A novel crystalline form of 6-hydroxy-3-(4-[2-(piperidine-1-yl)ethoxy] phenoxy)-2-(4-methoxyphenyl) benzo[b] thiophene hydrochloride

A technology of methoxyphenyl and thiophene hydrochloride, applied in 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4 - The field of new crystal forms of methoxyphenyl) benzo [b] thiophene hydrochloride, which can solve the problems of inappropriate drug preparation, toxicity, and difficult filtration

Inactive Publication Date: 2004-01-21
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the amorphous drug substance precipitates from the dosing solution, it may negatively affect the solubility and bioavailability of the drug
[0005] Also, because organic solvents are potentially toxic to the user and the potency of the drug can vary with these solvents, it is often not advisable to formulate drugs that contain large amounts of organic solvents, such as ethyl acetate
Also, from a manufacturing point of view, whenever said preparation involves filtration to collect the end product, the preparation of amorphous material is generally not advisable
Such filtration is often difficult when the collected material is amorphous

Method used

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  • A novel crystalline form of 6-hydroxy-3-(4-[2-(piperidine-1-yl)ethoxy] phenoxy)-2-(4-methoxyphenyl) benzo[b] thiophene hydrochloride
  • A novel crystalline form of 6-hydroxy-3-(4-[2-(piperidine-1-yl)ethoxy] phenoxy)-2-(4-methoxyphenyl) benzo[b] thiophene hydrochloride
  • A novel crystalline form of 6-hydroxy-3-(4-[2-(piperidine-1-yl)ethoxy] phenoxy)-2-(4-methoxyphenyl) benzo[b] thiophene hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Crystallization from methanol (in case of non-concentration)

[0040] A 20.00 g sample of arzoxifene was mixed with 500 ml of anhydrous methanol (HPLC grade) and heated to reflux. All solids dissolved to form a pale yellow homogeneous solution. The solution was cooled below reflux temperature and an additional 5.00 g of arzoxifene was added. The solution was reheated to reflux to dissolve all solids. The solution was cooled slowly with stirring. Seed at 50°C with a few milligrams of previously prepared F-V salt. The crystallization slurry was cooled from 50°C to 30°C over 1.25 hours. At this point a large amount of white solid was present. The stirred slurry was immersed in an ice bath and stirred for an additional 3 hours. The slurry was filtered using #1 Whatman filter paper, and the white solid was washed with 50 ml of methanol precooled to 0°C. The wet cake was dried under vacuum at 50°C for about 48 hours under a slow flow of N2. Yield 15.9...

Embodiment 2

[0042] Crystallization from methanol (in the case of concentration)

[0043] Mix 25.00g of arzoxifene sample with 500m1 of anhydrous methanol (HPLC grade) and heat to reflux. All solids dissolved to form a pale yellow homogeneous solution. The solution was concentrated by removing 375 ml of distillate by atmospheric distillation. At this point the reaction mixture was a yellow homogeneous transparent solution. Reflux was stopped and the solution was seeded with a few milligrams of previously prepared F-V. After seeding, the mixture was cooled to room temperature over 1 hour with slow stirring. A large white precipitate formed during this process. The slurry was immersed in an ice bath and stirred for another 3 hours. The slurry was filtered using #1 Whatman filter paper, and the resulting white solid was washed with 50 ml of methanol precooled to 0°C. in N 2 The wet cake was dried under vacuum at 50°C for about 48 hours under slow flow flushing. Yield ...

Embodiment 3

[0045] Crystallization with methanol (30 gallon scale)

[0046] Take 3.08kg of arzoxifene sample and mix with 60L of anhydrous methanol (HPLC grade) and heat to reflux. All solids dissolved to form a pale yellow homogeneous solution. The solution was concentrated by removing 40 L of distillate by atmospheric distillation. At this point the reaction mixture was a yellow homogeneous transparent solution. Stop the reflux, and open the manhole at about 40°C to check the crystallization situation. Crystal formation was observed and cooling was continued at a rate of 12°C per hour to a final temperature of 0°C. The slurry was stirred overnight at 0°C, then filtered through a single plate filter press. To remove all product from the crystallization tank, the mother liquor was used as tank wash and then passed through a filter press. The wet cake was then washed with 11.3 L of methanol pre-cooled to 0°C. The wet cake was dried by applying vacuum to the filter pre...

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Abstract

The present invention is directed to a novel, non-solvated, anhydrous crystal form 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

Background technique [0001] U.S. Patent 5,510,357 first described 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl) Benzo[b]thiophene hydrochloride (arzoxifene), later specifically disclosed in US Patent 5,723,474 ('474) and European Patent Application 0729956. Arzoxifene is a non-steroidal mixed estrogen antagonist / agonist particularly useful for lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen-dependent cancers including breast and uterine cancers , endometriosis, CNS disorders including Alzheimer's disease, aortic smooth muscle cell proliferation and restenosis. [0002] Specifically, arzoxifene is indicated for the treatment of receptor-positive metastatic breast cancer (under clinical evaluation); as adjuvant therapy for receptor-positive patients after appropriate systemic or local therapy; and to reduce the recurrence of invasive and non-invasive breast cancer; And reduce the incidence of invasive breast cancer a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/407A61K31/445A61K31/4535A61K31/473A61K31/565A61K31/57A61K47/20A61P3/06A61P9/00A61P9/10A61P13/08A61P15/00A61P19/08A61P19/10A61P25/00A61P25/28A61P35/00A61P43/00C07D333/64
CPCC07D333/64A61P13/08A61P15/00A61P19/00A61P19/08A61P19/10A61P25/00A61P25/28A61P35/00A61P3/06A61P43/00A61P9/00A61P9/10C07D409/12
Inventor W·D·卢克
Owner ELI LILLY & CO
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