CA1073917A - 1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazoles - Google Patents
1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazolesInfo
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- CA1073917A CA1073917A CA264,128A CA264128A CA1073917A CA 1073917 A CA1073917 A CA 1073917A CA 264128 A CA264128 A CA 264128A CA 1073917 A CA1073917 A CA 1073917A
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- methyl
- nitro
- imidazole
- oxymethyl
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
ABSTRACT OF THE DISCLOSURE
This invention is directed to new 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of the formula I
IMG> (I) wherein R1, R2 and R3 can be identical or different and represent hydrogen, straight-chain or branched alkyl having from 1 to 4 carbon atoms, or wherein R1 and R2 as alkylene chain, together with the nitrogen and carbon atom of the amidino group, are con-stituents of a pyrrolidine, piperidine or hexamethylene-imine ring, or wherein R2 and R3 as alkylene chain together with the nitrogen atom of the ammidino group, are constituents of a pyrrolidine, ppiperidine, morpholine or thiomorphiline ring, and the salts thereof with physiologically tolerable acids; and to a process for their preperation. The new compounds are suitable for the treatment of protozoal diseases.
This invention is directed to new 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of the formula I
IMG> (I) wherein R1, R2 and R3 can be identical or different and represent hydrogen, straight-chain or branched alkyl having from 1 to 4 carbon atoms, or wherein R1 and R2 as alkylene chain, together with the nitrogen and carbon atom of the amidino group, are con-stituents of a pyrrolidine, piperidine or hexamethylene-imine ring, or wherein R2 and R3 as alkylene chain together with the nitrogen atom of the ammidino group, are constituents of a pyrrolidine, ppiperidine, morpholine or thiomorphiline ring, and the salts thereof with physiologically tolerable acids; and to a process for their preperation. The new compounds are suitable for the treatment of protozoal diseases.
Description
. HOE 75/F-120 ` - 1073917-The present in~ention rela~es to 1-methyl-2-(phenyl_oxy_ methyl)-5-nitro-imidazoles and process for preparing them.
1-(2-Hydroxyethyl)-2-methyl-5-nitro-imidazOle (Metronidazol) - is used for the treatment of protozoal diseases, such as tri-" ~ chomoniasis and amoebiasis.
; . .
. The present invention provides 1-methyl-2-(phenyl-oxy-methyl)-5-nitro-lmidazoles o~ the formula I
~2 ~ ~ ~ ~
:
whereln R1, R2, R3 can be identical or dif~erent and represent hydrogen, straight-chain or branched alkyl having from ;I to 4 carbon atomsJ such as methyl, ethyl, propyl, isopropyl, . butyl, isobutyl, or in which R1 and R2 as alkylene chzin having :- from three to five carbon atoms, together with the nitrogen and carbon atoms o~ the amidino group, are constituents of .~ a pyrrolidine, piperidine or hexamethylene-imine ring, or in which R and R3 as alkylene chain having four or five carbon . atoms, together with the nitrogen atom of the amidino group, . can be consituents of a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, as well as the salts of these com-pounds (I) with a physiologically tolerable acid.
m e in~-ention also pro~ides a process for the preparation of 1-methyl-2-(phenyl_oxymethyl)_5_nitro_imidazoles of the formula (I) as well as of.the salts thereof with a physio-logically tolerable acid, which comprises 2g ~; - 2 ~
" .- ' ' ' , . ~i ':
. :
: HOE ?51~ 120 - -`- . 1073917 -A) reacting 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitFo_ ~midazole of the formula II
.. .. . . ... . .
-C~l2-- ~ _ ~2 ~ (II) -5 . 2~ 1 . . . .
. CH3. ..
. .
. . . . . . ~ , s , a) with a carboxylic acid amide, a carboxylic acid thio--amide~ a lactam or a thiolactam of the formula III
. . R1 R2 - Z ¦ ~ ~ : . (III) - R
r~ ,, . , _ _ . ~ . , wherein Z is oxygen or sul~ur, and R1, R2 and R3 have the meanings specified as above, in the presence of-a condensing agent, or . - .
b) with an acetal.of a carboxylic acid amide or of a . lactam of the formula IV
, . . R1 - --- -- --- .
R4 _ o- ¦ ~2 . ~ . -- -~ 20 - . R4 o / \ R3 (I~) , -..
wherein R1, R2l R3 have the meanings specified as above, and R4 stands for methyl or ethyl, . or .B) reacting a ?-methyl-2-halogenomethyl-5-nitro-imidazole of the formula V
CH2 - X (~j 1 . 29 . 2 . - C~3 . -3 _ . , , : .
. ; , . -~
.
,, - , ~ .
. .
'' ' ' ' ~ '' ~ . :
~ .
, . .
~ wherein X is a halogen atom, such as fluorine, chlorine, ~ -bromine, iodine, or an acyloxy group, such as acetyloxy, propionyloxy, butyryloxy, benzoyloxy, nitrobenzoyloxy, toloyloxy, or an aryl-sulfonyloxy group, such as benzoyl_.
.- - sulfonyloY.y, toluene-sulfonyloxy, nitrobenzene-sulfonyloxy, with a 4-amidinophenol or with the alkali metal or am-mon1um salt thereof of the formula VI
r - o .. . - . . ................................. .
wherein Y represents hydrogen, an alkali metal, in par-: ticular sodium or potassium, or ammoniumj and optionally , ., ~,r~, , adding a corresponding acid.
,J' ' The starting compounds of the formula II may be prepared by reacting 1-methyl-2-chloromethyl-5-nitro-Imidazoles of the = formula V with 4-acylaminophenols or the alkali metal salts . thereof and by saponifying the condensation product formed to . give the free amine. : .
The starting compounds of the ~ormula V may be prepared by reacting 1_methyl_2_hydroxymethyl 5-nitro-imidazole with the -~. - correæponding.acid chlorides.
The starting compounds of the formula VI may be prepared - by reacting 4-aminophenol with carboxylic acid amides of the . formula III.
.~ As starting compounds of the formula III (carboxylic acid amides and thioamides) there may be mentioned, for example, - formamide, thioformamide, N-methyl-, N-ethyl-, N-propyl-, i .. N-isopropyl-, N-butyl-, N-isobutyl, N,N-dimethyl-, N,N-diethyl-,.
N,N-dipropyl-, N,N-diisopropyl-, N,N-dibutyl-, N,N-diisobutyl-formamide, ~thioformamide, -acetamide, -thioacetamide, -propion-' .
. HOE _75 ~
- - 1073917:
amide, -thiopropionamide, -butyramide, -thiobutyramide, -valeramide, -thiovaleramide, moreover, N-formyl-, N-acetyl-, N-propionyl-, N-butyryl-, N-valeryl-pyrrolidine, -piperidine, -morpholine, -thiomorpholine.
5 . - As further starting compounds of the formuia III (lactams.
and thiolactams) there may be mentioned, for example, butyro-lactam (pyrrolidone-2), valerolactam (piperidone-2)~ capro-lactam (2-oxohexamethylene-imine), butyro-, valero-, capro-thiola~tam, N-methyl-, N-ethyl-, N-propyl-, N-butyl-butyro-, 10 -valero-, -capro-lactam, -butyro-, -valero-, -capro-thiolactam.
