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N-substituted indole derivative and application thereof

A technology of derivatives and indoles, applied in the field of preparing myeloid leukemia factor-1 and/or Bcl-2 protein inhibitors

Active Publication Date: 2017-03-08
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no small molecule inhibitor of Mcl-1 on the market. The small molecule inhibitor of Bcl-2, ABT-199, was approved for marketing in 2016, which also confirmed the positive significance of targeting Bcl-2 family proteins for tumor treatment.

Method used

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  • N-substituted indole derivative and application thereof
  • N-substituted indole derivative and application thereof
  • N-substituted indole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: 2-((2-carbamoyl-1-(2-phenoxyethyl)-1H-indol-6-yl)oxy)acetic acid

[0135] Compound 1A: 6-Methoxy-1H-indole-2-carboxamide

[0136] Add 6-methoxy-1H-indole-2-carboxylic acid (0.2g, 1.0mmol) and 30mL of anhydrous tetrahydrofuran to a 100mL eggplant-shaped flask, adjust the pH to 8 with DIEA, add HOBt (0.16g, 1.2 mmol), EDCI (0.23g, 1.2mmol) was reacted for 30min, 25% (w%) ammonia water (0.21g, 1.5mmol) was added, transferred to room temperature for 8h, and the reaction was stopped. Evaporate the solvent, add 100mL water and 100mL ethyl acetate for extraction, wash the organic layer with water (100mL×3), wash once with saturated aqueous sodium chloride solution, dry the organic layer with anhydrous sodium sulfate, filter with suction, and evaporate the filtrate to dryness to obtain light yellow Solid 6-methoxy-1H-indole-2-carboxamide (0.2 g), the crude product was directly carried on to the next reaction without isolation and purification. LC-MS: m / z=191.2[M+H]...

Embodiment 2

[0146] Example 2: 2-((2-carbamoyl-1-(2-(p-tolyloxy)ethyl)-1H-indol-6-yl)oxy)acetic acid

[0147] Compound 2A: ethyl 2-[(2-carbamoyl-1-(2-(p-tolyloxy)ethyl)-1H-indol-6-yl)oxy]acetate

[0148] Using compound 1C in Example 1 as a raw material, react with 1-(2-bromoethoxy)-4-methylbenzene according to the same reaction conditions to synthesize compound 2A, 2-[(2-carbamoyl-1- Ethyl (2-(p-tolyloxy)ethyl)-1H-indol-6-yl)oxy]acetate. Yield 56%. LC-MS: m / z=397.4[M+H] + .

[0149] Compound 2: 2-((2-carbamoyl-1-(2-(p-tolyloxy)ethyl)-1H-indol-6-yl)oxy)acetic acid

[0150] Using compound 2A as a raw material, the hydrolysis reaction was carried out under the same reaction conditions as compound 1 to obtain compound 2 as a white solid. Yield 78%, LC-MS m / z:367.0[M-H] - . 1 H-NMR (300MHz, DMSO-d6) δ: 7.94(d, J=10.5Hz, 1H), 7.54(d, J=8.7Hz, 1H), 7.28(s, 2H), 7.13(s, 1H), 7.03(d,J=8.3Hz,2H),6.85(dd,J=8.7,2.0Hz,1H),6.74(d,J=8.5Hz,2H),5.48(s,2H),4.91(t,J =5.2Hz, 2H), 4.23(t, J=5.4Hz, 2H)...

Embodiment 3

[0151] Example 3: 2-((2-carbamoyl-1-(2-(4-fluorophenoxy)ethyl)-1H-indol-6-yl)oxy)acetic acid

[0152] Compound 3A: Ethyl 2-[(2-carbamoyl-1-(2-(4-fluorophenoxy)ethyl)-1H-indol-6-yl)oxy]acetate

[0153] Using compound 1C in Example 1 as a raw material, react with 1-(2-bromoethoxy)-4-fluorobenzene according to the same reaction conditions to synthesize compound 3A, 2-[(2-carbamoyl-1-( 2-(4-Fluorophenoxy)ethyl)-1H-indol-6-yl)oxy]ethyl acetate. Yield 65%. LC-MS: m / z=401.4[M+H] + .

[0154] Compound 3: 2-((2-carbamoyl-1-(2-(4-fluorophenoxy)ethyl)-1H-indol-6-yl)oxy)acetic acid

[0155] Using compound 3A as a raw material, the hydrolysis reaction was carried out under the same reaction conditions as compound 1 to obtain compound 3 as a white solid. Yield 76%, LC-MS m / z:370.9[M-H] - . 1 H-NMR (300MHz, DMSO-d6) δ: 7.92(s, 1H), 7.54(d, J=8.7Hz, 1H), 7.32(d, J=8.5Hz, 2H), 7.13(s, 1H), 7.06(t, J=8.8Hz, 2H), 6.89(s, 1H), 6.87(s, 1H), 6.86-6.84(m, 1H), 5.51(s, 2H), 4.92(t, J=5.3Hz ,...

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Abstract

The invention belongs to the technical field of medicine, and relates to an N-substituted indole derivative, pharmaceutically acceptable salts and hydrates thereof, a pharmaceutical composition taking the derivative as an active component, and application of the derivative in preparing a myeloblastic leukemia factor-1(Mcl-1) and / or Bcl-2 protein inhibitor for treating cancer. The general structural formula of the derivative and definitions of substituents are as shown in the claims and specification.

Description

[0001] Technical field: [0002] The invention belongs to the technical field of medicine, and relates to N-substituted indole derivatives, pharmaceutically acceptable salts and hydrates thereof, pharmaceutical compositions containing the derivatives as active ingredients, and preparation of myeloid leukemia factor- 1 (Mcl-1) and / or Bcl-2 protein inhibitors and their use in the treatment of cancer. [0003] Background technique: [0004] Apoptosis, also known as programmed death, is a physiological process for the body to maintain the homeostasis of the human body and remove damaged or abnormal cells. The disorder of apoptosis process is an important symbol of tumor occurrence and development, and it is also one of the mechanisms of tumor resistance to chemotherapeutic drugs. [0005] The Bcl-2 protein family plays an important regulatory role in the mitochondrial pathway-induced apoptosis pathway of tumor cells. The protein family is mainly divided into three categories: ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D209/42C07D209/12A61K31/41A61P35/00
CPCC07D209/12C07D209/42C07D403/12
Inventor 赵临襄刘丹栾升霖葛琪代明阳景永奎
Owner SHENYANG PHARMA UNIVERSITY
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