(3R,4R)-trans-3,4-diarylchroman derivatives with estrogenic activity

A chroman and dihydropyran technology, which can be used in sexual diseases, organic chemistry, drug combination, etc., and can solve problems such as deep vein thrombosis and pulmonary embolism

Inactive Publication Date: 2006-09-27
COUNCIL OF SCI & IND RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] However, because tamoxifen also has estrogen-like effects, it can also ind

Method used

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  • (3R,4R)-trans-3,4-diarylchroman derivatives with estrogenic activity
  • (3R,4R)-trans-3,4-diarylchroman derivatives with estrogenic activity
  • (3R,4R)-trans-3,4-diarylchroman derivatives with estrogenic activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] 3R,4R-trans-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propoxy)-phenyl]-7-methanol Oxychroman (IXa: R 1 = methyl, R 2 = phenyl):

[0268] In anhydrous dimethylsulfoxide (DMSO) (10ml), 3R,4R-trans-2,2-dimethyl-3-phenyl-4-[4-hydroxyphenyl]-7-methoxy A mixture of phenylchroman (0.7g, 1.94mmol), anhydrous potassium carbonate (2.5g, 18mmol) and R(-)epichlorohydrin (0.4ml, 5.11mmol) was stirred at 65°C for 10 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated to give an oil, which was crystallized from benzene-hexane to give the target product.

[0269] Yield: 0.6 g (74.18%), (melting point) m.p.: 120°C, [α] D 20 (C=1, methanol): -201.96.

[0270] Infrared spectrum (IR) (KBr, cm -1 ): 1454, 1506, 1585, 1616 (ArH), 1217 (OMe), 2933 (CH), 1382 (gem dimethyl), 758 (C-O).

[0271] 1 H nuclear magnetic resonance (NMR) (δ, CDCl 3 ): 1.2(s, 3H, gem-dimethyl), 1.3(s...

Embodiment 2

[0274] 3R, 4R-trans-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(3-n-butylamino-2-hydroxy}propoxy]-phenyl) -7-Methoxychroman (hydrochloride) (XIa: R 1 = methyl, R 2 = phenyl, Y = butylamino):

[0275] 3R,4R-trans-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propoxy)-phenyl]-7-methanol A mixture of oxychroman (0.2g, 0.48mmol), n-butylamine (0.5ml, 5.06mmol) and ethanol (15ml) was refluxed for 3 hours. Ethanol was evaporated. The resulting residue was purified by perbasic alumina column using hexane-benzene as eluent. The resulting free base was thus converted to the hydrochloride salt by treatment with ethanol-hydrochloride followed by crystallization from absolute ethanol-ether to give the desired product.

[0276] Yield: 0.160 g, (63.33%) m.p.: 193°C [α] D 20 (C=1, methanol): -160.

[0277] IR (KBr, cm -1 ): 1506, 1585, 1614 (ArH), 1215 (OMe), 2935 (CH), 3417 (OH), 3719 (amine) 1380 (gem-dimethyl).

[0278] 1 HNMR (δ, CDCl 3): 1.2(s, 3H, gem-dimethyl), 1.3(s, 3H, gem-dimethyl...

Embodiment 3

[0282] 3R,4R-trans-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(3-n-butylamino-2-hydroxy}propoxy]-phenyl)- 7-Methoxychroman (citrate) (XIa: R 1 = methyl, R 2 = phenyl, Y = butylamino):

[0283] 3R, 4R-trans-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propoxy)-phenyl]-7- A mixture of methoxychroman (0.2g, 0.48mmol), n-butylamine (0.5ml, 5.06mmol) and ethanol (15ml) was refluxed for 3 hours. Ethanol was evaporated. The resulting residue was purified by perbasic alumina column using hexane-benzene as eluent. The obtained free base was converted into citrate, and then crystallized from absolute ethanol-ether to obtain the target product.

[0284] Yield: 0.165 g, (63.5%) m.p.: 142 °C [α] D 20 (C=1, methyl): -136.

[0285] IR (KBr, cm -1 ): 1437, 1506, 1589, 1614 (ArH), 1240 (OMe), 2966 (CH), 3429 (OH), 3758 (ammonia) 1380 (gem dimethyl).

[0286] 1 H NMR (δ, CDCl 3 ): 1.2(s, 3H, gem-dimethyl), 1.3(s, 3H, gem-dimethyl), 3.1(d, 1H, monobenzyl H, J=12Hz), 4.2(d, 1H, dibenzyl Base H,...

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Abstract

The present invention relates to compounds of the formula I in which substituents R<2> and R<3> are arranged in trans-configuration, Formula (I), wherein: R<1> is H or C1-C6 alkyl; C3-C7 cycloalkyl; R<2> is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR<4>, trihalo-C1-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R<4> is C1-C6 alkyl;R<3> is phenyl substituted with OR<5> wherein R<5> has the Formula (II), (III) or (IV) , wherein Y is chosen from NHR<4>, NR<4>2, NHCOR<4>, NHSO2R<4>, CONHR<4>, CONR<4>, CONR<4>2, COOH, COOR<4>, SO2R<4>, SOR<4>, SONHR<4>, SONR<4>2, a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR<4>, trihalo-C1-C6- alkyl, C1-C6-alkyl and C1-C6 -alkoxy, preferably NHR<4>, NR2<4>, or a nitrogen heterocycle, wherein R<4> is as defined above, and the esters, ethers, and salts of the compounds of formula I, optionally along pharmaceutically acceptable excipients, a process for the preparation of the same, and a method of preventing and/or treating estrogen-related disease conditions in a subject using compounds of formula (I), or its salts, optionally along with pharmaceutically acceptable excipients.

Description

technical field [0001] The present invention relates to compounds of formula I, wherein the substituent R 2 and R 3 Arrange for the trans configuration: [0002] [0003] Among them, R 1 Is H or C1-C6 alkyl; C3-C7 cycloalkyl; R 2 is phenyl, optionally substituted with 1 to 5 independently selected from OH, C1-C6 alkyl, halogen, nitro, cyano, SH, SR 4 , a substituent group consisting of trihalogenated C1-C6 alkyl, C1-C6 alkoxy and phenyl, wherein R 4 Is C1-C6 alkyl; R 3 is replaced with OR 5 of phenyl, where R 5 Have a structure of formula (II), (III) or (IV) [0004] [0005] where Y is selected from NHR 4 , NR 4 2 , NHCOR 4 , NHSO 2 R 4 , CONHR 4 , CONR 4 , CONR 4 2 , COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 4 2 , a C3-C7 heterocycle, which may be saturated or unsaturated, comprising one or two heteroatoms independently selected from the group consisting of O, S and N, optionally substituted with 1 to 3 heteroatoms independently selected...

Claims

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Application Information

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IPC IPC(8): C07D311/74A61K31/40A61P15/00
CPCC07D311/74A61P3/06A61P7/02A61P9/00A61P13/02A61P15/00A61P15/12A61P17/02A61P17/14A61P19/00A61P19/10A61P25/16A61P25/18A61P25/24A61P25/28A61P35/00
Inventor 桑吉塔阿图尔·库马尔曼·莫汉·辛格苏卜拉哈特·雷吉里什·库马尔·詹恩
Owner COUNCIL OF SCI & IND RES
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