2-Amino-benzoxazinones for the treatment of herpes simplex virus
a technology of benzoxazinone and herpes simplex virus, which is applied in the field of antiviral agents, can solve the problems of affecting the treatment effect of herpes simplex virus, few viable viruses and treatment options, and progressive decline in efficacy
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example 1
Compound 1
6-[[(1,1-Dimethlyethoxy)carbonyl]amino]-5-methyl-2-[methyl(phenylmethyl)amino]-4H-3,1-benzoxazin-4-one
A. Preparation of 3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-6-[[[methyl(phenylmethyl)-amino]carbonyl]amino]benzoic acid, 2-(trimethylsilyl)ethyl ester.
To a solution of 6-amino-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methylbenzoic acid, 2-(trimethylsilyl)ethyl ester (0.11 mmol in 3ml of CH2Cl2), was added a solution of p-Nitrophenyl chloroformate (0.1 mmol, 20.2 mg) in CH2Cl2 (0.2 ml). After stirring at room temperature for 3 hours, resulting solution was washed with 1N-HCl, water, and dried over MgSO4. To this solution of activated carbamate, methyl(phenylmethyl)amine (0.016 ml, 0.12 mmol) was added. After stirring at room temperature for 15 hours, a solution of tetrafluorophthalic anhydride (15 mg, 0.07 mmol) in CH2Cl2 (0.7 ml) was added and stirred for 3 hours, followed by polyamine resin prepared by the method of L. Flynn et al. (J. Amer. Chem. Soc., 119,...
example 2
Compound 2
6-(benzoylamino)-5-methyl-2-[methyl(phenylmethyl)amino]-4H-3,1-benzoxazin-4-one
A. Preparation of 3-amino-2-methyl-6-[[[methyl(phenylmethyl)amino]-carbonyl]amino]-benzoic acid, 2-(trimethylsilyl)ethyl ester.
To a solution of the product of example 1-step A (40.2 mg) in 1,4-doixane (2 ml) was added 4N-HCl solution in 1,4-dioxane (2 ml). After stirred at room temperature for 2 hours, the reaction mixture was concentrated. CH2Cl2 (4 ml) and DMF (0.5 ml) was added, dissolved, and Amberlyst A-21 (100 mg) was added. Shaken for 1 hour, the resin was filtered off, concentrated to afford 35.7 mg of product. 1H-NMR (270 MHz, CDCl3) δ 0.06(s, 9H), 0.9-1.0(m, 2H), 2.18(s, 3H), 3.97(s, 3H), 4.2-4.3(m, 2H), 4.58(s, 2H), 6.79(d, 1H, J=8.9 Hz), 7.2-7.4(m, 5H), 7.77(d, 1H, J=8.9 Hz), 8.14(s, 1H), HPLC(A) retention time=23.4 min.
B. Preparation of 3-(benzoylamino)-2-methyl-6-[[[methyl(phenylmethyl)amino]-carbonyl]amino]-benzoic acid, 2-(trimethylsilyl)ethyl ester.
To a solution of the...
example 3
Compound 4
6-[[(1,1-Dimethylethoxy)carbonyl]amino]-5-methyl-2-[[[4-(dimethylamino)phenyl]methyl]methylamino]-4H-3,1-benzoxazin-4-one.
A. Preparation of 3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-6-[[[N-[[4-(dimethylamino)phenyl]methyl]methylamino]carbonyl]amino]benzoic acid, 2-(trimethylsilyl)ethyl ester.
Proceeding in a manner similar to example 1A, substituting methyl(phenylmethyl)amine with N-[(4-dimethylamino)phenyl]methyl]methylamine.
1H-NMR(270 MHz, CDCl3) d 0.06(s, 9H), 1.0-1.1(m, 2H), 1.50(s, 9H), 2.28(s, 3H), 2.93(s, 9H), 4.2-4.3(m, 2H), 4.48(s, 2H), 6.11(br.s, 1H), 6.70(d, 2H, J=9 Hz), 7.19(d, 2H, J=9 Hz), 7.58(br.d, 1H), 8.06(d, 1H, J=9 Hz), 8.62(br. S, 1H).
B. Preparation of 6-[[(1,1-Dimethylethoxy)carbonyl]amino]-5-methyl-2-[[[4-dimethylamino)phenyl]methyl]methylamino]-4H-3,1-benzoxazin-4one.
To a solution of the product of step A (521 mg, 0.935 mmol) in 10 ml of THF, was added a solution of tetrabutylammonium fluoride in THF (1.0 M, 1.12 ml, 1.12 mmol). Stir...
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