: As starting compounds of the formula IV there may be mentioned, for example, formamide, 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 , N,N-diisobutylformamide-, -acetamide-, -propionamide-, -butyr-amide-, -valeramide-, dimethyl-, diethyl-acetal, moreover, N-formyl-, N-acetyl-, N-propionyl-, N-butyryl-, N-valeryl-pyrrolidine-, -piperidine-, -morpholine-, -thiomorpholine-, . dimethyl-, diethyl-acetal~-butyrolactam-, (pyrrolidone-2),:
. valerolactam-, (piperidone-2), caprolactam-, (2-oxohexa-- methylene-imine), butyro-, valero-, capro-thiolactam-, N-methyl-, N-ethyl-, N-propyl-, N-butyl-butyro-, -valero-, -capro-lactam-, -butyro-, -valero-, -capro-thiolactam--, dimethyl-,.-diethyl-. acetal.
As starting compounds of the formula V there may be men-tioned, for example, 1-methyl-2-chloro-, -2-bromo-, -2-iodo-~ethyl-5-nitro-imidazole, 1_methyl-2_acetyloxy_, -2-benzoyloxy-, -
1-(2-Hydroxyethyl)-2-methyl-5-nitro-imidazOle (Metronidazol) - is used for the treatment of protozoal diseases, such as tri-" ~ chomoniasis and amoebiasis.
; . .
. The present invention provides 1-methyl-2-(phenyl-oxy-methyl)-5-nitro-lmidazoles o~ the formula I
~2 ~ ~ ~ ~
:
whereln R1, R2, R3 can be identical or dif~erent and represent hydrogen, straight-chain or branched alkyl having from ;I to 4 carbon atomsJ such as methyl, ethyl, propyl, isopropyl, . butyl, isobutyl, or in which R1 and R2 as alkylene chzin having :- from three to five carbon atoms, together with the nitrogen and carbon atoms o~ the amidino group, are constituents of .~ a pyrrolidine, piperidine or hexamethylene-imine ring, or in which R and R3 as alkylene chain having four or five carbon . atoms, together with the nitrogen atom of the amidino group, . can be consituents of a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, as well as the salts of these com-pounds (I) with a physiologically tolerable acid.
m e in~-ention also pro~ides a process for the preparation of 1-methyl-2-(phenyl_oxymethyl)_5_nitro_imidazoles of the formula (I) as well as of.the salts thereof with a physio-logically tolerable acid, which comprises 2g ~; - 2 ~
" .- ' ' ' , . ~i ':
. :
: HOE ?51~ 120 - -`- . 1073917 -A) reacting 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitFo_ ~midazole of the formula II
.. .. . . ... . .
-C~l2-- ~ _ ~2 ~ (II) -5 . 2~ 1 . . . .
. CH3. ..
. .
. . . . . . ~ , s , a) with a carboxylic acid amide, a carboxylic acid thio--amide~ a lactam or a thiolactam of the formula III
. . R1 R2 - Z ¦ ~ ~ : . (III) - R
r~ ,, . , _ _ . ~ . , wherein Z is oxygen or sul~ur, and R1, R2 and R3 have the meanings specified as above, in the presence of-a condensing agent, or . - .
b) with an acetal.of a carboxylic acid amide or of a . lactam of the formula IV
, . . R1 - --- -- --- .
R4 _ o- ¦ ~2 . ~ . -- -~ 20 - . R4 o / \ R3 (I~) , -..
wherein R1, R2l R3 have the meanings specified as above, and R4 stands for methyl or ethyl, . or .B) reacting a ?-methyl-2-halogenomethyl-5-nitro-imidazole of the formula V
CH2 - X (~j 1 . 29 . 2 . - C~3 . -3 _ . , , : .
. ; , . -~
.
,, - , ~ .
. .
'' ' ' ' ~ '' ~ . :
~ .
, . .
~ wherein X is a halogen atom, such as fluorine, chlorine, ~ -bromine, iodine, or an acyloxy group, such as acetyloxy, propionyloxy, butyryloxy, benzoyloxy, nitrobenzoyloxy, toloyloxy, or an aryl-sulfonyloxy group, such as benzoyl_.
.- - sulfonyloY.y, toluene-sulfonyloxy, nitrobenzene-sulfonyloxy, with a 4-amidinophenol or with the alkali metal or am-mon1um salt thereof of the formula VI
r - o .. . - . . ................................. .
wherein Y represents hydrogen, an alkali metal, in par-: ticular sodium or potassium, or ammoniumj and optionally , ., ~,r~, , adding a corresponding acid.
,J' ' The starting compounds of the formula II may be prepared by reacting 1-methyl-2-chloromethyl-5-nitro-Imidazoles of the = formula V with 4-acylaminophenols or the alkali metal salts . thereof and by saponifying the condensation product formed to . give the free amine. : .
The starting compounds of the ~ormula V may be prepared by reacting 1_methyl_2_hydroxymethyl 5-nitro-imidazole with the -~. - correæponding.acid chlorides.
The starting compounds of the formula VI may be prepared - by reacting 4-aminophenol with carboxylic acid amides of the . formula III.
.~ As starting compounds of the formula III (carboxylic acid amides and thioamides) there may be mentioned, for example, - formamide, thioformamide, N-methyl-, N-ethyl-, N-propyl-, i .. N-isopropyl-, N-butyl-, N-isobutyl, N,N-dimethyl-, N,N-diethyl-,.
N,N-dipropyl-, N,N-diisopropyl-, N,N-dibutyl-, N,N-diisobutyl-formamide, ~thioformamide, -acetamide, -thioacetamide, -propion-' .
. HOE _75 ~
- - 1073917:
amide, -thiopropionamide, -butyramide, -thiobutyramide, -valeramide, -thiovaleramide, moreover, N-formyl-, N-acetyl-, N-propionyl-, N-butyryl-, N-valeryl-pyrrolidine, -piperidine, -morpholine, -thiomorpholine.
5 . - As further starting compounds of the formuia III (lactams.
and thiolactams) there may be mentioned, for example, butyro-lactam (pyrrolidone-2), valerolactam (piperidone-2)~ capro-lactam (2-oxohexamethylene-imine), butyro-, valero-, capro-thiola~tam, N-methyl-, N-ethyl-, N-propyl-, N-butyl-butyro-, 10 -valero-, -capro-lactam, -butyro-, -valero-, -capro-thiolactam.
: As starting compounds of the formula IV there may be mentioned, for example, formamide, 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 , N,N-diisobutylformamide-, -acetamide-, -propionamide-, -butyr-amide-, -valeramide-, dimethyl-, diethyl-acetal, moreover, N-formyl-, N-acetyl-, N-propionyl-, N-butyryl-, N-valeryl-pyrrolidine-, -piperidine-, -morpholine-, -thiomorpholine-, . dimethyl-, diethyl-acetal~-butyrolactam-, (pyrrolidone-2),:
. valerolactam-, (piperidone-2), caprolactam-, (2-oxohexa-- methylene-imine), butyro-, valero-, capro-thiolactam-, N-methyl-, N-ethyl-, N-propyl-, N-butyl-butyro-, -valero-, -capro-lactam-, -butyro-, -valero-, -capro-thiolactam--, dimethyl-,.-diethyl-. acetal.
As starting compounds of the formula V there may be men-tioned, for example, 1-methyl-2-chloro-, -2-bromo-, -2-iodo-~ethyl-5-nitro-imidazole, 1_methyl-2_acetyloxy_, -2-benzoyloxy-, -
-2-(4-nitrobenzoyloxy)-, 2-toluene-sul~onyloxy-methyl-5-nitro-29 imidazole. - ... -.
- 5 - :
. . -- . . . .
., ;
~ ' . ~ ..
.. . . .
