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Diaryl amide compound containing benzimidazole group as well as synthesis and application of diaryl amide compound

A technology of benzimidazolyl and arylamide, applied in the field of chemical medicine

Inactive Publication Date: 2014-11-19
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it is found that this drug has many shortcomings in clinical application. For example, in the treatment of patients with locally advanced basal cell carcinoma, the sum of partially effective, tumor shrinkage or disappearance accounts for only 43% of the total, while in the treatment of diffuse basal cell carcinoma This proportion is as low as 30% among patients; during the use of the drug, some patients gave up trying due to unbearable side effects

Method used

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  • Diaryl amide compound containing benzimidazole group as well as synthesis and application of diaryl amide compound
  • Diaryl amide compound containing benzimidazole group as well as synthesis and application of diaryl amide compound
  • Diaryl amide compound containing benzimidazole group as well as synthesis and application of diaryl amide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of 2-chloro-N-[4-chloro-3-(1H-benzimidazol-2-yl)phenyl]-4-thiamphenicol benzamide (Ⅰ-1)

[0053] ①Add 2.98mmol of compound ⅰ-1, 2.98mmol of o-phenylenediamine (compound ⅱ-1), 3.28mmol of HBTU, 5.96mmol of triethylamine and 20mL of THF into a 50mL pear-shaped flask, stir at room temperature for 5h under nitrogen protection, and react After adding 40 mL of water to the solution, CH 2 Cl 2 Extract three times, 30mL each time, combine the organic phases, wash with 30mL of water, wash with 30mL of saturated brine, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, the crude product is purified on a silica gel column, and the mobile phase is petroleum ether: ethyl acetate: triethylamine = 1:1:0.005, 714 mg of product was obtained with a yield of 82%. ESI-MS:m / z292.05[M+H] + .

[0054]

[0055] ②Add 1.714mmol of the product obtained in step ① (compound Ⅲ-1) and 12mL HOAc in a 25mL pear-shaped bottle, stir and ref...

Embodiment 2

[0062] Synthesis of 2-chloro-N-[4-chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl]-4-thiamphenicol benzamide (Ⅰ-2)

[0063] ①Add 2.98mmol of compound ⅰ-1, 2.98mmol of o-phenylenediamine (compound ⅱ-1), 3.28mmol of HBTU, 5.96mmol of triethylamine and 20mL of THF into a 50mL pear-shaped flask, stir at room temperature for 5h under nitrogen protection, and react After adding 40 mL of water to the solution, CH 2 Cl 2 Extract three times, 30mL each time, combine the organic phases, wash with 30mL of water, wash with 30mL of saturated brine, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, the crude product is purified on a silica gel column, and the mobile phase is petroleum ether: ethyl acetate: triethylamine = 1:1:0.005, 714 mg of product was obtained with a yield of 82%. ESI-MS:m / z292.05[M+H] + .

[0064]

[0065] ②Add 1.714mmol of the product obtained in step ① (compound Ⅲ-1) and 12mL HOAc in a 25mL pear-shaped bottle, sti...

Embodiment 3

[0074] 2-Chloro-N-[4-chloro-3-(4,7-dimethoxy-1H-benzimidazol-2-yl)phenyl]-4-thiamphenicol benzamide (Ⅰ-3) Synthesis

[0075] The difference with embodiment 1 is:

[0076] The o-phenylenediamine of step ① in embodiment 1 is replaced by 3,6-dimethoxy o-phenylenediamine;

[0077] Compound I-3. 1 H NMR (400MHz, CDCl 3 )δ10.90(1H,s),8.66-8.53(2H,m),7.61-7.52(2H,m),7.31(1H,d,J=7.9Hz),7.18(1H,d,J=7.9Hz ), 6.45(2H,s), 3.84(6H,s), 2.89(3H,s); ESI-MS: m / z520.03[M+H] + .

[0078]

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Abstract

The invention relates to a diaryl amide compound containing benzimidazole group as well as the synthesis and application of the diaryl amide compound and belongs to the field of chemical medicine. The compound has a general formula I shown in the specification, wherein R1 is hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 ester, C1-C6 alkylamino or C1-C6 acylamino; R2 is hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 ester, C1-C6 alkylamino or C1-C6 acylamino; R3 is hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 ester, C1-C6 alkylamino, C1-C6 acylamino, benzene ring or heteroaromatic ring; R4 is H or C1-C6 alkyl; and R5 is methylsulfone, nitro, trifluoromethyl or cyano. The invention also provides an application of the compound and pharmaceutically acceptable salts of the compound in preparation of anti-tumor drugs.

Description

technical field [0001] The invention relates to a class of diarylamide compounds containing benzimidazole groups and their synthesis and application, belonging to the field of chemical medicine. Background technique [0002] The Hedgehog signaling pathway not only plays a vital role in the growth and proliferation of embryos, but also plays a key role in maintaining physiological balance in adults (Taipale J, Varjosalo M. Hedgehog: functions and mechanisms. Genes Dev.2008, 22, 2454.; Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev. Cell, 2008, 15, 801.). The entire signaling pathway includes Hedgehog protein, Patched protein, Smoothened (SMO) protein, and downstream Gli transcription factors, etc. (Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. 2001.15(23): 3059-3087.). Among them, SMO protein inhibitors are the most promising anti-tumor drugs for clinical application. In January 2012, Vismodegib (GDC-0449), as...

Claims

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Application Information

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IPC IPC(8): C07D235/18A61K31/4184A61P35/00
CPCC07D235/18C07D401/04
Inventor 王世盛管童伟赵伟杰郑晓红王迪刘思慧
Owner DALIAN UNIV OF TECH
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