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Heterocyclic compounds and application thereof in medicine

A compound, isomer mixture technology, used in the field of medicine

Active Publication Date: 2019-05-21
KIND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although SERDs have shown compelling promise in the treatment of ER-related diseases such as breast cancer, so far, no small-molecule drugs that can be administered orally for SERDs have entered the market.

Method used

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  • Heterocyclic compounds and application thereof in medicine
  • Heterocyclic compounds and application thereof in medicine
  • Heterocyclic compounds and application thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0177] Preparation of intermediate compounds

[0178] Preparation of Intermediate I-100':

[0179]

[0180] 1-(2,3-difluoropropyl)azetidine-3-amine ( I-100’-1 )

[0181]

[0182] first step

[0183] 2-Benzyloxymethyloxirane ( I-100'-1-a )

[0184]

[0185] NaOH (3.7 g), tetra-n-butylammonium iodide TBAI (3.43 g) and DMF (150 ml) were added to the reaction flask, cooled in an ice-water bath, and then oxirane-2-ylmethanol (CAS: 556- 52-5; 6.85 g) was dropped into the reaction flask and stirred for 2 hours; then benzyl bromide BnBr (17.3 g) was slowly added dropwise; after the addition, the reaction was left overnight at room temperature. Then, add water to quench the reaction, extract with ethyl acetate; collect the ethyl acetate layer, then wash twice with dilute sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate; the residue is purified by silica gel column chromatography to obtain oily product, I-100'-1-a (12 grams...

Embodiment 1

[0260] 1-(3-fluoropropyl)-N-(4-((6R,7S)-7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo [3,4-h]isoquinolin-6-yl)phenyl)azetidine-3-amine ( 1 )

[0261]

[0262] first step

[0263] (2S)-2-(((1H-indazol-4-yl)methyl)(methyl)amino)-1-(4-bromophenyl)-4-methylpentan-1-ol ( 1a )

[0264]

[0265] compound I-60-1 (839 mg), 4-(chloromethyl)-1H-indazole (ADV947321888 purchased from Advanced ChemBlocks Inc., 739 mg), potassium carbonate (1.8 g) and sodium iodide (39 mg) were mixed in an water in DMF. The reaction was stirred overnight at room temperature. Then, add ethyl acetate and water for extraction; separate the organic phase, wash the organic phase twice with dilute sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate; the residue is purified by silica gel column chromatography to obtain a yellow solid product 1a (950 mg). 1 H NMR (500MHz, DMSO-d6) δ (ppm): 13.00 (1H, s), 8.07 (1H, s), 7.50 (2H, d, J = 8.0Hz), 7.40 (1H, d, J...

Embodiment 2

[0287] N-(3,5-difluoro-4-((6S,7S)-7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4 -h] isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine ( 2 )

[0288]

[0289] first step

[0290] (2S)-2-(((1H-indazol-4-yl)methyl)(methyl)amino)-1-(4-chloro-2,6-difluorophenyl)-4-methylpentane -1-ol ( 2a )

[0291]

[0292] compound I-60-2 (1130 mg), 4-(chloromethyl)-1H-indazole (ADV947321888 purchased from Advanced ChemBlocks Inc., 630 mg), potassium carbonate (2.5 g) and sodium iodide (54 mg) were mixed at room temperature in an water in DMF. The reaction was stirred overnight at room temperature. Then, add ethyl acetate and water for extraction; separate the organic phase, wash the organic phase twice with dilute sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate; the residue is purified by silica gel column chromatography to obtain a yellow solid product 2a (1660 mg). 1 H NMR (500MHz, dmso-d6) δ (in ppm): 12.98 (1H, s...

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Abstract

The invention relates to heterocyclic compounds and the application thereof in medicine. Specifically, the invention discloses heterocyclic compounds as shown in formula I, or isotopically-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or a mixture of isomers thereof, or medicinal salts thereof, or prodrugs thereof. The invention also relates to application of these compounds in medicine.

Description

technical field [0001] The invention belongs to the field of medicine, and particularly relates to a compound related to the treatment of estrogen receptor-related diseases (such as breast cancer) and its preparation and application in medicine. Background technique [0002] Estrogens include estrone, estradiol, etc., which are mainly secreted by the ovary, and a small amount is secreted by the liver, adrenal cortex and breast. As the main sex hormone of female animals, estrogen promotes the maturation of female accessory sex organs and the emergence of secondary sexual characteristics, and maintains normal sexual desire and reproductive function. Its role is mainly to diffuse into the nucleus and form a complex with estrogen receptor (estrogen receptor, ER). The activated estrogen receptor quickly forms a homologous or heterologous dimer and binds to DNA Enhancer (enhancer) includes estrogen response element (Estrogen Response Element, ERE) and so on, and calls other trans...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4745A61P35/00A61P19/10A61P25/28A61P9/00A61P5/50A61P15/00A61P37/06A61P3/04
CPCC07D471/04A61P35/00A61P15/00A61P25/28A61P9/00A61P19/10A61P37/06A61P5/50A61P3/04A61K31/4738A61K31/4745
Inventor 刘栋
Owner KIND PHARMA
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