WO1998018777A1 - Nouveaux derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes - Google Patents

Nouveaux derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes Download PDF

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Publication number
WO1998018777A1
WO1998018777A1 PCT/DK1997/000484 DK9700484W WO9818777A1 WO 1998018777 A1 WO1998018777 A1 WO 1998018777A1 DK 9700484 W DK9700484 W DK 9700484W WO 9818777 A1 WO9818777 A1 WO 9818777A1
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Prior art keywords
phenyl
hydroxy
chromane
phenylchromane
formula
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Application number
PCT/DK1997/000484
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English (en)
Inventor
Poul Jacobsen
Svend Treppendahl
Paul Stanley Bury
Anders Kanstrup
Lise Brown Christiansen
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Novo Nordisk A/S
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Filing date
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Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP10519943A priority Critical patent/JP2001502709A/ja
Priority to AU47721/97A priority patent/AU4772197A/en
Priority to CA002270055A priority patent/CA2270055A1/fr
Priority to EP97910265A priority patent/EP0937061A1/fr
Priority to IL12961797A priority patent/IL129617A0/xx
Publication of WO1998018777A1 publication Critical patent/WO1998018777A1/fr
Priority to NO992004A priority patent/NO992004L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • Novel c/s-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes
  • the present invention relates to new c/s-3,4-chroman derivatives and the use of such compounds in the prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, in particular bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing and urogenital atrophy, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, post-partum lactation, and the use of such compounds in a contraceptive method or as an aid in ovarian development
  • estrogen related diseases or syndromes preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, in particular bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing and urogenital atrophy, dysmenor
  • estrogen therapies would include the following: relief of menopausal symptoms (i.e. flushing and urogenital atrophy); oral contraception; prevention of threatened or habitual abortion, relief of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair in women (hirsutism); treatment of prostatic carcinoma: and suppression of post-partum lactation [Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1421-1423].
  • the present invention provides compounds of the formula I in which substituents R 2 and R 3 are arranged in cis-configuration:
  • R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 , trihalo-C r C 6 -alkyl, C,-C 6 - alkyl, and phenyl;
  • R 3 is phenyl substituted with -X-(CH 2 ) n -Y, wherein:
  • X is a valency bond or S
  • n is an integer in the range of 1 to 12,
  • Y is H, halogen, OH, OR 4 , NHR 4 , NR 4 , NHCOR 4 , NHS0 2 R 4 , CONHR 4 , CONR 4 ,
  • R 4 is C r C 6 -alkyl
  • Cj-Cg-alkyl includes straight-chained as well as branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl and isobutyl
  • halogen means chloro, bromo, lodo and fluoro
  • C 3 -C 7 -heterocycl ⁇ c ring include groups such as pyrrolidmyl, pyrrolmyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazoiinyl, pipe ⁇ dyl, piperazinyl, pyrrol, 2H-pyrrol, t ⁇ azolyl, pyndyl, pyrazinyl, py ⁇ midinyl, py ⁇ dazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl
  • the compounds of this invention are new estrogen agonists and are useful for prevention and treatment of bone loss, prevention and treatment of osteoporosis, the prevention and treatment of cardiovascular disease, treatment and prevention of physiological disorders associated with an excess of neuropeptide Y (e g obesity, depression, etc ), and for regulation of glucose metabolism m e g non-insulin dependent diabetes melitus, and the prevention and treatment of senile dementia-Alzheimer's type in women
  • these estrogen agonists are useful for oral contraception, relief of menopausal symptoms (e g hot flushes, urogenital atrophy, depression, mania, schizophrenia, etc ), incontinence, prevention of threatened or habitual abortion, relief of dysmenorrhea, relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne, diminution of excessive growth of body hair is women (hirsutism), treatment of prostatic carcinoma, and the suppression of post-partum lactation These agents also lower serum cholesterol and have a beneficial effect on plasma lipid profiles
  • the compounds of this invention are estrogen agonists in bone and cardiovascular tissues, they are also capable of acting as antiestrogens in other estrogen target organs
  • these compounds can act as antiestrogens in breast tissue and the colon and therefore would be useful for the prevention and treatment of estrogen-dependent cancers such as breast cancers and colon cancers
  • hydroxy substituent on the phenyl ring in formula I is preferably attached to the phenyl ring at the 6- or 7-pos ⁇ t ⁇ on Accordingly, compounds of the invention having one of the following formulae la or lb are preferred:
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • R is H or C r C 6 alkyl and X is as defined above.
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • m is an integer from 0 to 10 and X is as defined above.
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • the present invention is concerned with cis-forms of the compounds of the following formula:
  • R 6 represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.
  • the compounds of the invention may be prepared by resorting to the chroman chemistry which is well-known in the art, for example in P.K. Arora, P.L. Kole and S. Ray, Indian J. Chem. 20 B, 41-5, 1981 ; S. Ray, P.K. Grover and N. Anand, Indian J. Chem. 9, 727-8, 1971 ; S. Ray, P.K. Graver, V.P. Kamboj, S.B. Betty, A.B. Kar and N. Anand, J. Med. Chem. 19, 276-9, 1976; Md. Salman, S. Ray, A.K. Agarwal, S. Durani, B.S. Betty, V.P. Kamboj and N. Anand, J. Med. Chem. 26, 592-5, 1983; Teo, C, Sim, K., Bull. Singapore Natl. Inst. Chem. 22, 69-74, 1994.
  • R 5 represents 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-C r C 6 -alkyl, C r C 6 -alkyl and C Ce-alkoxy, and R 4 is as defined above,
  • R 5 is as defined above
  • R 5 is as defined above
  • R 5 is as defined above
  • R 5 is as defined above
  • R 5 is as defined above
  • R 5 is as defined above
  • n, R 5 and Y are as defined above,
  • R 5 is as defined above
  • R 5 is defined as above
  • R 5 is defined as above
  • R 5 is defined as above, and R 6 is H or methoxy
  • R 5 is defined as above, and R 6 is H or methoxy
  • Optical pure compounds of formula (I) can be obtained by introducing in the above method a resolution step The resolution can be carried out after any step of the process which results in a racemic mixture of enantiomers Any resolution technique may be used to separate a (-)-enant ⁇ omer and/or a (+)-enant ⁇ omer from a racemic mixture, including diastereome ⁇ c salt formation and chiral HPLC
  • appropriate electrophile typically means an alkylhalogenide of the formula Y-(CH 2 )n-Hlg, wherein Y is as defined above and Hlg is Cl, Br or I
  • appropriate cross-coupling partner typically means an organometallic reagent together with a transition metal catalyst, for example a G ⁇ gnard reagent with a Ni(0) catalyst
  • the present invention also relates to pharmaceutical compositions comp ⁇ sing an effective amount of a compound according to the invention and a pharmaceutical carrier or diluent
  • Such compositions are preferably in the form of an oral dosage unit or parenteral dosage unit
  • the invention is concerned with a method of treating or preventing estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen- deficient state in a mammal, comprising administering to a subject in need thereof an effective amount of a compound according to the invention
  • the compounds of this invention are new estrogen agonists and are useful for prevention and treatment of bone loss, prevention and treatment of osteoporosis, the prevention and treatment of cardiovascular disease, treatment and prevention of physiological disorders associated with an excess of neuropeptide Y (e g obesity, depression, etc ), and for regulation of glucose metabolism m e g non-insulin dependent diabetes mehtus, and the prevention and treatment of senile dementia-Alzheimer's type in women
