Abstract:
2-Nitroimidazole derivatives of the general formula ##SPC1## 
     Wherein R is a lower alkyl group and Y is a member of the group consisting of --CH 2  OH, --CHO, CH 3  CO--, vinyl, formylvinyl, styryl, substituted iminomethyl, 2-benzimidazolyl and 5-amino-1,3,4-thiadiazol-2-yl. The term &#34;lower alkyl&#34; designates aliphatic groups of from 1 to 4 carbon atoms; the term &#34;substituted iminomethyl&#34; designates nitrogen-containing functional derivatives of the aldehydic group. The compounds have antimicrobial activity.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This is a division of application Ser. No. 275,415, filed July 26, 1972, now U.S. Pat. No. 3,954,789. 
    
    
     SUMMARY OF THE INVENTION 
     The present invention relates to 2-nitroimidazole derivatives and methods for their preparation. More particularly, the invention relates to 2-nitroimidazole derivatives of general formula ##SPC2## 
     Wherein R is a lower alkyl group and Y is a member of the group consisting of --CH 2  OH, --CHO, CH 3  CO--, vinyl, formylvinyl, styryl, substituted iminomethyl, 2-benzimidazolyl and 5-amino-1,3,4-thiadiazol-2-yl. The term &#34;lower alkyl&#34; designates aliphatic groups having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl and butyl. The term &#34;substituted iminomethyl&#34; refers to imino functional derivatives of the aldehydic group such as, for example, the following derivatives of 1-lower alkyl-2-nitro-5-imidazolaldehyde: hydrazones, mono- and di-alkylhydrazones, aralkylhydrazones, cycloalkylhydrazones, mono- and di-arylhydrazones, hydroxyalkylhydrazones, acylhydrazones, semicarbazones, thiosemicarbazones, guanylhydrazones, oximes, substituted oximes, nitrones, aldazines, Schiff&#39;s bases, or substituted hydrazones in which the second nitrogen atom is a part of a 5 to 7 membered heterocyclic ring, which may also contain other heteroatoms selected from N, O and S. The term &#34;lower acyl&#34; refers to acyl groups having from 2 to 4 carbon atoms. The present invention also relates to methods of preparation of the new 2-nitroimidazoles, as described below. 
     In general, the growth-inhibiting activity of the previously known nitroimidazoles was essentially limited to the protozoa, their activity against bacteria and fungi being quite poor. It has now been found surprisingly that the compounds of this invention possess a broad spectrum growth inhibiting activity twoard gram-positive and gram-negative bacteria, fungi and protozoa. Particularly, their inhibitory activity against Clostridium perfringens, Salmonella typhi, Pseudomonas aeruginosa, Diplococcus pneumoniae, Streptococcus hemolyticus, E. coli and Mycobacterium tuberculosis is noteworthy. In fact, it has been found that concentrations varying from about 0.5 to about 20γ /ml. inhibit growth of these microorganisms in vitro. The compounds are active in the presence of bovine serum. In representative experiments, compounds of the general formula (I) such as, for instance, those described in Examples 1, 2, 3, 4, 6, 14 and 49 were found to be active also in the animals. Doses varying from about 50 to about 200 mg/kg p.o. are effective against experimental infection in mice from Salmonella typhi, E. Coli and Diplococcus pneumoniae. The compound of Example 60 was found to be active in mice infected with Trichomonas vaginalis at a dose of about 30 mg/kg p.o. The biological activity of the compounds is coupled with a low toxicity, since the LD 50  per os in mice is generally higher than 500 mg/kg. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The compounds of the invention are prepared by mixing a 1-lower alkyl-5-(2-chloroethyl)-2-nitroimidazole with a strong base such as, for example, an alkali metal hydroxide, a tertiary amine, an alkali metal lower alkoxide or an alkali metal amide in an inert organic solvent to obtain the corresponding 1-lower alkyl-5-vinyl-2-nitroimidazole. Other substituted 5-vinyl derivatives may be used as starting materials. Thus, for example, vinyl derivatives which are prepared by condensation of a 1-lower alkyl-5-methyl-2-nitroimidazole with an aliphatic, aromatic or heterocyclic aldehyde, in the presence of a strong base may be suitably utilized. 
