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Piperazinyl-containing indole derivatives, and preparation method and application thereof

A technology of indole and alkyl, applied in the field of indole derivatives containing piperazinyl and its preparation and application

Active Publication Date: 2016-08-17
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But clinically used tamoxifen and raloxifene can cause adverse reactions such as endometrial cancer and hot flashes (Fisher B, CostantinoJP, Wickerham DL, et al.J Nati Cancer Inst, 1998,90:1371-1388 ; Walsh BW, Kuller LH, Wild RA, et al. J Am Med Assoc, 1998, 279:1445-1451)

Method used

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  • Piperazinyl-containing indole derivatives, and preparation method and application thereof
  • Piperazinyl-containing indole derivatives, and preparation method and application thereof
  • Piperazinyl-containing indole derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 1-[4-(4-methylpiperazin-1-yl)butyl]-5-hydroxyl-2-(4-hydroxyphenyl)-3-methyl-1H-indole

[0034] Step A): Preparation of 1-(4-benzyloxyphenyl)-2-(4-benzyloxyphenylamino)-1-propanone

[0035] Place 4-benzyloxyaniline (7.8g, 0.039mol), 1-(4-benzyloxyphenyl)-2-bromo-1-propanone (10.5g, 0.033mol) in a 500mL round bottom flask, ethanol As a solvent, triethylamine (6.6g, 0.065mol) was added, and the reaction was refluxed for 5h. Naturally cooled to room temperature, and suction filtered to obtain 12.3 g of a milky white solid with a yield of 85.3%. m.p.125-126°C. ESI-MS: m / z 438 ([M+H] + ).

[0036] Step B): Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole

[0037] 1-(4-benzyloxyphenyl)-2-(4-benzyloxyphenylamino)-1-propanone (12.3g, 0.028mol), 4-benzyloxyaniline (14.0g, 0.070mol) Place in a 500mL flask, use ethylene glycol monoethyl ether as a solvent, and reflux for 6 hours. The solvent was evaporated under reduced pressure, ...

Embodiment 2

[0042] Example 2: Preparation of 1-[4-(4-ethylpiperazin-1-yl)butyl]-5-hydroxyl-2-(4-hydroxyphenyl)-3-methyl-1H-indole

[0043] According to the method of Example 1, 0.31 g of a yellow solid was obtained with a yield of 36.7%. m.p.106-107°C. ESI-MS: m / z 408 ([M+H] + ). 1 H-NMR (400MHz, DMSO-d 6 )δ8.53(s,1H),7.96(s,1H),7.23(d,J=8.7Hz,1H),7.17(d,J=8.6Hz,2H),6.89(d,J=8.5Hz, 2H), 6.77(d, J=2.2Hz, 1H), 6.64(dd, J=8.4, 1.9Hz, 1H), 4.22(t, J=6.6Hz, 2H), 3.95(t, J=7.1Hz, 2H),3.62(m,2H),3.47(m,2H),2.98(m,2H),2.67(m,2H),2.18(m,2H),2.04(s,3H),1.62(m,4H ), 1.06 (t, J=5.6Hz, 3H).

Embodiment 3

[0044] Example 3: Preparation of 1-[4-(piperazin-1-yl)butyl]-5-hydroxyl-2-(4-hydroxyphenyl)-3-methyl-1H-indole

[0045] According to the method of Example 1, 0.32 g of an orange solid was obtained, with a yield of 41.9%. m.p.155-156°C. ESI-MS: m / z 380 ([M+H] + ). 1 H-NMR (400MHz, DMSO-d 6 )δ9.78(s,1H),8.52(s,1H),7.23(d,J=8.7Hz,1H),7.17(d,J=8.6Hz,2H),6.89(d,J=8.5Hz, 2H), 6.77(d, J=2.2Hz, 1H), 6.64(dd, J 1 =8.7Hz,J 2 =2.2Hz,1H),4.22(t,J=6.6Hz,2H),3.95(m,2H),3.64(m,2H),3.47(m,2H),2.98(m,2H),2.39(s , 1H), 2.18(t, J=7.1Hz, 2H), 2.04(s, 3H), 1.07(m, 4H).

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Abstract

The invention belongs to the technical field of medicine, and relates to piperazinyl-containing indole derivatives and medical application thereof. The phenyl indole derivatives comprise stereomers and pharmaceutically applicable salts of the compounds, and the structural general formula is disclosed in the specification. The piperazinyl-containing indole derivatives and pharmaceutically applicable acid-added salts of the compounds can be mixed with the existing drug or independently used as an estrogen receptor regulator for treating or preventing various estrogen-function-related diseases, such as bone loss, fracture, osteoporosis, hectic fever, LDL cholesterol level increase, cardiovascular diseases, cognitive impairment, brain degeneration diseases, anxiety, depression caused by deficiency of estrogen, sexual disorder, hypertension, retinosis and cancer, and especially osteoporosis.

Description

technical field [0001] The invention relates to indole derivatives containing piperazinyl groups, their preparation methods, and their application in the preparation of estrogen receptor modulator medicines. Background technique [0002] Compounds that mimic estrogen-like effects have a wide range of therapeutic and prophylactic applications, including: treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, prostate cancer and prevention of cardiovascular disease. [0003] Studies have found that there are two types of estrogen receptors (ER): ERα and ERβ. After the ligand binds to these two isoforms, it exerts physiological effects with different tissue specificities. [0004] What is needed in the art is a compound that can produce a positive response like estrogen replacement therapy but without adverse side effects or with reduced side effects, and exert tissue-specific estrogen-like eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12A61K31/496A61P5/30A61P19/10A61P19/08A61P15/14A61P15/00A61P13/08A61P35/00
CPCC07D209/12
Inventor 胡春左莉滕雨刘晓平黄二芳金辄
Owner SHENYANG PHARMA UNIVERSITY
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