As starting compounds of the formula VI there may be mentioned, for example, 4-amino-,-methylamino-, -ethylamino_, -propylamino-, -isopropylamino-, -butylamino-,-isobutylamino-, -dimethylamino-, -diethylamino-, -di-n-propylamino-, -diiso_ propylamino-, -di-n-butylamino_, -diisobutyiamino-, -pyrro_ lidino-, -piperidino-, -morpholino-, -thiomorpholino-methylene-imino-, -1-ethylene-imino-, -1_propylene-imino-phenol, as well as 4-(pyrrolidone-2-imino)-, -(piperidone-2-imino)-, -(2-oxo-hex~methylene-'imino-2-imino)-, -(1-methyl-, 1-ethyl-, 1-pro_ pyl-,'1-butyl-pyrroiidone-, -piperidone-, -2-oxohexamethylene-imino-2-imino)-phenol.
, . . . . ", .
The'reactions' according to the variants A) and B) of the preparation process are suitably~carried out in equimolar - amounts of the respective starting compounds. In the case of volatile reactants, however, excess amounts are recommended.
~he reactions are advantageously carried out in a solvent or '- distributing agent, however, certain reactions may also be~
carried out without a solvent or distributing agent, as in-i . . . ........... .. . . .
- dicated below.
As solvents or distributing agents there may be mentioned, '~ '-for'example: ' ' ' ' ~or the process Aa), aromatic, optionally halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, chlorinated aliphatic hydro-carbonsj such as methylene chloride, chloroform, aliphatic ' ' ethers, such as di-isopropylether, ethylene-glycol-dimethyl-ether, -diethylether, diethylene-glycol-dimethylether, tetra-hydrofurane, and dioxane. ' 29 It is particularly advan~ageous to use excess amounts o~ 3 - 6 _ s .... , , . ,. ., , HOE 75~F 120 ~ ` 1073917 the carboxylic acid amides or lactams of the formula III used for the reaction. The excess may optionally be recovered in the processing of the reaction mixture.
For the process Ab) there are mentioned alcohols, such as methanol, ethanol, propanol, butanol, methoxyethanol, ethoxy-ethanol, or most advantageously, an excess amount of the acetals of the carboxylic acid amides or of the lactams of the formula IV used for the reaction.
For the process B) there are mentioned alcohols, such as ; 10 methanol, ethanol, propanol, isopropanol, butanol, methoxy-ethanol, ethoxy-ethanol; ketones, such as acetone, methylethyl-ketone, methylbutyl-ketone; amides, such as dimethylformamide, diethylformamide, dimethylacetamide, N-methyl-pyrrolidone, tetramethylurea, hexamethyl-phosphoric acid-triamide; further-more, dimethylsulfoxide.
The reactions according to process Aa) are ad~antageously carried out in the presence of a condensing agent. As con-densing agents there may be mentioned preferably inorganic and organic acid halides, for example, thionylchloride, phosphorus trichloride, phosphorus pentachloride, phosphoroxychloride, chlorosulfonic acid, phosgene, oxalylchloride, chloroformic acid-alkylester, benzoylchloride, benzene-sulfonic acid- ;-~-chloride, 4-toluene-sulfonic acid-chloride.
- If for the reaction according to process Aa), use is made -s 25 of carboxylic acid thioamides and/or thiolactams, the use of a sulfur-binding agent is also recommended.- As sulfur-binding agents there are mentioned, for example, heavy metal oxides, '''~? ' ' such as mercury oxide and lead oxide.
29 The reaction components according to process Aa) are 1-.. , . . ' :
-~
HOE 75 ~ 20 ~ i739~L7 suitably reacted in equimolar amounts. The three latter com-ponents, in particular the carboxylic acid amides and thio- -amides, lactams and thiolactams, may also advantageously be used in excess amounts.
For the process variant B) the use o~ an acid-binding agent - is recommended, if the free phenols of the formula VI are used.
- As acid-binding agents there are mentioned bases, such as triethyl-amine or pyridine, as well as allcali metal and alkaline earth metal carbonates and -bicarbonateS~ -hydroxides and -alkoxides, for example, -methoxides, -ethoxides, and -butoxides.
.
- ~or both steps of the process variants Aj and B) the ; . .
reaction temperatures are in the range of from O to 100C, - preferably from 25 to 80C.
Depending on the process variant and on the range of temperature, the reaction times are in a range of from a few minutes to several hours.
The reaction products prepared according to process Aa) are obtained in the form of their salts. They mày be isolated as such or may optionally be converted into the ~ree bases by - - alkalizing the a~ueous solutions.
In order to alkalize said solutions, use is com~only made of strong bases, such as ammonia, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or the æ 25 aqueous solutions thereof. The bases which have been set free may again be converted into salts by way of physiologically tolerable acids.
As physiologically tolerable acids there are mentioned, 29 ~or example, halogen hydracids, in particular hydrochloric acid, - 8 ' ... ..
.
moreover, sulfuric acid, phosphoric acid, acetic acid, pro-pionic acid, lactic acid, and tartaric acid.
If necessary, the reaction products may be purified by a recrystallization from a suita~le solvent or solvent mixture~
-The novel compounds of formula I are uell compatible and are suitable for the treatment of protozoal diseases in mammals, as they are caused, for example, by infections with Trichomonas vaginalis and Entamoeba hLstolytica. Besides, they show a marked activity against helminths, ectoparasites and ticks.
The novel compounds can be administered orally or locally.
The dosage unit for oral administration is given in the usual forms for pharmaceutical preparations, for example, tablets or capsules containing, per daily dosage unit, from about 10 to 750 mg of the active substance in combination with a usual carrier substance and/or constituent. For local application, 1 there may be used, for example, jellies, creams, ointments or ;` suppositories.
, ~ . ............... . . . .
The following Examples serve to illustrate the invention.
E X A M P L E S 0~ _ PREPARATION:
. Process Aa) - E X A M P L E 1.
1.1) 1-Meth~l-2-(4-dimethylamino-meth~lene~imino-phen~l-oxY-- meth~l~-5-nitro-imidazole 248 Grams (1 mole) of 1-methyl-2-(4-aminophenyl-oxy-methyl)-5-nitro-imidazole were dissolved in 1250 ml of . . .
dimethylformamide. At a temperature of from 30 to 40C, 154 g t1 mole) of phosphoroxichloride were added drop-29 wise, ~Jhlle stirring, to this mix~ure. Subsequently the reaction mixture was continued to be stirred for another g _ : . :.
, ~ :
~"
, 073917 ~æ
2 hours at 25C. The final product was precipitated, -~ while stirring, in the form of a salt, by adding 2.5 l of methylene chloride, it was then suction-filtered, washed with methylene chloride, suction-dried, dissolved in water, alkalized with aqueous concentrated ammonia, and the ~ree base was shaken out several times with methylene chloride.
; - The combined extracts were dried with sodium sulfate, were then evaporated, and the residue was recrystallized from alcohol, while adding charcoal. According to this method, 252 g (83 % of the theory) of 1-methyl-2-(4-di_ methylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole were obtained in the form of yellow crystals having a melting point of 145C.
From the free base, the hydrochloride having a melting point of 187C 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-nitro- -- imidaæole (orange red crystals, m.p. 152C)-used as starting compound could be prepared by saponifyl;ng 1-methyl-2-(4-acetaminophenyl-oxymethyl)-5-nitro~imidazoie by means of 40 7~ sulfuric acid (2 hours, 80 to 90C), in a yield of 85 %.
