WO1998018773A1 - Novel cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes - Google Patents
Novel cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes Download PDFInfo
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- WO1998018773A1 WO1998018773A1 PCT/DK1997/000480 DK9700480W WO9818773A1 WO 1998018773 A1 WO1998018773 A1 WO 1998018773A1 DK 9700480 W DK9700480 W DK 9700480W WO 9818773 A1 WO9818773 A1 WO 9818773A1
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- 0 CC1(C=CC(OCC(C2C*)C(C=C3)=CC=CC3(C)S)=C2C=C1)O Chemical compound CC1(C=CC(OCC(C2C*)C(C=C3)=CC=CC3(C)S)=C2C=C1)O 0.000 description 6
- NVVCVXVVCIEINH-UHFFFAOYSA-N CCOc1ccc(C2C(C=C[O](C)C=C3)=C3OCC2c2ccccc2)cc1 Chemical compound CCOc1ccc(C2C(C=C[O](C)C=C3)=C3OCC2c2ccccc2)cc1 NVVCVXVVCIEINH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
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, dysmen
- 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: r ief 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 1 is COR 4 , CONHR 4 , CONR 4 , , SO.NR , , S0 2 NHR 4 , C r C 3 -alkyl or benzyl;
- 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-CrCe-alkyl, alkyl, C.-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 C r C 6 -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.
- R 1 0 of 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 3 are as defined above.
- the present invention is concerned with cis-forms of the compounds of the following formula:
- R 1 is as defined above and R is H or C r C 6 alkyl.
- the present invention is concerned with cis-forms of the compounds of the following formula:
- R 1 is as defined above and m is an integer from 0 to 10.
- the present invention is concerned with cis-forms of the compounds of the following formula:
- R 1 and m are as defined above.
- the present invention is concerned with cis-forms of the compounds of the following formula:
- R 1 and m are 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:
- R 1 and R 4 are 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 1 is as defined above and 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., 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.-Cs-alkyl, C r C 6 -alkyl and C 1 -C 6 -alkoxy, and R 4 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,
- n, R 5 and Y are as defined above,
- R 5 is as defined above
- R 5 is as defined above
- R 4 and R 5 are 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,
- n, R 5 and Y are 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,
- 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 6 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,
- 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 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-C r C 6 -alkyl, C,-C 6 -alkyl and C r C 6 -alkoxy, and n, R 4 , and R 5 is defined as above, cc) deprotecting a compound of the formula (XXX) 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 (XXXI)
- 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-C.-C 6 -alkyl, C C 6 -alkyl and C C 6 -alkoxy, and n, R 4 and R 5 is defined as above.
- 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 (XVIII) 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.
- 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 (-)-enantiomer and/or a (+)-enantiomer from a racemic mixture, including diastereomeric 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.
- 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 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.
- 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).
- 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 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:
- 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.
- the aqueous layer was separated and further extracted with ethyl acetate (3 x 50 ml), then the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to a colourless oil.
- the product was purified by column chromatography on silica gel 60, with 5% methanol in dichloromethane eluent, giving the product as a colourless gum. This gum was dissolved in ethanol (20 ml) and concentrated hydrochloric acid (1 ml) added with swirling to ensure complete mixing. The solvents were then evaporated to give the title compound as a colourless solid.
- N,N-diethyl carbamoyl chloride (0.50 ml, 0.54 mmol) was added and stirring continued for 24 h.
- a final quantity of N,N- diethyl carbamoyl chloride (0.50 ml, 0.54 mmol) was added and stirring maintained for a further 20 h.
- the resulting mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran, and the filtrate evaporated to give an orange oil.
- the product was purified by column chromatography on silica gel 60, using a 5 to 10% methanol in dichloromethane gradient eluent. The product was thus isolated, on evaporation and vacuum drying, as an orange coloured foam.
- the resulting mixture was filtered to remove inorganic solids, the filter plug being washed with extra tetrahydrofuran, and the filtrate evaporated to give an orange oil.
- the product was purified by column chromatography on silica gel 60, using 10% methanol in dichloromethane as the eluent. Thus, the product was isolated, on evaporation and vacuum drying, as an orange coloured foam.
- Step 1
- (+,-) cis 7-methoxy-4-(4-hydroxy-phenyl)-3-phenyl-chroman (7.5 g, 22.6 mmol) was dissolved in pyridine (35 ml), and methanesulfonylchloride (3.85 ml, 49.6 mmol) was added dropwise in 5 min.
- the reaction mixture was refluxed for 30 min, cooled to room temperature, and ethyl acetate (100 ml) was added.
- the reaction mixture was acidified with 6N Hydrochloric acid (100 ml), and the separated aqueous phase extracted with ethyl acetate (25 ml).
