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A method of inhibiting bone loss or resorption, or lowering serum cholesterol, comprising administering to a human in need thereof a compound having the formula STR1 or a pharmaceutically acceptable salt or solvate thereof, in a low dosage amount. Also encompased by the invention is a a pharmaceutical formulation in unit dosage form comprising, per unit dosage, a low dosage amount.

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The instant invention provides an amorphous form of a compound of formula I. wherein: R1and R3are independently hydrogen, -CH3,-CO(C1-C6alkyl), or -COAr, wherein Ar is optionally substituted phenyl; R2is selected from the group consisting of pyrrolidinyl, hexamethyleneimino, and piperidinyl; or a pharmaceutically acceptable salt or solvate thereof. Methods of preparing the material, as well as methods of using same, are also provided.

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In this study we extended our studies on heterocyclic antiestrogens to 2-phenylbenzo[b]thiophenes which can be considered as isosteric to the 2- phenylindole system. We synthesized a number of 6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophenes with carbamoyl and amino functions in the side chain at carbon-3 and analyzed their biological properties. The binding affinities for the estrogen receptor are mainly influenced by the chain length whereas the hormonal profile depends on the nature of the functional group. From this study 3-[10-(2,2,3,3,4,4,4,-heptafluorobutyl- methylcarbamoyl)decyl]-6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene (6e) emerged as an antiestrogen with all the characteristics of a pure antagonist. It did not stimulate gene expression in HeLa cells cotransfected with the expression vector for the human estrogen receptor HEGO and the luciferase reporter plasmid EREwtc luc nor did it show any estrogenic activity in the mouse uterus weight test. In the latter assay, it completely abrogated the stimulatory effect of estrone. Due to its antiestrogenic potency it strongly inhibited the growth of estrogen-sensitive human MCF-7 breast cancer cells with an IC50 value of 5 nM. These data suggest that an amide function is combination with the fluorination of the terminal carbon atoms is an appropriate modification to abolish the estrogenic action of the 2- phenylbenzothiophene system.

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This invention provides methods which are useful for the inhibition of the various medical conditions associated with estrogen deprivation syndrome including osteoporosis and hyperlipidemia utilizing compounds of formula I: STR1

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Radiolabelled raloxifene (LY156758) has been prepared by tritium gas hydrogenolysis of a 3-aroyl-bis-brominated precursor. The requisite halogenated intermediate was accessed by regioselective aroylation of benzothiophene 6 with the acid chloride of 3,5-dibromo-4-[2-(1-piperdinyl)ethoxy]benzoic acid (5). Selective deprotection of the aryl methyl ethers in the presence of the ethoxy side-chain followed by palladium catalyzed halogen-tritium exchange provided the target compound with a specific activity of 30.1 Ci/mmol.

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Mild and high-yielding synthesis is described for raloxifene via piperdine nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and 2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such as low cost, and is suitable for industrial production.

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The aim of this study was the identification of the essential structural elements in the 12-formyl-5,6-dihydroindolo[2,1-a]isoquinoline system required for the inhibition of tubulin polymerization which is understood to be the predominant mode of action of this class of cytostatics. Since 2- phenylindole forms the main fragment of this tetracycle, it was used as the basic structure and modified with respect to the number and positions of the oxygen functions in the aromatic rings. Further modifications related to the nitrogen, which was both replaced by oxygen and sulfur and alkylated. All derivatives were tested for cytostatic activity in human breast cancer cells (MDA-MB 231, MCF-7) and inhibition of tubulin polymerization. The spectrum of activity ranged from inactive to IC50 values of 35 nM (cell growth inhibition) and 1.5 muM (tubulin polymerization), respectively, for the most active derivative 3e (3-formyl-6-methoxy-2-(4-methoxyphenyl)indole). Although the correlation between antiproliferative activity and inhibition of tubulin polymerization was not very pronounced, all of the potent cytostatic agents in this study disrupted microtubule assembly completely at the standard concentration of 40 muM. By fluorescence microscopy it was demonstrated that the derivative 3e degrades the cytoskeleton in a similar fashion as colchicine does leading to the condensation of the microtubules around the nucleus after treatment. The comparison between hydroxy and methoxy derivatives revealed a striking difference between the 2-phenylindole derivatives and the indoloisoquinolines. In the 2-phenylindole series, the methoxy compounds were much more effective than the free phenols, whereas in the tetracyclic system the effect of the hydroxy derivatives exceeded that of the methylated compounds by 1 order of magnitude. Preliminary studies on the binding mode showed that both the 2-phenylindole derivatives and the indoloisoquinolines bind to the colchicine site on tubulin.

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The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERalpha degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 (32). ERD-308 achieves DC50 (concentration causing 50% of protein degradation) values of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines, respectively, and induces >95% of ER degradation at concentrations as low as 5 nM in both cell lines. Significantly, ERD-308 induces more complete ER degradation than fulvestrant, the only approved selective ER degrader (SERD), and is more effective in inhibition of cell proliferation than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may lead to a new therapy for advanced ER+ breast cancer.

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2-(p-Methoxyphenyl)-6-methoxybenzothiophene (3) was synthesized by acid-catalyzed cyclization and rearrangement of the beta-ketosulfide precursor 1. The use of Amberlyst 15 resin as a catalyst for the cyclization increased the isomer ratio from 75: 25 to 88:12, compared to a conventional approach using polyphosphoric acid (PPA). Although solid acid catalysts were also evaluated for the rearrangement, a two-phase mixture of methanesulfonic acid in toluene was found to be the best alternative to the use of PPA for this reaction. The rearrangement, which was shown to be equilibrium controlled, was driven towards completion by crystallization of the product as it formed. An Amberlyst 15 catalyzed cyclization, combined with an MsOH-catalyzed rearrangement, raised the overall isolated yield from 70 to 80%, and difficulties associated with the use of PPA on a large scale were eliminated. This process has been successfully scaled to a pilot plant and manufacturing scale.

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The invention provides 2,3-aryl-benzothiophene compounds, formulations, and methods of inhibiting bone loss or bone resorption, particularly osteoporosis, and cardiovascular-related pathological conditions including hyperlipidemia, and estrogen-dependent cancer.

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