WO2005035517A1 - Derives de (3r, 4r)-trans-3,4-diarylchromane a activite oestrogenique - Google Patents

Derives de (3r, 4r)-trans-3,4-diarylchromane a activite oestrogenique Download PDF

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WO2005035517A1
WO2005035517A1 PCT/IB2003/004559 IB0304559W WO2005035517A1 WO 2005035517 A1 WO2005035517 A1 WO 2005035517A1 IB 0304559 W IB0304559 W IB 0304559W WO 2005035517 A1 WO2005035517 A1 WO 2005035517A1
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phenyl
dimethyl
hydroxy
methoxy
propyloxy
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PCT/IB2003/004559
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. Sangita
Atul Kumar
Man Mohan Singh
Suprabhat Ray
Girish Kumar Jain
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Council Of Scientific And Industrial Research
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Priority to CNB2003801104741A priority Critical patent/CN100545158C/zh
Priority to PCT/IB2003/004559 priority patent/WO2005035517A1/fr
Priority to AU2003267773A priority patent/AU2003267773A1/en
Priority to EP03748468A priority patent/EP1675843A1/fr
Priority to CA002539502A priority patent/CA2539502A1/fr
Priority to JP2005509433A priority patent/JP2007516155A/ja
Publication of WO2005035517A1 publication Critical patent/WO2005035517A1/fr

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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
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • A—HUMAN NECESSITIES
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to compounds of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration:
  • R 1 is H or C1-C6 alkyl; C3-C7 cycloalkyl; R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 - alkyl, halogen, nitro, cyano, SH, SR 4, trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein
  • R 4 is C1-C6 alkyl
  • R 3 is phenyl substituted with OR 5 wherein R 5 has the formula (II), (III) or (IV) (H) (BO) (IV) wherein Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 ,
  • CONR 4 2 COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2> a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy, preferably NHR 4 , NR 2 4 , or a nitrogen heterocycle, wherein R 4 is as defined above, and the esters, ethers, and salts of the compounds of formula I, optionally along with pharmaceutically acceptable excipients, a process for the preparation of the same, and a method of preventing and/or treating estrogen-related disease conditions in a subject using compounds of formula 1, or its salts,
  • Menopause in women's life is the most critical stage of the life when she undergoes dramatic physiological changes and is defined as the transition in women from reproductive to non-reproductive stage of life, which is due to the cessation of menstruation and occurs at an average age of fifty years. More particularly, the post- menopausal stage is characterized by the changes in the levels of circulating sex hormones, the most dramatic of which is the reduction in plasma levels of 17-beta-estradiol to less than ten percent of pre-menopausal values, which results in a number of chronic disorders and is often referred to as Post Menopausal Syndrome.
  • Estrogen deficiency is the most important risk factor associated with Post Menopausal Syndrome.
  • Some of the major effects of the Post Menopausal Syndrome that are source of greatest long-term medical concern include osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor disorders, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy, depression, mania, schizophrenia, urinary incontinence, relief of dysmenorrhea; relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne, hirsutism.
  • Osteoporosis can be defined as a reduction in bone mass per unit volume with an alteration in bone microarchitecture that results in an increased susceptibility to fractures. It is not surprising that the most common fractures are those associated with bones, which are highly dependent on trabecular support, for example the vertebrae, the neck, and the weight bearing bone such as the femur, and the fore arm. Indeed the hip fracture, collies fractures and vertebrae crush fractures are hallmarks of post-menopausal osteoporosis. In most cases, bone loss occurs as a result of increased bone destruction (resorption) relative to bone formation and most women lose from about 20% to 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the menopause.
  • Osteoporosis more particularly the post-menopausal osteoporosis represents a major problem in women health care and poses a risk to quality of life during old age. Efforts to reduce this risk factor and incidence of fractures have resulted in the development of compounds that conserve skeletal mass by inhibiting bone resorption and/or by enhancing bone formation (Dwivedi I, Ray S, 1995 "Recent developments in the chemotherapy of osteoporosis" Progress in Drug Research 45, 289-338, Editor E Jucker, Birkhauser Vela; Marshall DH, Horsmann A, Nordin BEC, 1977, "The prevention and management of post- menopausal osteoporosis” Acta Obstet Gynecol Scand (Suppl) 65:49-56; Hutchinson TA, Polansky SM, Feinstein AR, 1979, "Postmenopausal estrogen protect against fractures of hip and distal radius: A care-control study” Lancet 2:705-709.
  • Estrogen replacement therapy also has positive effect on CVS & CNS related disorders (Lobo RA, 1990, "Cardiovascular implication of estrogen replacement therapy” Obstetrics & Gynaecology 75:185-245; Mendelson ME, Karas RH, 1994, “Estrogen and the blood vessel wall” Current opinion in Cardiology 1994:619-626; Stampfer MJ, Colditz GA, 1991, "Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence” Preventive Medicine 20:47-63).
  • Cardiovascular disease is another leading cause of morbidity and mortality in older women. Menopause and ageing increase risk of atherosclerosis and coronary artery disease. An altered lipid profile is thought to be associated with this increased risk. Compared to men, pre-menopausal women are relatively more protected from cardiovascular diseases. This protection is gradually lost following menopause. This loss of protection has been linked to the loss of estrogen and in particular to the loss of estrogen's stationary phase ability to regulate the level of serum lipids. The nature of estrogens ability to reduce serum lipids is not well understood, but evidences indicate that estrogen can up-regulate LDL receptors in the liver which act to remove excess cholesterol.
