180915-78-0

(Matrix presented) A potent and selective estrogen receptor modulator (SERM), Lasofoxifene (CP-336156), was prepared by an enzyme-catalyzed asymmetric deacylation with high optical purity and excellent yield even though the hydrolytic site is remote from

-

The present invention found that lasofoxifene is an antagonist of ER-α36. It not only inhibits the growth of ER-α36 positive lung, colon and gastric cancers, and also it can inhibit the growth of acquired or de novo tamoxifen-resistant MCF-7 cells. Our finding also provides methods and compositions for treating cancer comprising lasofoxifene alone or in combination with at least one other agent selected from the group consisting of gefitinib and/or trastuzumab or functional equivalent thereof, and an inhibitor in hormonal or epidermal growth factor signal transduction pathways.

An intramolecular reductive coupling process of diketone with low-valent titanium species to form a dihydronapthalene skeleton was an important step in the synthesis of nafoxidine (1) and lasofoxifene (2). Diketone 6 was prepared in a convenient, three-st

Lasofoxifene, a third-generation selective estrogen receptor modulator, could be synthesized via regio-and stereoselective [4 + 2] cycloaddition between an ortho-quinodimethane and a borylalkene. This protocol was also applicable to the synthesis of antie

The present invention relates to solid state chemistry of 1-(2-[4-(6-methoxy-3,4-dihydronaphthalene-1-yl) phenoxy]ethyl)pyrrolidine, a process for its preparation and its use as an intermediate in the synthesis of lasofoxifene.

A method of preparing (?)-cis-(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate-lasofoxifene of formula 1, comprising the following steps a) Preparation of cis-1-{2-[4-(2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-phenoxy]ethyl}pyrrolidine of formula (3) by alkylation of cis-1-(4-hydroxyphenyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene with 1-(2-chloroethyl)pyrrolidine base or its salt, b) Deprotection of the hydroxyl group in the substance of formula (3) by the effect of hydrobromic acid generating cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide of formula (2a), c) Conversion of the substance of formula (2a) into cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol of formula (2b), d) Preparation of lasofoxifene of formula (1) by conversion into the corresponding diasteroisomer by reaction with D-tartaric acid and crystallization.

A Lewis acid-mediated three-component coupling reaction was successfully applied for the synthesis of lasofoxifene (1), nafoxidine (2), and their positional isomers, inv-lasofoxifene (3) and inv-nafoxidine (4). In the presence of HfCl4, the des

Disclosed is a novel process for production of lasofoxifene, nafoxidine or an analogue thereof, which comprises reduced number of reaction steps, has a high efficiency, and is practically advantageous. For the production of lasofoxifene or an analogue the

The simple and efficient synthesis of lasofoxifene (4), a possible candidate for alleviating osteoporosis, via the novel three-component coupling reaction among 4-pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane (6), and anisole in the presence of HfCl4 is illustrated. The successive cationic cyclization of the coupling product, olefin formation, and migration of the double-bond are performed to afford the common synthetic intermediate of lasofoxifene (4) and nafoxidine (3) via a very concise procedure. Copyright

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an estrogen agonistlantagonist or a pharmaceuticall

Pharmaceutical compositions having uniform drug distribution and potency utilizing laxofoxifene as an active ingredient and containing a silicon dioxide to reduce loss of the active ingredient during the manufacturing process and methods for manufacturing such compositions are disclosed.

A method for manufacturing a pharmaceutical composition having uniform drug distribution and potency is described which utilizes silicon dioxide to reduce the loss of active ingredient during the manufacturing process. The method is particularly useful for the manufacture of low dosage tablet compositions.

A method for removing impurities from racemic cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol and purified cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol useful as an estrogen agonist/antagonist.

The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma using an estrogen agonist/antagonist. The present invention also provides kits that contain an estrogen agonist/antagonist for treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.

The present invention provides methods and kits for treating depression, perimenopausal depression, schizophrenia, anxiety, panic attacks, binge eating, social phobia, or preventing deterioration of cognitive function by administering to a patient in need thereof a therapeutically effect amount of an estrogen agonist/antagonist of formula I

This invention relates to methods for treating bone loss in a mammal by administering to the mammal a therapeutically effective amount of leptin or a leptin mimetic. This invention also relates to methods for treating bone fracture, enhancing bone healing following facial reconstruction, maxillary reconstruction or madibular reconstruction, enhancing long bone extension, enhancing the healing rate of a bone graft, enhancing prosthetic growth and inducing vertebral synostosis by administering a therapeutically effective amount of leptin or a leptin mimetic. This invention further relates to methods and compositions comprising leptin or a leptin mimetic and estrogen, a selective estrogen receptor modulator or a bisphonate for treating the above-recited diseases and conditions.

