GB1560078A - 1-methyl 2-(phenyl - oxymethyl) - 5 - nitro - imidazole and process for their manufacture - Google Patents
1-methyl 2-(phenyl - oxymethyl) - 5 - nitro - imidazole and process for their manufacture Download PDFInfo
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- GB1560078A GB1560078A GB4395976A GB4395976A GB1560078A GB 1560078 A GB1560078 A GB 1560078A GB 4395976 A GB4395976 A GB 4395976A GB 4395976 A GB4395976 A GB 4395976A GB 1560078 A GB1560078 A GB 1560078A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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Description
(54) 1-METHYL-2-(PHENYL-OXYMETHYL)-5-NITRO
IMIDAZOLES AND PROCESS FOR THEIR
MANUFACTURE
(71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Franifurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to 1-methyl-2-(phenyloxymethyl)-5-nitro-imidazoles and to processes for preparing them.
1-(2-Hydroxyethyl)-2-methyl-5-nitro-imidazole (Metronidazol) is used for the treatment of piotozoal diseases, such as trichomoniasis and amoebiasis.
The present invention provides 1-methyl-2-(phenyloxymethyl)-5-nitro-imidazoles) of the formula I
in which each of R1, R2 and R is hydrogen, a straightshain or branched alkyl group having from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl and isobutyl, or R1 and R2, together with the intermediate nitrogen and carbon atoms, form a pyrrolidine, piperidine or hexamethylene-imine ring, or in which R2 and R3, together with the intermediate nitrogen atom, form a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, as well as acid addition salts of these compounds a), especially physiologically tolerable acid addition salts.
The present invention also provides a process for the preparation of l-methyS2- (phenyl-oxymethyl)-5-nitroimidazoles of the formula (I) which comprises reacting at a temperature of from 0 to 100 C either
(A) 1 - methyl - 2 - (4 - amlnophenyl - oxymethyl) - 5 - nitroiniidazole of the
formula II
with either:
(a) a carboxylic acid amide, a carboxylic acid thioamide, a lactam or a
thiolactam of the formula III
in which Z is oxygen or sulfur, and R, R and R3 have the meanings
specified above, in the presence of a condensing agent, or (b) an acetal of a carboxylic acid amide or of a lactam of the formula IV
in which R1, R2, R have the meanings specified above, and R4 is a
methyl or ethyl group; or (B) a 1-methyl-2-halomethyl-5-nitro-imidazole of the formula V
in which X is a halogen atom, such as fluorine, chlorine, bromine or iodine, or an acyloxy group, such as acetyloxy, propionyloxy, butyryloxy, benzoyloxy, nitrobenzoyloxy or toloyloxy, or an aryl-sulfonyloxy group, such as benzoylsulfonyloxy, toluene-sulfonyloxy or nitrobenzene-sulfonyloxy, with a 4 amidinophenol or an alkali metal or anononium salt thereof of the formula
VI
in which Y is hydrogen, an alkali metal, especially sodium or potassium, or ammonium.
The starting compounds of the formula II may be prepared by reacting a 1methyl-2-chloromethyl-5-nitro-imidazole of the formula V with a 4-acylaminophenol or an alkali metal salt thereof and by saponifying the condensation product formed to give the free amine.
The starting compounds of the formula V may be prepared by reacting 1-methyl2-hydroxymethyl-5-nitro-imidazole with a corresponding acid chloride.
The saarting compounds of the formula VI may be prepared by reacting 4-aminophenol with a carboxylic acid amide of the formula m.
As starting compounds of the formula III there may be mentioned, for example, formamide, thioformamide, N-methyl-, N-ethyl-, N-propyl-, N-isopropyl-, N-butyl-,
N-isobutyl, N,N-dimethyl-, N,N-diethyl-, N,N-dipropyl-, N,N,-diisopropyl-, N,N-dibutyl- and N,N-diisobutylformamides, and the corresponding N-monosubstituted and
N,N-disubstituted thioformamides, acetamides, thioacetamides, propionamides, thiopropionamides, butyramides, thiobutyramides, valeramides, and thiovaleramides, and
N-formyl-, N-acetyl-, N-propionyl-, N-butyryl- and N-valeryl-pyrrolidines and the corresponding N-substitured piperidines, morpholines and thiomorpholines.
