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Indole carboxamide compounds and use thereof

A formamide and compound technology, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve the problems of reduced bioavailability, prolonged cardiac QT interval, etc.

Active Publication Date: 2017-07-14
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Existing epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, erlotinib, lapatinib, etc., all have skin reactions such as diarrhea, rash, itching, and possible headache, heart attack, etc. Prolonged QT interval and decreased bioavailability, etc.

Method used

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  • Indole carboxamide compounds and use thereof
  • Indole carboxamide compounds and use thereof
  • Indole carboxamide compounds and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Synthesis of 3-substituted amino-2-butenoic acid ethyl ester

[0042] General synthesis method: put ethyl acetoacetate (15.01g, 0.12mol) in a 100mL eggplant-shaped bottle, slowly add 0.36mol of substituted amine aqueous solution dropwise under stirring, continue to react at room temperature for 3h after the dropwise addition, and let stand to separate layers , the organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and used for the next step.

[0043] (1) Synthesis of 3-methylamino-2-butenoic acid ethyl ester

[0044] According to the general method of synthesis, 15.08 g of light yellow liquid was obtained, yield: 91.4%.

[0045] (2) Synthesis of 3-ethylamino-2-butenoic acid ethyl ester

[0046] According to the general method of synthesis, 16.31 g of colorless liquid was obtained, yield: 86.5%.

Embodiment 2

[0047] Example 2: Synthesis of ethyl 1-alkyl-2-methyl-5-hydroxyl-1H-indole-3-carboxylate

[0048] Synthetic general method: put p-benzoquinone (11.89g, 0.11mol) and acetone 120mL in a 250mL eggplant-shaped bottle, add dropwise under stirring to obtain the intermediate 3-substituted amino-2-butenoic acid ethyl ester 0.11 mol, after the dropwise addition was completed, the temperature was controlled at 30°C to continue the reaction for 2 h, the solvent was evaporated, and the crude product acetone was recrystallized.

[0049] (1) Synthesis of ethyl 1,2-dimethyl-5-hydroxy-1H-indole-3-carboxylate

[0050] According to the general synthesis method, 18.92g of white solid was obtained, yield: 73.7%, M.p.: 208-210°C (lit.: 208-209°C). ESI-MS, m / z: calcd.233.11 (M + ); found 234.1([M+H] + ),356.1([M+Na] + ).

[0051] (2) Synthesis of 2-methyl-1-ethyl-5-hydroxyl-1H-indole-3-carboxylic acid ethyl ester

[0052] According to the general synthesis method, 20.89g of yellow solid was ob...

Embodiment 3

[0053] Example 3: Synthesis of 1-alkyl-2-methyl-5-hydroxyl-1H-indole-3-carboxylic acid

[0054] Synthetic general method: put 0.043mol of ethyl 1-alkyl-2-methyl-5-hydroxy-1H-indole-3-carboxylate, sodium hydroxide (17.15g, 0.43mol), 100mL of ethanol and 50mL of water into In a 250mL eggplant-shaped bottle, heat to reflux for 12 hours, cool the reaction solution to room temperature, adjust the pH to 2 with 6mol / L hydrochloric acid aqueous solution, a large amount of solid precipitates, filter with suction, and recrystallize the crude product with ethanol.

[0055] (1) Synthesis of 1,2-dimethyl-5-hydroxy-1H-indole-3-carboxylic acid

[0056] According to the general method of synthesis, 6.79g of yellow solid was obtained, the yield was 76.98%, M.p.: 216-217°C; ESI-MS, m / z: calcd.205.07 (M + ); found 204.1([M-H] - ); 1 H NMR (400MHz, DMSO-d6): δ11.76(s, 1H), 8.84(s, 1H), 7.38(d, J=2.3Hz, 1H), 7.25(d, J=8.7Hz, 1H), 6.63 (dd, J = 8.7, 2.4 Hz, 1H), 3.63 (s, 3H), 2.65 (s, 3H).

[...

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Abstract

The invention belongs to the technical field of medicine and relates to indole carboxamide compounds and a use thereof. The indole carboxamide compounds comprise derivatives of indole carboxamide and pharmaceutically acceptable salts thereof. The indole carboxamide compounds have a general formula shown in the description. R1, R2 and R3 are defined in the claims and the specification. The indole carboxamide compounds and pharmaceutically acceptable acid salts can be used as epidermal growth factor tyrosine kinase inhibitors for treatment on epidermal growth factor receptor transfer disorder associated diseases such as small cells lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, colorectal cancer, breast cancer, ovarian cancer and renal cell carcinoma.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to indole carboxamide compounds and their application and preparation method as epidermal growth factor receptor tyrosine kinase inhibitors. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health, and the mortality rate caused by it accounts for the second place in the mortality rate of all diseases, second only to cardiovascular and cerebrovascular diseases. Lung cancer is a malignant lung tumor with a rapidly increasing morbidity and mortality worldwide. Most lung cancers originate from the bronchial mucosal epithelium. There are many classification methods for lung cancer. According to different classification methods, lung cancer can be divided into different types. According to the degree of differentiation and morphological characteristics of lung cancer cells, lung cancer is currently divided into two c...

Claims

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Application Information

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IPC IPC(8): C07D209/42C07D405/12A61K31/404A61K31/454A61K31/5377A61P35/00
CPCC07D209/42C07D405/12
Inventor 胡春张兰柯佳金辄姚东鸣郭万欣刘晓平
Owner SHENYANG PHARMA UNIVERSITY
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