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Polycyclic viral inhibitors

A technology of heterocyclyl and cycloalkyl, applied in the field of medicinal chemistry, can solve problems such as the lack of progress in compounds

Inactive Publication Date: 2009-09-09
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] However, none of the above compounds has progressed in clinical trials

Method used

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Examples

Experimental program
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example

[0402] In the following examples and the above synthetic schemes, the following abbreviations have the following meanings. Where an abbreviation is not defined, it has its generally accepted meaning.

[0403] μL = microliter

[0404] μM = micromole

[0405] μg = microgram

[0406] NMR = nuclear magnetic resonance

[0407] br = broad peak

[0408] d = doublet

[0409] δ = chemical shift

[0410] dd = two sets of doublets

[0411] DMEM = Dulbeco's Modified Eagle's Medium (Dulbeco's

[0412] Modified Eagle's Medium)

[0413] DMF = N,N-Dimethylformamide

[0414] DMSO = dimethyl sulfoxide

[0415] DTT = dithiothreitol

[0416] EDTA = ethylenediaminetetraacetic acid

[0417] ESI = Electrospray Ionization

[0418] g = gram

[0419] h or hr = hour

[0420] HCV = hepatitis C virus

[0421] HPLC = High Performance Liquid Chromatography

[0422] Hz = hertz

[0423] IPTG = Isopropyl-β-D-thiogalactopyranoside

[0424] IU = International Unit

[0425] IC 50 ...

example 1

[0453] Synthesis of compound 225

[0454] Step 1: 3-Cyclohexyl-6-methylformate-1H-indole-2-boronic acid pinacol ester (10.2)

[0455]3g (8.9mmol) of 10.1, 6.8g (26.8mmol, 3eq) of bis(pinacolyl) diboron, 2.6g (26.5mmol, 3eq) of potassium acetate and 312mg (0.45mmol, 0.05eq) of Pd(PPh 3 ) 2 Cl 2 Pack into a 250mL reaction bottle. The mixture was then suspended with 60 mL of dioxane, and then degassed and flushed with argon (3 times). The reaction mixture was then heated gently to 90 °C for 16.5 h. HPLC analysis demonstrated complete consumption of 10.1. The reaction mixture was allowed to cool to room temperature and then concentrated. The crude residue was dissolved with EtOAc and passed through SiO 2 Chromatography (10→20% EtOAc in Hex) twice afforded 1.76 mg (52%) of 10.2 as a white powder. MS: 384.2 (M+H + ).

[0456] Step 2: Methyl 2-(1H-benzimidazol-2-yl)-3-cyclohexyl-1H-indole-6-carboxylate (10.3)

[0457] 100mg (0.26mmol) of 10.2, 64mg (0.33mmol, 1.25eq) of 2-...

example 2

[0461] Synthesis of compound 226

[0462] 97 mg (0.26 mmol) of 10.3 was charged to a reaction vessel and dissolved with 10 mL DMF. Then NaH (31 mg, 0.78 mmol, 3 eq, 60% in mineral oil) was added and the mixture was stirred at room temperature for 15 minutes. 1,4-Diiodobutane (43 μL, 0.33 mmol, 1.25 eq) was then added via syringe and stirring of the reaction mixture continued at room temperature. HPLC and LC-MS analysis demonstrated that 10.3 was completely consumed after 4 h, during which additional portions of NaH and 1,4-diiodobutane were added. The reaction mixture was poured into a 50 mL flask and concentrated. By adding cold H 2 O to induce precipitation to separate the methyl esters. The resulting solid was then collected by centrifugation and dissolved with 3 mL THF, 1 mL MeOH and 1 mL LiOH (1M, aq.). The reaction mixture was stirred at 50°C and monitored by HPLC analysis. Upon completion, the reaction mixture was neutralized with 0.5 mL HCl (2M, aq.) and concentr...

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Abstract

The present invention discloses compounds and compositions of Formula (A) and their uses for treating Flaviviridae family virus infections.

Description

[0001] This application claims priority to co-pending US Provisional Patent Application Serial No. 60 / 832,520, filed July 20, 2006, which is hereby incorporated by reference in its entirety. technical field [0002] The present invention relates to the field of medicinal chemistry and, in particular, to compounds, compositions and methods for treating viral infections in mammals mediated at least in part by viruses of the Flaviviridae family. [0003] references [0004] The following publications are cited in this application in superscripted numeral form: [0005] 1. Szabo. E. (Szabo, E.) et al., Pathol. Oncol. Res. 2003, 9: 215-221. [0006] 2. Hoofnagle J.H. (Hoofnagle J.H.), Hepatology 1997, 26: 15S-20S. [0007] 3. Thomson B.J. and Finch R.G. (Finch R.G.), Clin Microbial Infect. 2005, 11:86-94. [0008] 4. Moriishi K. and Matsuura Y., Antiviral Chemotherapeutics (Antivir.Chem.Chemother.) 2003, 14:285-297. [0009] 5. Fried, M.W. et al. N. Engl. J Med 2002, 347:975-98...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D495/04A61K31/47A61P31/12
CPCC07D471/04C07D495/04A61P31/12A61P31/14A61P43/00A61K31/47
Inventor 罗纳德·康拉德·格里菲斯克里斯托弗·唐·罗伯茨弗朗兹·乌尔里希·施米茨亚诺什·博詹斯基雷切尔·伊丽莎白·马雷克史东方松·明·范
Owner SMITHKLINE BECKMAN CORP
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