As further starting compounds of the formula III there may be mentioned, for example, butyrolactam (pyrrolidone-2), valerolactam (piperidone-2) and caprolactam (2-oxohexamethyleneimine), butyro-, valero- and caprothiolactams, and the corresponding N-methyl-, N-ethyl-, N-propyl and N-butyl-lactams and thiolactams.
As starting compounds of the formula IV there may be mentioned, for example, the dimethyl and diethyl acetals of formamide, N-methyl-, N-ethyl-, N-propyl-, N-isopropyl-, N-butyl-, N-isobutyl-, N,N-dimethyl-, N,N-diethyl-, N,N-dipropyl-, N,Ndiisopropyl-, N,N-dibutyl-, and N,N-diisobutylformamides and of the corresponding acetamides, propionamides, butyramides and valeramides, the dimethyl and diethyl acetals of N4onnyl-, N-acetyl-, N-propionyl-, N-butyryl- and N-valerylpyrrolidines, and of the corresponding piperidines, morpholines and thiomorpholines, and the dimethyl and diethyl acetals of butyrolactam (pyrrolidone-2), valerolactam (piperidone2) and caprolactam (2-oxohexamethylene-imine), and of the corresponding thiolactams, and of the corresponding N-methyl-, Nethyl-, N-propyl- and N-butyl lactams and thiolactams.
As string compounds of the formula V there may be mentioned, for example,
1-methyl-2-chloromethyl-5-nitroimidazole and the corresponding 2-bromomethyl, 2iodomethyl, 2-acetyloxymethyl, 2-benzoyloxymethyl, 2-(4-nitrobenzoyloxy) methyl and 2-toluenesulfonyloxymethyl compounds.
As starting compounds of the formula VI there may be mentioned, for example 4"aminomethyleneiminophenol,
4-( l-aminoethylideneimino)-phenol,
6( 1 -aminopropylideneimino)-phenol, and the corresponding compounds which are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethyl, diethyl, di-n-propyl, diisopropyl, di-n-butyl and diisobutyl substituted on the amino nitrogen atom,
4-(pyrrolidin-1-ylmethyleneimino)-phenol,
4-(1-pyrrolidin-1-ylethylideneimino)-phenol,
4-(1-pyrrolidin-1-ylpropylideneimino)-phenol, and the corresponding piperidino, morpholino and thiamorpholino compounds, and
4-(pyrrolidin-2-ylideneimino)-phenol,
4-(piperidin-2-ylideneimino)-phenol,
4-(perhydroazepin-2-ylideneimino)-phenol, and the corresponding compounds which are 1-methyl, methyl, l-propyl and l-butyl substituted on the heterocyclic ring.
Each of the processes (A) and (B) is suitably carried out with equimolar amounts of the respective starting compounds. In the case of volatile reactants, however, the use of excess amounts is recommended. The reactions are advantageously carried out in a solvent or diluent, although certain reactions may be carried out without a solvent or diluent, as indicated below.
As solvents and diluents there may be mentioned, for example:
for the process (Aa), aromatic, optionally halogenated hydrocarbons, for example
benzene, toluene, xylene, chlorobenzene, dichlorobenzene and trichioro- benzene; chlorinated aliphatic hydrocarbons, for example methylene chloride
and chloroform; and aliphatic ethers, for example di-isopropylether, ethylene
glycol-dimethyl and iethylethersss diethylene-glycol-dimethylether, tetra
hydrofuran, and dioxane;
for the process (Ab) alcohols, for example methanol, ethanol, propanol, butanol, methoxyethanol, ethoxyethanol, or most advantageously, an excess of the
acetal of the carboxylic amide or of the lactam of the formula IV used for
the reaction;
for the process (B) alcohols, for example methanol, ethanol, propanol, isopropanol,
butanol, methoxyethanol and ethoxyethanol; ketones, for example acetone, methylethylketone and methylbutyl-ketone; amides, for example dimethyl
formamide, diethyfformamide, dimethylacetaamide, N-methylpyrrolidone,
tetramethylurea and hexamethylphosphoramide; and dimethylsulfoxide.