     By oxidizing these vinyl compounds with potassium permanganate in a neutral solution or with osmium tetroxide, the corresponding 5-(1,2-dihydroxyethyl)substituted compounds are obtained, which in turn may be converted into aldehydes by a subsequent oxidizing treatment. Suitable oxidizing agents for this latter step are sodium periodate and lead tetraacetate. The following typical scheme wherein X may be hydrogen, an alkyl, aryl or a heterocyclic moiety, illustrates such a process: ##SPC3## 
     Alternatively, a 5-vinyl derivative of a 2-nitroimidazole may be directly oxidized to the corresponding aldehyde by treating it with sodium periodate in the presence of osmium tetroxide. 
     The derivatives wherein Y represents a CH 2  OH group may be obtained by reduction of the corresponding aldehyde with a metal hydride such as, for example, calcium borohydride or sodium borohydride. 
     Compounds in which Y is CH 3  CO are obtained by treating the corresponding derivative in which Y is a CHO group with diazomethane in ethyl ether solution. 
     Another method for preparing a 2-nitroimidazolaldehyde of the present invention consists in the reduction with a mixed metal hydride of the carbalkoxy group of a 1-lower alkyl-5-carbalkoxy-2-nitroimidazole to give the corresponding alcohol. The alcoholic function is then oxidized to a 1-lower alkyl-2-nitro-5-imidazolaldehyde by oxidation with an agent selected from the group consisting of chromic acid, chromic anhydride and pyridine, manganese dioxide, lead tetraacetate or ceric salts. 
     The starting 1-lower alkyl-5-carbalkoxy-2-nitroimidazoles are obtained according to known procedures, using as the starting compounds cyanamide and an α-alkylaminoacetals containing a carbalkoxy group in a suitable position. Thus, for example, using α-methylamino-α -carbethoxyacetaldehyde diethylacetal and cyanamide, 2-amino-5-carbethoxy-1-methylimidazole is obtained, which is further transformed into the corresponding 2-nitro derivative by treatment with NaNO 2  according to the method of U.S. Pat. No. 3,420,842. 
     The compound of formula (I) wherein Y is a formylvinyl group are prepared from the nitroimidazole aldehydes by condensation with acetaldehyde in the presence of a basic catalyst such as an alkali hydroxide or an alkali metal alkoxide. 
     The method for preparing compounds wherein Y is a substituted iminomethyl group comprises treating a 1-lower alkyl-2-nitro-5-imidazolealdehyde with a suitable nitrogen-containing reactant of the carbonyl group such as amines, hydrazines and hydroxylamines or their acid salts in the presence of a solvent. The reaction is generally carried out at a temperature ranging between room temperature and the boiling point of the solvent. The solvent is advantageously selected from the lower alkanols, water and their mixtures. The proportions of the two reagents is not critical. Advantageously they are used in substantially equimolecular proportions of aldehyde and nitrogen compound, the proportions in which they react. If the nitrogen-containing reagent is employed in the form of a salt with an acid, the presence of at least one equimolecular amount of an acid acceptor is required. 
     The compounds wherein Y is a 2-benzimidazole radical are prepared by reaction of a selected nitroimidazolaldehyde with o-phenylenediamine, followed by a subsequent treatment with lead tetraacetate or other equivalent oxidizing agent such as, for example, atmospheric oxygen, mercuric oxide, manganese dioxide, potassium ferricyanide, a cupric salt and the like. 
     The compounds wherein Y is a 5-amino-1,3,4-thiadiazol-2-yl radical are prepared by oxidizing a thiosemicarbazone of a 1-lower alkyl-2-nitro-5-imidazolaldehyde with a ferric salt such as, for example, ferric chloride, calcium ferricyanide or ferric ammonium sulfate. 
    
    
     The following non-limitative examples illustrate the preparation of representative compounds falling within the scope of the present invention. 