  • estrogen appears to have some effects on the biosynthesis of cholesterol and other beneficial effects on cardiovascular health. Estrogen is also believed to directly influence vessel wall compliance, reduce peripheral resistance and prevent atherosclerosis. It is also reported that serum lipids in post-menopausal women having estrogen replacement therapy (ERT) return to concentrations found in the pre-menopausal state (Gruber CJ, Tschugguel W, Schneeberger C, Huber JC, 2002, "Production and actions of estrogens” The New England Journal of Medicine 346:340-352; Bellino FL, Wise PM, 2003 "Nonhuman primate models of menopause workshop” Biology of Reproduction 68:10-18; Lobo RA 1990, ⁇ 'Cardiovascular implication of estrogen replacement therapy", Obstetrics and Gynaecology 75:18S-24S; Medelson ME, Karas RD 1994, “Estrogen and the blood vessel wall”, Current opinion in Cardiology, 1994 (9):619-626).
  • ERT estrogen replacement therapy
  • Estrogen is also known to increase density of N-methyl-D-aspartate receptors and increase neuronal sensitivity to input mediated by these receptors in neurons of hippocampus, the area involved in memory.
  • the estradiol-depleted state in post-menopausal women has been correlated with increased incidence of stroke, cognitive defects, hot flashes, mood changes, and early onset and severity of Alzheimer disease.
  • Tamoxifen ('Nolvadex'), a selective estrogen receptor modulator (SERM), is currently the most widely used drug for the treatment of estrogen receptor positive (ER+ve) breast cancer. Tamoxifen inhibits the estrogen- dependent growth of cancer cells by competitive binding to estrogen receptors of the cells. However, as tamoxifen has also estrogen-like effects, it induces, among other adverse effects, endometrial cancer, deep vein thrombosis and pulmonary embolism in women undergoing the therapy.
  • SERM selective estrogen receptor modulator
  • tamoxifen is known to induce DNA adduct formation and produced liver tumors in rodent life-term bioassays.
  • SERMs for the treatment of breast cancer
  • SERMs due to their tissue selective action
  • SERMs have also been successfully used for induction of ovulation in amenorrhic women under the assisted reproduction programmes (Roy SN, Kumari GL, Modoiya K, Prakash V, Ray S, 1976, "Induction of ovulation in human with centchroman, a preliminary report", Fertility and Sterility 27: 1108-1110) and suppression of post-partum lactation (Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1321-1423).
  • the present invention provides new compounds, pharmaceutically acceptable salts and compositions thereof and methods of using such compounds for the prevention or treatment of: (a) estrogen deficient or deprivation state in a mammal, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor system, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy, depression, mania, schizophrenia and the like, urinary incontinence, relief of dysmenorrhea; relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne and hirsutism; (b) estrogen dependent or estrogen independent cancers such as prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon; (c) an aid in ovarian development or function; (d) control or regulation of fertility in humans and in other animals; (e) prevention of fertility
  • the main object of the present invention is to develop compounds of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration:
  • R 1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R 4 is Cl- C6 alkyl;
  • R 3 is phenyl substituted with OR 5 wherein R 5 has the formula (II), (III) or (IV)
  • Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2 , a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH,
  • SR 4 trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy, preferably NHR 4 , NR 2 4 , or a nitrogen heterocycle, wherein R 4 is as defined above, and the esters, ethers, and salts of the compounds of formula I, optionally along pharmaceutically acceptable excipients.
  • Another main object of the present invention is to develop a process for the preparation of compounds of formula I.
  • Yet another object of the present invention is to develop a method of preventing and/or treating estrogen-related disease conditions in a subject in need thereof, said method comprising step of administering to the subject, a pharmaceutically effective amount of compounds of formula 1, or its salts, optionally along with pharmaceutically acceptable' excipients.
  • Still another object of the present invention is to develop a method of prevention and/or treatment as claimed in claim 14, wherein said method helps in preferably diseases or syndromes caused by an estrogen-deficient state, with Relative Binding affinity (RBA) to estrogen receptors ranging between 5 to 7.
  • RBA Relative Binding affinity
  • Still another object of the present invention is to develop A method of prevention and/or treatment as claimed in claim 14, wherein said method helps in disease conditions caused by osteoporosis, bone loss, and bone formation, with T/C ratio of ⁇ 0.6.
  • Still another object of the present invention is to develop A method of prevention and/or treatment as claimed in claim 14, wherein said method helps in disease conditions affecting cardiovascular systems, more particularly hyperlipidaemia, thrombosis and vasomotor system.
  • Still another object of the present invention is to develop a method to help in disease conditions showing neurodegenerative effects, more particularly, stroke, senile dementia- Alzheimer type and Parkinson disease.
  • Still another object of the present invention is to develop a method to help in the management of certain physiological disorders, more particularly, obesity and depression. Still another object of the present invention is to develop a method to help regulate of glucose metabolism in non-insulin dependent diabetes mellitus.
