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Macrocyclic compound for suppressing replication of hepatitis c viruses

A compound and solvate technology, applied in antiviral agents, enzyme inhibitor components, drug combinations, etc., can solve problems such as low living activity, large therapeutic dosage, and general pharmacokinetic properties

Inactive Publication Date: 2012-08-01
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The NS3 protease inhibitors currently on the market include telaprevir and boceprevir, but both of these two drugs have the disadvantages of low in vivo activity and general pharmacokinetic properties, which lead to a large amount of treatment. Therefore, the development of protease inhibitors with high efficiency and good pharmacokinetic properties Drugs have become the main direction for the development of HCV protease inhibitors

Method used

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  • Macrocyclic compound for suppressing replication of hepatitis c viruses
  • Macrocyclic compound for suppressing replication of hepatitis c viruses
  • Macrocyclic compound for suppressing replication of hepatitis c viruses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1 Compound IIa-1

[0152] N-[(1R, 12E, 17S, 20S, 23S)-20-tert-butyl-23-{[(1R, 2S)-1-[(cyclopropylsulfone)carbamoyl]-2-vinyl Cyclopropyl]carbamoyl}-3,18,21-trioxo-2,15-dioxa-4,19,22-triazatetracyclo[20.2.1.1 4，7 .0 6，11 ]Tert-Butyl Carbamate

[0153]

[0154] According to scheme I, III, the method for IV is synthesized.

[0155] Intermediate A3: (2S,4R)-4-(4-Vinylisoindole-2-carbonyloxy)pyrrolidine-1-carboxylic acid tert-butyl 2-methyl carboxylate

[0156]

[0157] According to Scheme I, starting material A2 (2.21 g, 9.03 mmol) was dissolved in DMF (20 mL), and CDI (1.47 g, 9.03 mmol) was added in portions at 0°C. After stirring at room temperature for 18 hours, slowly add the DMF solution of A1 (prepared with reference to the literature, J.Me d.Chem.2010, 53, 2443-2463) (1.4g, 9.03mmol), and stir after heating to 60°C after dropping 2 hours. After cooling to room temperature, ice water and 5% KHSO4 (35 mL) solution were added successively, and then e...

Embodiment 2

[0206] Example 2 Compound IIa-2

[0207] (1R, 12E, 17S, 20S, 23S)-17-amino-20-tert-butyl-N-[(1R, 2S)-1-[(cyclopropylsulfone)carbamoyl]-2-vinyl Cyclopropyl]-3,18,21-trioxo-2,15-dioxa-4,19,22-triazatetracyclo[20.2.1.1 4，7 .0 6，11 ] Hexadecyl-6,8,10,12-tetraene-23-carboxamide

[0208]

[0209] Compound IIa-1 (10mg, 0.012mmol) was dissolved in dichloromethane (5mL), then added dropwise into trifluoroacetic acid (1mL, 20%), stirred at room temperature for 2 hours, the reaction was completed, after concentration, water and di Chloromethane, and adjust the pH to 12 with 2N NaOH, and extract three times. The organic phase was washed with water, washed with saturated brine, Na 2 SO 4 Drying, filtration and concentration, white solid IIa-2 (2.3 mg, 26.1%) after column chromatography.

[0210] ESI-MS m / z 727.00(M+H) + .

Embodiment 3

[0211] Example 3 Compound IIa-3

[0212] N-[(1R, 12E, 17R, 20S, 23S)-20-tert-butyl-23-{[(1R, 2S)-1-[(cyclopropylsulfone)carbamoyl]-2-vinyl Cyclopropyl]carbamoyl}-3,18,21-trioxo-2,15-dioxa-4,19,22-triazatetracyclo[20.2.1.1 4，7 .0 6，11 ]Tert-Butyl Carbamate

[0213]

[0214] According to the method in Example 1, compound IIa-3 can be prepared from N-Boc-D-serine methyl ester.

[0215] 1 H NMR (400MHz, CDCl 3 )δ9.97 (brs, 1H), 7.28-7.08 (m, 3H), 6.55 (d, J=17.6Hz, 1H), 5.90-5.65 (m, 3H), 5.52 (s, 1H), 5.28-5.14 (m, 2H), 4.82-4.60(m, 6H), 4.47-4.26(m, 6H), 3.94-3.79(m, 2H), 3.42-3.32(m, 1H), 2.92-2.82(m, 1H) , 2.50-2.36(m, 2H), 2.11-1.96(m, 3H), 1.52(s, 9H), 1.35-1.30(m, 3H), 1.06(s, 9H), 1.06-1.02(m, 2H) ,; ESI-MS m / z 849.00 (M+Na) + .

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Abstract

The invention relates to a compound which is inhibitor for replication of one or multiple types of hepatitis c viruses. In addition, the invention discloses a medicinal component and preparation containing the compound and application of the inhibitor for replication of the hepatitis c viruses. The compound can be used individually or used with other compounds to treat symptoms caused by infection of the hepatitis viruses.

Description

technical field [0001] The present invention relates to a compound, a method for preparing the compound, a pharmaceutical composition and a medicament of the compound, and the compound is used for treating, preventing, and diagnosing one or more diseases or symptoms related to hepatitis C virus. Background technique [0002] Hepatitis C virus (HCV) infection is the main cause of liver disease in the world. According to the World Health Organization (WHO) estimates, there are currently 170 million to 200 million people with chronic hepatitis C infection in the world, accounting for about 3% of the global population, and new ones are added every year. There are 3 to 4 million hepatitis C patients. Although the clinical manifestations of acute hepatitis C are mild, it is easy to develop into chronic. About 50-80% of patients will develop chronic hepatitis or even liver cirrhosis and liver cancer. According to reports, 20 years after infection with hepatitis C, cirrhosis occurs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/097A61K38/06A61P31/14A61K38/08
CPCC07K5/0812C07K5/06034C07K5/0808C07K5/06078A61K38/06C07K5/08A61K38/005A61K38/55A61P31/14A61P43/00A61K38/08A61K2300/00A61K38/07A61K45/06C07K5/1013C07K7/06
Inventor 李本陈力翟培彬何松涛江涛甘立斌肖本良文小伟孙利
Owner GINKGO PHARMA
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