     EXAMPLE 1: α-(1-Methyl-2-nitroimidazole-5-yl)-N-methylnitrone 
     A mixture of 0.250 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde, 0.150 g. of N-methylhydroxylamine hydrochloride and 0.150 g. of sodium bicarbonate is refluxed in 80 ml. of anhydrous ethanol for 2 hours and after filtration is concentrated to small volume. The title compound crystallizes on cooling. Yield: 0.24 g, m.p. 208°-209° C. 
     EXAMPLES 2 - 11 
     Pursuant to the procedure of Example 1, an N-substituted hydroxylamine or its acid salt is reacted with a specified 1-lower alkyl-2-nitro-5-imidazolecarboxaldehyde to give the following nitrones. When an acid salt is employed, sodium bicarbonate, potassium acetate or triethylamine are added as acid acceptors. Melting points are in centigrade degrees. 
     2. α-(1-methyl-2-nitroimidazole-5-yl)-N-ethylnitrone, m.p. 138°-139°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-ethylhydroxylamine hydrochloride 
     3. α-(1-methyl-2-nitroimidazole-5-yl)-N-n-propylnitrone, m.p. 124°-126°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-(n-propyl)hydroxylamine hydrochloride 
     4. α-(1-methyl-2-nitroimidazole-5-yl)-N-isopropylnitrone, m.p. 125°-127°, by reacting 1-methyl-2-nitroimidazolecarboxaldehyde with N-isopropylhydroxylamine hydrochloride 
     5. α-(1-methyl-2-nitroimidazole-5-yl)-N-(2-hydroxyethyl)nitrone, m.p. 210°-211°, by reacting 1-methyl-2-nitroimidazolecarboxaldehyde with N-(2-hydroxyethyl)hydroxylamine hydrochloride 
     6. α-(1-methyl-2-nitroimidazole-5-yl)-N-(2-hydroxypropyl)nitrone, m.p. 160°-161°, by reacting 1 -methyl-2-nitro-5-imidazolecarboxaldehyde with N-(2-hydroxypropyl)hydroxylamine hydrochloride 
     7. α-(1-methyl-2-nitroimidazole-5-yl)-N-phenylnitrone, m.p. 191°-192°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-phenylhydroxylamine hydrochloride. 
     8. α-(1-methyl-2-nitroimidazole-5-yl)-N-cyclohexylnitrone, m.p. 122°-123°, prepared by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-cyclohexylhydroxylamine hydrochloride 
     9. α-(1-methyl-2-nitroimidazole-5-yl)-N-(p-chlorophenyl)nitrone, m.p. 195°-197°, prepared by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-(p-chlorophenyl)hydroxylamine hydrochloride 
     10. α-(1-ethyl-2-nitroimidazole-5-yl)-N-methylnitrone, m.p. 162°-163°, prepared by reacting 1-ethyl-2-nitro-5-imidazolecarboxaldehyde with N-methylhydroxylamine hydrochloride 
     11. α-(1-ethyl-2-nitroimidazole-5-yl)-N-(2-hydroxypropyl)nitrone, m.p. 125°-128°, prepared by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with N-(2-hydroxypropyl)hydroxylamine hydrochloride 
     EXAMPLE 12: 1-Methyl-2-nitro-5-imidazolcarboxaldehyde oxime 
     To a solution of 0.400 g. of hydroxylamine hydrochloride in 15 ml. of methanol, 0.400 g. of 1-methyl-2-nitro-5-imidazolcarboxaldehyde in 20 ml. of ethanol and 0.810 ml. of triethylamine are added at room temperature. After standing overnight, the solution is concentrated to a small volume and the solid which precipitates is collected on the filter. After crystallization from water, 0.10 g. of the title compound is obtained which melts at 203°-205° C. 
     EXAMPLE 13: 1-Methyl-2-nitro-5-imidazolcarboxaldehyde 0-decyloxime 
     To a solution of 0.3 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 74 ml. of methanol, 0.335 g. of 0-decylhydroxylamine is added. After standing overnight the title compound is recovered by filtration. Yield: 0.228 g., m.p. 70° C. 
