Description
Enviroxime is an antiviral agent. It inhibits coxsackievirus B3-, rhinovirus-, or poliovirus-induced plaque formation in HeLa monolayer cell cultures when used at concentrations of 0.1, 1, and 10 μg/ml. Enviroxime (1 μg/ml) inhibits production of poliovirus PV1 viral RNA in HeLa monolayer cell cultures. It reduces viral titers in DRAW macrophages infected with the DA strain of Theiler''s murine encephalomyelitis virus.
Manufacturing Process
300 g (1.52 mole) of 4-aminobenzophenone were added in portions to a
stirred solution of 250 ml of acetic anhydride in 250 ml of benzene. Thetemperature of the mixture rose to about 70°C. The reaction mixture was
stirred overnight. The product was filtered, washed with benzene and dried.
The yield of 4-acetamidobenzophenone was 333.8 g (91.5 % yield), melting
point 150-152°C (Lit. melting point 155°C).
23 g (0.1 mole) of 4-acetamidobenzophenone, 50 ml of acetic anhydride and
20 ml of acetic acid were stirred together. A solution of 90 % (15 ml), 10 ml
of acetic acid and 0.2 g of urea was added dropwise to the mixture. The
reaction mixture was maintained at a temperature of about 50°C. The mixture
was stirred at ambient temperature whereupon the mixture became very
thick. The thick slurry was poured over ice and the insoluble product was
filtered to yield 17.7 g (62.5 % yield) of 4-acetamido-3-nitrobenzophenone.
10 g of 4-acetamido-3-nitrobenzophenone were added portion-wise to 40 ml
of sulfuric acid. The reaction temperature was moderated with a water bath.
After stirring about 45 min the reaction mixture was carefully poured over ice.
The precipitated product was filtered to yield 4-amino-3-nitrobenzophenone.
50 g of 4-amino-3-nitrobenzophenone were hydrogenated at room
temperature in 945 ml of tetrahydrofuran with 15 g of Raney nickel. After 4
hours 3 equivalents of hydrogen were absorbed. The catalyst was filtered and
the filtrate was evaporated in vacuo to a solid residue. The residue was
chromatographed over silica gel using ethyl acetate as eluent. Fractions 5-9
were combined to yield 43.6 g (100 % yield) of 3,4-diaminobenzopheone.
42.4 g (o.2 mole) of 3,4-diaminobenzophenone were dissolved in 100 ml of
methanol and mixed into one liter of water. 21.8 g (0.2 mole) of cyanogen
bromide were added in portions to the reaction mixture with stirring The
reaction was continued overnight. The reaction mixture was filtered and the
filtrate was neutralized (pH 7.0) with concentrated ammonium hydroxide. The
precipitated product was collected, washed with water, and dried in a vacuum
to yield 31 g (68.5%) of 2-amino-5(6)-benzoylbenzimidazole.
4.5 g (20 mmole) of 2-amino-5(6)-benzoylbenzimidazole were dissolved in 30
ml of acetone and 4.0 g of triethylamine. A solution of 2.9 g (20 mmole) of
dimethylsulfamoyl chloride in 10 ml of acetone was added dropwise to the
reaction mixture. The mixture was heated at reflux overnight. The reaction
mixture was poured into 400 ml of water. The product was extracted with
chloroform. The extract was washed with water, dried (Na2SO4) and
evaporated in vacuo. The residue was crystallized from ethyl acetate to yield
1.06 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole, melting
point 206-208°C.
172 mg of 1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 100
mg of hydroxylamine hydrochloride and 20 ml of methanol were refluxed for
16 hours. The reaction mixture was concentrated to one-half the original
volume by heating on the steam bath. 10 ml of buffer (pH=7.0) were added
to the mixture. The product precipitated and was filtered to yield 116 mg of 1-
dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole,
melting point 180-183°C.
