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WO1998018775A1 - Nouveaux (+)-enantiomeres de derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes - Google Patents

Nouveaux (+)-enantiomeres de 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
WO1998018775A1
WO1998018775A1 PCT/DK1997/000482 DK9700482W WO9818775A1 WO 1998018775 A1 WO1998018775 A1 WO 1998018775A1 DK 9700482 W DK9700482 W DK 9700482W WO 9818775 A1 WO9818775 A1 WO 9818775A1
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Prior art keywords
phenyl
hydroxy
formula
compound
chromane
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PCT/DK1997/000482
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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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Priority to JP10519941A priority Critical patent/JP2001502707A/ja
Priority to CA002269970A priority patent/CA2269970A1/fr
Priority to EP97910263A priority patent/EP0934298A1/fr
Priority to AU47719/97A priority patent/AU4771997A/en
Priority to IL12962497A priority patent/IL129624A0/xx
Publication of WO1998018775A1 publication Critical patent/WO1998018775A1/fr
Priority to NO992008A priority patent/NO992008L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • 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
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel (+)-enantiomers of c/s-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes.
  • the present invention relates to new (+)-enantiomers of 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
  • osteopenia that accompanies the menopause continues to represent a major public health problem. Left unchecked, the cumulative loss of bone can potentially compromise the skeleton's structural integrity, resulting in painful and debilitating fractures of the wrist, spine and femur. Efforts to reduce the risk and incidence of fractures have focused on the development of therapies that conserve skeletal mass by inhibiting bone resorption.
  • estrogen replacement therapy remains the preferred means to prevent the development of post menopausal osteoporosis (Lindsey R, Hart DM, MacClean A 1978, "The role of estrogen/progestogen in the management of the menopause", Cooke ID, ed, Proceedings of University of Sheffield symposium on the role of estrogen and progestogen in the management of the menopause, Lancaster, UK: MTP Press Ltd. pp.
  • 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 (+)-enantiomers of 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 r C 6 - alkyl, C r C 6 -alkoxy and phenyl;
  • R 3 is:
  • X is a valency bond, O 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 Cj-Ce-alkyl
  • C r C 6 -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, iodo and fluoro.
  • C 3 -C 7 -heterocyclic ring include groups such as pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 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 in 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.
  • 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. For example, 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-position. Accordingly, compounds of the invention having one of the following formulae la or lb are preferred:
  • R 1 , R 2 and R are as defined above.
  • the present invention is concerned with (+)-cis-forms of the compounds of the following formula:
  • R is H or C ⁇ Ce alkyl.
  • the present invention is concerned with (+)-cis-forms of the compounds of the following formula:
  • m is an integer from 0 to 10.
  • 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 4 is as defined above.
  • the present invention is concerned with (+)-cis-forms of the compounds of the following formula:
  • R 4 is as defined above.
  • 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. Grover, 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 procedura 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-CrCe-alkyl, C r C 6 -alkyl and
  • 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 4 and R 5 are 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 as defined above
  • n, R 5 and Y are as defined above,
  • n, R 5 and Y are 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 8 is H or methoxy
  • n, R 5 and Y is defined as above, and R 6 is H or methoxy
  • n, R 5 and Y is defined as above,
  • an appropriate dihalogenated alkane such as 1 ,2-dibromoethane, 1-bromo-2-chloroethane, 1 ,4-dibromobutane, 1 ,6- dibromohexane, 1 ,8-dibromooctane, 1 ,10-dibromodecane, preferably catalysed by potassium iodide, to form a compound of
  • n and R 5 is defined as above, R 6 is H or methoxy, and Hal is chloro, bromo, or iodo,
  • R 6 is H or methoxy
  • Z is NHR 4 , NR j , or a C 3 -C 7 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-CrCe-alkyl, CrCs-alkyl and C 1 -C 6 -alkoxy, and n, R 4 , and R 5 is defined as above, cc) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXVI)
  • R 6 is H or methoxy
  • Z is NHR 4 , NR 4 , or a C 3 -C 7 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-CrCe-alkyl, C r C 6 -alkyl and C Cg-alkoxy, and n, R 4 and R 5 is defined as above.
  • Any resolution technique may be used to separate the (+)-enantiomer from the racemic mixture, including diastereomeric salt formation and chiral HPLC.
  • the starting benzophenones of the formula (II) are easily prepared via Friedel-Craft acylation of the appropriate dimethyl ether with p-hydroxybenzoic acid followed by selective monode- methylation with hydrobromic acid in acetic acid.
  • the starting deoxybenzoins of the formula (XIV) are easily prepared via the Hoesch reaction of the appropriate dimethyl ether and the appropriate substituted phenyl acetic acid derivative followed by selective monodemethylation by hydrobromic acid in acetic acid.
  • 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.
  • the cyclization step of the above method can be performed with for example a suitable activated carboxylic acid derivative followed by dehydration.
  • appropriate cross-coupling partner typically means an organometallic reagent together with a transition metal catalyst, for example a Grignard reagent with a Ni(0) catalyst.
  • appropriate Grignard reagent typically means an organometallic compound of the formula M-(CH 2 )-Y, wherein M is MgHIg, Hlg is Cl, Br or I and Y is as defined above.
  • the present invention also relates to pharmaceutical compositions comprising 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 in 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.
  • 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. For example, 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 ⁇ -estradiol (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 m 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
  • 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 28
  • 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:
  • compositions and unit dosages 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 monoglyce des and diglyce des, 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:
  • 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 l
  • the combined organic phase was washed with water (250 ml) and evaporated to an oil.
  • the oil was dissolved in boiling ethanol (600 ml).
  • the solution was cooled and water was slowly added (400 ml) and the mixture was seeded.
  • the crystals were filtered off, washed with water/ethanol; 25/75 (200 ml) and dried.
  • the catalyst was filtered off, while the suspension was warm, and the filtrate evaporated to an oil which solidified during the evaporation.
  • the product was identified by 1 H-NMR and elemental analysis.
  • the compound crystallised with half a mole of crystal bound 2-propanol.
  • Chiral HPLC The enantiomeric purity of the product was verified by Chiral HPLC to be better than 98 %.
  • Step 1
  • Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (200 ml) solution of 4-(4-acetoxyphenyl)-7-methoxy-3-(4- (trifluoromethyl)phenyl)-coumarin (4.54 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric acid (30 ml). The resulting mixture was heated to 60-65°C for 3 h, cooled and diluted with water (100 ml) and ethyl acetate (50 ml).
  • the aqueous layer was separated and further extracted with ethyl acetate (3 x 100 ml).
  • the combined organic solutions were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an orange solid.
  • the mother liquors were evaporated to give an orange gum, which was subjected to a second aqueous ethanol recrystallisation to give a second crop of colourless needles.
  • the solids were combined and vacuum dried.
  • Step 4 ( ⁇ )-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)- phenyl)chromane
  • the aqueous layer was basified to pH 14 by adding 10M sodium hydroxide, then 1M hydrochloric acid was added until pH 8- 9.
  • the organic layer was collected and the aqueous layer further extracted with dichloromethane (2 x 75 ml).
  • the combined organics were washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to a dark coloured gum, which was purified by column chromatography on silica gel, with 6% methanol in di- chloromethane as eluent, giving the product as a colourless solid.

