5-Nitroimidazoles

The chemical synthesis and biological testing of numerous nitroimidazoles occurred following the discovery in 1955 of azomycin, a 2-nitroimidazole compound, and the demonstration of its trichomonacidal properties a year later. The trichomonacidal activity of metronidazole, a 

5-nitroimidazole, was reported in 1960. The chemical synthesis of other 5-nitroimidazole compounds, including dimetridazole, ipronidazole, ronidazole, and tinidazole, followed. In addition to antiprotozoal activity, these compounds display concentration-dependent activity against anaerobic bacteria. Both activities are utilized in human and veterinary medicine, although the use of nitroimidazoles in food-producing species is prohibited in Australia, Canada, the EU, and the United States. 

The emergence of resistance to 5-nitroimidazoles is rare. When it does emerge, resistance is generally attributed to a decrease in the reduction of the 5-nitro group to form an unstable intermediate. 

Residues of nitroimidazoles in the environment have not been reported. (See list of nitroimidazoles in Table 1.8). 

Although JECFA has not established ADI values for metronidazole, dimetridazole, or ipronidazole, they did allocate a temporary ADI for ronidazole in 1989 but it was withdrawn in 1995.  

Their antibacterial and mutagenic activity is closely related to the reduction of the 5-nitro group, which is common to all nitroimidazole drugs, and the subsequent formation of reactive metabolites that bind to bacterial DNA, inhibiting DNA and protein synthesis in the microorganisms. Metabolism of 5-nitroimidaz-oles in mammals usually leads to covalently bound residues with a persistent imidazole structure. 

Dimetridazole has been traditionally used for treatment and prevention of histomoniasis in turkeys and chickens, trichomoniasis in cattle, and dysentery in swine. Concentrations of 125-500 ppm are satisfactory feed levels for turkeys, 75-500 ppm for chickens, and 1000 ppm for pigs. The drug has also been used as a feed or water additive in pigs for gi owth-promoting purposes. A 5-day withdrawal period is required to ensure absence of residues in edible tissues. 

Orally administered dimetridazole is well absorbed from the gastrointestinal tract (7). Approximately 88% of the administered dose is eliminated within 3 days in turkeys, whereas around 76% is eliminated within 7 days in pigs. In 

When pigs were given a single oral dose of radiolabeled dimetridazole, the concentrations of total residues in muscle, liver, kidney, and fat were found to be 8.6, 15.4, 36.1, and 3.6 ppm, respectively, at 0 withdrawal time, declining to 

Other residue depletion studies of dimetridazole in chickens, turkeys, and swine generally showed that the concentrations of dimetridazole residues decreased to less than 0.1 ppm in the edible tissues of chickens at 1 day withdrawal, and to less than 2 ppm in the edible tissues of turkeys and swine at 2-day withdrawal (9, 10). 

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Nitroimidazoles and 2-azidoimidazoles are available via the diazonium fluoroborates, and photolytic decomposition of the fluoroborates gives 2-fluoroimidazoles (80AHC(27)24i). 

These are rate constants for the catalyzed hydrolysis of N-(3,3-dimethylbutyryl)-4(5)-nitroimidazole in water at 30°C. ... 

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

Chloro-l-methyl-4-nitroimidazole (204) was also used as a heterocyclic component in the Turpin reaction. Intermediate 205 was formed under mild conditions and its cyclization was achieved by heating with ethanolic dimethylamine in a sealed tube to give a blue-colored substance, which was attributed structure 206 (Scheme 32) (52JCS784). 

Amoebal infections, particularly of farm animals and the female human genitalia, are at best only annoying. All too often the problem encountered leads to difficult diarrheas. A group of nitroimidazoles have activity against the causative organisms and consequently have been widely synthesized. 

Similarly, reaction of 2-nitroimidazole with l,2-epoxy-3-methoxypropane in the presence of potassium carbonate gives misonidazole This agent also has the interesting and... 

Many nitroimidazoles possess antiprotozoal activity. One of these is bamnidazole (29). Synthesis involves reaction of imidazole carbonate 28 with ammonia. 

Crozet and co-workers have used Spj l reactions for synthesis of new heterocycles, which are expected to be biologically active fsee iilso Section 7 3, which discusses synthesis of alkenesi For example, 2-chloromethyl-5-nitroimidazole reacts v/ith theanionof 2-nitropropane to give 2-isopropylidene-5-nitroimida2ole It is formed via C-alkyladon of the nitronate ion followed by eliminadon of HNCk fEq 5 33 Other derivadves of nitroimidazoles are idso good substrates for Spj ... 

The reacdon of l,2-dimethyl-5-nitroimidazole v/ith 2-nitropropane anion gives the new highly branched imidazole derivadve, which is formed via cine-snbsdtudon and Spj l subsdni-don fEq 5 67 ... 