  • the present invention relates to compounds of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration:
  • R 1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR 4, trihalo-Cl-C6- alkyl, C1-C6 -alkoxy and phenyl, wherein R 4 is C1-C6 alkyl;
  • R 3 is phenyl substituted with OR 5 wherein R 5 has the formula (II), (III) or (IV) (H) (UI) (IV) wherein Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2> a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting
  • the present invention relates to compounds of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration:
  • R 1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR 4,' trihalo-Cl-C6 alkyl, C1-C6 -alkoxy and phenyl, wherein R is C1-C6 alkyl;
  • R is phenyl substituted w ,..i:(t-h , w.,h!,e «_repetiti»n.
  • R r>5 has the formula (JJ), (III) or (IV)
  • Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2> a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy, preferably NHR 4 , NR 2 4 , or a nitrogen heterocycle, wherein R 4 is as defined above, and the esters, ethers, and salts of the compounds of formula I, optional
  • the substituents R 2 and R 3 are arranged in trans-configuration in compounds of formula I, wherein compounds of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration:
  • R 1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR 4 ' trihalo-Cl-C6- alkyl, C1-C6 -alkoxy and phenyl, wherein R 4 is C1-C6 alkyl;
  • R 3 is phenyl substituted with OR 5 wherein R 5 has the formula (II), (HI) or (IV) (ID (DD (IV)
  • Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2 , a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy, preferably NHR 4 , NR 2 4 , or a nitrogen heterocycle, wherein R 4 is as defined above, and the esters, ethers, and salts of the compounds of formula I, optionally along pharmaceutically acceptable excipients
  • R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula II and wherein Y is a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group comprising O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cj-C 6 - alkyl, Cl-C6-alkyl, Cl-C6-alkyl and Cl-C6-alkoxy.
  • R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula III and wherein Y is a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group comprising O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6- alkyl, Cl-C6-alkyl, Cl-C6-alkyl and Cl- C6-alkoxy.
  • R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula IV and wherein Y is a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group comprising O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6- alkyl, Cl-C6-alkyl, Cl-C6-alkyl and Cl-C6-alkoxy.
  • R 1 is preferably methyl.
  • R 2 is preferably phenyl
  • R 4 is preferably butyl.
  • the preferred compounds are: a. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[ ⁇ 2R)-3-methylamino-2- hydroxy ⁇ propyloxy] phenyl)-3-phenylchroman. b. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[ ⁇ 2R)-3-ethylamino-2- hydroxy ⁇ propyloxy] phenyl)-3-phenylchroman. c.
  • salts are selected from a group comprising acid addition salts consisting of formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate
  • the invention includes alkyl or aryl halides addtion salts of the compounds of this invention, wherein the alkyl halide is selected from a group comprising Cj to Cj alkyl halide, and aryl halide is selected from a group comprising benzyl halide and substituted benzyl halide.
  • salts are fumerate, ascorbate, hydrochloride, and methyl iodide.
  • the compounds or its salts are in the physical forms of the gelatin capsules or compressed into tablets or pills or may be formulated in the form of lozenges, inclusion complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, and targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
  • the pharmaceutically acceptable excipients are selected from a group comprising: i. diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; ii. a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; iii.
  • diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof
  • a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of
  • a disintegrating agent such as agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof;
  • a lubricant such as magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone or in a suitable combination thereof;
  • a glidant such as colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; vi.
  • a sweetening agent such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof
  • a flavoring agent such as peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • a wetting agents such as cetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • a absorbents such as kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • a solution retarding agents such as wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
  • a process for the preparation of compounds of formula I comprising steps of: a. reacting a compound of formula V in which substituents R 2 and R 6 are arranged in the (3R,4R) configuration: wherein R 1 and R 2 are as defined in formula 1 and R 6 is phenyl substituted with a hydroxy substituents at C2, C3 or C4, preferably at C4 with a compound of formula VI, VII, VIII, neat or in an aprotic solvent which includes dimethylsulphoxide, dimethylformamide in the presence of a base such as K 2 CO 3 at a temperature ranging between 50 to 120°C,
  • the salts are selected from a group comprising acid addition salts consisting of formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydr
  • the invention includes alkyl or aryl halides addtion salts of the compounds of this invention, wherein the alkyl halide is selected from a group comprising to C 18 alkyl halide, and aryl halide is selected from a group comprising benzyl halide and substituted benzyl halide.
  • alkyl halide is selected from a group comprising to C 18 alkyl halide
  • aryl halide is selected from a group comprising benzyl halide and substituted benzyl halide.
  • most preferred salts are fumerate, ascorbate, hydrochloride, and methyl iodide.
  • the administration is through various routes selected from a group comprising oral, systemic, local, and topical delivery selected from a group consisting of intravenous, intra-arterial, intra-muscular, subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal, and transdermal.
  • the preferred route of administration is oral route.
  • the physical forms of the compound of formula 1 and its salts could be gelatin capsules or compressed into the tablets or pills or may be formulated in the form of lozenges, inclusion complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, and targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
  • the pharmaceutically acceptable excipients are selected from a group comprising: i. diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; ii. a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; iii.
  • diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof
  • a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of
  • a disintegrating agent such as agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof;
  • a lubricant such as magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone or in a suitable combination thereof;
  • a glidant such as colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; vi.
  • a sweetening agent such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof
  • a flavoring agent such as peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • a wetting agent such as acetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • an absorbent such as kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • a solution retarding agent such as wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
  • said method helps in preferably diseases or syndromes caused by an estrogen-deficient state, with Relative Binding affinity (RBA) to estrogen receptors ranging between 5 to 7.
