Benzopyran-containing compounds and method for their use

A technology of compounds and compositions, applied in the treatment of estrogen-sensitive diseases, anti-estrogen compounds, stereoselective substances

Inactive Publication Date: 2004-07-21
ENDORES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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However, the true response of this tumor remains unacceptably low

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  • Benzopyran-containing compounds and method for their use
  • Benzopyran-containing compounds and method for their use
  • Benzopyran-containing compounds and method for their use

Examples

Experimental program
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Effect test

Embodiment 1

[0108] 7-Hydroxy-3-(4′-hydroxyphenyl)-4-methyl-2-(4″-(2-piperidinoethoxy)phenyl)-2H-benzopyran (EM -343) Synthesis Synthesis A (this synthesis is described in Scheme 1 below)

[0109] Process 1

[0110]

[0111] The foregoing synthesis was carried out as follows:

[0112] Triphenol 3

[0113] Resorcinol 1 (89.2 mg.0.810 mol) and acid 2 (135.4 mg, 0.890 mol) (both compounds were purchased from Aldrich Chemical Co., Milwaukee, Wis.) in boron trifluoride etherate ( 300ml) and toluene <240ml) were heated at 100°C for 3 hours and then cooled to room temperature. The resulting suspension was stirred overnight with 12% aqueous sodium acetate (400ml). The resulting precipitate was filtered off and washed with distilled water (2 x 1 L) and 12% aqueous sodium acetate (400 ml). The solid was then stirred overnight with 12% aqueous sodium acetate (1.2 L). The precipitate was filtered off, washed with distilled water (500ml) and recrystallized (ethanol:wate...

Embodiment 2

[0133] Separation of (+)-7-hydroxy-3-(4′-hydroxyphenyl)-4-methyl-2-(4″-(2-piperidinoethoxy)phenyl)-2H-benzene Pyran (EM-652)

[0134] Separation of the enantiomers of EM-343 (209 g) (see scheme 4 below) was carried out at room temperature using a 10 x 50 cm Daicel Chiralpark  ADTM columns (available from Chiral Technologies, Inc. Extons, P.A.) were performed several times. The eluent is hexane / ethanol / diethylamine: 80 / 20 / 0.02 (volume ratio). The final product was evaporated to dryness under vacuum at 40°C. At room temperature, using Daicel Chiralpark  AD YM Column (purchased from Chiral Technologies, Inc. Extons, P.A.), enantiomeric purity was checked by analytical HPLC, UV detection: 254 nm. The eluent is hexane / ethanol / diethylamine: 80 / 20 / 0.02, the flow rate is 1.0ml / min., and the following sequence of eluents is obtained:

[0135] Fraction 1 (the first eluting fraction)

[0136] (+)-7-Hydroxy-3-(4′-hydroxyphenyl)-4-methyl-2-(4″-(2-piperidinoethoxy)phenyl)-2H-benz...

Embodiment 3

[0144] Chemical Resolution Separation of Enantiomers of EM-343

[0145] To a solution of EM-343 (918 mg, 2.00 mmol) in methanol (5 ml) was added a solution of (1S)-(+)-10-camphorsulfonic acid (466 mg, 2.00 mmol) in methanol (20 mL). The resulting solution was left at room temperature for one day and then at -20°C for two days. Scrape occasionally to aid in crystallization. The crystals were filtered off, washed with a minimum amount of methanol, dried and determined for optical rotation ([α] D 25 +41°, methanol), yielding 507 mg of the salt. If necessary, the crystals were recrystallized once or twice with a minimal amount of hot methanol under the same conditions as above to obtain 100 mg of the salt ([α] D 25 +99°, methanol). The mother liquor additionally gave 129 mg of the salt ([α] D 25 +115°).

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Abstract

Certain benzopyran antiestrogens are disclosed for treating estrogen sensitive diseases such as breast cancer. Prodrug forms provide ease of manufacturing, good shelf life, and bioavailibility, and preferred stereoisomers are shown to be more effective than racemic mixtures.

Description

field of invention [0001] The present invention relates to novel inhibitors of steroidal sex hormone activity, such as antiestrogens, which possess potent antagonistic properties and are substantially non-stimulating. More particularly, some preferred embodiments of the present invention relate to certain substituted benzopyran compounds, especially certain prodrug substances and certain stereospecific substances, and their use in the treatment of estrogen-sensitive diseases. Background of the invention [0002] During the treatment of certain steroid hormone dependent disorders it is important to substantially reduce or, if possible, eliminate certain steroid hormone induced effects. For this purpose, it is desirable not only to block the receptor sites stimulated by steroid sex hormones, but also to reduce the amount of steroid sex hormones that can act at these sites. For example, alternating or simultaneous therapy with antiestrogens involves seeking to block estrogen p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12A61K31/10A61K31/135A61K31/138A61K31/165A61K31/35A61K31/352A61K31/353A61K31/38A61K31/382A61K31/40A61K31/4025A61K31/445A61K31/4453A61K31/453A61K31/4535A61K31/47A61K31/4709A61K31/472A61K31/4725A61P35/00C07C215/64C07C217/18C07C235/34C07C317/18C07D215/14C07D217/16C07D295/092C07D295/096C07D295/185C07D311/60C07D335/06C07J1/00C07J17/00C07J21/00C07J41/00C07J51/00C07J53/00C07J71/00
CPCC07J41/0094C07C235/34C07D295/185C07D217/16A61K31/4535A61K31/47C07J17/00C07J41/0072C07D335/06A61K31/135A61K31/352C07C317/18A61K31/453A61K31/4025A61K31/472C07D295/096C07J1/0059A61K31/382C07C217/18C07D295/088C07C215/64C07C2102/10A61K31/10A61K31/138C07J1/0085A61K31/165A61K31/4453C07J53/008A61K31/4709C07J71/0021C07J1/0074A61K31/445C07J1/007A61K31/35A61K31/4725C07J71/001C07D215/14C07J51/00C07J21/008A61K31/38C07J21/006C07D311/60C07J1/0055A61K31/40C07C2602/10A61P35/00A61P5/00A61P5/32
Inventor F·拉布里Y·梅兰德S·高思尔
Owner ENDORES & DEV
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