     EXAMPLE 14: 1-Methyl-2-nitro-5-imidazolecarboxaldehyde thiosemicarbazone 
     A solution of 1.42 g. of thiosemicarbazide in water is added to a solution of 1.8 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in methanol. The solid which precipitates is recovered on the filter. Yield: 2.2 g., m.p. 282°-287° C. 
     EXAMPLE 15: 1-Ethyl-2-nitro-5-imidazolecarboxaldehyde thiosemicarbazone 
     The title compound is prepared by reacting 1-ethyl-2-nitro-5-imidazolealdehydecarboxaldehyde with thiosemicarbazide accordinng to the procedure of the previous example. M.p. 220°-22° C. 
     EXAMPLE 16: 1-Methyl-5-[1-(2-hydroxyethyl)-5-ethyl-2-imidazolyl]iminomethyl-2-nitroimidazole 
     To a solution of 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde dissolved in 25 ml. of ethanol, 0.494 g. of 1-(2-hydroxyethyl)-2-amino-5-ethylimidazole hydrochloride and 0.175 ml. of sodium ethoxide in 2.89 ml. of ethanol are added. After standing overnight, the solid which precipitates is collected on the filter and washed with water. Yield: 0.269 g., m.p. 185°-187° C. 
     EXAMPLE 17: 1-Methyl-2-nitro-5-imidazolecarboxaldehyde-2-hydroxyethylhydrazone 
     A solution of 0.300 g. of 2-hydroxyethylhydrazine and 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 20 ml. of methanol is allowed to stand for two days. The solid which precipitates is recovered on the filter and washed with water. Yield: 0.245 g., m.p. 138°-140° C. 
     EXAMPLES 18 - 48 
     By reacting a 1-lower alkyl-2-nitro-5-imidazolecarboxaldehyde with an amino compound having a free NH 2  group, as characterized below or its acid salt in the presence of an acid acceptor such as, for example, an alkali metal acetate, alkali metal bicarbonate, alkali metal carbonate, alkali metal hydroxide, alkali metal alkoxide, triethylamine, pyridine or the like, similarly to the procedure of Example 17, the following compounds are obtained. Their melting points are in centigrade degrees. 
     18. 1-methyl-2-nitro-5-imidazolecarboxaldehyde dimethylhydrazone, m.p. 133°-134°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with dimethyl hydrazine 
     19. 1-ethyl-2-nitro-5-imidazolecarboxaldehyde dimethylhydrazone, m.p. 80°-82°, by reacting 1-ethyl-2-nitro-5-imidazolecarboxaldehyde with dimethyl hydrazine 
     20. 1-methyl-2-nitro-5-imidazolecarboxaldehyde phenylhydrazone, m.p. 220°-221°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with phenyl hydrazine 
     21. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 2,4-dinitrophenylhydrazone m.p. 276°-279°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 2,4-dinitrophenyl hydrazine 
     22. 1-ethyl-2-nitro-5-imidazolecarboxaldehyde 2,4-dinitrophenylhydrazone, m.p. 215°-216°, by reacting 1-ethyl-2-nitro-5-imidazolecarboxaldehyde with 2,4-dinitrophenyl hydrazine 
     23. 1-methyl-2-nitro-5-imidazolecarboxaldehyde cyclopentylhydrazone, m.p. 135°-136°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with cyclopentylhydrazine 
     24. 1-ethyl-2-nitro-5-imidazolecarboxaldehyde 2-hydroxyethylhydrazone, m.p. 120°-121°, by reacting 1-ethyl-2-nitro-5-imidazolecarboxaldehyde with 2-hydroxyethylhydrazine 
     25. 1-methyl-2-nitro-5-imidazolecarboxaldehyde acetylhydrazone, m.p. 224°-226°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with acetyl hydrazine 
     26. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (cyanoacetyl)hydrazone, m.p. 232°-233°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with (cyanoacetyl)hydrazine 
     27. 1-methyl-2-nitro-5-imidazolecarboxaldehyde ((trimethylammonio)acetyl)hydrazone chloride, m.p. 241°-242°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with ((trimethylammonio)acetyl)hydrazine chloride 
     28. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (pyridinioacetyl)hydrazone chloride, m.p. 270°-271°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with (pyridinioacetyl)hydrazine chloride 