  • RBA Relative Binding affinity
  • said method helps in disease conditions caused by osteoporosis, bone loss, and bone fo ⁇ nation, with T/C ratio of ⁇ 0.6.
  • said method helps in disease conditions affecting cardiovascular systems, more particularly hyperlipidaemia, thrombosis and vasomotor system.
  • said method helps in disease conditions showing neurodegenerative effects, more particularly, stroke, senile dementia- Alzheimer type and Parkinson disease.
  • said method helps in disease conditions showing menopausal symptoms, more particularly, hot flushes, urogenital atrophy, depression, mania, schizophrenia, urinary incontinence, dysmenorrhea, dysfunctional uterine bleeding, acne, hirsutism, improper ovarian development.
  • said method helps in disease conditions showing cancers, more particularly, prostatic carcinoma, breast cancer, cancer of uterus, cancer of the cervix and colon cancer, with LC 50 ranging between 17 to 20 ⁇ M.
  • the volume of the tumor decreases by about 25%.
  • the present invention provides a class of novel (3R, 4R)-trans-3,4-diarylchroman derivatives of the formula (1) or pharmaceutically acceptable salts or pharmaceutically acceptable compositions thereof in which substituents R andR are arranged in the (3R,4R)-trans-configurati on wherein:
  • R' is H or Cl-C ⁇ alkyl
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, Cl-C6-alkyl, halogen, nitro, cyano, SH, SR 4, trihalo-Cl-C6- alkyl, Cl-C6-alkoxy and phenyl, wherein R 4 is C1-C6 alkyl; C3-C7 cycloalkyl; R 3 is phenyl substituted with O-R 5 wherein R 5 has the formula (II), (III) or (IV)
  • Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2 , a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH,
  • Cl-C6-alkyl includes straight chain as well as branched alkyl groups such as methyl as ethyl, propyl, isopropyl, butyl and isobutyl.
  • halogen means chloro, bromo, iodo and fluoro.
  • C3-C7-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, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, alone or in a combination of an estrogen or a progestin or both and one or more pharmaceutically acceptable carrier or excipients.
  • the present invention provides a medical method of employing the compounds of the present invention or pharmaceutically acceptable salts and compositions thereof and methods of using such compounds for the prevention or treatment of symptoms of estrogen deficiency or deprivation including estrogen deficient or deprivation states in mammals, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia.
  • the compounds of the present invention or pharmaceutically acceptable salts and compositions thereof are employed in the prevention or the treatment of estrogen dependent cancers such as cancer of breast.
  • the compounds of the present invention are employed in the prevention or the treatment of disease conditions or disorders associated with an aberrant physiological response to endogenous estrogen including regulation of fertility in humans and in other animals.
  • the present invention relates to the field of pharmaceuticals and organic chemistry and provides new (3R,4R)-trans-3,4-diarylchroman derivatives, their pharmaceutically acceptable salts and compositions that are useful for the prevention or treatment of various medical indications associated with estrogen dependent or independent diseases or syndromes, preferably in prevention or treatment of diseases and syndromes caused by: (a) estrogen deficient or deprivation state in a mammal, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor system, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy, depression, mania, schizophrenia and the like, urinary incontinence, relief of dysmenorrhea; relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne and hirsutism; (b) estrogen dependent or estrogen independent cancers such as prostatic carcinoma,
  • the present invention provides novel (3R,4R)-trans-3,4-diarylchroman derivatives of the formula (1) or pharmaceutically acceptable salts or pharmaceutically acceptable compositions thereof in which substituents R 2 and R 3 are arranged in the (3R,4R)-trans- configuration wherein:
  • R 2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, Cl-C6-alkyl, halogen, nitro, cyano, SH, SR 4 ' trihalo-Cl-C6- alkyl, Cl-C6-alkoxy and phenyl, wherein R 4 is C1-C6 alkyl; C3-C7 cycloalkyl;
  • R 3 is phenyl substituted with O-R 5 wherein R 5 has the formula (II), (III) or (IV)
  • Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2> a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH,
  • Cl-C6-alkyl includes straight chain as well as branched alkyl groups such as methyl as ethyl, propyl, isopropyl, butyl and isobutyl.
  • halogen means chloro, bromo, iodo and fluoro.
  • C3-C7-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, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.
  • the compounds of this invention or pharmaceutically acceptable salts and compositions thereof are novel Selective Estrogen Receptor Modulators and provide methods of using such compounds for the prevention or treatment of symptoms of estrogen deficiency or deprivation including estrogen deficient or deprivation state in mammals, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, prevention or the treatment of estrogen dependent or estrogen independent cancers such as cancer of breast and control or regulation of fertility in humans and in other animals.
  • estrogen deficiency or deprivation is meant to imply the conditions where the optimal level of estrogen is absent. This level varies from one tissue to another depending on the function of the tissue.
  • estrogen deficiency or deprivation may be total absence of estrogen, whereas in other cases, deficiency or deprivation may involve estrogen levels, which are too low for proper tissue function.
  • deficiency or deprivation may involve estrogen levels, which are too low for proper tissue function.
  • menopause and ovariectomy the two most common causes of estrogen deprivation are menopause and ovariectomy, although other conditions may be causative.
