (HSA, State Serum Institute, Denmark), 0,23 mM pyrubate (Sigma, Cat. No.
  • Hx-medium 2 mM glutamine (Flow Cat. No. 16-801 ), 100 lU/ml penicillin and 100 ⁇ g/ml streptomycin (Flow, Cat No. 16-700).
  • This medium was designated Hx-medium.
  • the oocytes were rinsed three times in Hx-medium and cultured in 4-well multidishes (Nuncion, Denmark) in which each well contained 0.4 ml of Hx- medium and 35 - 45 oocytes.
  • One control i.e. 35 - 45 oocytes cultured in Hx- medium with no addition of test compound was always run simultaneously with the test cultures, which were made with different concentrations of the compounds to be tested.
  • the cultures were performed at 37 °C and 100 % humidity with 5 % C0 2 in air.
  • the culture time was 22 - 24 hours.
  • the number of oocytes with germinal vesicle (GV) or germinal vesicle breakdown (GVB) and those with polar body (PB) was counted using a stereo microscope or an inverted microscope with differential interference contrast equipment.
  • the percentage of oocytes with GVB per total number of oocytes and the percentage of oocytes with PB per total number of oocytes was calculated in the test cultures and compared to the control culture.
  • Example 12 Test of meiosis-inhibiting substances in the oocyte test
  • Germinal vesicle (GV) oocytes were obtained from immature FSH treated female mice using the same methods as described in Example 11 (see above). Naked oocytes (NO) were rinsed three times in Hx-medium. 4,4-Dimethyl-5 ⁇ -cholesta- 8,14,24-trien-3 ⁇ -ol (FF-MAS) has previously been shown to induce meiosis in NO in vitro (Byskov, A.G. et al. Nature 374 (1995) 559 - 562).
  • Hx-medium supplemented with 5 ⁇ M FF-MAS in co-culture with the test compounds in different concentrations in 4-well multidishes (Nuncion, Denmark) in which each well contained 0.4 ml of Hx-medium and 35 - 45 oocytes.
  • One positive control i.e., 35 - 45 oocytes cultured in Hx-medium containing FF-MAS with no addition of test compound
  • one negative control 35 - 45 oocytes cultured in Hx-medium alone was run simultaneously with the positive control.
  • the number of oocytes with germinal vesicle (GV) or germinal vesicle breakdown (GVB) and those with polar body (PB) was counted using a stereo microscope or an inverted microscope with differential interference contrast equipment.
  • the percentage of oocytes with GVB per total number of oocytes and the percentage of oocytes with PB per total number of oocytes was calculated in the test cultures and compared to the control culture.
  • Example 13 Testing of meiosis-activating substances in the ,in-vitro fertilisation' assay
  • NkO Naked oocytes
  • CEO cumulus enclosed oocytes
  • the oocytes (NkO and CEO) were pooled and cultured for approx. 20 hours in a modified ⁇ -MEM medium containing 3 mM hypoxanthine (Hx-medium) and 1 mg fetuin/ml culture medium.
  • Two oocyte-groups were used: (a) control oocytes, cultured in Hx-free medium (positive control group) and (b) oocytes, cultured in Hx-medium containing the test compound. After approx.
  • VVB germinal vesicle breakdown
  • GV germinal vesicle
  • GVB germinal vesicle breakdown
  • PB polar bodies
  • n number of oocytes
  • GVB germinal vesicle breakdown
  • PB polar bodies
  • n number of oocytes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de cholestane insaturés pharmaceutiquement actifs, des compositions pharmaceutiques qui les contiennent comme principes actifs, et l'utilisation de ces nouveaux composés pour préparer des médicaments. On a en particulier découvert que les dérivés de cholestane insaturés de cette invention peuvent être utilisés pour réguler la méiose.
EP00910664A 1999-02-10 2000-02-09 Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose Withdrawn EP1150993A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00910664A EP1150993A1 (fr) 1999-02-10 2000-02-09 Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99250040 1999-02-10
EP99250040 1999-02-10
PCT/EP2000/001074 WO2000047604A1 (fr) 1999-02-10 2000-02-09 Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose
EP00910664A EP1150993A1 (fr) 1999-02-10 2000-02-09 Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose

Publications (1)

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EP1150993A1 true EP1150993A1 (fr) 2001-11-07

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EP00910664A Withdrawn EP1150993A1 (fr) 1999-02-10 2000-02-09 Derives de cholestane insatures et leur utilisation pour preparer des medicaments destines a reguler la meiose

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EP (1) EP1150993A1 (fr)
JP (1) JP2002536456A (fr)
KR (1) KR20010101820A (fr)
CN (1) CN1368977A (fr)
AU (1) AU3279700A (fr)
BR (1) BR0008065A (fr)
CA (1) CA2359687A1 (fr)
CZ (1) CZ20012866A3 (fr)
HU (1) HUP0200280A2 (fr)
IL (1) IL143735A0 (fr)
NO (1) NO20013901L (fr)
PL (1) PL350557A1 (fr)
SK (1) SK11382001A3 (fr)
WO (1) WO2000047604A1 (fr)
ZA (1) ZA200107387B (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5716777A (en) * 1994-06-23 1998-02-10 Novo Nordisk A/S Regulation of meiosis using sterols
EP0813595A1 (fr) * 1995-03-06 1997-12-29 Novo Nordisk A/S Stimulation de la meiose
CN1191543A (zh) * 1995-06-23 1998-08-26 诺沃挪第克公司 减数分裂调控化合物
IL130249A0 (en) * 1996-12-20 2000-06-01 Novo Nordisk As Meiosis regulating compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0047604A1 *

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Publication number Publication date
HUP0200280A2 (hu) 2002-07-29
CZ20012866A3 (cs) 2002-01-16
CA2359687A1 (fr) 2000-08-17
IL143735A0 (en) 2002-04-21
AU3279700A (en) 2000-08-29
PL350557A1 (en) 2002-12-16
CN1368977A (zh) 2002-09-11
KR20010101820A (ko) 2001-11-14
SK11382001A3 (sk) 2002-01-07
WO2000047604A1 (fr) 2000-08-17
BR0008065A (pt) 2001-11-06
NO20013901D0 (no) 2001-08-10
NO20013901L (no) 2001-08-10
JP2002536456A (ja) 2002-10-29
ZA200107387B (en) 2002-12-06

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