The 1-methyl-2-(4-acetaminophenyl-oxymethyl)-5-nitro-imidazole (pale yellow crystals, m.p. 163C) used for the ; - preparation of the starting compound could be obtained by reacting molar amounts of 4-acetaminophenol with 1_methyl-2-chloromethyl-5-nitro-imidazole in dimethylform~mide 2g (for 1 hour at 30 to 40C), in the presence o~ potassium ,, . . . i -,' '' ' ' ' ,' " , ' `
.. . .
073~:7 carbonate, in a yield of 95 ~.
The preparation of 1-methyl-2-chloromethyl-5-nitro_ imidazole has been described in German OffenleO~ungs-schrift No. 1 595.~29; it was effected by reacting the 1-methyl-2-hydroxymethyl compound with thionyl chloride.
It is also possible to use 1-methyl-2-benzoyloxy-methyl-5-nitro-imidazole or 1-methyl-2 (4-nitrobenzoyl-oxymethyl)-5-nitro-imidazole instead of 1-methyl-2-chloro_ methyl-5-nitro~imidazole, the ~ormer compounds being obtained from the 1-methyl-2-hydroxymethyl compound with benzoylchloride and/or 4-nitrobenzoylchloride.
.
According to the process described in ExampIe 1, the - ~ollowing compounds were obtained;
- 1~2) From 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole (APNI) and formamide, 1-methyl-2-(4-amino_ methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole;
1.~) from APNI and N-methyleneformamide, 1-methyl-2-(4-methyl-u amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.4) from APNI and N-ethylformamide, 1-methyl-2-(4-ethyl-amino-methyleneimino~phenyloxymethyl)-5-nitro-imidazole;
- 1.5) from APNI and N-n-propylformamide, 1-methyl-2-(4-n-propyi-amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.6) from APNI and N-isopropylformamide, 1-methyl-2-(4-iso-- propylamino-methyleneimino-phenyloxymethyl)-5-nitro-2~ imidazole;
1.7) from APNI and N-n-butylformamide, 1-methyl-2-(4-n-butyl-amino-methyleneimino-phenyloxymethyl)-5-nitro-imida~ole;
1.8) from APNI and N-isobutylformamide, 1-methyl-2-(4-iso-29 butyl-amino-methyleneimino-phenyloxymethyl)-5-nitro - 11 _ . ' .. . . . .
" ''' ' . `
.
., ' '' ' ' .
HOE 75/~_120 .
imidazole;
1.9 from APNI and N-diethylformamide, 1-methyl-2-(4-diethyl_ amino-methyleneimino-phenyloxymethyl3-5-nitro-imidazole, m.p. 120C (hydrochloride m.p. 164 C);
- 5 1.10 from APNI and N-di-n-propyl~ormamide, 1-methyl-2-(4-di-- n-propylamino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole; -1.11 from APNI and N-diisopropylformamide, 1-methyl-2-(4 di-isopropylamino-methyleneimino-phenyloxymethyl)-5~nitro-imidazole;
1.12 from APNI and N-d~-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-diiso-butylamino-rnethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.14 from APNI and N-~ormylpyrrolidine, 1-methyl-2-~4-pyrroli-dino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole m.p. 135C;
1.15 from APNI and N-formylpiperldine, 1-methyl-2-(4-piperidi--no-methyleneimino-phenyloxymethyl)-5-nitro-imidazole, m.p. 104C; .
- 1.16) from APNI and N-formylmorpholine, 1-methyl-2-(4-morpho-lino-methyleneimino_phenyloxymethyl)_5_nitro_imidazole, m.p. 145C;
1.17 from APNI and N-~ormylthiomorpholine, 1-methyl-2-(4-thio-morpholino-methyleneimino-phenyloxymethyl)-5-nitrp- ~
imidazole; , , f .. . . ..
29 1.18 from 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro- s - ~ - 12 - ;
,' ' . ~
.
, .
HOR ~ ~ 120 : 1073917 imidazole (APNI) and acetamide, 1-methyl-2-(4-amino_1_ ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.19)~rom APNI and N-methylacetamide, 1-methyl-2-(4-methyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.20)from APNI and N-ethylacetarnide, 1-methyl-2-(4-ethylamino_ 1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; -1.21)from APNI and N-n-propylacetamide, 1-methyl-2-(4-n-propyl--amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.22) from APNI and N-isopropylacetamide, 1-methyl-'2-(4-isopro-'~i'' 10 pylamino-1-ethyleneimino phenyloxymethyl)-5-nitro-imida-zole; ' - - '' ' ' ; ' 1.23) from APNI and N-n-butylacetamide, 1-methyl-2-(4-n-butyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.24) from APNI and N-isobutylacetamide, 1-methyl-2-(4-iso'outyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.25) from APNI and N-dimethylacetamide, 1-methyl-2-(4-dimethyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole ' m.p. i37C;
1.26) from APNI and N-diethylacetamide, 1-methyl-2-(4-~iethyl-' amino-1 ethyleneimino-phenyloxymethyl)_5_nitro-imidazole, m-p. g2oc;
. . . . .
1.27) from APNI and N-di-n-propylacetamide, 1-methyl-2-(4-di-n-propylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-' ' imidazole; '' ; 25 1.28) frorn APNI and N-diisopropylacetamide, 1-methyl-2-(4-di-'' isopropylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imid'azole;
1.29) from APNI and N-di-n-butylacetamide, 1-methyl-2-(4-di-n-29 butylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-- . , .. . ~ .
' . ' ' ' ' ' , . . .
HOE 7~/F 120 - - - i0739i7 ~ . . imidazole;
- 1.30) from APNI and N-diisobutylacetamide, 1-methyl-2-(4_di_ isobutylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.3.1) from APNI and N-acetylpyrrolidine, 1-methyl-2-(4-pyrrolidi-.. no-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.32) from APNI and N-acetylpiperidine, 1-methyl-2-(4-piperidi-no-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.33) from APNI and N-acetylmorpholine, 1-methyl-2-(4-morpholi-.10 no-1-ethyieneimino-phenyloxymethyl)-5-nitro-imidazole;
1.34) from APNI and N-acetylthiomorpholine, 1-methyl-2-(4-thio-.. morpholino-1-ethyieneimino-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-ox~nethyl)-5-nitro-imidazole;
1.36) from APNI and N-methylpropionamide, 1-methyl~2-(4-methyl-amino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
: 1.37~ from APNI and N-ethy.lpropionamide, 1-methyl-2-(4-ethyl-. amino-1-propyleneimino-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-iso-propylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-- imidazole;
. - 1 40) from APNI and N-n-butylpropionamide, 1-methyl-2-(4-n- -. 29 butylamino-1-propyleneimino-phenyloxymethyl)-5-nitro- -- 14 ~- .
- : ' . ' : ,- : - I
, HOE _~ /F 120 imidazole;
1.41) from APNI and N-isobutylpropionamide, 1-methyl-2-(4_iso_ butylamino-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. 115C;
1.4~) from APNI and N-diethylpropionamide, 1-methyl-2-(4_ diethylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.~4) 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-- 15 (4-diisopropylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.46) ~rom 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-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1 49) from APNI and N-propionylpiperidine, 1-methyl-2-(4-piperidino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
29 - 1.50) from APNI and N-propionylmorpholine, 1-methyi-2-(4-- 15 _ -~
:~ ' .
: .
., ' ' ' ... .
- 1073917 ~
.