     29. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 4-pyridylcarbonylhydrazone, m.p. 257°-258°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 4-pyridylcarbonylhydrazine 
     30. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone, m.p. 223°-224°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with hydrazine 
     31. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-nitrofurfurylidenehydrazone, m.p. 247°-248°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 5-nitrofurfurylidenehydrazine 
     32. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-4-methyl-piperazine m.p. 165°-167°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 1-amino-4-methyl-piperazine 
     33. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-4-benzylpiperazine, m.p. 165°-168°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 1-amino-4-benzylpiperazine 
     34. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-3-hydroxypiperidine, m.p. 152°-153°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 1-amino-3-hydroxypiperidine 
     35. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-tetrahydro-1,4-thiazine S-dioxide, m.p. 177°-179°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 1-amino-tetrahydro-1,4-thiazine S-dioxide 
     36. 1-methyl-2-nitro-5-imidazolecarboxaldehyde carbamylhydrazone, m.p. 245°-246°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with carbamylhydrazine 
     37. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-(2-hydroxyethyl)oxime, m.p. 95°-97°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 0-(2-hydroxyethyl)hydroxylamine 
     38. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-hydantoin, m.p. 273°-274°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 1-amino-hydantoin 
     39. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 3-amino-5-(diethylaminomethyl)-2-oxazolidinone, m.p. 189°-190°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 3-amino-5-(diethylaminomethyl)-2-oxazolidinone 
     40. 1-methyl-2-nitro-5-imidazolecarboxaldehyde p-hydroxyphenethylhydrazone, m.p. 221°-222°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with p-hydroxyphenethylhydrazine 
     41. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 2,4,6-trichlorophenylhydrazone, m.p. 218°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 2,4,6-trichlorophenylhydrazine 
     42. 1-methyl-2-nitro-5-imidazolecarboxaldehyde dodecylhydrazone, m.p. 122°-124°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with dodecylhydrazine 
     43. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 4-allylthiosemicarbazone, m.p. 217°-218°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 4-allylthiosemicarbazide 
     44. 1-methyl-2-nitro-5-imidazolecarboxaldehyde p-(2-chloro-1,1,2-trifluoroethylsulfonyl)phenylhydrazone, m.p. 190°-193°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with p-(2-chloro-1,1,2-trifluoroethylsulfonyl)phenylhydrazine 
     45. 1-methyl-2-nitro-5-imidazolecarboxaldehyde p-fluorophenylhydrazone, m.p. 221°-222°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with p-fluorophenylhydrazine 
     46. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(2-chloroethyl)-1-n-propyl-2-imidazolylimine, m.p. 131°-132°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 2-amino-5-(2-chloroethyl)-1-n-propyl-2-imidazolylimine 
     47. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 1,5-dimethyl-2-imidazolylimine, m.p. 225°-227°, by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 2-amino-1,5-dimethyl-2-imidazolylamine 
     48. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(3,4-dichlorophenyl)-2-imidazolylimine, m.p. 247°(-dec.), by reacting 1-methyl-2-nitro-5-imidazolecarboxaldehyde with 2-amino-5-(3,4-dichlorophenyl)-2-imidazolylamine 
     Pursuant to the procedures described in foregoing examples, many other compounds of formula (I) may be prepared, of which the following are representative. 