The present invention provides methods and kits for treating osteoarthritis using an estrogen agonist/antagonist.

This invention relates to methods and kits useful for improving or maintaining urogenital health using an estrogen agonist/antagonist. The methods of treatment are effective for improving or maintaining urogenital health while substantially reducing the concomitant liability of adverse effects associated with estrogen administration. This invention also relates to methods of assessing vaginal health.

The present invention provides methods and kits for improving or maintaining vascular health, including preventing myocardial infarction or stroke; maintaining or improving vascular reactivity; treating acute or chronic renal failure, peripheral arterial occlusive disease, coronary artery disease, or Raynaud's phenomenon; or lowering plasma levels of Lp(a) using an estrogen agonist/antagonist.

This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.

Pharmaceutical combination compositions including certain estrogen agonists/antagonists and prostaglandins or prostaglandin agonists/antagonists. The compositions are useful for the treatment of bone disorders including osteoporosis.

Prostaglandin agonists of formula (I), in which, for example, A is a sulphonyl or acyl group, B is N or CH, M contains a ring and K and Q are linking groups, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits useful for the treatment of bone disorders including osteoporosis. STR1

Compounds of formula A inhibit bone resorption and bone turnover, prevent bone loss, preserve bone strength and decrease serum cholesterol without causing prostate hypertrophy in male mammals: and E and B are selected from CH and N. R4 is H, OH, F or Cl.

Compounds of this formula are useful for treating or preventing, obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease and prostatic disease.

A method of treating atherosclerosis, independent of lipid lowering, in mammals, including humans, in need of treatment by inhibiting progression of an atherogenic lesion or by stabilizing plaque. Such lesion progression inhibition or plaque stabilization is preferably achieved by directly inhibiting chemokine expression leading to excessive inflammatory cell recruitment by administering a therapeutically effective amount of a compound of formula I.

The present invention provides novel methods of inhibiting pathological conditions related to organ systems which respond to estrogen agonists comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I

This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.

Pharmaceutical compositions for the treatment of diseases involving cognitive dysfunction in a mammal comprising an estrogen agonist or antagonist or a pharmaceutically acceptable salt thereof; an acetyl cholinesterase inhibitor or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The estrogen agonists or antagonists and acetylcholinesterase inhibitors are present in amounts that render the composition effective in the treatment of diseases of cognitive dysfunction including Alzheimer's Disease and Dementia. The method of using these composition is also disclosed. The compositions may help memory inhancement.

-

This invention relates to methods for treating bone loss in a mammal by administering to the mammal a therapeutically effective amount of leptin or a leptin mimetic. This invention also relates to methods for treating bone fracture, enhancing bone healing following facial reconstruction, maxillary reconstruction or madibular reconstruction, enhancing long bone extension, enhancing the healing rate of a bone graft, enhancing prosthetic growth and inducing vertebral synostosis by administering a therapeutically effective amount of leptin or a leptin mimetic. This invention further relates to methods and compositions comprising leptin or a leptin mimetic and estrogen, a selective estrogen receptor modulator or a bisphonate for treating the above-recited diseases and conditions.

The use of a compound of the formula (I):- wherein A is CH2or NR in which R is H or C1-C6alkyl; B,D,E are each CH or N; Y, Z1and G are certain stated substituents: and, ???e is 0, 1 or 2; for the manufacture of a medicament for treating atherosclerosis.

The use of a compound of the formula I, or of an optical or geometric isomer thereof; or of a non-toxic pharmacologically acceptable acid addition salt, N-oxide, ester or quaternary ammonium salt thereof, for the manufacture of a medicament for inhibiting a pathological condition selected from Alzheimer's disease, premenstrual syndrome, perimenopausal syndrome, a deficiency of thrombomodulin, uterine fibrosis, excessive myeloperoxidase activity, excessive thrombin, autoimmune disease, reperfusion damage of ischemic myocardium and insufficient testosterone:- wherein: A is selected from CH2and NR; B, D and E are independently selected from CH and N;, and Y, Z1and G are certain specified substituents.

A pharmaceutical composition comprising a compound of formula I: wherein: A is selected from CH2 and NR;B, D and E are independently selected from G, H and N;e is 0, 1 or 2; and Y, Z1 and G are a specified substituent, in combination with a bone resorption inhibiting polyphosphonate or a progestin. The compositions are useful for treating or preventing osteoporosis.

Compounds of this formula STR1 are useful for treating or preventing, obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease and prostatic disease.