- morpholino-1-propyleneimino-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_ - ~ -(pyrrolidone-2-imino)-phenyloxy~ethyl7-5-nitro-imidazole;
1.53) from APNI and 1-methylpyrrolidone-2, 1-methyl-2- ~ -(1 methylpyrrolidone-2-imino)-phenyloxymethylJ-5-nitro-imidazole, m.p. 130C;
1.54~ from APNI and 1-ethylpyrrolidone-2, 1-methyl-2- ~
- ethylpyrrolidone-2-imino)-phenyloxymethyl~-5-nitro-- imidazole;
1.55) from APNI and 1-propylpyrrolidone-2, 1-methyl-2-~4~
propylpyrrolidone-2-imino)-phenyloxymethyl~-5-nitro-imidazole;
1.56) from APnI and 1-butylpyrrolidone-2, 1-methyl-2 ~ -(1-butylpyrrolidone-2-imino ? -phenyloxymethyl~-5-nitro-imidazole;
.. . .. .
1.57) from APNI and piperidone-2 (valerolactam), 1-methyl-2-~ -(piperidone-2-imino)-phenyloxymethyl~-5-nitro~
imidazole, m.p. 141C;
1.58) from APNI and i-methylpiperidone-2, 1-methyl-2- ~ ~
methylpiperidone-2-imino)-phenyloxymethyl~-5-nitro-; imidazole;
- 1.59) from APNI and 1-ethylpiperidone-2~ 1-methyl-2- ~ -(1- 7 ethylpiperidone-2-imino)-phenyloxymethyl7-5-nitro-9 imidazole;
- 16 ~
- ': ` ' -- .' - . . :
:: ..
' 107:39~7 ; 1.60) from APNI and 1-propylpiperidone-2, 1-methyl-2~
propylpiperidone-2-imino)-phenyloxymethyl~-5-nitro-imidazole;
1.61) from APNI and 1-butylpiperidone-2, 1-methyl-2-~-(1- -b~tylpiperidone-2-imino)-phenyloxymethyl~-5-nitro--imidazole;
1.62) from APNI and 2-oxohexamethyleneimine (caprolactam), 1-methyl-2- ~ -(2-oxohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.63) from APNI and 1-methyl-2-oxohexamethyleneimine, 1 methyl_ 2-~4-(1-methyl-2-oxohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.64) from APNI and 1_ethyl-2-oxohexamethyleneimine, 1-methyl-2- ~ -(1-ethyl-2-oxohexamethleneimino-2-imino)-phenyloxy-methyl~-5-nitro-imidazole;
1.65) from APNI and 1-propyl-2-oxohexamethyleneimine, 1-methyl-2-~4-(1-propyl-2-~xohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.66) from APNI and 1-butyl-2-oxohexamethyleneimine, 1-methyl-2- ~ -(1-butyl-2-oxohexamethy;leneimino-2-imino)-phenyl-- oxymethyl]-5-nitro-imldazole.
,' , ' :
i.'-. . - .
.
- !
"~ . . , . ~
~ - . . ' r .
: ' ' ' ., . , , ,~
; . . . . . ~, .. .
- .
.
o739~7 Example fo~ process variant A bL
2.11 1-Methyl-2-(4-dimethylamino-methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole 24.8 g (0.1 mol) of 1-methyl-2-(4-aminophenyl-oxyme-thyl)-nitro-imidazole were suspended in 250 ml of pyridine, 25 g (excess) of dimethylformamide-diethyl acetate were added and '.he reaction mixture was heated under reflux for
- 5 - :
. . -- . . . .
., ;
~ ' . ~ ..
.. . . .
As starting compounds of the formula VI there may be mentioned, for example, 4-amino-,-methylamino-, -ethylamino_, -propylamino-, -isopropylamino-, -butylamino-,-isobutylamino-, -dimethylamino-, -diethylamino-, -di-n-propylamino-, -diiso_ propylamino-, -di-n-butylamino_, -diisobutyiamino-, -pyrro_ lidino-, -piperidino-, -morpholino-, -thiomorpholino-methylene-imino-, -1-ethylene-imino-, -1_propylene-imino-phenol, as well as 4-(pyrrolidone-2-imino)-, -(piperidone-2-imino)-, -(2-oxo-hex~methylene-'imino-2-imino)-, -(1-methyl-, 1-ethyl-, 1-pro_ pyl-,'1-butyl-pyrroiidone-, -piperidone-, -2-oxohexamethylene-imino-2-imino)-phenol.
, . . . . ", .
The'reactions' according to the variants A) and B) of the preparation process are suitably~carried out in equimolar - amounts of the respective starting compounds. In the case of volatile reactants, however, excess amounts are recommended.
~he reactions are advantageously carried out in a solvent or '- distributing agent, however, certain reactions may also be~
carried out without a solvent or distributing agent, as in-i . . . ........... .. . . .
- dicated below.
As solvents or distributing agents there may be mentioned, '~ '-for'example: ' ' ' ' ~or the process Aa), aromatic, optionally halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, chlorinated aliphatic hydro-carbonsj such as methylene chloride, chloroform, aliphatic ' ' ethers, such as di-isopropylether, ethylene-glycol-dimethyl-ether, -diethylether, diethylene-glycol-dimethylether, tetra-hydrofurane, and dioxane. ' 29 It is particularly advan~ageous to use excess amounts o~ 3 - 6 _ s .... , , . ,. ., , HOE 75~F 120 ~ ` 1073917 the carboxylic acid amides or lactams of the formula III used for the reaction. The excess may optionally be recovered in the processing of the reaction mixture.
For the process Ab) there are mentioned alcohols, such as methanol, ethanol, propanol, butanol, methoxyethanol, ethoxy-ethanol, or most advantageously, an excess amount of the acetals of the carboxylic acid amides or of the lactams of the formula IV used for the reaction.
For the process B) there are mentioned alcohols, such as ; 10 methanol, ethanol, propanol, isopropanol, butanol, methoxy-ethanol, ethoxy-ethanol; ketones, such as acetone, methylethyl-ketone, methylbutyl-ketone; amides, such as dimethylformamide, diethylformamide, dimethylacetamide, N-methyl-pyrrolidone, tetramethylurea, hexamethyl-phosphoric acid-triamide; further-more, dimethylsulfoxide.
The reactions according to process Aa) are ad~antageously carried out in the presence of a condensing agent. As con-densing agents there may be mentioned preferably inorganic and organic acid halides, for example, thionylchloride, phosphorus trichloride, phosphorus pentachloride, phosphoroxychloride, chlorosulfonic acid, phosgene, oxalylchloride, chloroformic acid-alkylester, benzoylchloride, benzene-sulfonic acid- ;-~-chloride, 4-toluene-sulfonic acid-chloride.
- If for the reaction according to process Aa), use is made -s 25 of carboxylic acid thioamides and/or thiolactams, the use of a sulfur-binding agent is also recommended.- As sulfur-binding agents there are mentioned, for example, heavy metal oxides, '''~? ' ' such as mercury oxide and lead oxide.
29 The reaction components according to process Aa) are 1-.. , . . ' :
-~
HOE 75 ~ 20 ~ i739~L7 suitably reacted in equimolar amounts. The three latter com-ponents, in particular the carboxylic acid amides and thio- -amides, lactams and thiolactams, may also advantageously be used in excess amounts.
For the process variant B) the use o~ an acid-binding agent - is recommended, if the free phenols of the formula VI are used.
- As acid-binding agents there are mentioned bases, such as triethyl-amine or pyridine, as well as allcali metal and alkaline earth metal carbonates and -bicarbonateS~ -hydroxides and -alkoxides, for example, -methoxides, -ethoxides, and -butoxides.
.