     a. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-(2-phenoxyethyl)oxime 
     b. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-(2-methoxyethyl)oxime 
     c. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-(2-(2-ethoxyethoxy)ethyl)oxime 
     d. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-(2-butoxyethyl)oxime 
     e. 1-ethyl-2-nitro-5-imidazolecarboxaldehyde 0-(7-phenoxyheptyl)oxime 
     f. 1-propyl-2-nitro-5-imidazolecarboxaldehyde thiosemicarbazone 
     g. 1-isopropyl-2-nitro-5-imidazolecarboxaldehyde methylnitrone 
     h. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (2-ethoxyethyl)nitrone 
     i. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(p-chlorophenyl)-2-imidazolylimine 
     j. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(p-fluorophenyl)-2-imidazolylimine 
     k. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 2-(carbethoxyethyl)nitrone 
     l. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 2-(acetoxyethyl)nitrone 
     m. 1-ethyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-amino-4-methylpiperazine 
     n. 1-methyl-2-nitro-5-imidazolecarboxaldehyde hydrazone of 1-aminopiperazine 
     o. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(4-biphenylyl)-2-imidazolylimine 
     p. 1-butyl-2-nitro-5-imidazolecarboxaldehyde ethylnitrone 
     q. 1-methyl-2-nitro-5-imidazolecarboxaldehyde allylnitrone 
     r. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 0-cyclopentyloxime 
     s. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (p-methoxyphenyl)nitrone 
     t. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (3,4-dichlorophenyl)nitrone 
     u. 1-methyl-2-nitro-5-imidazolecarboxaldehyde (2-methoxyethyl)nitrone 
     v. 1-methyl-2-nitro-5-imidazolecarboxaldehyde 5-(2-naphthyl)-2-imidazolylimine 
     EXAMPLE 49: 2-Amino-5-(1-methyl-2-nitro-5-imidazolyl)-1,3,4-thiadiazole 
     2 Grams of 1-methyl-2-nitro-5-imidazolecarboxaldehyde thiosemicarbazone are added to a solution of 17.1 g. of FeNH 4  (SO 4 ) 2 . 12H 2  O in 35 ml. of water. The mixture is stirred at 80°-90° C. for 2 hours, and, after cooling, the solid product is collected on the filter and washed with water. The crude compound is crystallized from a mixture of methanol and dimethylformamide. Yield 0.95 g. (48%), m.p. 263°-265° C. 
     EXAMPLE 50: 5-(2-Benzylidimidazolyl)-1-methyl-2-nitroimidazole 
     A solution of 0.5 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde and 0.348 g. of o-phenylenediamine in 10 ml. of ethanol is refluxed for two hours. The solid which precipitates is collected on the filter, washed with ethanol and dissolved in 10 ml. of acetic acid with the addition of 0.750 g. of Pb(CH 3  COO) 4 . The mixture is heated for 20 minutes at about 50° C., then cooled and diluted with 50 ml. of water. The resulting precipitate is collected on the filter and recrystallized from acetone, giving 0.15 g. of the title compound, m.p. 268°-270° C. 
     EXAMPLE 51: 1-Methyl-2-nitro-5-vinylimidazole 
     To a solution of 18.9 g. of 5-(2-chloroethyl)-1-methyl-2-nitroimidazole (prepared according to the procedure of British Patent 1,222,486) in 2.8 liters of anhydrous benzene cooled to 5°-10° C., 16.8 g. of potassium tert-butoxide is added. Stirring is continued for 2 hours at 5°-10° C. After filtration and concentration to dryness under vacuum at a temperature lower than 50° C., the resulting yellow oily residue is washed 3 times with 50 ml. of ethyl ether (or light petroleum). The title product is obtained, which is dried under vacuum at 40° C.; yield 12 g. (77.7%). A sample crystallized from ethyl ether melts at 106°-108° C. 
     EXAMPLE 52: 1-Methyl-2-nitro-5-(1,2-dihydroxyethyl)imidazole 
     To a solution of 6.2 g. of 1-methyl-2-nitro-5-vinylimidazole in 570 ml. of ethanol cooled to about -10° C., a solution of 5.46 g. of KMnO 4  and 8.85 g. of MgSO 4 .7H 2  O in 750 ml. of H 2  O is added with stirring. The reaction mixture is filtered through Celite and washed with ethanol. The filtrate is concentrated to dryness under vacuum at 50° C., and the residue is taken up with acetone. The resulting solution is filtered and concentrated to dryness under vacuum. The resulting solid is crystallized from methyl ethyl ketone. Yield 3.15 g. (41.6%), m.p. 119°-121° C. 
