Fused tricyclic hepatitis virus inhibitor and application thereof

A compound, cycloalkyl technology, applied in the field of medicinal chemistry

Active Publication Date: 2016-10-05
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the treatment of HCV infection is generally recombinant interferon α alone or combined with nucleoside analo

Method used

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  • Fused tricyclic hepatitis virus inhibitor and application thereof
  • Fused tricyclic hepatitis virus inhibitor and application thereof
  • Fused tricyclic hepatitis virus inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Example 1 N-((2S)-1-((S)-2-(5-(3-(2-((2S)-1-((S)-2-methoxycarbonylamino-3-methyl ylbutyryl)pyrrol-2-yl)-1H-benzo[d]imidazol-6-yl)-5-phenyl-5H-benzo[e]imidazo[1,2-c][1,3 ]oxazin-8-yl)-1H-imidazol-2-yl)pyrrol-1-yl)-3-methyl-1-oxobutane-2-yl)methyl carbamate

[0140]

[0141] Step 1 Preparation of 5-bromo-2-(1H-imidazol-2-yl)phenol

[0142]

[0143] Weigh 11.0g of 4-bromo-2-hydroxybenzaldehyde in a dry 500mL single-necked bottle, add 200mL of methanol, add 40.0g of glyoxal (40%wt) at 0°C, continue to drop 50mL of ammonia (17%-22 %wt), stirring in an ice bath to naturally rise to room temperature, and reacting for 2 hours. After the reaction, the reaction solution was concentrated at 60°C and purified by column chromatography to obtain the title compound.

[0144] 1 H NMR: (500MHz, DMSO-d 6 )δ13.16-13.02 (brs, 2H), 7.80 (d, 1H), 7.28-7.25 (brs, 2H), 7.15-7.10 (m, 2H).

[0145] MS(ESI):[M+H] + =239.

[0146] Step 2 Preparation of 8-bromo-5-phenyl-5H-benzo[e]imid...

Embodiment 2

[0198] Example 2 N-((2S)-1-((S)-2-(5-(3-(2-((2S)-1-((S)-2-methoxycarbonylamino-3,3 -Dimethylbutyryl)pyrrol-2-yl)-1H-benzo[d]imidazol-6-yl)-5-phenyl-5H-benzo[e]imidazo[1,2-c][ 1,3]oxazin-8-yl)-1H-imidazol-2-yl)pyrrol-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)methyl carbamate

[0199]

[0200] Compound (S)-2-(5-(3-(2-((2S)-pyrrol-2-yl)-1H-benzo[d]imidazol-6-yl)- 5-Phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-8-yl)-1H-imidazol-2-yl)pyrrole and N-methoxycarbonyl- Using L-tert-leucine as the starting material, the title compound was prepared according to the method in Step 14 of Example 1.

[0201] 1 H NMR: (300MHz, DMSO-d 6 )δ12.23-12.28(brs,1H),11.80-11.83(brs,1H),8.16-8.19(m,1H),7.70-7.73(m,1H),6.98-7.63(m,14H),5.01- 5.20 (m, 2H), 4.20-4.23 (m, 2H), 3.73-3.82 (m, 4H), 3.68 (s, 6H), 1.98-2.13 (m, 8H), 0.83-0.96 (m, 18H).

[0202] MS(ESI):[M+H] + =911.

Embodiment 3

[0203] Example 3 N-((2S)-1-((S)-2-(5-(3-(2-((2S)-1-((S)-2-methoxycarbonylamino-3-methyl ylbutyryl)pyrrol-2-yl)-1H-benzo[d]imidazol-6-yl)-5-(4-tert-butylphenyl)-5H-benzo[e]imidazo[1,2 -c][1,3]oxazin-8-yl)-1H-imidazol-2-yl)pyrrol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate ester

[0204]

[0205] Step 1 Preparation of 8-bromo-5-(4-tert-butylphenyl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazine

[0206]

[0207] Using the compound 5-bromo-2-(1H-imidazol-2-yl)phenol and 1-(dibromomethyl)-4-tert-butylbenzene prepared in step 1 of embodiment 1 as raw materials, according to step 1 of embodiment 2 to obtain the title compound.

[0208] MS(ESI):[M+H] + =383.

[0209] Step 2 of 8-(1-ethoxyvinyl)-5-(4-tert-butylphenyl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazine preparation

[0210]

[0211] The compound 8-bromo-5-(4-tert-butylphenyl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazine obtained in step 1 is used as raw material, according to The title compound was prepared by the method in Step 3 of Ex...

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Abstract

The invention belongs to the field of medical chemistry, relates to a fused tricyclic hepatitis virus inhibitor and application thereof, and particularly, provides a compound of the general formula I or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a medicine composition containing the compounds and application of the compounds or the composition in medicine preparation. The compound has the good inhibiting activity on hepatitis C virus, meanwhile has the low toxicity on host cells, and is high in effectiveness, good in safety and likely to become the medicine for treating and/or preventing diseases relevant to HCV infection.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of compounds with fused tricyclic structures capable of inhibiting the activity of hepatitis viruses or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, and compounds containing these compounds Pharmaceutical compositions and the application of these compounds or compositions in the preparation of medicines. Background technique [0002] Viral hepatitis C (Viral hepatitis C) is an infectious disease of acute and chronic inflammation of the liver caused by hepatitis C virus (HCV). Cirrhosis and liver cancer etc. seriously affect people's health. [0003] HCV belongs to Flaviviridae, and can be divided into 6 genotypes and different subtypes at present. According to the internationally accepted method, the HCV genotype is represented by Arabic numerals, and the genotype is represented by lowercase English letters, of which geno...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61K31/5365A61P31/14
Inventor 王勇赵立文王德忠沈晗张先叶嘉伟葛崇勋刘欣张景忠陈宏雁
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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