The reaction according to process (Aa) is carried out in the presence of a condensing agent The condensing agent is preferably an inorganic or organic acid halide, for example, thionylchloride, phosphorus trichloride, phosphorus pentachloride, phos phorusoxychioride, chlorosulfonic acid, phosgene, oxalychloride, a chloroformic acid alkylester, benzoylchloride, benzene-sulfonyl chloride or 4-toluene-sulfonyl chloride.
If a thioamide. and/or thiolactam is used as a starting material in process (Aa), the reaction is preferably carried out in the presence of a sulfur-binding agent, for
example, a heavy meal oxide such as mercury oxide or lead oxide.
The starting materials for process (Aa) are suitably reacted in equimolar amounts.
It may be advantageous, however, to use excess amounts of the carboxylic acid amides, thioamides, lactams and thiolactams, especially the amides and lactams the excess of which may be recovered during work-up of the reaction mixture.
In the process (B) the use of an acid-binding agent is recommended when the
starting material VI is a free phenol. As acid-binding agents, there are mentioned
organic bases, such as triethyl-amine and pyridine, and alkali metal and alkaline earth metal carbonates, bicarbonates, hydroxides and alkoxides, for example, methoxides, ethoxides, and butoxides.
For both processes (A) and (B), the reaction temperature is in the range of from
O to 100 C, preferably from 25 to 80 C Depending on the process and on the temperature in each case, the reaction times are in a range of from a few minutes to several hours.
The reaction products of process (Aa) are obtained in the form of their salts.
They may be isolated as such or may be converted into the free bases by rendering
the aqueous solutions thereof alkaline.
In order to render such solutions alkaline, use may be made of strong bases, suct as ammonia, sodium carbonate, potassium carbonate, sodium hydroxide, potassium
hydroxide, or the aqueous solutions thereof. The bases which are set free, and the free base products of processes (Ab) and (B) may be salified with appropriate acids, especially physiologically tolerable acids.
As physiologically tolerable acids there are mentioned for example, halogen hydracids, especially hydrochloric acid, and sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, and tartaric acid.
If necessary, the reaction products may be purified by recrystallization from a suitable solvent or solvent mixture.
The compounds of the formula I are physiologically tolerable and are suitable for the treatment of protozoal diseases in mammals, caused, for example, by infections with Trichomonas vaginalis and Entamoeba histolytica. They also exhibit a marked activity against helminths, ectoparasites and ticks.
The present invention therefore also provides pharmaceutical compositions comprising as active ingredient a compound of the formula I or a physiologically tolerable acid addition salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.
The present invention further provides a method for combating protozoa, helminths and ectoparasites in non-human mammals which comprises administering a compound of the formula I or a physiologically tolerable add addition salt thereof to the host mammal.
The pharmaceutical compositions may be in a form suitable for oral or local administration. Compositions for oral administration may be in the form of, for example tablets and capsules which suitably contain from 10 to 750 mg of active ingredient per daily dosage unit Compositions for local administration may be in the form of, for example jellies, creams, ointments and suppositories.
The following Examples illustrate the invention.
Examples of Preparation:
Process (Aa)
EXAMPLE 1
1.1) 1 - Methyl -2 - (4- dimethylamino - methylene - imino - phenyloxymethyl)
5 - nitro - imidazole
248 Grams (1 mole) of 1-methyl-2-(4-aminophenyloxymethyl)-5-nitro-imidazole were dissolved in 1250 nil of dimethylformamide. At a temperature of from 30 to 40 C, 154 g (1 mole) of phosphorus oxychloride were added dropwise, while stirring, to this mixture. Subsequently the reaction mixture was stirred for another 2 hours at 25 C The final product was precipitated, while stirring, in the form of a salt, by adding 2.5 1 of methylene chloride, it was then suction-filtered off, washed with methylene chloride, suction-dried, dissolved in water, rendered alkaline with aqueous concentrated ammonia, and the free base was extracted by shaking several times with methylene chloride. The combined extracts were dried over sodium sulfate, and were then evaporated, and the residue was recrystallized from alcohol, after being decolourized with charcoal. According to this method, 252 g (83% of the theory) of 1 - methyl 2 - (4 - dimethylamino - methylene - imino - phenyl - oxymethyl) - 5 - nitroimidazole were obtained in the form of yellow crystals having a melting point of 145 C.