- ~or both steps of the process variants Aj and B) the ; . .
reaction temperatures are in the range of from O to 100C, - preferably from 25 to 80C.
Depending on the process variant and on the range of temperature, the reaction times are in a range of from a few minutes to several hours.
The reaction products prepared according to process Aa) are obtained in the form of their salts. They mày be isolated as such or may optionally be converted into the ~ree bases by - - alkalizing the a~ueous solutions.
In order to alkalize said solutions, use is com~only made of strong bases, such as ammonia, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or the æ 25 aqueous solutions thereof. The bases which have been set free may again be converted into salts by way of physiologically tolerable acids.
As physiologically tolerable acids there are mentioned, 29 ~or example, halogen hydracids, in particular hydrochloric acid, - 8 ' ... ..
.
moreover, sulfuric acid, phosphoric acid, acetic acid, pro-pionic acid, lactic acid, and tartaric acid.
If necessary, the reaction products may be purified by a recrystallization from a suita~le solvent or solvent mixture~
-The novel compounds of formula I are uell compatible and are suitable for the treatment of protozoal diseases in mammals, as they are caused, for example, by infections with Trichomonas vaginalis and Entamoeba hLstolytica. Besides, they show a marked activity against helminths, ectoparasites and ticks.
The novel compounds can be administered orally or locally.
The dosage unit for oral administration is given in the usual forms for pharmaceutical preparations, for example, tablets or capsules containing, per daily dosage unit, from about 10 to 750 mg of the active substance in combination with a usual carrier substance and/or constituent. For local application, 1 there may be used, for example, jellies, creams, ointments or ;` suppositories.
, ~ . ............... . . . .
The following Examples serve to illustrate the invention.
E X A M P L E S 0~ _ PREPARATION:
. Process Aa) - E X A M P L E 1.
1.1) 1-Meth~l-2-(4-dimethylamino-meth~lene~imino-phen~l-oxY-- meth~l~-5-nitro-imidazole 248 Grams (1 mole) of 1-methyl-2-(4-aminophenyl-oxy-methyl)-5-nitro-imidazole were dissolved in 1250 ml of . . .
dimethylformamide. At a temperature of from 30 to 40C, 154 g t1 mole) of phosphoroxichloride were added drop-29 wise, ~Jhlle stirring, to this mix~ure. Subsequently the reaction mixture was continued to be stirred for another g _ : . :.
, ~ :
~"
, 073917 ~æ
2 hours at 25C. The final product was precipitated, -~ while stirring, in the form of a salt, by adding 2.5 l of methylene chloride, it was then suction-filtered, washed with methylene chloride, suction-dried, dissolved in water, alkalized with aqueous concentrated ammonia, and the ~ree base was shaken out several times with methylene chloride.
; - The combined extracts were dried with sodium sulfate, were then evaporated, and the residue was recrystallized from alcohol, while adding charcoal. According to this method, 252 g (83 % of the theory) of 1-methyl-2-(4-di_ methylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole were obtained in the form of yellow crystals having a melting point of 145C.
From the free base, the hydrochloride having a melting point of 187C 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-nitro- -- imidaæole (orange red crystals, m.p. 152C)-used as starting compound could be prepared by saponifyl;ng 1-methyl-2-(4-acetaminophenyl-oxymethyl)-5-nitro~imidazoie by means of 40 7~ sulfuric acid (2 hours, 80 to 90C), in a yield of 85 %.
The 1-methyl-2-(4-acetaminophenyl-oxymethyl)-5-nitro-imidazole (pale yellow crystals, m.p. 163C) used for the ; - preparation of the starting compound could be obtained by reacting molar amounts of 4-acetaminophenol with 1_methyl-2-chloromethyl-5-nitro-imidazole in dimethylform~mide 2g (for 1 hour at 30 to 40C), in the presence o~ potassium ,, . . . i -,' '' ' ' ' ,' " , ' `
.. . .
073~:7 carbonate, in a yield of 95 ~.
The preparation of 1-methyl-2-chloromethyl-5-nitro_ imidazole has been described in German OffenleO~ungs-schrift No. 1 595.~29; it was effected by reacting the 1-methyl-2-hydroxymethyl compound with thionyl chloride.
It is also possible to use 1-methyl-2-benzoyloxy-methyl-5-nitro-imidazole or 1-methyl-2 (4-nitrobenzoyl-oxymethyl)-5-nitro-imidazole instead of 1-methyl-2-chloro_ methyl-5-nitro~imidazole, the ~ormer compounds being obtained from the 1-methyl-2-hydroxymethyl compound with benzoylchloride and/or 4-nitrobenzoylchloride.
.
According to the process described in ExampIe 1, the - ~ollowing compounds were obtained;
- 1~2) From 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole (APNI) and formamide, 1-methyl-2-(4-amino_ methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole;
1.~) from APNI and N-methyleneformamide, 1-methyl-2-(4-methyl-u amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.4) from APNI and N-ethylformamide, 1-methyl-2-(4-ethyl-amino-methyleneimino~phenyloxymethyl)-5-nitro-imidazole;
- 1.5) from APNI and N-n-propylformamide, 1-methyl-2-(4-n-propyi-amino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.6) from APNI and N-isopropylformamide, 1-methyl-2-(4-iso-- propylamino-methyleneimino-phenyloxymethyl)-5-nitro-2~ imidazole;
1.7) from APNI and N-n-butylformamide, 1-methyl-2-(4-n-butyl-amino-methyleneimino-phenyloxymethyl)-5-nitro-imida~ole;
1.8) from APNI and N-isobutylformamide, 1-methyl-2-(4-iso-29 butyl-amino-methyleneimino-phenyloxymethyl)-5-nitro - 11 _ . ' .. . . . .
" ''' ' . `
.
., ' '' ' ' .
HOE 75/~_120 .
imidazole;
1.9 from APNI and N-diethylformamide, 1-methyl-2-(4-diethyl_ amino-methyleneimino-phenyloxymethyl3-5-nitro-imidazole, m.p. 120C (hydrochloride m.p. 164 C);
- 5 1.10 from APNI and N-di-n-propyl~ormamide, 1-methyl-2-(4-di-- n-propylamino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole; -1.11 from APNI and N-diisopropylformamide, 1-methyl-2-(4 di-isopropylamino-methyleneimino-phenyloxymethyl)-5~nitro-imidazole;
1.12 from APNI and N-d~-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-diiso-butylamino-rnethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.14 from APNI and N-~ormylpyrrolidine, 1-methyl-2-~4-pyrroli-dino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole m.p. 135C;
1.15 from APNI and N-formylpiperldine, 1-methyl-2-(4-piperidi--no-methyleneimino-phenyloxymethyl)-5-nitro-imidazole, m.p. 104C; .
- 1.16) from APNI and N-formylmorpholine, 1-methyl-2-(4-morpho-lino-methyleneimino_phenyloxymethyl)_5_nitro_imidazole, m.p. 145C;
1.17 from APNI and N-~ormylthiomorpholine, 1-methyl-2-(4-thio-morpholino-methyleneimino-phenyloxymethyl)-5-nitrp- ~
imidazole; , , f .. . . ..
29 1.18 from 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro- s - ~ - 12 - ;
,' ' . ~
.
, .