  • Suitable pharmaceutically acceptable salts include salts formed by in-organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, hypophosphoric acid, and the like, as well as the salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, aromatic acids, aliphatic and aromatic sulphonic acids. Also, the salts derived from alkyl halides (preferably, methyl iodide) and aryl halides.
  • Such pharmaceutically acceptable acid addition salts include formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate,
  • the invention includes alkyl or aryl halides addtion salts of the compounds of this invention, wherein the alkyl halide is selected from a group comprising to C 18 alkyl halide, and aryl halide is selected from a group comprising benzyl halide and substituted benzyl halide.
  • Most preferred salts are fumarate or ascorbate or hydrochloride.
  • Pharmaceutical compositions of the compound of the present invention or a pharmaceutically acceptable salt thereof may be prepared by procedures known in the art using pharmaceutically acceptable excipients known in the art.
  • Methods of preventing or treating disorders or disease conditions mentioned herein comprise administering, to an individual human being or any other mammal or any other animal in need of such treatment, a therapeutically effective amount of one or more of the o compounds of this invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof with one or more of the pharmaceutically acceptable carriers, excipients etc.
  • the dosage regimen and the mode of administration of the compound of this invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof with one or more of the pharmaceutically acceptable carriers, excipients etc. will vary according to the type of disorder or disease conditions described herein and will be subject to the judgment of the medical practitioner involved.
  • the compound of this invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof with one or more of the pharmaceutically acceptable carriers, excipients etc. may be effectively administered in doses ranging from
  • 0.1 mg to 1000 mg more preferably in doses ranging from 0.5 to 500 or still more preferably in the doses ranging from 1 mg to 100 mg weekly or bi-weekly or daily or twice a day or three times a day or in still more divided doses.
  • Therapeutically effective amounts of a compound of the present invention or a pharmaceutically acceptable salt thereof may be enclosed in gelatin capsules or compressed into the tablets or pills or may be formulated in the form of lozenges, inclusion o complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
  • Such doses may be administered by any appropriate route for example, oral, systemic, local or topical delivery for example, intravenous, intra-arterial, intra-muscular, subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal, transdermal or any other suitable means in any conventional liquid or solid dosage form to achieve, conventional delivery, controlled delivery or targeted delivery of the compounds of this invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof with one or more of the pharmaceutically acceptable carriers, excipients etc.
  • a preferred mode of administration of a compound of the present invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof is oral.
  • Oral compositions will generally comprise of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more of the pharmaceutically acceptable excipients.
  • compositions such as tablets, pills, capsules, powders, granules, and the like may contain any of the following pharmaceutically acceptable excipients: 1. a diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; 2. a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; 3.
  • a diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof
  • a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyviny
  • a disintegrating agent such as agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; 4.
  • a lubricant such as magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone or in a suitable combination thereof; 5.
  • a glidant such as colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable' combination thereof; 6.
  • a sweetening agent such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; 7.
  • a flavoring agent such as peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • 8. wetting agents such as cetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • absorbents such as kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof
  • solution retarding agents such as wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
  • the present invention is concerned with compounds where R 3 is phenyl substituted with OR 5 wherein R 5 has the formula II.
  • the present invention is concerned with compounds wherein R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula III and wherein Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 2 , COOH, COOR 4 ,
  • the present invention is concerned with compounds wherein R 3 is phenyl substituted with - OR 5 wherein R 5 has the formula III and wherein Y is a C3-C7 heterocychc ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H,
  • the present invention is concerned with compounds wherein R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula IV.
  • the present invention is concerned with compounds wherein R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula IV and wherein Y is chosen from NHR 4 , NR 4 2 , NHCOR 4 , NHSO2R 4 , CONR, CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2 .
  • the present invention is concerned with compounds wherein R 3 is phenyl substituted with -OR 5 wherein R 5 has the formula IV and wherein Y is a C3-C7 heterocychc ring, saturated or containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-Cl-C6 - alkyl and C1-C6 -alkoxy.
  • the present invention is concerned with compounds in which OR 1 is substituted at C5, C6, C7, or C8 position. In another preferred embodiment, the present invention is concerned with compounds in which OR 1 is placed at C7 position. In another preferred embodiment, the present invention is concerned with compounds in which R 1 is H, methyl or ethyl, preferably methyl.
  • the present invention is concerned with compounds in which R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, Cl-C6-alkyl halogen, cyano, trihalo-Cl-C6 -alkyl and Cl-C6-alkoxy, preferably R 2 is phenyl.
  • the present invention is concerned with compounds in which R 4 is methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, phenyl, hexyl, preferably butyl.
  • the compounds of the invention may be prepared by resorting to the chroman chemistry which is well-known in the art, for example in PK Arora, PL Kole and S Ray, Indian J Chem 20 B, 41-5, 1981; S Ray, PK Grover and N Anand, Indian J Chem 9, 727-8, 1971; S Ray, PK Grover, VP Kamboj, BS Setty, AB Kar and N Anand, J Med Chem 19, 276-9, 1976; M Salman, S Ray, AK Agarwal, S Durani, BS Setty, VP Kamboj and N Anand, J Med Chem 26, 592 : 5, 1983; C Teo, K Sim, Bull Singapore Natl Inst Chem 22, 69-74, 1994; M Salman, PK Arora, S Ray, RC Srimal, Indian J Pharm Sci 49, 43-47, 1987.
