9-alpha-substituted estratrienes as selectively active estrogens

A representative, alkenyl-based technology, applied in the field of 9α-substituted estratriene as a selective estrogen, can solve the problem of not showing estrogen receptor selectivity in vivo

Inactive Publication Date: 2007-01-03
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Subtype-specific ligands of estrogen receptors have not previously been shown to have in vivo selective effects on estrogen sensitivity parameters

Method used

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  • 9-alpha-substituted estratrienes as selectively active estrogens
  • 9-alpha-substituted estratrienes as selectively active estrogens
  • 9-alpha-substituted estratrienes as selectively active estrogens

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] 9α-Vinylestradiol-1,3,5(10)-triene-3,16α-diol

[0175] step 1

[0176] 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate

[0177] A solution of 2.21g (9.73mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 80ml of dichloromethane was added dropwise to 2.13g (6.49mmol) under stirring. 3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate, 2.07ml (16.54mmol) of trimethylsilyl cyanide and 0.14g of perchlorate Lithium oxide was suspended in 100 ml of dichloromethane. The reaction mixture is green. After 1 hour at room temperature, the mixture was admixed with sodium bicarbonate solution. The separated organic phase was washed with water and evaporated in vacuo. The product mixture is chromatographed on silica gel (cyclohexane / ethyl acetate, 6 / 1). This gave 0.44 g (21%) of 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate.

[0178] step 2

[0179] 9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate

[0180] Under argon atmosphere, 7.51 g (50.1 mmol) of s...

Embodiment 2

[0193] 9α-vinyl-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

[0194] step 1

[0195] 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra 1,3,5(10)-triene-9-carbonitrile

[0196] 1.03g (2.26mmol) of 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene, 48.2 mg (0.45 mmol) of lithium perchlorate and 0.71 ml (5.66 mmol) of trimethylsilyl cyanide were introduced into 10 ml of dichloromethane (molecular sieves) and cooled to about -70° C. while stirring. A solution of 0.77 g (3.39 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 65 ml of dichloromethane was added dropwise over a period of 1 hour. After about 1 hour (warming to room temperature), the reaction mixture was mixed with sodium bicarbonate solution, and the reaction product was extracted with dichloromethane. The crude product obtained by concentrating the organic phase by evaporation is purified by chromatography. After chromatography on silica gel (cyclohexane / ethyl acetate, 4 / 1), 0.74 g (68% of theo...

Embodiment 3

[0208] 9α-(2′,2′difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

[0209] step 1

[0210] 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

[0211] Similar to Step 1 of Example 1, 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene was reacted to produce 3,16α- Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile.

[0212] Yield: 58% of theory

[0213] step 2

[0214] 3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde

[0215] Similar to step 2 of Example 1, 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile was reacted, 3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde is produced.

[0216] Yield: 83% of theoretical value

[0217] step 3

[0218] 9α-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

[0219] 1.5 ml of dimethoxyethane (molecular sieves), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl(difluoromethyl)-phosphate were introduced into an inert reaction flask and cooled to ab...

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Abstract

This invention describes the new 9alpha-substituted estratrienes of general formula (I) in which R3, R7, R7', R13, R16 as well as R17 and R17' have the meanings that are indicated in the description and R9 means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop-1-inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.

Description

field of invention [0001] The present invention relates to novel compounds as active ingredients of pharmaceuticals, which have a higher affinity in vitro to estrogen receptor preparations obtained from the rat prostate than from the rat uterus, and preferably in vivo to The ovaries have a preferential effect on the uterus. The invention also relates to a process for the preparation of the compound, its therapeutic use and pharmaceutical preparations containing the novel compound. [0002] The compounds of the present invention are novel, steroidal, tissue-selective estrogens. Background of the invention [0003] The efficacy of estrogen in the treatment of symptoms induced by hormone deficiency such as hot congestion (Hitzewallungen), atrophy of estrogen target organs, and incontinence, and the successful use of estrogen therapy to prevent bone loss in menopausal and postmenopausal women, have It is well documented and widely accepted (Grady et al., 1992, Ann Intern Med 1...

Claims

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Application Information

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IPC IPC(8): C07J1/00A61P15/00A61K31/4535A61K31/565A61P5/30A61P13/08A61P19/10A61P25/00A61P29/00A61P37/04A61P37/06C07J41/00C07J63/00
CPCC07J1/0066C07J41/0072C07J1/0055C07J63/008A61P13/08A61P15/00A61P15/08A61P19/00A61P19/10A61P25/00A61P29/00A61P37/02A61P37/04A61P37/06A61P5/30A61P9/00C07J1/00A61K31/565C07J41/00A61K31/56
Inventor 迪尔克·科泽蒙德格尔德·米勒亚历山大·希利施卡尔-海因里希·弗里策迈尔彼得·穆恩
Owner BAYER IP GMBH
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