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Alkyl and heterocyclic compound serving as hepatitis-c-virus inhibitor and application of alkyl and heterocyclic compound in medicine

A compound and solvate technology, applied in the field of hepatitis C virus inhibitors and applications, can solve problems such as inability to treat for a long time

Active Publication Date: 2019-01-04
ZHEJIANG PALOALTO PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Currently, the standard approach for hepatitis C treatment is the combination of alpha-interferon and the broad-spectrum antiviral drug ribavirin, and pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy, The latest clinical results show that the combination of pegylated α-interferon and ribavirin is significantly improved compared with the previous combination of α-interferon and ribavirin, but it is still ineffective for some patients with chronic HCV infection, and many Patients are often accompanied by some side effects, and cannot be treated for a long time

Method used

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  • Alkyl and heterocyclic compound serving as hepatitis-c-virus inhibitor and application of alkyl and heterocyclic compound in medicine
  • Alkyl and heterocyclic compound serving as hepatitis-c-virus inhibitor and application of alkyl and heterocyclic compound in medicine
  • Alkyl and heterocyclic compound serving as hepatitis-c-virus inhibitor and application of alkyl and heterocyclic compound in medicine

Examples

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preparation example Construction

[0087] In another preferred example, the preparation method provided by the present invention includes the steps of:

[0088] (a) in an inert solvent, compound 1 and reacting to form compound 2;

[0089]

[0090] (b) reacting compound 2 and benzophenone imine in an inert solvent to form compound 3;

[0091]

[0092] (c) reacting compound 3 with an acid in an inert solvent to form compound 4;

[0093]

[0094] (d) In an inert solvent, compound 4 and reacting to form compound 5;

[0095]

[0096] (e) reacting compound 5 with an acid in an inert solvent to form compound 6;

[0097]

[0098] (f) in an inert solvent, compound 6 and reacting to form a compound of formula (I);

[0099]

[0100] In various forms, R 1 , R 2 , R 3 , R 4 , m and n are defined the same as before.

[0101] In another preferred example, the inert solvent used in the preparation method of the present invention is selected from the following group: acetic acid, ethanol, N,N-dim...

Embodiment 1

[0136] Example 1: PA6034

[0137] synthetic route:

[0138]

[0139] Experimental part:

[0140] Step 1) Synthesis of compound PA6034-1:

[0141] Compound PA6016-B-6 (1.17g, 3mmol) was dissolved in acetonitrile (15ml), and 4-formaldehyde pyridine (0.48g, 4.5mmol) and trifluoroacetic acid (0.1g) were added at room temperature, under nitrogen protection, and the reaction solution was heated Stir at 35°C for 3 hours, cool to room temperature, and suction filter to obtain a crude solid (1.05g) of compound PA6034-1 with a yield of 77%, which is directly used for the next step.

[0142] Step 2) Synthesis of compound PA6034-2:

[0143] Compound PA6034-1 (1.0g, 2.15mmol), DDQ (0.73g, 3.22mmol) was dissolved in toluene (15ml), and the reaction solution was stirred overnight at 110°C. After the reaction was complete, it was suction filtered, the filtrate was spin-dried, and saturated saline ( 20mL), extracted with ethyl acetate (3×25mL), combined the organic phases, washed with s...

Embodiment 2

[0154] Example 2: PA6038

[0155] synthetic route:

[0156]

[0157] Experimental part:

[0158] Step 1) Synthesis of compound PA6038-1:

[0159] Compound PA6016-B-6 (3.73g, 10mmol) was dissolved in acetonitrile (20ml), and 4-methylthiazole-5-carbaldehyde (1.27g, 10mmol) and trifluoroacetic acid (1.2mL) were added at room temperature, nitrogen protection , stirred overnight at room temperature, added saturated sodium carbonate solution (50mL) and water (50mL) to the reaction solution, stirred for 0.5 hours, extracted with ethyl acetate (3×100mL), combined organic phases, washed with saturated brine, anhydrous Na 2 SO 4 Dry, remove the solvent under reduced pressure, separate and purify by silica gel column chromatography (eluent: PE:EA(V:V)=3:1) to obtain PA6038-1 (2.23g), yield 46.9%.

[0160] Step 2) Synthesis of compound PA6038-2:

[0161] Compound PA6038-1 (2.07g, 4.3mmol) was dissolved in toluene (50mL), DDQ (2.9g, 12.9mmol) was added, and the reaction solution wa...

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PUM

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Abstract

The invention relates to an alkyl and heterocyclic compound serving as a hepatitis-c-virus inhibitor and application of the alkyl and heterocyclic compound in medicine. Particularly, the invention discloses a compound which is shown in a formula (I) and can be used for the hepatitis-c-virus inhibitor, or discloses an optical isomer of the compound or a pharmaceutically acceptable salt and water compound or a solvate. The compound can be used for treating hepatitis c virus (HCV) infection or hepatitis c disease, and can also serve as a HCV non-structural 5A (NS5A) calcineurin inhibitor.

Description

technical field [0001] The invention belongs to the field of chemical medicine. Specifically, the present invention relates to a hepatitis C virus inhibitor and its application. Background technique [0002] Hepatitis C virus (HCV) is a major human pathogen, estimated to infect approximately 200 million people worldwide. People with chronic HCV infection can develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Thus, chronic HCV infection is one of the leading causes of liver disease-related mortality worldwide. According to data released by the Health and Family Planning Commission, the number of reported cases of hepatitis C virus (HCV) infection in my country has been increasing year by year in the past 10 years, and the overall trend is still not optimistic. [0003] HCV is a positive-strand RNA virus. The genome consists of about 9600 nucleotides, including a non-coding region at both ends, namely the ribosome entry sequence (IRE...

Claims

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Application Information

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IPC IPC(8): C07K5/072C07K1/02A61K38/05A61P31/14A61P1/16
CPCA61K38/00C07K5/06104C07K19/00
Inventor 席志坚徐华强陆春平童志强伍中山孙锋张振伟虞华曹中莹
Owner ZHEJIANG PALOALTO PHARMA TECH CO LTD
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