  • the invention is further more concerned with a general method of preparation of compounds of formula 1 comprising the steps: a) reacting a compound of formula V in which substituents R 2 and R 6 are arranged in the (3R, 4R) configuration: wherein R 1 and R 2 are as defined in formula 1 and R 6 is phenyl substituted with a hydroxy substituent at C2, C3 or C4, preferably at C4 with a compound of formula VI, VII, VIII, neat or in an aprotic solvent which includes dimethylsulphoxide, dimethylformamide in the presence of a base such as K 2 CO 3 at elevated temperature (50-120°C) to form a compound of structure IX (a-c) wherein R 1 and R 2 are as defined above.
  • formula 1 compounds may then be formed as desired.
  • Specific preparations of the compounds of the present invention are described below. Modifications to the above methods may be necessary to accommodate reactive functionalities of particular substituents. Such modification would be both apparent to, and readily ascertained by, those skilled in the art.
  • the free base form of the compounds of the formula 1 can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form.
  • the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in the pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, hypophosphoric, and the like.
  • Salts derived from the organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyl alkanoic acids, and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulphonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenyl acetate, triflurocacetate, acrylate, ascorbate, benzoate, chlorobenzoate, nitrobenzoate, dinitrobenzoate, hydroxyl benzoate, methoxy benzoate, methyl benzoate, acetoxy benzoate, hydrochloride, hydrobromide, hydroiodide, butyrate, phenyl butyrate, hydroxyl butyrate, caprate, caprylate, cinnamate, citrate, formate, succinate, fumarate, glycolate, heptanoate, hippurate, maleate, lactate, malate, hydroxyl maleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrpphosphate, propioplate,
  • the invention includes alkyl or aryl halides addtion salts of the compounds of this invention, wherein the alkyl halide is selected from a group comprising C ⁇ to C 18 alkyl halide, and aryl halide is selected from a group comprising benzyl halide and substituted benzyl halide.
  • the preferred salts are fumerate, ascorbate, methyl iodide, and hydrochloride salt.
  • Ethanol was distilled off.
  • the obtained residue was purified by passing through basic alumina column using hexane-benzene as eluant.
  • the free base thus obtained was converted into its hydrochloride by treating with ethanolic HCI and crystallized from anhydrous ethanol-diethylether to give the desired product.
  • This compound showed promising antiresorptive activity in vitro using chick fetal bone assay with T/C ratio of 0.4 to 0.7 at 25-100 ⁇ M concentration in repeat tests, in comparison to Raloxifene having T/C of 0.6. It also prevents pregnancy in rats when administered during the pre-implantation period and has an MED of 0.05 mg/kg dose and is devoid of any estrogenic activity at the MED.
  • Ethanol was distilled off and the residue purified by passing through basic alumina column using hexane-benzene as eluent.
  • the compounds of the present invention were evaluated for use for the prevention or treatment of symptoms of estrogen deficiency or deprivation including estrogen deficient or deprivation state in mammals, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, prevention or the treatment of estrogen dependent or estrogen independent cancers such as cancer of breast and control or regulation of fertility in humans and in other animals.
  • Detailed procedures for the evaluation of the compounds of the present invention or pharmaceutically acceptable salts or compositions thereof are described hereunder:
  • Test solutions of the compounds of the present invention are prepared in appropriate solvents in concentration range of 5 millimolar to 400 millimolar, most preferably in concentrations of 20 millimolar. 5 ⁇ l of each concentration are used for evaluation of antireso ⁇ tive activity in vitro. In control experiments, 5 ⁇ l of appropriate solvent is used in lieu of test compound.
  • Femur bones are isolated from chick embryos on day 11 post- ovulation. The adhering soft connective tissue is completely removed. Each femur bone is then placed in a drop of phosphate buffered saline (PBS) and is transferred to BGJ b culture medium containing 45 CaCl 2 and incubated for 2 h.
  • PBS phosphate buffered saline
  • Labeled femur bones are washed 2-3 times with PBS and transferred to BGJ b medium containing parathyroid hormone and cultured for 96 h in the presence or absence of the compound of invention or the vehicle in BGJb medium.
  • Contralateral femur of each fetus serves as corresponding control.
  • Culture medium with the respective treatment in each well is changed after 48 h.
  • bones are transferred to 0.1 N HCI for 24 h.
  • Radioactivity due to 45 Ca in the spent medium collected at 48 and 96 h of culture and HCI extract at 96 h of culture is quantified by Liquid Scintillation Spectrophotometer in 10 ml of the scintillation fluid. Bone resorbing activity is expressed as percentage of 45 Ca released into the culture medium and the effect of the compound of invention as percent of the corresponding contra-lateral control or T/C ratio as shown below:
  • Appropriate solvents are selected from solvents like water, normal (physiological) saline, phosphate buffered saline, phosphate buffer, DMSO alone or in a suitable combinations thereof.
  • the compounds of the present invention on employing or administering their effective amounts, exhibit positive response by inhibiting the PTH induced reso ⁇ tion of 45 Ca from chick fetal bones in culture.
  • the compounds showing T/C ratio of ⁇ 0.6 at ⁇ 100 micromolar ( ⁇ M) concentration are considered active (Table 1).
  • Activity in the above test procedure indicates that the compounds of the present invention are useful as antiresorptive agents in the treatment of post-menopausal osteoporosis.
