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Hcv protease inhibitors

A technology of inhibitors and compounds, applied in antiviral agents, medical preparations containing active ingredients, cyclic peptide components, etc., can solve problems such as side effects

Active Publication Date: 2009-11-18
DONGGUAN HEC TAIGEN BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, sustained response rates were found to be <50% for interferon-alpha or interferon-alfa / ribavirin combinations, and patients are largely affected by the side effects of these agents

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 : {4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furo(furo)[3 ,2-d]pyrimidin-4-yloxy]-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-14-yl}-carbamic acid cyclopentyl ester (compound 1) Synthesis of

[0056] First, compound 1-3 was prepared from commercially available ethyl 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylate via the following route:

[0057]

[0058] To a solution of ethyl 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylate (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added LiOH (0.13 g , 5.3 mmol) in water (1.4 mL). After stirring overnight at room temperature, the reaction was quenched with 10% HCl (2 mL) and the solvent was removed in vacuo. The obtained solid powder was washed with water (10 mL) to obtain compound I-1 (0.27 g, 90%). MS m / z249.9 (M + +23); 1 H NMR (CDCl 3 )δ10.35(brs, 1H), 5.84-5.71(m, 1H), 5.29(d, J=17.4Hz, 1H), 5.12(d, J=10.2Hz, 1H), 2.23-2.14(m,...

Embodiment 2

[0072] Example 2 : {4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furfurylfuro[3, 2-d]pyrimidin-4-yloxy]-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl}-carbamic acid cyclopentyl ester (compound 2) Synthesis of

[0073] Compound 2 was prepared by the route shown below:

[0074]

[0075] Add compound I-11 (0.11 g, 0.14 mmol) in 5 mL CH at room temperature 2 Cl 2 The solution in was added with 4N HCl in dioxane (2 mL) for 4 hours. Removal of HCl, dioxane and CH by evaporation 2 Cl 2 , the crude product compound I-12 was obtained, and the crude product I-12 was directly used in the next step without further purification.

[0076] Dissolve the crude product I-12 in 2 mL of acrylonitrile, then add saturated NaHCO 3 aqueous solution (1 mL). After stirring for 10 minutes, cyclopentyl chloroformate (0.02 g, 0.15 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for an additional 2...

Embodiment 3-52

[0078] Example 3-52 : Synthesis of Compound 3-52

[0079] Each of Compounds 3-52 was prepared in a manner similar to that described in Examples 1 and 2.

[0080] Compound 3: MS: m / z 857.3 (M + +1); 1 H NMR (CDCl 3 ) 10.42(s, 1H), 8.41(d, 2H), 7.97(s, 1H), 7.51-7.35(m, 2H), 7.20(s, 1H), 7.02(d, 2H), 6.10(s, 1H) , 5.68(q, 1H), 5.16(d, 1H), 4.96(dd, 1H), 4.75(dd, 1H), 4.65(d, 1H), 4.34-4.07(m, 2H), 3.90(s, 3H ), 2.97-2.50 (m, 3H), 2.51 (s, 3H), 2.30 (q, 1H), 2.05-0.81 (m, 25H).

[0081] Compound 4: MS: m / z 869.3 (M + +1);

[0082] Compound 5: MS: m / z 803.3 (M + +1); 1 H NMR (CDCl 3 ) 10.31(s, 1H), 8.29(d, 1H), 7.67-7.54(m, 3H), 7.44(dd, 1H), 7.27(d, 1H), 7.03(s, 1H), 6.58(dd, 1H) , 6.09(s, 1H), 5.69(q, 1H), 5.05(d, 1H), 4.97(dd, 1H), 4.74(dd, 1H), 4.63(d, 1H), 4.26-4.04(m, 2H ), 2.95-2.20 (m, 4H), 1.95-1.15 (m, 14H), 1.08 (s, 9H), 0.98-0.81 (m, 2H).

[0083] Compound 6: MS: m / z 815.3 (M + +1); 1 H NMR (CDCl 3 )δ10.38(s, 1H), 8.29(d, 1H), 7.67-7.38(m, 4H), 7.2...

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Abstract

This invention relates to HCV protease inhibitors, in particular a macrocyclic compound shown in formula (I) or (II). Definition of each substituent R1, R2, U, W, X, Y and Z in formula (I) and R1, R2, R3, R4, R5, R6, R7, U, W, X, T and Z in formula (II) is described in instruction. The compound can be used for treating HCV. The invention further discloses a medicine composition containing the macrocyclic compound and an application of the macrocyclic compound for treating HCV.

Description

Background technique [0001] Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus ((+)-sensesingle-stranded RNA), and it is also a pathogenic factor that mainly causes non-A and non-B hepatitis. HCV infection is a problem that threatens human health. See eg WO 05 / 007681; WO 89 / 04669; EP 381216; Alberti et al. J. Hepatology, 31 (Suppl. 1), 17-24 (1999); Alter, J. Hepatology, 31 (Suppl. 1), 88- 91 (1999); and Lavanchy, J. Viral Hepatitis, 6, 35-47 (1999). [0002] Because HCV virus can mutate rapidly and escape the natural immune response, hepatitis caused by HCV infection is difficult to cure. The only anti-HCV therapies currently available are interferon-alpha, the interferon-alpha / ribavirin combination and pegylated interferon-alpha. However, sustained response rates for interferon-alpha or interferon-alpha / ribavirin combinations were found to be <50%, and patients are largely affected by the side effects of these therapeutic agents. See eg Walker, DDT, 4, 5...

Claims

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Application Information

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IPC IPC(8): C07K5/12C07D519/00C07D487/04A61K38/12A61K31/473A61K31/4741A61K31/4745A61P1/16A61P31/12
CPCC07K5/0804C07D519/00C07D487/04C07K5/081A61P1/16A61P31/12A61P31/14
Inventor 林助强李广元刘永庆罗斌陈荣峻刘振富陈志明金其新
Owner DONGGUAN HEC TAIGEN BIOPHARMACEUTICALS CO LTD
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