The mtrodncdon of a formyl or acyl group can be achieved by transformadon of VNS products. Hydrolysis ofthchloromethylnitroarenes, VNS products betweenheteroaromadcnitro compoimds and chloroform, is amethodof choice for the preparadon of heterocyclic Mdehydes, as shown in Eq. 9.41, in which 4-nitroimida2oleis converted into 5-formyl-4-nitroimidazole. ... 

Amino-4-methylpyrimidine 2-Formyl-1-m ethyl-5-nitroimidazole Sulfuric Acid... 

Into a mixture of 1.6 g of 2-amino-4-methylpyrlmidine with 10 ml of glacial acetic acid is slowly added 2.13 g of concentrated sulfuric acid. A mixture of 2.4 g of 2-formyl-1-methyl-5-nitroimidazole in 20 ml of glacial acetic acid is slowly added to the mixture of the pyrimidine under stirring. The reaction mixture is maintained at a temperature of about 55°C for 4 hours. The resultant mixture is then diluted with 200 ml of distilled water and neutralized with a saturated aqueous solution of sodium bicarbonate. A brownish-yellow precipitate (MP 232° to 235°C) is formed and recovered. The product is analyzed by infrared spectroscopy and is found to conform to 2-amino-4-[2-(1-methyl-5-nitro-2-imidazolyI)vinyl] pyrimidine. 

Chemical Name 6-[(1-methyl-4-nitroimidazol-5-yl)thio] purine... 

N,N -dimethyloxaldiamide is reacted with PCI5 to give 4-chloro-1-methyl imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4-chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6-mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated at 100°C for 7 hours. 

Chemical Name 1-Methyl-2-(1-methylethyl)-5-nitro-1 H-imidazole Common Name 2-lsopropyl-1-methyl-5-nitroimidazole... 

Isopropyl-4(or 5-nitroimidazole) (31 g = 0.2 mol), dioxane (70 g) and dimethylsulfate (28 g = 0.22 mol) were heated on a steam bath under reflux for 45 minutes. The solvent was removed in vacuo on a steam bath, the residue dissolved in 20 ml of water and the product precipitated by the gradual addition of 80 g of 25% sodium hydroxide solution at 0°C. A small additional amount was obtained by extraction of the mother liquor with methylene chloride. The product melted at 60°C. 

Methyl-4(or 5)-nitroimidazole (127 g) is heated with ethylene chlorohydrin (795 g) for 18 hours at 128° to 130°C and the chlorohydrin (660 g) Is then distilled under reduced pressure (30 mm Hg). The residue is treated with water (300 cc) and filtered, and the filtrate is made alkaline by the addition of sodium hydroxide solution (d = 1.33, 100 cc). 

It is then extracted with chloroform (1,000 cc) and, after evaporation of the chloroform in vacuo, there is obtained a pasty mass (77 g) which is recrystallized from ethyl acetate (450 cc) in the presence of animal charcoal. There is thus obtained 1-(2-hvdroxvethyl)-2-methyl-5-nitroimidazole (24 g) as a creamy white crystalline powder melting at 158° to 160°C. 

Crystallization from water results in N- -ethylmorpholino-(5)-nitroimidazole (melting point 110°Cto 111°C) from mother liquors N- 3-ethylmorpholino-(4)-nitroimidazole (malting point 104°Cto 106°C) is obtained. 

The following procedure is given in U.S. Patent 3,458,528 78 grams (0.675 mol) of 5-nitroimidazole is dissolved in 1,500 ml of acetic acid upon the addition of 72 ml (0.57 mol) of boron trifluoride etherate. 175 ml (3.5 mols) of ethylene oxide in 175 ml of hexane, in a dropping funnel topped with a cold finger, is added slowly over 1 hour to the above solution maintained at 32° to 35°C with a water cooling bath. The mixture is concentrated under high vacuum to 100 to 150 ml volume. The residue is diluted with 500 ml of water, neutralized to pH 7 with aqueous sodium hydroxide, and extracted with 1.5 liters of ethyl acetate. The extract is dried and evaporated to yield 1-(2 -hydroxyethyl)-5-nitroimidazole. 

The solution obtained is treated with ammonium hydroxide (d = 0.92 106 cc), saturated with sodium chloride, and then extracted with ethyl acetate (total 660 cc). The combined organic extracts are washed with a saturated aqueous sodium chloride solution (60 cc) and then dried over sodium sulfate. The volatile products are evaporated under reduced pressure (20 mm Hg) and a mixture of 1-(2-acetoxypropyl)-2-methyl-4-nltrolmidazole and 1-(2-acetoxypropyl)-2-methyl-5-nitroimidazole (18.6 g) is obtained in the form of a red oil. 

Chemical Name 1-[2-(ethylsulfonyl)ethyl] -2-methyl-5-nitroimidazole Common Name —... 

Ethyl sulfonyl ethanol p-Toluenesulfonyl chloride 2-Methyl-5-nitroimidazole... 

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