  • Test procedure for evaluation of antiosteoporosis activity in vivo The in vivo antiosteoporosis activity is evaluated in colony-bred adult (3-4 month old) female Sprague-Dawley rats or female retired breeder Sprague-Dawley rats (12-14 months old; parity >3).
  • Animals are bilaterally ovariectomized (OVX) under light ether anesthesia and treated with the compound of the present invention, 17-alfa-ethynylestradiol (EE) or the vehicle once daily on days 1-30 post-ovariectomy (day 1: day of bilateral ovariectomy) by the oral route.
  • OVX bilaterally ovariectomized
  • EE 17-alfa-ethynylestradiol
  • day 1 day of bilateral ovariectomy
  • Animals of all the groups are autopsied 24 h after the last treatment. Before autopsy, 24 h fasting urine samples are collected in fresh containers using all-glass metabolic cages and stored at -20°C until analyzed for calcium, phosphorus and creatinine. At autopsy, about 5 ml blood samples are collected by cardiac puncture from each rat under light ether anesthesia and serum is isolated and stored at - 20°C until analyzed for total and bone specific alkaline phosphatase, osteocalcin and calcium.
  • the in vivo anti-hyperlipidaemic activity is evaluated in colony-bred adult (3-4 month old) female Sprague-Dawley rats or female retired breeder Sprague-Dawley rats (12-14 months old; parity >3).
  • Animals are bilaterally ovariectomized (OVX) under light ether anesthesia and treated with the compound of the present invention, 17-alfa-ethynylestradiol (EE) or the vehicle once daily on days 1-30 post-ovariectomy (day 1: day of bilateral ovariectomy) by the oral route.
  • OVX ovariectomized
  • EE 17-alfa-ethynylestradiol
  • day 1 day of bilateral ovariectomy
  • the procedure is based on the following methods: New colorimetric assay for anticancer drug screening, Skehan et al., J Natn Cancer Inst, 82,1107, 1990 and Feasibility of a high- flux anticancer drug screen using a diverse panel of cultured human tumor cell lines 83,757, 1991.
  • a fully confluent flask of MCF-7 cells in trypsinized and 10 4 cells/well are plated in a 96 welled flat bottomed plate in 200 ⁇ l Minimum Essential Medium (MEM), pH 7.4 and allowed to attach for 24 h at 37°C in a humidified CO 2 incubator.
  • MEM Minimum Essential Medium
  • the compound of invention dissolved in DMSO or ethanol is added at a specified concentration and further incubated for 48 h as before.
  • the cells are then fixed in 50 ⁇ l cold 50% TCA and incubated for 1 h at 4°C. The supernatant is discarded and the plate is washed five times with deionized water and air dried.
  • 100 ⁇ l of 0.4% (w/v) Sulforhodamine B (SRB) in 1% acetic acid is added to each well and incubated at room temperature for 30 minutes. Unbound SRB is removed by five washes with chilled 1% acetic acid and the plate is air dried.
  • DMBA 7,12-dimethylbenz anthracene
  • the animals have free access to standard rodent pellet diet and safe drinking water and are housed in temperature and photoperiod-controlled animal quarters throughout the experimental period.
  • palpable mammary tumors develop and reach approximately 0.5 cm in diameter
  • the tumor bearing rats are grouped and receive oral administration of the test compound at a daily dose of 10 mg/kg body weight for 4 weeks.
  • Tumor incidence, number and area/volume are recorded at the commencement of the treatment and at weekly intervals.
  • the diameter of tumors is measured using calipers and the tumor volume is derived using the formula for sphere volume.
  • the compound is considered active against mammary tumor if, by the end of treatment period, the tumor volume decreases by more than 25% or remains static or when the volume shows less than 25% increase over the pre-treatment volume.
  • Rats are caged overnight with coeval males of proven fertility and their vaginal smears are checked on the following morning. The day of presence of spermatozoa in the vaginal smear is taken as day 1 of pregnancy. Mated rats are isolated and randomized into various treatment groups and treated orally with the compound of invention or the vehicle on days 1-7/1-5 post-coitum. Animals of all the groups are autopsied on day 10 post-coitum and number and status of corpora lutea and implantation sites in each rat are recorded. The compounds of the present invention are considered active if there is complete absence of implantations in the uterus of all rats, in comparison to presence of normal implantations in the uterus of rats of vehicle control group.
  • Twenty-one-day-old immature female rats are bilaterally ovariectomized under light ether anaesthesia and, after post-operative rest for 7 days, are randomized into different treatment groups. Each rat receives the compound of the invention once daily for 3 consecutive days on days 28-30 of age. A separate group of animals receiving only the vehicle for similar duration serves as control.
  • vaginal smear of each rat is taken and uterus is carefully excised, gently blotted, weighed and fixed for histology and histomo ⁇ hometry using image analysis.
  • Premature opening of vagina, comification of vaginal epithelium, increase in uterine fresh weight, total uterine and endometrial area and uterine luminal epithelial cell height are taken as parameters for evaluation of estrogen agonistic activity in comparison to rats of vehicle control group.
  • Table 4 Increase in uterine weight in immature ovariectomized rats: Percent of OVX+ vehicle treatment group
  • paraffin sections (6 ⁇ m thick) of the uterus stained with haematoxylin and eosin were analysed microscopically.
  • areas of whole uterus and endometrium and the thickness of uterine epithelium were measured using a computer- image analysis system (Bio Vis, Expert Vision, India). Briefly, microscopic images of uterus acquired through a CCD camera were loaded in to the image analysis program and spatially calibrated against a stage micrometer image taken at the same magnification.
