Ophthalmologic treatment methods using selective iNOS inhibitors
An ophthalmological, disease-based technology applied in the field of prevention and treatment of ophthalmic conditions and diseases involving excessive iNOS activity, capable of solving problems that do not include selective inhibitors of iNOS
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Embodiment A
[0194]
[0195] (2S,5E)-2-Amino-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride, monohydrate
[0196]
[0197]EX-A-1) Trimethylsilyl chloride (107.8 g, 1.00 mol) was added dropwise to a cold solution of L-glutamic acid (30.00 g, 0.20 mol) in 300 mL of methanol at 0°C. The resulting clear, colorless solution was stirred at room temperature. After 18 hours, analysis by thin layer chromatography (30% ethyl acetate in hexanes) showed no starting material remaining. The reaction was then cooled to 0°C and triethylamine (134 g, 1.33 mol) was added, forming a white precipitate. Di-tert-butyl dicarbonate (49 g, 0.23 mol) was added and the mixture was allowed to warm to room temperature. After 3 hours, the solvent was removed and 700 mL of ether was added. The solution was filtered and the filter cake was washed with an additional 500 mL of ether. The filtrate was concentrated to afford 60.8 g (>95%) of a brown oil which was used in the next step without fu...
Embodiment B
[0222]
[0223] (2S,5E / Z)-2-Amino-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride
[0224]
[0225] EX-B-1) To L-glutamic acid 5-methyl ester (50.00g, 0.31mol) in 400mL 1: 1H 2 To a cold (0° C.) solution in O / dioxane was added triethylamine (38.35 g, 0.38 mol) followed by di-tert-butyl dicarbonate (80.00 g, 0.37 mol). The resulting clear, colorless solution was stirred at room temperature. After 18 hours, analysis by thin layer chromatography (30% ethyl acetate in hexanes) showed no remaining starting material. With 200mL 1.0N KHSO 4 The reaction mixture was worked up with aqueous solution. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and washed with MgSO 4 Drying, filtration and concentration afforded 72.00 g (89%) of the desired product as a pale yellow oil.
[0226] LCMS: m / z = 284.1 [M+Na] + . 1 H NMR (CDCl 3 )? 1.50(s, 9H), 2.00(m,...
Embodiment C
[0260]
[0261] (2S,5Z)-2-Amino-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride
[0262]
[0263]EX-C-1) Dissolve triethyl 2-fluoro-phosphonoacetate (3.54 g, 14.6 mmol) in 20 mL of dichloromethane at 0°C, add 1,8-diazabicyclo[5.4.0] Undec-7-ene (2.4 mL, 16.4 mmol). The mixture was stirred at 0 °C for 20 minutes, resulting in an orange solution. A solution of the EX-A-3 aldehyde product (4.04 g, 11.7 mmol) was then added at 0°C, and the resulting brown mixture was stirred at room temperature overnight, at which point LCMS indicated no remaining starting material. The solvent was removed and the residue was partitioned between water (60 mL) and ethyl acetate (120 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (60 mL) and 10% KHSO 4 aqueous solution (60 mL), washed with MgSO 4 Dry, filter and concentrate. The crude product, 5.7 g of an orange...
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