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Benzimidazole amide compound as well as preparation method and application thereof

A technology of benzimidazole and compound, which is applied in the field of preparation of benzimidazole amide compounds, and can solve problems such as unreachable, high blood drug concentration, and ineffectiveness

Active Publication Date: 2013-09-11
郎恒元 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, GDC-0449, the only Hh signaling pathway inhibitor currently on the market, also has some problems in its application. Some Smo site mutations, GDC-0449 drug efficacy is reduced or even ineffective

Method used

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  • Benzimidazole amide compound as well as preparation method and application thereof
  • Benzimidazole amide compound as well as preparation method and application thereof
  • Benzimidazole amide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Synthesis of N-{5-chloro-2-[6-(4-hydroxypiperidinyl)(3-pyridyl]benzimidazol-6-yl}-3-chlorobenzamide (I-1)

[0050]

[0051] Experimental procedure

[0052] Compound 1 (20.0g) was dissolved in 600ml mixed solution (EtOH: H 2 O=5:1), ammonium chloride (20g) and acetic acid (20ml) were added, the system was heated to 60°C, and iron powder (32.4g) was added in batches. Keep at 60°C for 1 hour. The temperature was lowered, extracted with ethyl acetate, and spin-dried to obtain compound 2 (14 g, yield 85%).

[0053] Compound 2 (14.0g) was dissolved in pyridine (315ml), p-toluene chloride (39.3g) was added in batches, and the temperature was raised to 75°C for 1.5 hours. The reaction solution was spin-dried, dissolved in ethyl acetate, washed three times with 0.1N HCl aqueous solution, dried, and spin-dried to obtain compound 3 (29 g, yield 65.6%).

[0054] Compound 3 (21g) was dissolved in acetic acid (170ml), the reaction was heated to 70°C, the mixed solution (7ml of s...

Embodiment 2

[0065] synthesis

[0066] N-{5-chloro-2-[6-(4-methylpiperazinyl)(3-pyridyl]benzimidazol-6-yl}-3-chlorobenzamide (I-2)

[0067]

[0068] Experimental procedure

[0069] Compound 7 (500mg), N-methylpiperazine (488mg), N,N-diisopropylethylamine (1.26g) dissolved in N-methylpyrrolidone (20ml), added to a sealed tube under nitrogen protection React overnight at 130°C. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water five times, dried and spin-dried to obtain compound 12 (450 mg, yield 75%).

[0070] Compound 12 (450mg) was dissolved in EtOH / H2O=5 / 1 (96ml), ammonium chloride (450mg) was added, the system was heated to 60°C, and iron powder (408mg) was added in batches. Keep at 60°C for 1 hour. The temperature was lowered, extracted with ethyl acetate, and spin-dried to obtain compound 13 (200 mg, yield 48%).

[0071] Compound 13 (100mg), N,N-diisopropylethylamine (113mg), dissolved in (15ml) tetrahydrofuran, the reaction system...

Embodiment 3

[0073] synthesis

[0074] N-{5-chloro-2-[6-(4-methylpiperazinyl)(3-pyridyl]benzimidazol-6-yl}-3-trifluoromethylbenzamide (I-3)

[0075]

[0076] Experimental procedure

[0077] Compound 13 (100mg), N,N-diisopropylethylamine (113mg), was dissolved in (15ml) tetrahydrofuran, the reaction system was lowered to 0°C, and the mixed solution (72.6mg m-trifluoromethylbenzyl acid chloride / 5ml tetrahydrofuran), react at room temperature for 2 hours. Spin to dry, dissolve in ethyl acetate, wash with water, spin dry and separate by column chromatography to obtain compound I-3 (65 mg). LCM S=515.9(M+1)

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Abstract

The invention discloses a benzimidazole amide compound as well as pharmaceutically acceptable salts and a preparation method thereof. The compound is used for tumors relevant to the continuous activation of hedgehog (Hh) signaling pathways, such as skin basal cell carcinoma, brain tumors, medulloblastoma, lung cancer, gastrointestinal tumors, breast cancer or pancreatic cancer, and illnesses relevant to the Hh signaling pathways.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a benzimidazole amide compound, a preparation method and an application thereof. Background technique [0002] The Hedgehog gene was first discovered in Drosophila in the early 1980s by Wieschaus and Nusslein-Vollhard. Hedgehog (Hh) signaling pathway is mainly composed of secreted glycoprotein ligand Hedgehog, transmembrane protein receptor Ptched (Ptch), transmembrane protein Smoothened (Smo), nuclear transcription factor Gli protein and downstream target genes. In normal body, the expression of Hh ligands in tissues is closed, and the combination of Ptch and Smo inhibits the activity of Smo, and the pathway is closed. When Hh binds to Ptch, it releases the inhibitory effect of Ptch on Smo, and Smo transmits the signal to the cytoplasm, activates the downstream Gli transcription factor and activates the entire signaling pathway. [0003] In recent years, the relationship betw...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/04C07D413/14A61K31/4545A61K31/496A61K31/5377A61P35/00
CPCA61P35/00C07D401/04C07D401/14C07D413/14
Inventor 郎恒元余科赵荟
Owner 郎恒元
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