     EXAMPLE 53: 1-Methyl-2-nitro-5-imidazolecarboxaldehyde 
     To a solution of 3.15 g. of 1-methyl-2-nitro-5-(1,2-dihydroxyethyl)imidazole in 200 ml. of methanol, a solution of 3.6 g. of NaIO 4  in 85 ml. of water is added with stirring. The precipitate which forms is filtered off and washed with methanol which is then added to the filtrate. By evaporation to dryness under vacuum a residue is obtained which is extracted several times with ethyl acetate. After concentration of the collected extracts, a crystalline product is obtained, which after recrystallization from ethyl acetate melts at 114°-115° C. Yield 2.5 g. (96%). 
     EXAMPLE 54: 1-Methyl-2-nitro-5-imidazolaldehyde 
     To a solution of 0.67 g. of 1-methyl-2-nitro-5-vinylimidazole in 20 ml. of 1,2-dimethoxyethane, a solution of 2 g. of NaIO 4  in 5 ml. of water, followed by 0.025 g. of OsO 4  is added with stirring at room temperature. After stirring for four hours, the mixture is allowed to stand overnight. The residue which is obtained by evaporation of the reaction medium to dryness under vacuum is extracted with ethyl acetate. The resulting solution after filtering is concentrated, yielding 0.43 g. of a product which, after crystallization from ethyl acetate, melts at 114°-115° C. Yield 63%. 
     EXAMPLE 55: 1-Methyl-2-nitro-5-styrylimidazole 
     A mixture of 7.2 g. of 1,5-dimethyl-2-nitroimidazole, 41.2 ml. of benzaldehyde and 7.9 g. of potassium dazole, tert-butoxide in 300 ml. of ethanol is refluxed for 35 minutes under nitrogen. The residue, which is obtained by evaporation of the reaction mixture under vacuum, is extracted with ethyl ether and filtered. The ethyl ether solution after concentration yields an oily residue which is chromatographed through 300 g. of silica gel by eluting with chloroform. After evaporation of the solvent under vacuum at 40° C., an oily residue is obtained which crystallizes on standing. After washing with a small amount of methyl ethyl ketone, 1.9 g. (16%) of a product which melts at 170°-180° C. is obtained. 
     EXAMPLE 56: 1-Methyl-2-nitro-5-imidazolaldehyde 
     To a solution of 0.8 g. of 1-methyl-2-nitro-5-styrylimidazole in 300 ml. of methanol, a solution of 1.6 g. of NaIO 4  in 40 ml. of water, and 0.02 g. of OsO 4  are added. The mixture is stirred at room temperature for ten hours, then an additional 0.01 g. of OsO 4  is added and stirring is carried on for eight hours. The reaction mixture is filtered and evaporated to dryness under vacuum at room temperature. The residue is extracted with ethyl acetate. After concentration of the resulting solution, 0.325 g. of the product are obtained. Yield 60%. 
     EXAMPLE 57: 1-Methyl-2-nitro-5-hydroxymethylimidazole 
     To a solution of 1.55 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 200 ml. of ethanol, a solution of 1.9 g. of NaBH 4  in 150 ml. of ethanol is added at about -4° C. After stirring for 15 minutes at 0° C., the excess of NaBH 4  is decomposed with 10% hydrochloric acid and the reaction mixture is filtered. The residue, which is obtained by evaporation of the filtrate, is crystallized from acetone and yield 1 g. of the title product which melts at 142°-144° C. 
     EXAMPLE 58: 2-Amino-5-carbethoxy-1-methylimidazole hydrochloride 
     Following the method described in U.S. Pat. No. 3,450,709 and starting from 10 g. of α-methylamino-α-carbethoxyacetaldehyde diethylacetal and 5.2 g. of cyanamide, 5.8 g. (62%) of 2-amino-5-carbethoxy-1-methylimidazole hydrochloride are obtained, which melts at 209°-211° C. after crystallization from isopropyl alcohol. 
     EXAMPLE 59: 5-Carbethoxy-1-methyl-2-nitroimidazole 
     Pursuant to the method described in U.S. Pat. No. 3,420,842 and starting from 6.8 g. of the product of the Example 58, 1.8 g. (27%) of 5-carbethoxy-1-methyl-2-nitroimidazole is obtained, which melts at 65°-66° C. after crystallization from hexane. 