  • Luminal epithelial thickness data was the Average of measurements made at 6 randomly selected sites are taken as parameters for evaluation.
  • Test procedure for evaluation of estrogen antagonistic activity Twenty-one-day-old immature female rats are bilaterally ovariectomized under light ether anaesthesia and after post-operative rest for 7 days, are randomized into different treatment groups. Each rat receives the compounds of the invention and 0.02 mg/kg dose of 17-alfa- ethynylestradiol in 10% ethanol-distilled water once daily for 3 consecutive days on days 28-30 of age. A separate group of animals receiving only 17-alfa-ethynylestradiol (0.02 mg/kg) in 10% ethanol-distilled water for similar duration are used for comparison.
  • vaginal smear of each rat is taken and uterus is carefully excised, gently blotted, weighed and fixed for histology and histomorphometry using image analysis.
  • Inhibition in 17-alfa-ethynylestradiol-induced premature opening of vagina, comification of vaginal epithelium, increase in uterine fresh weight, total uterine and endometrial area and uterine luminal epithelial cell height are taken as parameters for evaluation of estrogen antagonistic activity.
  • Table 6 Percent inhibition in EE induced uterine weight gain in immature ovariectomized rats
  • the relative binding affinity (RBA) of the compounds for estrogen receptor was determined by competition assay, employing 3 H-estradiol ( 3 H-E 2 ) as the radioligand.
  • the test ligands and 3 H-E 2 were incubated at 4°C with cytosol estrogen receptors obtained from uteri of immature estradiol-primed (1 ⁇ g/rat 24 h before autopsy) 20-21 days old rats.
  • RBA of the text compound was computed from a graph plotted between percent bound radioactivity verses log concentration of the test substance. At 50% inhibition, log of the competitor concentration relative to that of 17-beta-estradiol, gave the affinity of the test compound to estrogen receptor relative to estradiol. This when multiplied with 100 gave the percentage value designated as RBA.
  • Table 7 Relative binding affinity (RBA) to estrogen receptors

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Abstract

L'invention concerne des composés de la formule (I), dans laquelle les substituants R2 et R3 sont disposés en configuration trans, R1 étant H ou C1-C6 alkyle; C3-C7 cycloalkyle; R2 étant phényle, éventuellement substitué par 1 à 5 substituants choisis indépendamment dans le groupe constitué par OH, C1-C6-alkyle, halogène, nitro, cyano, SH, SR4, trihalo-C1-C6-alkyle, C1-C6-alkoxy et phényle, R4 étant C1-C6-alkyle;R3 étant phényle substitué par OR5, R5 ayant la formule (II), (III) ou (IV), Y étant choisi parmi NHR4, NR42, NHCOR4, NHSO2R4, CONHR4, CONR4, CONR42, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR42, un noyau hétérocyclique C3-C7, saturé ou insaturé, contenant un ou deux hétéroatomes choisis indépendamment dans le groupe constitué par O, S et N, éventuellement substitué par 1 à 3 substituants choisis indépendamment dans le groupe constitué par H, OH, halogène, nitro, cyano, SH, SR4, trihalo-C1-C6-alkyle, C1-C6-alkyle et C1-C6-alkoxy, de préférence NHR4, NR24, ou bien un hétérocycle d'azote, R4 étant tel que défini ci-dessus, et les esters, éthers, et sels des composés de la formule (I), éventuellement avec des excipients pharmaceutiquement acceptables, un procédé pour leur préparation, et une méthode pour prévenir et/ou traiter chez un sujet les états pathologiques d'origine oestrogénique au moyen des composés de la formule (I), ou de leurs sels, éventuellement avec des excipients pharmaceutiquement acceptables.
PCT/IB2003/004559 2003-10-14 2003-10-14 Derives de (3r, 4r)-trans-3,4-diarylchromane a activite oestrogenique WO2005035517A1 (fr)

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CNB2003801104741A CN100545158C (zh) 2003-10-14 2003-10-14 具有雌激素活性的(3r,4r)-反-3,4-二芳基苯并二氢吡喃衍生物
PCT/IB2003/004559 WO2005035517A1 (fr) 2003-10-14 2003-10-14 Derives de (3r, 4r)-trans-3,4-diarylchromane a activite oestrogenique
AU2003267773A AU2003267773A1 (en) 2003-10-14 2003-10-14 (3r, 4r)-trans-3,4-diarylchroman derivatives with estrogenic activity
EP03748468A EP1675843A1 (fr) 2003-10-14 2003-10-14 Derives de (3r, 4r)-trans-3,4-diarylchromane a activite oestrogenique
CA002539502A CA2539502A1 (fr) 2003-10-14 2003-10-14 Derives de (3r,4r)-trans-3,4-diarylchromane a activite oestrogenique
JP2005509433A JP2007516155A (ja) 2003-10-14 2003-10-14 エストロゲン活性を有する（３ｒ，４ｒ）−トランス−３，４−ジアリールクロマン誘導体

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CN102887882B (zh) * 2012-10-15 2014-12-10 柳忠全 一种早熟素及其类似物的合成方法
CN117924262A (zh) * 2022-10-14 2024-04-26 中国科学院上海药物研究所 二氢苯并噻喃类衍生物及其制备方法和用途

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