HOR ~ ~ 120 : 1073917 imidazole (APNI) and acetamide, 1-methyl-2-(4-amino_1_ ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.19)~rom APNI and N-methylacetamide, 1-methyl-2-(4-methyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.20)from APNI and N-ethylacetarnide, 1-methyl-2-(4-ethylamino_ 1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole; -1.21)from APNI and N-n-propylacetamide, 1-methyl-2-(4-n-propyl--amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.22) from APNI and N-isopropylacetamide, 1-methyl-'2-(4-isopro-'~i'' 10 pylamino-1-ethyleneimino phenyloxymethyl)-5-nitro-imida-zole; ' - - '' ' ' ; ' 1.23) from APNI and N-n-butylacetamide, 1-methyl-2-(4-n-butyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.24) from APNI and N-isobutylacetamide, 1-methyl-2-(4-iso'outyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.25) from APNI and N-dimethylacetamide, 1-methyl-2-(4-dimethyl-amino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole ' m.p. i37C;
1.26) from APNI and N-diethylacetamide, 1-methyl-2-(4-~iethyl-' amino-1 ethyleneimino-phenyloxymethyl)_5_nitro-imidazole, m-p. g2oc;
. . . . .
1.27) from APNI and N-di-n-propylacetamide, 1-methyl-2-(4-di-n-propylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-' ' imidazole; '' ; 25 1.28) frorn APNI and N-diisopropylacetamide, 1-methyl-2-(4-di-'' isopropylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imid'azole;
1.29) from APNI and N-di-n-butylacetamide, 1-methyl-2-(4-di-n-29 butylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-- . , .. . ~ .
' . ' ' ' ' ' , . . .
HOE 7~/F 120 - - - i0739i7 ~ . . imidazole;
- 1.30) from APNI and N-diisobutylacetamide, 1-methyl-2-(4_di_ isobutylamino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.3.1) from APNI and N-acetylpyrrolidine, 1-methyl-2-(4-pyrrolidi-.. no-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.32) from APNI and N-acetylpiperidine, 1-methyl-2-(4-piperidi-no-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.33) from APNI and N-acetylmorpholine, 1-methyl-2-(4-morpholi-.10 no-1-ethyieneimino-phenyloxymethyl)-5-nitro-imidazole;
1.34) from APNI and N-acetylthiomorpholine, 1-methyl-2-(4-thio-.. morpholino-1-ethyieneimino-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-ox~nethyl)-5-nitro-imidazole;
1.36) from APNI and N-methylpropionamide, 1-methyl~2-(4-methyl-amino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
: 1.37~ from APNI and N-ethy.lpropionamide, 1-methyl-2-(4-ethyl-. amino-1-propyleneimino-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-iso-propylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-- imidazole;
. - 1 40) from APNI and N-n-butylpropionamide, 1-methyl-2-(4-n- -. 29 butylamino-1-propyleneimino-phenyloxymethyl)-5-nitro- -- 14 ~- .
- : ' . ' : ,- : - I
, HOE _~ /F 120 imidazole;
1.41) from APNI and N-isobutylpropionamide, 1-methyl-2-(4_iso_ butylamino-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. 115C;
1.4~) from APNI and N-diethylpropionamide, 1-methyl-2-(4_ diethylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.~4) 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-- 15 (4-diisopropylamino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1.46) ~rom 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-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
1 49) from APNI and N-propionylpiperidine, 1-methyl-2-(4-piperidino-1-propyleneimino-phenyloxymethyl)-5-nitro-imidazole;
29 - 1.50) from APNI and N-propionylmorpholine, 1-methyi-2-(4-- 15 _ -~
:~ ' .
: .
., ' ' ' ... .
- 1073917 ~
.
- morpholino-1-propyleneimino-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_ - ~ -(pyrrolidone-2-imino)-phenyloxy~ethyl7-5-nitro-imidazole;
1.53) from APNI and 1-methylpyrrolidone-2, 1-methyl-2- ~ -(1 methylpyrrolidone-2-imino)-phenyloxymethylJ-5-nitro-imidazole, m.p. 130C;
1.54~ from APNI and 1-ethylpyrrolidone-2, 1-methyl-2- ~
- ethylpyrrolidone-2-imino)-phenyloxymethyl~-5-nitro-- imidazole;
1.55) from APNI and 1-propylpyrrolidone-2, 1-methyl-2-~4~
propylpyrrolidone-2-imino)-phenyloxymethyl~-5-nitro-imidazole;
1.56) from APnI and 1-butylpyrrolidone-2, 1-methyl-2 ~ -(1-butylpyrrolidone-2-imino ? -phenyloxymethyl~-5-nitro-imidazole;
.. . .. .
1.57) from APNI and piperidone-2 (valerolactam), 1-methyl-2-~ -(piperidone-2-imino)-phenyloxymethyl~-5-nitro~
imidazole, m.p. 141C;
1.58) from APNI and i-methylpiperidone-2, 1-methyl-2- ~ ~
methylpiperidone-2-imino)-phenyloxymethyl~-5-nitro-; imidazole;
- 1.59) from APNI and 1-ethylpiperidone-2~ 1-methyl-2- ~ -(1- 7 ethylpiperidone-2-imino)-phenyloxymethyl7-5-nitro-9 imidazole;
- 16 ~
- ': ` ' -- .' - . . :
:: ..
' 107:39~7 ; 1.60) from APNI and 1-propylpiperidone-2, 1-methyl-2~
propylpiperidone-2-imino)-phenyloxymethyl~-5-nitro-imidazole;
1.61) from APNI and 1-butylpiperidone-2, 1-methyl-2-~-(1- -b~tylpiperidone-2-imino)-phenyloxymethyl~-5-nitro--imidazole;
1.62) from APNI and 2-oxohexamethyleneimine (caprolactam), 1-methyl-2- ~ -(2-oxohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.63) from APNI and 1-methyl-2-oxohexamethyleneimine, 1 methyl_ 2-~4-(1-methyl-2-oxohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.64) from APNI and 1_ethyl-2-oxohexamethyleneimine, 1-methyl-2- ~ -(1-ethyl-2-oxohexamethleneimino-2-imino)-phenyloxy-methyl~-5-nitro-imidazole;
1.65) from APNI and 1-propyl-2-oxohexamethyleneimine, 1-methyl-2-~4-(1-propyl-2-~xohexamethyleneimino-2-imino)-phenyl-oxymethyl~-5-nitro-imidazole;
1.66) from APNI and 1-butyl-2-oxohexamethyleneimine, 1-methyl-2- ~ -(1-butyl-2-oxohexamethy;leneimino-2-imino)-phenyl-- oxymethyl]-5-nitro-imldazole.
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.
- !
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- .
.
o739~7 Example fo~ process variant A bL
2.11 1-Methyl-2-(4-dimethylamino-methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole 24.8 g (0.1 mol) of 1-methyl-2-(4-aminophenyl-oxyme-thyl)-nitro-imidazole were suspended in 250 ml of pyridine, 25 g (excess) of dimethylformamide-diethyl acetate were added and '.he reaction mixture was heated under reflux for
3 hours. The reaction medium pyridine was then distilled off under reduced pressure, the residue was recrystallized from alcohol while adding charcoal. According to this pro-.. . . .
cess, 24.0 g (79 % of the theory) of 1-methyl-2-(4-dimethyl-; amino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole were obtained; which melted at 145C.
Exam~le for ~rocess variant Bl 3.1) 1-Methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxyme-thyl)-5-nitro-imidazole_ _ _ ; 17.55 g (0.1 mol) of 1-methyl-2-chlo~ethyl-5-nitro-imida-zole were dissolved in 150 ml of dimethyl formamide, 16.4 g (0.1 mol) of 4-dimethylamino-methyleneimino-phenol (melting point 199C) were added, 10.8 g (0.2 mol) of sodium methy-late were added to the reaction mixture and the reaction mixture was heated to 40C for 1 hour. Then, the solution was poured on to ice water, the precipitate was filtered off and recrystallized from alcohol while adding charcoal.