  • these estrogen agonists are useful for oral contraception, relief of menopausal symptoms (e g hot flushes, urogenital atrophy, depression, mania, schizophrenia, etc ), incontinence, prevention of threatened or habitual abortion, relief of dysmenorrhea, relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne, diminution of excessive growth of body hair is women (hirsutism), treatment of prostatic carcinoma, and the suppression of post-partum lactation These agents also lower serum cholesterol and have a beneficial effect on plasma hpid
  • the compounds of this invention are estrogen agonists in bone and cardiovascular tissues, they are also capable of acting as antiestrogens in other estrogen target organs
  • these compounds can act as antiestrogens in breast tissue and the colon and therefore would be useful for the prevention and treatment of estrogen-dependent cancers such as breast cancers and colon cancers
  • an in vitro receptor binding assay was used to determine the estrogen receptor binding affinity of the compounds of this invention This assay measures the ability of the compounds of this invention to displace 3 H-17 ⁇ -estrad ⁇ ol (17 ⁇ -E2), from estrogen receptor (ER) obtained from rabbit uterus
  • ER estrogen receptor
  • the ER rich cytosol from rabbit uterine tissue is diluted with ER poor cytosol isolated from rabbit muscle to achieve approximately 20 - 25% maximal binding of 0 5 nM 3 H-17 ⁇ -E2
  • fresh aliquots of cytosol are thawed on the day of analysis and diluted with assay buffer to ca. 3 mg cytosol protein/ml.
  • the assay buffer (PB) is as follows: 10 mM K 2 HP0 4 /KH 2 P0 4 , 1.5 mM K 2 EDTA, 10 mM monothioglycerol, 10 mM Na 2 Mo0 4 .2H 2 0, 10 % glycerol (v/v); pH 7.5. Radio-inert 17 ⁇ -E2 is obtained from Sigma.
  • Test solutions are prepared in appropriate solvents (ethanol or DMSO) at a concentration of 8 x 10-3M and serial dilutions prepared with PB or DMSO. Aliquots of 10 ⁇ l are incubated in duplicate for each concentration tested in microtitre plates to which have been added 20 ⁇ l 3 H-17 ⁇ -E2 (assay concentration equals 0.4 nM) and 50 ⁇ l cytosol. For control samples as well as maximal binding sample, 10 ⁇ l PB is added in lieu of test compound.
  • solvents ethanol or DMSO
  • Titertek plates are centrifuged for 10 min (800 x g) at 4°C and aliquots of 100 ⁇ l are removed from each sample for scintillation counting using Optiflour scintillation liquid. Standard and control samples are incubated in quadruplicate, while test compounds are incubated in duplicate. The mean counts per minute (cpm) in each sample is calculated, background (DCC) is subtracted, and the percent of maximal 3H-17 ⁇ -E2 binding is determined. Individual cpm's are plotted against their respective concentrations of test compound (logarithmic scale), and the IC50 expressed as the compound concentration required to displace 50% of the maximal binding.
  • Bone mineral density as a measure of bone mineral content (BMC) accounts for greater than 80% of a bone's strength.
  • BMD bone mineral density
  • the loss of BMD with ageing and the accelerated loss following the menopause reduce the strength of the skeleton and render specific sites more susceptible to fracture; i.e. most notably the spine, wrist and hip.
  • True bone density can be measured gravimetrically using Archimede's Principle (an invasive technique).
  • the BMD can also be measured non-invasively using dual energy x-ray absorptiometry (DEXA). In our laboratory, we have utilized a gravimetric method to evaluate changes in BMD due to estrogen deficiency in ovariectomized rodents.
  • ovariectomy the surgical removal of the ovaries
  • the animals are treated with vehicle, 17 ⁇ -E2 as a positive control, and/or other estrogen agonists.
  • the objective of these investigations is to evaluate the ability of the compounds of this invention to prevent bone loss in rodent models of human disease.
  • mice Female Sprague-Dawley rats (ca. 3 to 5 months old), or female Swiss-Webster mice (ca. 3 to 5 months old) underwent bilateral ovariectomy or sham surgery. Following recovery from anesthesia the animals are randomized to the following groups, minimum of 8 animals per group:
  • sham animals treated with vehicle; ovariectomized animals treated with vehicle; ovariectomized animals treated with 25 ⁇ g estradiol/kg; and ovariectomized animals treated with 200 ⁇ g/kg of test compound.
  • the hydrated bones were weighed in air and weighed while suspended in water on a Mettler balance equipped with a density measurement kit. The weight of each sample in air is divided by the difference between the air weight and the weight in water to determine total bone density; i.e. organic matrix plus mineral per unit volume of tissue. After the determination of total bone density the samples are ashed overnight in a muffle furnace at 600 °C. The mineral density can then be determined by dividing the ash weight of each sample by the tissue volume (i.e. air weight - weight suspended in water). The mean bone densities (total and mineral bone densities) are calculated for each group and statistical differences from the vehicle-treated and estrogen-treated controls are determined using computerized statistical programs.
  • the effects of the compounds of the present invention on the serum levels of total cholesterol were measured either in blood samples taken from the animals in the bone density studies described above or from ovariectomized female rats or mice that had been treated with compound for a period of not less than 28 days.
  • blood from treated animals was collected via cardiac puncture and placed in a tube containing 30 ⁇ l of 5% EDTA 1 ml of blood. Following centrifugation at 2500 rpm for 10 minutes at 20° C the plasma was removed and stored at -20° C until assayed.
  • Cholesterol was measured using a standard enzymatic determination kit purchased from Sigma Diagnostics (Kit No. 352).
  • the compounds of the invention together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of a compound of the invention commensurate with the intended daily dosage range to be employed.
  • Tablets containing ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • a syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
  • the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains: Active compound 5.0 mg
  • the compounds of the invention may be administered to a subject, e.g., a living animal body, including a human, in need of a compound of the invention, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobro- mide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an amount which is effective for the treatment of the disease.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydrobro- mide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid
  • Suitable dosage ranges are 1- 200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • Step 1
  • the reaction mixture was filtered, the solvents evaporated, and the residue partitioned between dichloromethane (200 ml) and 10% aqueous acetic acid (200 ml).
  • the organic layer was separated, washed with 10% aqueous acetic acid (100 ml), sodium hydrogen carbonate solution (3x100 ml), brine (100 ml), dried over sodium sulfate, and evaporated.
  • the product was purified by column chromatography on silica gel 60, with dichloromethane as the eluent. This gave the product as a clear gum, which was crystallised from diethylether and petrol, to afford the title product as colourless crystals.
  • the mixture was cooled to room temperature and diluted with hexane (20 ml), then 2M sodium hydroxide (1.6 ml) and 30% hydrogen peroxide (1 ml) were added, and the mixture stirred for 2 hours to destroy the excess borane.
  • the resulting mixture was diluted with ethyl acetate (200 ml) and water (200 ml), and the organic layer separated, washed with water (100 ml), brine (100 ml), dried over sodium sulfate, and evaporated.
  • the crude product was purified by column chromatography on silica gel 60, with 2% methanol in dichloromethane as the eluent. This gave the title compound as a clear oil.

