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2-substituted-benzimidazole-4-formamide compound, preparation method, and application thereof

A compound, unsubstituted technology for medicinal chemistry and pharmacotherapeutics that addresses poor subtype selectivity and low bioavailability

Inactive Publication Date: 2017-01-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most PARP1 / 2 inhibitors suffer from low bioavailability and poor isoform selectivity

Method used

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  • 2-substituted-benzimidazole-4-formamide compound, preparation method, and application thereof
  • 2-substituted-benzimidazole-4-formamide compound, preparation method, and application thereof
  • 2-substituted-benzimidazole-4-formamide compound, preparation method, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1. 2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide, I-1 Preparation of:

[0120] Step 1. Tert-butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate:

[0121]

[0122] Weigh 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride (13-1) (10g, 56.9mmol) in a reaction flask (500mL), add dichloromethane (300mL) . Triethylamine (8.7 mL) was added under ice-cooling, and a solution of di-tert-butyl dicarbonate (13.7 g, 62.8 mmol) in dichloromethane (20 mL) was added slowly. After the dropwise addition was completed, the reaction was tracked for 1 hour, and the reaction of the raw materials was complete. The reaction solution was washed with water and saturated NaCl aqueous solution successively, and the organic layer was retained, washed with anhydrous NaCl 2 SO 4 After drying, filtration and concentration under reduced pressure, the crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 20:...

Embodiment 2

[0144] Example 2. 2-(5-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-methanol Preparation of amides, 1-2:

[0145]Step 1. 2-(5-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylic acid ester:

[0146]

[0147] 2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylic acid methyl ester (4-1)( 198mg, 0.63mmol) was dissolved in formic acid (3mL), and formaldehyde solution (37%, 0.3mL) was added. The reaction solution was raised to 95°C and reacted for 4 hours until the raw materials were completely reacted. Most of the solvent was evaporated under reduced pressure, and Na was added to the residue 2 CO 3 Adjust the pH to alkaline with a saturated aqueous solution, extract with ethyl acetate (50mL×3), wash the organic layer with water and saturated brine in turn, keep the organic layer, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and the crude product ...

Embodiment 3

[0153] Example 3. 2-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-methanol Preparation of amides, 1-3:

[0154] Step 1. 2-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylic acid ester:

[0155]

[0156] 2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylic acid methyl ester (4-1)( 160mg, 0.51mmol) was dissolved in anhydrous DMF (5mL), added Cs 2 CO 3 (183mg, 0.56mmol) and ethyl bromide (67mg, 0.61mmol), the temperature was raised to 80°C for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate (50mL×3), the organic layer was washed with water and saturated brine successively, the organic layer was retained, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to column chromatography ( Dichloromethane:methanol=80:1) to obtain 150 mg of a light yellow gum with a yield of 86%.

...

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Abstract

The invention relates to a 2-substituted-benzimidazole-4-formamide compound, a preparation method, and an application thereof. The structure of the 2-substituted-benzimidazole-4-formamide compound is represented as the general formula (I), wherein R1, R2, Y1, Y2, R3 and X are defined as the claims and the specifications. The invention also discloses a medicine composition comprising the 2-substituted-benzimidazole-4-formamide compound or pharmaceutically acceptable salts thereof. The 2-substituted-benzimidazole-4-formamide compound and the medicine composition can be used for preparing medicines for treating diseases related to Poly ADP-ribose polymerase, e.g., malignant tumor.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics. Specifically relate to a class of 2-(thiophene or thiazolotetrahydropyridin-2-yl)-1H-benzimidazole-4-carboxamide compounds or pharmaceutically acceptable salts thereof, their preparation methods and their use in the preparation of therapeutic and Application in the medicine of polyadenosine diphosphate-ribose polymerase (PARP) related diseases such as malignant tumors. Background technique [0002] Every day in the human body there are approximately 10 13 A cell is subjected to tens of thousands of DNA damages, exposure to harsh environments (such as ultraviolet radiation, ion radiation, etc.), normal cell metabolism by-products, and cytotoxic drugs can all cause DNA damage. These damages include base modification, single strand breaks (Single strand breaks, SSB), double strand breaks (Double strand breaks, DSB), cross-linking and so on. DNA damage seriously affects ...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D513/04A61P35/00A61P29/00A61P9/10A61P9/00A61P3/10A61P19/02
CPCC07D495/04C07D513/04A61K31/55
Inventor 杨春皓缪泽鸿陈旭星宦霞娟王玉勤陈奕丁健
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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