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Compounds containing benzimidazole structure as well as preparation method and application thereof

A compound and benzene ring technology, applied in the preparation of ROS1 inhibitors, compounds containing benzimidazole structures and their preparation fields, can solve the problems of not having high selectivity, easily lead to drug resistance, etc., and achieve improved treatment safety, The effect of reducing off-target effects and reducing toxic side effects

Active Publication Date: 2021-10-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the clinical trial of crizotinib for the treatment of ROS1-mutant NSCLC has been successful, it is found from the current clinical results that, like most anti-tumor drugs, long-term use can easily lead to drug resistance
In addition, both crizotinib and entrectinib are non-specific ROS1 inhibitors, so far there is no highly selective ROS1 inhibitor

Method used

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  • Compounds containing benzimidazole structure as well as preparation method and application thereof
  • Compounds containing benzimidazole structure as well as preparation method and application thereof
  • Compounds containing benzimidazole structure as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 2-(1-((2-amino-5-(4-methylphenyl)pyridin-3-yl)oxy)ethyl)-N-methyl-1H-benzo[d]imidazole-4- Formamide (I-1:R 1 =CONHCH 3 , R 2 =CH3 , R 3 =4-methylphenyl) synthesis

[0039] Synthesis of ethyl 2-((5-bromo-2-nitropyridin-3-yl)oxy)propionate (IV-1)

[0040] Dissolve compound II (5g, 22.8mmol) in 50mL N,N-dimethylformamide, cool in an ice bath, add sodium hydride (1.10g, 0.0274mol), stir, remove the ice bath, slowly add 2-bromo Ethyl acetate (III-1) (1.50mL×3, 34.20mmol), after the dropwise addition, was heated to 80°C for a constant temperature reaction for 12h, TLC (petroleum ether:ethyl acetate=4:1) detected that the reaction of the raw materials was complete. Stop heating, after cooling to room temperature, add 120mL of water and stir, extract with ethyl acetate (30mL×3), combine organic layers, wash with saturated sodium chloride solution (30mL×2), dry over anhydrous magnesium sulfate, suction filter, reduce The solvent was removed by pressure evaporation, and pur...

Embodiment 2

[0050] 2-(1-((2-amino-5-(4-fluorophenyl)pyridin-3-yl)oxy)ethyl)-N-methyl-1H-benzo[d]imidazole-4-carba Amide (I-2:R 1 =CONHCH 3 , R 2 =CH 3 , R 3 =4-fluorophenyl) synthesis

[0051] Synthesis of ethyl 2-((5-(4-fluorophenyl)-2-nitropyridin-3-yl)oxy)propionate (VI-2)

[0052] Dissolve IV-1 (0.50g, 1.57mmol) and 4-fluorophenylboronic acid (V-2) (0.33g, 2.35mmol) in 10mL of tetrahydrofuran, and dissolve potassium carbonate (0.61g, 4.39mmol) in 1mL of water to configure Potassium carbonate solution was added dropwise to the reaction solution, then tetrakis(triphenylphosphine)palladium (0.18g, 0.16mmol) was added, the reaction was refluxed under nitrogen protection for 24h, and the raw material was detected by TLC (petroleum ether:ethyl acetate=4:1) The response is complete. Heating was stopped, cooled to room temperature, the reaction system was evaporated to remove the solvent under reduced pressure, 10 mL of ethyl acetate and 15 mL were added for layering, the aqueous phase...

Embodiment 3

[0060] 2-(1-((2-amino-5-(3-methylphenyl)pyridin-3-yl)oxy)ethyl)-N-methyl-1H-benzo[d]imidazole-4- Formamide (I-3:R 1 =CONHCH 3 , R 2 =CH 3 , R 3 =3-Methylphenyl) Synthesis

[0061] Synthesis of Ethyl 2-((2-nitro-5-(3-methylphenyl)pyridin-3yl)-oxy)propionate (VI-3)

[0062] Dissolve IV-1 (1.00g, 3.13mmol) and 3-methylphenylboronic acid (V-3) (0.64g, 4.70mmol) in 20mL of tetrahydrofuran, and dissolve potassium carbonate (1.22g, 8.77mmol) in 2mL of water to configure Potassium carbonate solution was added dropwise to the reaction solution, then tetrakis(triphenylphosphine)palladium (0.36g, 0.33mmol) was added, the reaction was refluxed under nitrogen protection for 24h, and the raw material was detected by TLC (petroleum ether:ethyl acetate=4:1) The response is complete. Heating was stopped, cooled to room temperature, the reaction system was evaporated to remove the solvent under reduced pressure, 15 mL of ethyl acetate and 20 mL were added for layering, the aqueous phase ...

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Abstract

The invention relates to the field of medicinal chemistry, and discloses compounds containing a benzimidazole structure as well as a preparation method and application thereof. The invention discloses the compounds of general formula (I) or pharmaceutically acceptable salts thereof, wherein: R1 represents H, COOH, COOR4 or CONHR4, and R4 represents hydrogen, C1-C6 alkyl; R2 represents hydrogen and C1-C5 alkyl; R< 3 > represents an optionally substituted benzene ring or heteroaromatic ring, the heteroaromatic ring is a six-membered or five-membered heteroaromatic ring, the substituent group is halogen, C1-C3 alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, OH, NR5R6 or CN, and R < 5 > and R < 6 > represent hydrogen and C1-C6 alkyl. The compound can be used for treating tumors.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and discloses a compound containing a benzimidazole structure, a preparation method and an application thereof. The present invention also discloses a composition containing the benzimidazole compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and its application in the preparation of ROS1 inhibitors. The compounds of the present invention are useful in the treatment of tumors. [0002] technical background [0003] c-ROS proto-oncogene 1 tyrosine kinase (c-ros oncogene 1 tyrosine kinase, ROS1) was discovered in 1987 in the avian sarcoma RNA tumor virus, is a proto-encoding receptor tyrosine kinase (RTK) Oncogene, belonging to the insulin receptor family. Studies have found that ROS1 is not expressed in normal human lung tissue, but it is expressed in kidney, cerebellum, peripheral nerve tissue, stomach, small intestine and colon in normal adul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P35/00A61K31/4439
CPCC07D401/12A61P35/00
Inventor 朱启华徐云根施锦渝
Owner CHINA PHARM UNIV
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