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Oxadiazoles as ester bioisosteric replacements in compounds related to disoxaril. Antirhinovirus activity

A series of 1,2,4-oxadiazoles has been prepared as ester bioisosteres and tested against 15 human rhinovirus serotypes, and the MIC80, the concentration which inhibits 80% or 12 of the serotypes tested, was determined. Homologation of the alkyl group attached to the oxadiazole ring resulted in a reduction in activity with increased chain length. Introduction of hydrophilic groups in this position rendered the compounds inactive. Increasing the length of the side chain attached to the isoxazole ring resulted in an increase in activity. Replacement of the methyl with alkoxyalkyl substituents retained activity; however, introduction of a hydroxyl group on to the side chain reduced activity. Compound 8a, where both the isoxazole and oxadiazole rings were substituted with methyl groups, was one of the most active compounds in the series. A comparison was made between 8a and the two isomeric oxadiazoles 41 and 46, and an attempt was made to explain the difference in activity by examining electrostatic potential maps and by an energy profiling study. No conclusive results were obtained from these studies.

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SYNTHESIS AND CYCLISATION OF beta-ENAMINOKETO ESTERS. PREPARATION OF HYDROXYPHTHALIDES

The synthesis of some isoxazole esters, their hydrogenation to beta-enaminoketo esters and the cyclisation of the latter (in acidic media) to hydroxyphthalide derivatives, is described.

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Di-heterocyclic compounds and their use as antiviral agents

Compounds of the formulas: STR1 wherein Het is an oxazole or oxazine moiety; X is O, S or SO, n is an integer from 3 to 9, Y is an aliphatic bridge; and the various R groups represent hydrogen or various substituents as described herein, are useful as antiviral agents, especially against picornaviruses. N-(Chloroalkyl)amide intermediates for the compounds of Formula I are also active as antiviral agents. Related compounds outside the scope of the above formulas are also disclosed.

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Isoxazoles as antiviral agents

Compounds of the formulas: STR1 wherein R is alkyl, X is O or CH2, n is an integer from 4 to 8, and Ar is phenyl or substituted phenyl are useful as antiviral agents especially against picornaviruses.

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Step 2 3-(chIoromethyl)-5-methylisoxazole To a solution of (5-methylisoxazol-3-yl)methanol (370 mg, 3.27 mmol) in DCM (5 mL) was added thionyl chloride (5 mL) dropwise. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated to give 3-(chloromethyl)-5-methylisoxazole (350 mg, crude) as brown oil, which was used without purification. LCMS retention time 0.768 min; LCMS MH+ 132.

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Reference£º
Patent; HYDRA BIOSCIENCES, INC.; CHENARD, Bertrand; GALLASCHUN, Randall; WO2014/143799; (2014); A2;,
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Example 22 3- [ (4-METHOXYPHENYL) AMINO]-1- [ (5-METHYLISOXAZOL-3-YL) METHYL]-4-PHENYL-LH-PYRROLE- 2,5-dione To a solution of 3- [ (4-methoxyphenyl) amino]-4-phenyl-lH-pyrrole-2, 5-dione (0.17 mmol, 50 mg), 5-methylisoxazole-3-methanol (0.19 mmol, 21 mg) and diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130C for six min.. After cooling, the reaction mixture was purified by HPLC (95% 0. 1M ammonium acetate buffer: 5% CH3CN E 100% CH3CN) to give 14 mg (21%) of the title compound. IH NMR (400 MHz, CDCL3) 6 7.23 (bs, 1H), 7. 16-7. 06 (m, 3H), 7. 01-6. 96 (m, 2H), 6.63-6. 53 (m, 4H), 6. 03 (d, J=0.7 Hz, 1H), 4. 82 (s, 2H), 3.70 (S, 3H), 2.39 (d, J=0.7 Hz, 3H)., 35166-33-7

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Reference£º
Patent; ASTRAZENECA AB; WO2005/5417; (2005); A1;,
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(c) 3-Chloromethyl-5-methylisoxazole A solution of 3-hydroxymethyl-5-methyl isoxazole (6.50 g, 57.5 mmol) and triphenylphosphine (15.1 g, 57.5 mmol) in carbon tetrachloride (120 ml) were heated at reflux in 18 h. Solvent was removed from the cooled mixture under reduced pressure then the residue taken up in ether and filtered. The filtrate was concentrated under reduced pressure then flash chromatographed through silica using 1:1 ether: 40-60 C. petroleum ether fraction as eluant to give 3-chloromethyl-5-methylisoxazole (5.43 g, 41.3 mmol, 72%); numax (film) 3130, 2960, 2920, 1610, 1475, 1400, 1270, 1250, 1160, 1130, 1010, 920, 890, 800, 750 cm-1; deltaH (CDCl3) 2.40 (3H, s, CH3 -5), 4.55 (2H, s, CH2 –Cl), 6.10 (1H, s, CH-4).

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Reference£º
Patent; Beecham Group p.l.c.; US4812470; (1989); A;,
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Example 253 (5-Methyl-3-isoxazolyl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl)methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100 C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (5-methyl-3-isoxazolyl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (18 mg, 0.038 mmol). 1H NMR (CDCl-d) delta2.06(m, 4H), 2.44 (s, 3H), 3.64 (m, 2H), 3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12(s, 1H), 6.95 (s, 1H), 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21(s, 1H). LC/MS: MH+479., 35166-33-7

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Reference£º
Patent; Hirst, Gavin C.; Calderwood, David; Munschauer, Rainer; Arnold, Lee D.; Johnston, David N.; Rafferty, Paul; US2003/153752; (2003); A1;,
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a) 3-(tert-Butyldimethylsilyloxymethyl)-5-methylisoxazole To a chilled (5 C.) solution of 3-hydroxymethyl-5-methylisoxazole (16.8 g, 148 mmol) and tert-butyldimethylsilyl chloride (24.6 g, 163 mmol) in dry methylene chloride (100 mL) was added over 15 minutes a solution of triethylamine (22.7 mL, 163 mmol) in methylene chloride (25 mL). 4-Dimethylaminopyridine (1.81 g, 14.8 mmol) was added and the thick reaction mixture was stirred at room temperature for 48 hours. Water (100 mL) was added and the aqueous layer extracted with methylene chloride (3*). The combined organic phases were washed with brine, dried (MgSO4), filtered through a pad composed of a layer of Florisil and a layer of Silica Gel 60, and concentrated in vacuo. The yellow oil obtained (36.6 g) was purified by chromatography (Silica Gel 60, 2% ethyl acetate in hexanes) to give 27.7 g (81.9%) of pure title compound as a pale yellow oil.

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Reference£º
Patent; Sterling Winthrop Inc.; US5349068; (1994); A;,
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