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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/DK1997/000482 1996-10-28 1997-10-28 Nouveaux (+)-enantiomeres de derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes WO1998018775A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP10519941A JP2001502707A (ja) 1996-10-28 1997-10-28 エストロゲン関連疾患又は症候群の予防又は治療において有用な新規のシス―３、４―クロマン誘導体の（＋）―エナンチオマー
CA002269970A CA2269970A1 (fr) 1996-10-28 1997-10-28 Nouveaux (+)-enantiomeres de derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes
EP97910263A EP0934298A1 (fr) 1996-10-28 1997-10-28 Nouveaux (+)-enantiomeres de derives de cis-3,4-chromane utiles pour la prevention ou le traitement de maladies ou de syndromes relatifs aux oestrogenes
AU47719/97A AU4771997A (en) 1996-10-28 1997-10-28 Novel (+)-enantiomers of (cis)-3,4-chroman derivatives useful in the preve ntion or treatment of estrogen related diseases or syndromes
IL12962497A IL129624A0 (en) 1996-10-28 1997-10-28 Novel (+)-enantiomers of CIS-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes
NO992008A NO992008L (no) 1996-10-28 1999-04-27 Nye (+)-enantiomerer av cis-3,4-kromanderivater som kan anvendes ved forhindring eller behandling av °strogenrelaterte sykdommer eller syndromer

Applications Claiming Priority (2)

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DK120296 1996-10-28
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JP2002533456A (ja) * 1998-12-30 2002-10-08 シグナル ファーマシューティカルズ， インコーポレイテッド エストロゲン受容体のモジュレートを行うための化合物および方法
US6756401B2 (en) 2000-01-26 2004-06-29 Pfizer Inc. Compositions and methods for treating osteoporosis and lowering cholesterol
EP2120925A4 (fr) * 2007-03-16 2010-04-07 Novogen Res Pty Ltd Procédé d'induction d'autophagie
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

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Publication number Priority date Publication date Assignee Title
JP2002533456A (ja) * 1998-12-30 2002-10-08 シグナル ファーマシューティカルズ， インコーポレイテッド エストロゲン受容体のモジュレートを行うための化合物および方法
US6756401B2 (en) 2000-01-26 2004-06-29 Pfizer Inc. Compositions and methods for treating osteoporosis and lowering cholesterol
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
EP2120925A4 (fr) * 2007-03-16 2010-04-07 Novogen Res Pty Ltd Procédé d'induction d'autophagie
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US12318364B2 (en) 2010-11-01 2025-06-03 Aardvark Therapeutics, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US12329739B2 (en) 2010-11-01 2025-06-17 Aardvark Therapeutic, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies
US12414934B2 (en) 2015-02-02 2025-09-16 Aardvark Therapeutics, Inc. Combination therapies

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CA2269970A1 (fr) 1998-05-07
EP0934298A1 (fr) 1999-08-11
NO992008D0 (no) 1999-04-27
AU4771997A (en) 1998-05-22
JP2001502707A (ja) 2001-02-27
IL129624A0 (en) 2000-02-29
ZA979644B (en) 1998-04-28
NO992008L (no) 1999-06-25

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