From the free base, the hydrochloride having a melting point of 187 C and having the form of slightly yellowish crystals could be prepared according to common methods, by using molar amounts of alcoholic hydrochloric acid.
The 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitroimidazole (orange red crystals, m.p. 152 C) used as starting compound could be prepared by saponifying 1-methyl-2
(4-acetamidophenyl-oxymethyl)-5-nitro-imidazole with 40% sulfuric acid (2 hours, 80 to 90 C), in a yield of 85%.
The 1-methyl-2-(4-acetamidophenyl-oxymethyl)-5-nitro-imidazole (pale yellow crystals, m.p. 163 C) used for the preparation of the starting compound could be obtained by reacting molar amounts of 4-acetamidophenol with 1-methyl-2-chloro- methyl-5-nitro-imidazole in dimethylformamide (for 1 hour at 30 to 40 C), in the presence of potassium carbonate, in a yield of 95%.
The preparation of I-methyl-2-chloromethyl-5-nitro-idazole is described in German Offeulegungsschrift No. 1,595,929; it is effected by reacting the 1-methyl-2 hydroxymethyl compound with thionyl chloride.
It is also possible to use l-methyl-2-benzoyloxy-methyl-5-nitro-imidazole or 1methyl-2-(4-nitrobenzoyloxymethyl)-5-nitro-imidazole instead of 1-methyl-2-chloro- methyl-5-nitro-imidazole, the former compounds being obtained from the 1-methyl-2hydroxymethyl compound with benzoylchloride and/or 4nitrobenzoylchloride.
According to the process described in Example 1, the following compounds were
obtained: 1.2) From 1 - methyl - 2 - (4 - aminophenyl - oxymethyl) - 5 - nitro - imidazole
(APNI) and formamide, 1-methyl-2-(4-aminomethyleneimido-phenyl-oxy
methyl)-5-nitro-imidazole; 1.3) from APNI and N-methyieneformamide, 1 - methyl - 2 - (4 - methylamino
methyleneimino - phenyloxymethyl) - 5 - nitro - imidazole; 1.4) from APNI and N-ethylformnmide, 1 - methyl - 2 - (4 - ethylamino - methyl
eneimino - phenyloxymethyl) - 5 - nitro - imidazole; 1.5) from APNI and N-n-propylformamide, 1 - methyl - 2 - (4 - n - propylamino
methyleneimido-phenyloxymethyl)-5-nitro-imidazole; 1.6) from APNI and N-isopropylformamide, 1-methyl-2-(4-isopropyl
amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.7) from APNI and N-n-butylformamide, 1-methyl-2-(4-n-butylamino
methyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.8) from APNI and N-isobutylformamide, 1-methyl-2-(4-isobutyl
amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.9) from APNI and N-diethylformamide, 1-methyl-2-(4-diethylamino
methyleneimino-phenyloxymethyl)-5-nitro-imidazole, m.p. 120 C
hydrochloride m.p. 164 C); 1.10) from APNI and N-di-n-proylformamide, l-methyl-2-(4-di-n-propylamino- methyleneimido-phenyloxymethyl)-5-nitro-imidazole; 1.11) from APNI and N-isopropylformamide, 1-methyl-2-(4-diisopropylamino methyleneimino-phenyloxymethyl)-5-nitro-imid ole; 1.12) from APNI and N-di-n-butylformamide, 1-methyl-2-(4-di-n-butylamino
methyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.13) from APNI and N-diisobutylformamide, 1-methyl-2-(4-diisobutylamino
methyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.14) from APNI and N-formylpyrrolidine, 1-methyl-2-(4-pyrrolidino-methylene
imino-phenyloxymethyl)-5-nitro-imidazole, m.p. 135 C; 1.15) from APNI and N-formylpiperidine, 1-methyl-2-(4-piperidine-methylene
imino-phenyloxymethyl)-5-nitro-imidazole, m.p. 104 C;
1.16) from APNI and N-formylmorpholine, 1-methyl-2-(4-morpholino-methylene
imino-phenyloxymethyl)-5-nitro-imidazole, m.p. 145 C;
1.17) from APNI and N-formylthiomorpholine, 1-methyl-2-(4-thiomorpholino methyleneirnino-phenyloxymethyl)-5-nitro-imidazole; 1.18) from 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole (APNI) and
acetamide, 1 - methyl - 2 - (4 - amino - 1 - ethyleneimino - phenyloxy