- (+,-) cis Methanesulfonic acid 4-(7- methoxy-3-phenyl-chroman-4-yl)-phenyl ester (5.0 g, 12.2 mmol) was dissolved in dry methylene chloride (150 ml), and cooled to - 78°C. A solution of 1 M boron tribromide in methylene chloride was added dropwise with stirring at such a rate that the temperature did not exceed -70°C. The reaction mixture was stirred at -78°C for 60 min, and for 60 min. after the cooling was removed.
- (+,-) cis Methanesulfonic acid 4-(7-benzyloxy-3-phenyl-chroman-4-yl)-phenyl ester (35 g, 71.9 mmol) was added to a solution of potassium hydroxide (350 g) in ethanol (2500 ml) and refluxed for 90 min. The reaction mixture was cooled, acetic acid (350 ml) was slowly added, and the resulting mixture was stirred overnight. Water (1.5 I) was added dropwise over 60 min, stirring was continued for 120 min, and the precipitated product was filtered. The precipitate was vacuum dried with sicapent (Merck) at 45°C for 4 days.
- Step l 4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene
- 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.
- Step 1
- 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 a content of half a mole of crystal bound 2-propanol.
- the aqueous phase was further extracted with ethyl acetate (2 x 100 ml).
- the combined organic extracts were washed with water, and saturated sodium chloride solution, then dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 2:1 ethanol/water (600ml) to give the product as an off-white solid, which was vacuum dried.
- Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (150 ml) solution of 4-(4-acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxy- coumarin (4.04 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 1
- Butyllithium (2.0M in hexanes, 6.6 ml, 13.2 mmol) was added dropwise under nitrogen, at - 78°C to a stirred tetrahydrofuran (20 ml) solution of 4-benzyloxy-bromobenzene (3.15 g,
- aqueous phase was further extracted with ethyl acetate (2 x 20 ml).
- the combined organic extracts were washed with water, then brine, dried over sodium sulfate and evaporated to give a yellow/orange gum. This gum was dissolved in a minimum of ether and petrol added to precipitate the title compound as an off white powder.
- Lithium aluminium hydride (0.96 g, 2.54 mmol) was added in small portions to a stirred solution of 4-(4-acetoxyphenyl)-3-phenyl-6-methoxy-coumarin (0.49 g, 1.27 mmol) in tetrahydrofuran (75 ml). The resulting mixture was stirred for 30 min., 6M hydrochloric acid (4 ml) added dropwise, and the mixture heated to 65°C for 3 h. The mixture was cooled to room temperature, diluted with 100 ml water, and the product extracted into ethyl acetate (2 x 100 ml). The extracts were washed with brine, dried over sodium sulfate and evaporated to give a yellow gum.
- This gum was dissolved in ethanol (100 ml), and palladium on carbon (5%, 0.045 g, 0.02 mmol) added, then the mixture was hydrogenated for 18 h.
- the catalyst was removed by filtration and the solvents evaporated to give an orange gum, which was vacuum dried.
- the gum was dissolved in dry acetone (20 ml) then potassium carbonate (1.87 g, 13.50 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.257 g, 1.51 mmol) and sodium iodide (0.01 g, catalyst) were added and the mixture heated to 60°C for 20 h.
- Step l
- 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.
- (+,-) cis 7-Benzyloxy-4-[4-(2-chloroethyloxy)-phenyl]-3-phenyl-chroman (235 mg, 0.5 mmol), N,N-dibutylamine (323 mg, 2.5 mmol), potassium carbonate (138 mg, 1 mmol) and potassium iodide (16 mg, 0.1 mmol) in dimethylformamide (5 ml) was stirred at 60°C for 2 weeks. The reaction mixture was cooled and ether and water was added. The aqueous phase was extracted with ether, and the combined organic phases were washed with water and brine, dried (magnesium sulphate), and evaporated. The product was isolated by silica column chromatography using methanol - methylenechloride (1 +19) as eluent.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97909217A EP0937058A1 (en) | 1996-10-28 | 1997-10-28 | NOVEL $i(CIS)-3,4-CHROMAN DERIVATIVES USEFUL IN THE PREVENTION OR TREATMENT OF ESTROGEN RELATED DISEASES OR SYNDROMES |
JP10519939A JP2001502705A (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 |
CA002270113A CA2270113A1 (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 |
AU47000/97A AU4700097A (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 |
IL12962297A IL129622A0 (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 |
NO992010A NO992010L (en) | 1996-10-28 | 1999-04-27 | New cis-3,4-chromane derivatives that can be used in the prevention or treatment of ° estrogen-related diseases or syndromes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK120096 | 1996-10-28 | ||
DK1200/96 | 1996-10-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998018773A1 true WO1998018773A1 (en) | 1998-05-07 |
Family
ID=8102107
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1997/000480 WO1998018773A1 (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 |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0937058A1 (en) |
JP (1) | JP2001502705A (en) |
AU (1) | AU4700097A (en) |
CA (1) | CA2270113A1 (en) |
IL (1) | IL129622A0 (en) |
NO (1) | NO992010L (en) |
WO (1) | WO1998018773A1 (en) |
ZA (1) | ZA979642B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002533456A (en) * | 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 | Compounds and methods for modulating estrogen receptors |
EP1809618A1 (en) * | 2004-09-21 | 2007-07-25 | Novogen Research Pty Ltd | 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 |
WO2015117202A1 (en) * | 2014-02-07 | 2015-08-13 | Novogen Limited | Functionalised benzopyran compounds and use thereof |
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 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2516067T3 (en) * | 2004-09-21 | 2014-10-30 | Mei Pharma, Inc. | Substituted Chroman Derivatives, Medicines and Therapy |
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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 (en) * | 1993-03-11 | 1994-09-15 | Zymogenetics, Inc. | Methods for inhibiting bone loss with 3,4-diarylchroman |
WO1996021444A1 (en) * | 1995-01-13 | 1996-07-18 | Novo Nordisk A/S | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of gynaecological disorders |
-
1997
- 1997-10-28 CA CA002270113A patent/CA2270113A1/en not_active Abandoned
- 1997-10-28 IL IL12962297A patent/IL129622A0/en unknown
- 1997-10-28 WO PCT/DK1997/000480 patent/WO1998018773A1/en not_active Application Discontinuation
- 1997-10-28 AU AU47000/97A patent/AU4700097A/en not_active Abandoned
- 1997-10-28 ZA ZA9709642A patent/ZA979642B/en unknown
- 1997-10-28 EP EP97909217A patent/EP0937058A1/en not_active Withdrawn
- 1997-10-28 JP JP10519939A patent/JP2001502705A/en active Pending
-
1999
- 1999-04-27 NO NO992010A patent/NO992010L/en not_active Application Discontinuation
Patent Citations (4)
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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 |
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WO1996021444A1 (en) * | 1995-01-13 | 1996-07-18 | Novo Nordisk A/S | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of gynaecological disorders |
Non-Patent Citations (1)
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JP2002533456A (en) * | 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 | Compounds and methods for modulating estrogen receptors |
US9198895B2 (en) | 2004-09-21 | 2015-12-01 | Mei Pharma, Inc. | Chroman derivatives, medicaments and use in therapy |
EP2407462A1 (en) * | 2004-09-21 | 2012-01-18 | Marshall Edwards, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
US9381186B2 (en) | 2004-09-21 | 2016-07-05 | Mei Pharma, Inc. | Substituted 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 |
US8697891B2 (en) | 2004-09-21 | 2014-04-15 | Marshall Edwards, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
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US8461361B2 (en) | 2004-09-21 | 2013-06-11 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
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US8957109B2 (en) | 2004-09-21 | 2015-02-17 | Mei Pharma, Inc. | 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 |
US9138478B2 (en) | 2004-09-21 | 2015-09-22 | Mei Pharma, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
EP1809618A1 (en) * | 2004-09-21 | 2007-07-25 | Novogen Research Pty Ltd | Chroman derivatives, medicaments and use in therapy |
US11723893B2 (en) | 2010-11-01 | 2023-08-15 | Mei Pharma, Inc. | Isoflavonoid compositions 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 |
US9663484B2 (en) | 2010-11-01 | 2017-05-30 | Mei Pharma, Inc. | Isoflavonoid compounds 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 |
US9981936B2 (en) | 2010-11-01 | 2018-05-29 | Mei Pharma, Inc. | Isoflavonoid compositions 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 |
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US10973799B2 (en) | 2010-11-01 | 2021-04-13 | Mei Pharma, Inc. | Isoflavonoid compositions and methods for the treatment of cancer |
US9701655B2 (en) | 2014-02-07 | 2017-07-11 | Novogen Limited | Functionalised benzopyran compounds and use thereof |
US10370349B2 (en) | 2014-02-07 | 2019-08-06 | Kazia Therapeutics Limited | Functionalised benzopyran compounds and use thereof |
RU2676766C2 (en) * | 2014-02-07 | 2019-01-11 | Новоген Лимитед | Functionalised benzopyran compounds and use thereof |
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US10980774B2 (en) | 2015-02-02 | 2021-04-20 | Mei Pharma, Inc. | Combination therapies |
Also Published As
Publication number | Publication date |
---|---|
IL129622A0 (en) | 2000-02-29 |
JP2001502705A (en) | 2001-02-27 |
AU4700097A (en) | 1998-05-22 |
EP0937058A1 (en) | 1999-08-25 |
CA2270113A1 (en) | 1998-05-07 |
NO992010D0 (en) | 1999-04-27 |
NO992010L (en) | 1999-06-25 |
ZA979642B (en) | 1998-04-28 |
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