     EXAMPLE 60: 1-Methyl-2-nitro-5-hydroxymethylimidazole 
     To 0.2 g. of 5-carbethoxy-1-methyl-2-nitroimidazole in 30 ml. of tetrahydrofuran, 0.044 g. of LiBH 4  is gradually added under stirring at room temperature. After stirring for 48 hours, the excess of LiBH 4  is decomposed with 10% hydrochloric acid, the reaction mixture is filtered and the filtrated is evaporated to dryness under vacuum. The residue is taken up with acetone. Inorganic salts are filtered off and the solution is evaporated. The oily residue is chromatographed through 7 g. of silica gel, by eluting with chloroform containing from 1% to 3% (v/v) of methanol. After concentration of the portions containing the product, 0.052 g. (33%) of 1-methyl-2-nitro-5-hydroxymethylimidazole is obtained. 
     EXAMPLE 61: 1-Methyl-2-nitro-5-imidazolaldehyde 
     To a solution of 0.15 g. of 1-methyl-2-nitro-5-hydroxymethylimidazole in 20 ml. of benzene, 0.33 g. of MnO 2  is added and the reaction mixture is heated on the steambath for two hours. After filtration and evaporation to dryness under vacuum, the crude product is crystallized from ethyl acetate and 0.060 g. (40.5%) of 1-methyl-2-nitro-5-imidazolaldehyde is obtained. 
     EXAMPLE 62: 5-Acetyl-1-methyl-2-nitroimidazole 
     To a solution of 0.70 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 180 ml. of diethyl ether, a solution of 0.43 g. of diazomethane in 86 ml. of diethyl ether is added under cooling at about 0° C. After standing at room temperature for 7 days, the reaction mixture is filtered and then evaporated to dryness. The residue (0.60 g.), dissolved in 6 ml. of chloroform, is chromatographed on 6 plates of silica gel, eluting with a 9:1 (v/v) chloroform:methanol mixture, and TLC spots are visualized under U.V. light. The silica gel, which corresponds to an Rf value from 0.64 up to 0.76 is collected and extracted with methanol. From this solution, after filtration and concentration, 0.065 g. of 5-acetyl-1-methyl-2-nitroimidazole is obtained, m.p. 81°-83° C. 
     EXAMPLE 63: 1-Ethyl-2-nitro-5-vinylimidazole 
     Pursuant to the same procedure described in Example 51, and using as starting material 2.2 g. of 5-(2-chloroethyl)-1-ethyl-2-nitroimidazole (prepared according to the method of British Patent 1,222,486), 1.5 g. of the title compound is obtained, m.p. 45°-47° C. 
     EXAMPLE 64: 1-Ethyl-2-nitro-5-imidazolaldehyde 
     Following the same procedure described in Example 54 and using as a starting material 1.35 g. of 1-ethyl-2-nitro-5-imidazolaldehyde is obtained, m.p. 38°-40° C. 
     EXAMPLE 65: 1-Methyl-2-nitro-5-imidazoleacrolein 
     To a suspension of 1.5 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 4.5 g. of acetaldehyde, 0.2 ml. of 25% KOH methanol solution is added at room temperature. Then 3 ml. of acetic anhydride is added and the mixture is refluxed for 20 minutes. After cooling, 9 ml. of water and 1.5 ml. of concentrated HCl acid are added to the mixture which is further refluxed for 30 minutes. Evaporation to dryness gives a residue which is taken up with hot ethyl acetate. The hot solution is filtered and the filtrate is concentrated in vacuo. The title compound crystallizes out on cooling. Yield 0.2 g., m.p. 165°-168° C. 
     EXAMPLE 66: 1-Ethyl-2-nitro-5-styrylimidazole 
     By reacting 0.33 g. of 1-ethyl-5-methyl-2-nitroimidazole with benzaldehyde according to the procedure of Example 55, 0.030 g. of 1-ethyl-2-nitro-5-styrylimidazole is obtained, m.p. 154°-156° C.