methyl)-5-nitro-imidazole; 1.19) from APNI and N-methylacetamide, 1-methyl-2-(4-methylamino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.20) from APNI and N-ethylacetamide, 1-methyl-2-(4-ethylamino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.21) from APNI and N-n-propylacetamide, 1-methyl-2-(4-n-propylamino-1-ethyl
eneimino-phenyloxymethyl)-5-nitro-imidazole; 1.22) from APNI and N-isopropylacetamide, 1-methyl-2-(4-isopropylamino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.23) from APNI and N-n-butylacetamide, 1-methyl-2-(4-n-butylamino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.24) from APNI and N-isobutylacetamide, 1-methyl-2-(4-isobutylamino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.25) from APNI and N-dimethylacetamide, 1-methyl-2-(4-dimethylamino-1-ethyl
eneimino-phenyloxymethyl)-5-nitro-imidazole, m.p. 137 C; 1.26) from APNI and N-diethylacetamide, 1-methyl-2-(4-diethylamino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole, m.p. 92 C; 1.27) from APNI and N-di-n-propylacetamide, 1-methyl-2-(4-di-n-propylamino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.28) from APNI and N-diisopropylacetamide, 1-methyl-2-(4-diisopropylamino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.29) from APNI and N-di-n-butylacetamide, 1-methyl-2-(4-di-n-butylamino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.30) from APNI and N-diisobutylacetamide, 1-methyl-2-(4-diisobutylamino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.31) from APNI and N-acetylpyrrolidine, 1-methyl-2-(4-pyrrolidino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.32) from APNI and N-acetylpiperidine, 1-methyl-2-(4-piperidino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole;
1.33) from APNI and N-acetylmorpholine, 1-methyl-2-(4-morpholino-1-ethylene
imino-phenyloxymethyl)-5-nitro-imidazole;
1.34) from APNI and N-acetylthiomorpholine, 1-methyl-2-(4-thiomorpholino-1
ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.35) from 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole
(APNI) and propionamide, 1-methyl-2-(4-amino-1-propyleneimino-phenyl
oxymethyl)-5-nitro-imidazole;
1.36) from APNI and N-methylpropionamide, 1-methyl-2-(4-methylamino-1-pro
phenyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.37) from APNI and N-ethylpropionamide, 1-methyl-2-(4-ethylamino-1-propylene
imino-phenyloxymethyl)-5-nitro-imidazole;
1.38) from APNI and N-n-propylpropionamide, 1-methyl-2-(4-n-propylamino-1
propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.39) from APNI and N-isopropylpropionamide, 1-methyl-2-(4-isopropylamino-1
propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.40) from APNI and N-n-butylpropionamide, l-methyl-2-(4-n-butylamino-1- propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.41) from APNI and N-isobutylpropionamide, 1-methyl-2-(4-isobutylamino-1
propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.42) from APNI and N-dimethylpropionamide, 1-methyl-2-(4-dimethylamino-1
propyleneimino-phenyloxymethyl)-5-nitro-imidazole, m.p. 115 C; 1.43) from APNI and N-diethylpropionamide, 1-methyl-2-(4-diethylamino-1-pro
pyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.44) from APNI and N-di-n-propylpropionamide, 1-methyl-2-(4-di-n-propylamino
1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.45) from APNI and N-diisopropylpropionamide, 1-methyl-2-(4-diisopropylamino
1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.46) from APNI and N-di-n-butylpropionamide, 1-methyl-2-(4-di-n-butylamino
1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.47) from APNI and N-diisobutylpropionamide, 1-methyl-2-(4-diisobutylamino-1
propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.48) from APNI and N-propionylpyrrolidine, 1-methyl-2-(4-pyrrolidino-1-propyl
eneimino-phenyloxymethyl)-5-nitro-imidazole; 1.49) from APNI and N-propionylpiperidine, 1-methyl-2-(4-piperidino-1-propylene
imino-phenyloxymethyl)-5-nitro-imidazole; 1.50) from APNI and N-propionylmorpholine, 1-methyl-2-(4-morpholino-1-propyl
eneimino-phenyloxymethyl)-5-nitro-imidazole; 1.51) from APNI and N-propionylthiomorpholine, 1-methyl-2-(4-thiomorpholino
1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole; 1.52) from APNI and pyrrolidone-2 (butyrolactam), 1-methyl-2-[4-(pyrrolidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.53) from APNI and 1-methylpyrrolidone-2, 1-methyl-2-[4-(1-methylpyrrolidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole, m.p. 130 C; 1.54) from APNI and 1-ethylpyrrolidone-2, 1-methyl-2-[4-(1-ethylpyrrolidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.55) from APNI and 1-propylpyrrolidone-2, 1-methyl-2-[4-(1-propylpyrrolidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.56) from APNI and 1-butylpyrrolidone-2, 1-methyl-2-[4-(1-butylpyrrolidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.57) from APNI and piperidone-2 (valerolactam), 1-methyl-2-[4-(piperidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole, m.p. 141 C; 1.58) from APNI and 1-methylpperidone-2, 1-methyl-2-[4-(1-methylpiperidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.59) from APNI and 1-ethylpiperidone-2, 1-methyl-2-[4-(1-ethylpiperidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.60) from APNI and 1-propylpiperidone-2, 1-methyl-2-[4-(1-propylpiperidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.61) from APNI and 1-butylpiperidone-2, 1-methyl-2-[4-(1-butylpiperidin-2
ylideneimino)-phenyloxymethyl]-5-nitro-imidazole; 1.62) from APNI and 12-oxohexamethyleneimine (caprolactam), 1-methyl-2-[4
(perhydroazepin-2-ylideneimino)-phenyloxymethyl]-5-nitro- imidazole; 1.63) from APNI and 1-methyl-2-oxohexamethyleneimine, 1-methyl-2-[4-(1
methyl-perhydroazepin-2-ylideneimino)-phenyloxymethyl]-5-nitro
imidazole;
1.64) from APNI and l-ethyl-2-oxohexamethyleneimine, 1 - methyl - 2 - [4 - (1
ethyl - perhydroazepin - 2 - ylideneimino) - phenyloxymethyl] - 5 - nitro
imidazole;
1.65) from APNI and l-propyl-2-oxohexamethyleneimine, 1 - methyl - 2 - [4 - (1
propyl - perhydroazepin - 2 - ylideneimino) - phenyloxymethyl] - 5 - nitro
imidazole;
1.66) from APNI and l-butyl-2-oxohexamethyleneimine, 1 - methyl - 2 - [4 - (1
butyl - perhydroazepin - 2 - ylideneimino) - phenyloxymethyl] - 5 - nitro
imidazole.
Example of process (A.b)
2.1) 1 - methyl - 2 - (4 - dimethylamino - methyleneimino - phenyl - oxymethyl)
5 - nitro - imidazole
24.8 g (0.1 mol) of 1-methyl-2 < 4-aminophenyl-oxymethyl)-nitro-imidazole were suspended in 250 ml of pyridine, 25 g (excess) of dimethylformamide-diethyl acetate were added and the reaction mixture was heated under reflux for 3 hours. The pyridine was then distilled off under reduced pressure, the residue was recrystallized from alcohol after being decolourized with charcoal. According to this process, 24.0 g (79% of the theory) of 1-methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole were obtainde; this compound melted at 145 C.
Example of process (B)
3.1) 1 - Methyl - 2 - (4 - dimethylamino - methylene - imino - phenyl - oxy
methyl)-5-nitro-imidazole
17.55 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole were dissolved in
150 ml of dimethyl formamide, 16.4 g (0.1 mol) of 4-dimethylamino-methyleneiminophenol (melting point 199 C) were added, 10.8 g (0.2 mol) of sodium methylate were
added to the reaction mixture and the reaction mixture was heated to 40 C for 1 hour.
