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Hepatitis C virus inhibitors

An alkyl, selected technology, applied in the field of antiviral compounds, can solve problems such as viral load reduction

Inactive Publication Date: 2011-06-15
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with experimental regimens involving the combination of PEGylated interferon-alpha and ribavirin, a substantial number of patients did not experience sustained reductions in viral load

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0286] Embodiment 1: the preparation of compound 1A and 1B

[0287]

[0288] plan 1

[0289]

[0290] step 1:

[0291] 6-Phenyl-4-(thiophen-2-yl)pyridin-2(1H)-one (1.07 mg, 4.23 mmol) (prepared according to S. Wang et al., Synthesis 4, 487-490, 2003) in A solution in phosphorus oxychloride (15 mL) was heated to reflux for three days. Excess phosphorus oxychloride was removed in vacuo and the residue was triturated with ice water. The trituration was basified with aqueous NaOH and the product was extracted into DCM. The organic layer was washed with brine, dried, filtered through celite and evaporated. The crude product was purified by flash column chromatography to give the product as a white solid (624 mg, 54% yield). 1 H NMR (CDCl 3 )δppm 7.16(dd, J=5.13, 3.7Hz, 1H), 7.44-7.52(m, 5H), 7.55(dd, J=3.7, 1.1Hz, 1H), 7.79(d, J=1.5Hz, 1H) , 8.02 (dd, J=8.1, 1.5Hz, 2H). LC-MS MS m / z 272 (M + +H).

[0292] Option 3

[0293]

[0294] Step 2:

[0295] To a solutio...

Embodiment 2

[0304] Embodiment 2: the preparation of compound 2

[0305]

[0306] Scenario 2

[0307]

[0308] step 1:

[0309] The product of step 1 of example 2 was prepared by the same procedure as the product of step 3 of example 1 starting from Boc-Hyp-OH instead of the product of step 2 of example 1 . 1 H NMR (500MHz, MeOD) δppm 1.09 (d, J = 7.63Hz, 2H) 1.16-1.22 (m, 1H) 1.25-1.32 (m, 1H) 1.42 (dd, J = 9.46, 5.49Hz, 1H) 1.47 ( s, 1.7H) 1.50 (s, 7.3H) 1.88 (dd, J = 8.09, 5.34Hz, 1H) 1.94-2.03 (m, 1H) 2.13 (dd, J = 12.97, 6.87Hz, 1H) 2.26 (q, J = 8.85Hz, 1H) 2.97 (ddd, J = 12.51, 8.09, 4.73Hz, 1H) 3.47 (d, J = 11.60Hz, 1H) 3.56-3.62 (m, 1H) 4.25 (dd, J = 9.61, 6.87 Hz, 1H) 4.42 (s, 1H) 5.15 (d, J = 10.38Hz, 1H) 5.34 (d, J = 17.09Hz, 1H) 5.74-5.85 (m, 1H). LCMS, MS m / z=442 (M-H) - .

[0310] Step 2:

[0311] To a solution of the product from Example 2, Step 1 (1.0 g, 2.25 mmol) in DCM (20 mL) was added 1,1'-carbonyldiimidazole (439 mg, 2.71 mmol). After stirring at ro...

Embodiment 3

[0318] Embodiment 3: the preparation of compound 3

[0319]

[0320] Scheme 1 of Example 3

[0321]

[0322] step 1:

[0323] To a solution of 3-methoxyaniline (300 g, 2.44 mol) and ethyl benzoyl acetate (234.2 g, 1.22 mol) in toluene (2.0 L) was added HCl (4.0 N in dioxane, 12.2 mL, 48.8 mmol). The resulting solution was refluxed for 6.5 hours using a Dean-Stark apparatus (approximately 56 mL of aqueous solution was collected). The mixture was cooled to room temperature, partitioned several times with aqueous HCl (10%, 3 x 500 mL), aqueous NaOH (1.0 N, 2 x 200 mL) and water (3 x 200 mL), and the organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo to give an oily residue (329.5 g). The crude product was heated in an oil bath (280° C.) for 80 minutes using a Dean-Stark apparatus (approximately 85 mL of liquid was collected). The reaction mixture was cooled to room temperature, and the solid residue was washed with CH 2 Cl 2 (400 mL), the resulting...

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Abstract

Hepatitis C virus inhibitors having general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 61 / 053,477, filed May 15,2008. technical field [0003] The present invention relates generally to antiviral compounds, and more particularly to compounds that inhibit the function of the NS3 protease (also referred to herein as "serine protease") encoded by hepatitis C virus (HCV), compositions comprising said compounds, and A method of inhibiting the function of NS3 protease. Background technique [0004] HCV is a major human pathogen, infecting approximately 170 million people worldwide - roughly five times the number of human immunodeficiency virus type 1 infections. A substantial fraction of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. [0005] Currently, the most effective HCV therapy uses a combination of alpha-interferon and ribavirin, which produces sustained effects in...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D409/14C07D417/14A61K31/4025A61P31/14
CPCC07D417/14C07D409/14C07D401/14A61P1/16A61P31/12A61P31/14A61P43/00
Inventor 奈.西恩布莱恩.L.维纳布尔斯保罗.M.斯科拉
Owner BRISTOL MYERS SQUIBB CO
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