- 25 According to this process, 22.7 g (67 ~ of the theory) of 1-methyl-2-(4-dimethyl-amino-methyleneimino-phenyl-oxymethyi)-5-nitro-imidazole were obtained, which melted at 145C.
. . -The preparation of the 4-dimethyl-amino-methyleneimino-phe- t, , nol used as starting substance is described in the US Patent No. q 3,184,482, example 48.
- . . , : .
- . , : , : . , ~, : : ' :
.
~ . HOE 75/F 120 The substances according to Examples 1.2 to 1.66 can be prepared according to the process variant A.b) in analogy to Example 2.1 and according to the process variant B.) in analogy . . to Example 3.1.
,' , .
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.
~ . ' ' ' ' . . .
, .. . .
:'. .
.
.;. - , . . . . ..
.. . .
''' :
.~, ,. . . . .
., , ' ' , ' ' , , - - . ~-. .
:
.
': '
cess, 24.0 g (79 % of the theory) of 1-methyl-2-(4-dimethyl-; amino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole were obtained; which melted at 145C.
Exam~le for ~rocess variant Bl 3.1) 1-Methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxyme-thyl)-5-nitro-imidazole_ _ _ ; 17.55 g (0.1 mol) of 1-methyl-2-chlo~ethyl-5-nitro-imida-zole were dissolved in 150 ml of dimethyl formamide, 16.4 g (0.1 mol) of 4-dimethylamino-methyleneimino-phenol (melting point 199C) were added, 10.8 g (0.2 mol) of sodium methy-late were added to the reaction mixture and the reaction mixture was heated to 40C for 1 hour. Then, the solution was poured on to ice water, the precipitate was filtered off and recrystallized from alcohol while adding charcoal.
- 25 According to this process, 22.7 g (67 ~ of the theory) of 1-methyl-2-(4-dimethyl-amino-methyleneimino-phenyl-oxymethyi)-5-nitro-imidazole were obtained, which melted at 145C.
. . -The preparation of the 4-dimethyl-amino-methyleneimino-phe- t, , nol used as starting substance is described in the US Patent No. q 3,184,482, example 48.
- . . , : .
- . , : , : . , ~, : : ' :
.
~ . HOE 75/F 120 The substances according to Examples 1.2 to 1.66 can be prepared according to the process variant A.b) in analogy to Example 2.1 and according to the process variant B.) in analogy . . to Example 3.1.
,' , .
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.
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.
.;. - , . . . . ..
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., , ' ' , ' ' , , - - . ~-. .
:
.
': '
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a l-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazole of the formula I
(I) wherein R1, R2 and R3 can be identical or different and repre-sent hydrogen, straight-chain or branched alkyl having from 1 to 4 carbon atoms, or wherein R1 and R2 as alkylene chain, together with the nitrogen and carbon atom of the amidino group, are constituents of a pyrrolidine, piperidine or hexamethylene-imine ring, or wherein R2 and R3 as alkylene chain, together with the nitrogen atom of the amidino group, are constituents of a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, and the salts thereof with physio-logically tolerable acids, in which A) l-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole of the formula II
(II) is reacted with (a) a carboxylic acid amide, a carboxylic acid thioamide, a lactam or a thiolactam of the formula III
(III) wherein Z represents oxygen or sulfur, and R1, R2 and R3 are as defined 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
(IV) wherein R1, R2 and R3 are as defined above, and R4 represents methyl or ethyl, or B) a 1-methyl-2-halogenomethyl-5-nitro-imidazole of the formula V
(V) wherein X represents a halogen atom or an acyloxy group or an arylsulfonyloxy group, is reacted with a 4-amidino-phenol or with the alkali metal or ammonium salt thereof of the formula VI
(VI) wherein Y represents hydrogen, an alkali metal, or ammonium, and the compound of the formula I so obtained may be converted with a physiologically tolerable acid into the corresponding salt.
(I) wherein R1, R2 and R3 can be identical or different and repre-sent hydrogen, straight-chain or branched alkyl having from 1 to 4 carbon atoms, or wherein R1 and R2 as alkylene chain, together with the nitrogen and carbon atom of the amidino group, are constituents of a pyrrolidine, piperidine or hexamethylene-imine ring, or wherein R2 and R3 as alkylene chain, together with the nitrogen atom of the amidino group, are constituents of a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, and the salts thereof with physio-logically tolerable acids, in which A) l-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole of the formula II
(II) is reacted with (a) a carboxylic acid amide, a carboxylic acid thioamide, a lactam or a thiolactam of the formula III
(III) wherein Z represents oxygen or sulfur, and R1, R2 and R3 are as defined 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
(IV) wherein R1, R2 and R3 are as defined above, and R4 represents methyl or ethyl, or B) a 1-methyl-2-halogenomethyl-5-nitro-imidazole of the formula V
(V) wherein X represents a halogen atom or an acyloxy group or an arylsulfonyloxy group, is reacted with a 4-amidino-phenol or with the alkali metal or ammonium salt thereof of the formula VI
(VI) wherein Y represents hydrogen, an alkali metal, or ammonium, and the compound of the formula I so obtained may be converted with a physiologically tolerable acid into the corresponding salt.
2. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction A).
3. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction B).
4. A 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazole of the formula I as defined in claim 1 whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole in which 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole is reacted with dimethylformamide in the presence of phosphoroxichloride and the resultant product is subsequently isolated.
6. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole in which 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole is reacted with dimethylformamide-diethylacetate in pyridine at the reflux temperature and the resultant product is subsequently isolated.
7. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-dimethylamino-methyleneimino-phenyl-oxymethyl)-5-nitro-imidazole in which 1-methyl-2-chloromethyl-5-nitro-imidazole is reacted with 4-dimethylamino-methyleneimino-phenol in a solvent in the presence of sodium methylate and the product is subsequently isolated.
8. 1-Methyl-2-(4-dimethylamino-methylene-imino-phenyl-oxymethyl)-5-nitro-imidazole, whenever obtained according to a process as claimed in claim 5, claim 6 or claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-diethylamino-methyleneimino-phenyloxymethyl)-5-nitro-imidazole in which 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole is reacted with N-diethylformamide in the presence of phosphoroxichloride and the product is subsequently isolated.
10. 1-Methyl-2-(4-diethylamino-methyleneimino-phenyloxy-methyl)-5-nitro-imidazole, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-morpholino-1-ethyleneimino-phenyloxymethyl)-5-nitro-imidazole in which 1-methyl-2-(4-aminophenyl-oxymethyl)-5-nitro-imidazole is reacted with N-acetylmorpholine in the presence of phosphoroxichloride and the product is subsequently isolated.
12. 1-Methyl-2-(4-morpholino-1-ethyleneimino-phenyloxy-methyl)-5-nitro-imidazole whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA264,128A CA1073917A (en) | 1976-10-25 | 1976-10-25 | 1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA264,128A CA1073917A (en) | 1976-10-25 | 1976-10-25 | 1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1073917A true CA1073917A (en) | 1980-03-18 |
Family
ID=4107123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA264,128A Expired CA1073917A (en) | 1976-10-25 | 1976-10-25 | 1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazoles |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1073917A (en) |
-
1976
- 1976-10-25 CA CA264,128A patent/CA1073917A/en not_active Expired
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