Then, the solution was poured onto ice/water, and the precipitate obtained was filtered
off and recrystallized from alcohol after being decolourized with charcoal. According
to this process, 22.7 g (67 % of the theory) of 1-methyl-2-(4-dimethyl-amino-methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole were obtained, which melted at 145 C.
The preparation of the 4-dimethyl-amino-methyleneimino-phenol used as starting
material is described in the U.S. Patent No. 3,184,482, Example 48.
The compounds according to Examples 1.2 to 1.66 can also be prepared accord
ing to the process (A.b) in analogy to Example 2.1 and according to the process (B.) in
analogy to Example 3.1.
Claims (13)
1. A 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazole of the formula
in which each of R1, R2 and R3 is hydrogen, a straight-chain or branched alkyl group
having from 1 to 4 carbon atoms, or in which R' and R2, together with the intermediate nitrogen and carbon atoms, form a pyrrolidine, piperidine or hexamethylene
imine ring, or in which R2 and R3, together with the nitrogen atoms form a pyrrolidine,
piperidine, morpholine, or thiomorpholine ring.
2. An acid addition salt of a compound according to claim 1.
3. An acid addition salt according to claim 2 which is physiologically tolerable.
4. 1 - Methyl - 2 - (4 - dimethylarninomethyleneimino phenyloxymethyl) - 5 nitro - imidazole.
5. 1 - Methyl - 2 - (4 - diethylaminomethyleneimino - phenyloxymethyl) - 5 nitro-imidazole.
6. 2-(4-Morpholinomethyleneimino-phenyloxymethyl)-5-nitro-imidazole.
7. A process for the preparation of a compound according to claim 1 which com
prises reacting at a temperature of from (A) 0 to 100 C either 1-methyl-2-(4-amino
phenyl-oxymethyl)-5-nitro-imidazole of the formula with either
(a) a carboxylic acid amide, carboxylic acid thioamsde, lactam or miolacram or the formula
in which Z is oxygen or sulfur, and R1, R2 and R3 have the meanings specified
in claim 1, in the presence of a condensing agent, or (b) an acetal of a carboxylic acid amide or of a lactam of the formula
in which R1, R2 and R3 have the meanings specified in claim 1, and R4 is a methyl or ethyl group; or
(B) a l-methyl-2-halomethyl-5-nitro-imidazole of the formula
in which X is a halogen atom, an acyloxy group or an arylsulfonyloxy group, with a Samidinophenol or an alkali metal or ammonium salt thereof of the formula
in which Y is hydrogen, an alkali metal, or ammonium.
8. A process according to claim 7 which includes the additional step of salifying the product obtained with an acid.
9. A process according to claim 8, wherein the acid is physiologically tolerable.
10. A process according to claim 7 carried out substantially as described in any one of the Examples herein.
11. A compound according to claim 1 or an acid addition salt thereof whenever obtained by a process according to any one of claims 7 to 10.
12. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 or a physiologically tolerable acid addition salt thereof in admixture or conjunction with a pharmaceutically suitable carrier.
13. A method for combating protozoa, helminths and ectoparasites in non-human mammals which comprises administering to the host mammal a compound according to claim 1 or a physiologically tolerable acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4395976A GB1560078A (en) | 1976-10-22 | 1976-10-22 | 1-methyl 2-(phenyl - oxymethyl) - 5 - nitro - imidazole and process for their manufacture |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4395976A GB1560078A (en) | 1976-10-22 | 1976-10-22 | 1-methyl 2-(phenyl - oxymethyl) - 5 - nitro - imidazole and process for their manufacture |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1560078A true GB1560078A (en) | 1980-01-30 |
Family
ID=10431130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4395976A Expired GB1560078A (en) | 1976-10-22 | 1976-10-22 | 1-methyl 2-(phenyl - oxymethyl) - 5 - nitro - imidazole and process for their manufacture |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB1560078A (en) |
-
1976
- 1976-10-22 GB GB4395976A patent/GB1560078A/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |