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6-hydroxy-3(4-[2-(piperidine-1-group)oxyethyl group]phenoxy)-2-(4-methoxy phenyl) benzo[b] thiophene hydrochloride salt

A technology of methoxyphenyl and thiophene hydrochloride, applied to 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4 -Methoxyphenyl)benzo[b]thiophene hydrochloride in the field of new crystal forms, which can solve the problems of arzoxifene's inferior crystallinity, potential toxicity to users, and changes in drug efficacy.

Inactive Publication Date: 2004-02-18
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For the formulation process, poorly crystalline arzoxifene is less desirable than highly crystalline arzoxifene
In addition, it is generally not advisable to formulate drugs that contain large amounts of organic solvents, such as ethyl acetate, due to their potential toxicity to the drug user and the fact that these solvents can alter the potency of the drug

Method used

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  • 6-hydroxy-3(4-[2-(piperidine-1-group)oxyethyl group]phenoxy)-2-(4-methoxy phenyl) benzo[b] thiophene hydrochloride salt
  • 6-hydroxy-3(4-[2-(piperidine-1-group)oxyethyl group]phenoxy)-2-(4-methoxy phenyl) benzo[b] thiophene hydrochloride salt
  • 6-hydroxy-3(4-[2-(piperidine-1-group)oxyethyl group]phenoxy)-2-(4-methoxy phenyl) benzo[b] thiophene hydrochloride salt

Examples

Experimental program
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Effect test

Embodiment 1

[0052] With 6-isopropoxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene Hydrochloride Preparation F-III

[0053] At -10°C - 20°C, under a nitrogen atmosphere, the BCl was kept at a rate below -10°C 3(g) (4.23g, 34mmol) was added to 6-isopropoxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl ) in dichloromethane solution (100ml) of benzo[b]thiophene hydrochloride (10g, 18mmol). After the addition was complete, the reaction mixture was stirred for 2 hours. Isopropanol (IPA, 12.35ml, 167mmol) was slowly added to the reaction mixture at a temperature below -10°C and stirring was continued for 30 minutes. Put 100ml of water in a separatory bottle and cool to about 0°C with an ice bath. The product solution was transferred to water via cannula while maintaining vigorous stirring. The resulting white slurry was stirred at 0 °C for 1 hour. Through filtration, and sequentially with 25ml 40% CH 2 Cl 2 / water and 25ml of cold water to reco...

Embodiment 2

[0055] With 6-benzyloxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene- (S-Oxide) Preparation of F-III

[0056] At room temperature, deionized water (5.25ml), 1M hydrochloric acid (7.74ml, 7.75mmol), 10% Pd / C (A32110 type, 1.37g, 1.29mmol Pd), 6-benzyloxy-3-(4- [2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene-(S-oxide) (3g, 5.16mmol) , and isopropanol (32ml) were added to a 250mL Parr bottle. The bottle was mounted on a Parr shaker, then evacuated and filled with nitrogen twice, then evacuated and filled with hydrogen to a pressure of 30 psig. The shaker was turned on and the reaction mixture was heated to 60°C. After about 4 hours, the reaction was determined to be complete by HPLC analysis. The reaction mixture was filtered through a pad of celite and the filter pad was washed with 0.1M hydrochloric acid (2 x 10ml). The solvent was removed in vacuo at about 50°C. The resulting residue was dissolved in 50% isopropanol...

Embodiment 3

[0058] With [6-isopropoxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)]benzo[b ] Thiophene-(S-oxide) to prepare F-III

[0059] Dichloromethane (105L) and [6-isopropoxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxybenzene base)]benzo[b]thiophene-(S-oxide) (10.5kg) and cooled to -15°C--20°C. Boron trichloride (4.6 kg) was added while maintaining the reaction temperature at -10-20°C. Stirring was continued until the area % of starting material was less than 1% by HPLC analysis. HPLC system (4.6mm ID×25cm Zorbax SB-Phenyl column 30°C, 70:30 methanol:0.01N sulfuric acid; flow rate 1.5ml / min; detection at 300nm). Isopropanol (10.28 kg) was added while maintaining the reaction temperature at -10-20°C. The reaction mixture was stirred for 30-45 minutes. The reaction crude product was isolated by adding the reaction mixture to 105 L of water pre-cooled to 2-7°C while maintaining the reaction temperature at 2-7°C. It was then washed with dichloromethane (20 L...

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Abstract

The present invention is directed to a novel crystalline hydrate of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride and uses for same, including inhibition of disease states associated with estrogen deprivation including cardiovascular disease, hyperlipidemia, and osteoporosis; and inhibition of other pathological conditions such as endometriosis, uterine fibrosis, estrogen-dependent cancer (including breast and uterine cancer), prostate cancer, benign prostatic hyperplasia, CNS disorders including Alzheimer's disease, prevention of breast cancer, and up-regulating ChAT.

Description

technical field [0001] The present invention relates to arzoxifene hydrate crystal and medicine, preparation method and application. Background technique [0002] US 5510357 is the first to 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene The hydrochloride (arzoxifene) is described generally and US 5723474 ('474) and European Patent Application 0729956 disclose this compound in detail. Arzoxifene is a non-steroidal mixed estrogen antagonist / agonist that is particularly useful in lowering serum cholesterol, inhibiting hyperlipidemia, osteoporosis, estrogen-dependent cancers including breast and uterine cancers, endometrial Ectopia, CNS disorders including Alzheimer's disease, aortic smooth muscle cell proliferation, and restenosis. [0003] Specifically, arzoxifene is indicated (and has been clinically evaluated) for the treatment of receptor-positive metastatic breast cancer; for adjuvant therapy in receptor-positive patients following...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61K31/4433A61K31/445A61K31/4535A61K31/565A61K35/22A61K38/09A61P3/06A61P5/32A61P9/00A61P13/08A61P15/00A61P19/00A61P19/10A61P25/00A61P25/28A61P35/00C07D333/64
CPCA61K31/4535C07D333/64A61K31/565A61K35/22A61K31/445A61K38/09A61P13/08A61P15/00A61P19/00A61P19/08A61P19/10A61P25/00A61P25/28A61P35/00A61P3/06A61P43/00A61P5/30A61P5/32A61P9/00A61P9/10A61K31/00A61K2300/00C07D409/12
Inventor J·K·布斯P·C·康拉德M·G·弗洛姆
Owner ELI LILLY & CO
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