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  • Health & Medical Sciences (AREA)
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  • Hospice & Palliative Care (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des composés actifs sur le plan thérapeutique représentés par la formule (I) un procédé servant à préparer ces composés et des compositions pharmaceutiques contenant ces composés. Ces nouveaux composés sont utiles pour la prévention ou le traitement de maladies ou de syndromes relatifs aux oestrogènes.
PCT/DK1997/000484 1996-10-28 1997-10-28 Nouveaux derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes WO1998018777A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP10519943A JP2001502709A (ja) 1996-10-28 1997-10-28 エストロゲン関連疾患または症候群の予防または治療に有用な新規なシス―３，４―クロマン誘導体
AU47721/97A AU4772197A (en) 1996-10-28 1997-10-28 Novel (cis)-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes
CA002270055A CA2270055A1 (fr) 1996-10-28 1997-10-28 Nouveaux derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes
EP97910265A EP0937061A1 (fr) 1996-10-28 1997-10-28 Nouveaux derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes
IL12961797A IL129617A0 (en) 1996-10-28 1997-10-28 Novel CIS-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes
NO992004A NO992004L (no) 1996-10-28 1999-04-27 Nye cis-3,4-kromanderivater som kan anvendes ved forhindring eller behandling av °strogenrelaterte sykdommer eller syndromer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1198/96 1996-10-28
DK119896 1996-10-28

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WO1998018777A1 true WO1998018777A1 (fr) 1998-05-07

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EP (1) EP0937061A1 (fr)
JP (1) JP2001502709A (fr)
AU (1) AU4772197A (fr)
CA (1) CA2270055A1 (fr)
IL (1) IL129617A0 (fr)
NO (1) NO992004L (fr)
WO (1) WO1998018777A1 (fr)
ZA (1) ZA979648B (fr)

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
ES2377073T3 (es) * 2004-09-21 2012-03-22 Marshall Edwards, Inc. Derivados de cromano sustituidos, medicamentos y utilización en terapia

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340276A (en) * 1964-04-01 1967-09-05 Ciba Geigy Corp 3, 4-diphenyl-chromans
US3535344A (en) * 1966-02-16 1970-10-20 Merck Ag E 3,4-cis-4-aryl-isoflavanes
WO1994020098A1 (fr) * 1993-03-11 1994-09-15 Zymogenetics, Inc. Procedes d'inhibition des pertes osseuses par le 3,4-diarylchromanne
WO1996021444A1 (fr) * 1995-01-13 1996-07-18 Novo Nordisk A/S Utilisation de 3,4-diphenyl chromannes pour la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie de troubles gynecologiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340276A (en) * 1964-04-01 1967-09-05 Ciba Geigy Corp 3, 4-diphenyl-chromans
US3535344A (en) * 1966-02-16 1970-10-20 Merck Ag E 3,4-cis-4-aryl-isoflavanes
WO1994020098A1 (fr) * 1993-03-11 1994-09-15 Zymogenetics, Inc. Procedes d'inhibition des pertes osseuses par le 3,4-diarylchromanne
WO1996021444A1 (fr) * 1995-01-13 1996-07-18 Novo Nordisk A/S Utilisation de 3,4-diphenyl chromannes pour la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie de troubles gynecologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Volume 26, 1983, Md. SALMAN et al., "Antifertility Agents. 38. Effect of the Side Chain and Its Position on the Activity of 3,4-Diarylchromans", pages 592-595. *

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NO992004D0 (no) 1999-04-27
JP2001502709A (ja) 2001-02-27
NO992004L (no) 1999-06-25
AU4772197A (en) 1998-05-22
ZA979648B (en) 1998-04-28
EP0937061A1 (fr) 1999-08-25
CA2270055A1 (fr) 1998-05-07
IL129617A0 (en) 2000-02-29

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