CA1097355A - 1-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles and process for their manufacture - Google Patents
1-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles and process for their manufactureInfo
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- CA1097355A CA1097355A CA290,219A CA290219A CA1097355A CA 1097355 A CA1097355 A CA 1097355A CA 290219 A CA290219 A CA 290219A CA 1097355 A CA1097355 A CA 1097355A
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- oxymethyl
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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Abstract
Abstract of the Disclosure This invention is directed to 1-ethyl-2-(phenyl-oxy-methyl)-5-nitro-imidazoles of the formula I
(I) wherein A represents a sulfur atom or a sulfoxide group (-SO-) and R1 represents methyl or ethyl and R2 represents hydrogen, methyl or halogen, and to a process for preparing these compounds.
The compounds of the invention are suitable for the treatment of protozoal diseases caused in humans and animals and of bacteria and fungi.
(I) wherein A represents a sulfur atom or a sulfoxide group (-SO-) and R1 represents methyl or ethyl and R2 represents hydrogen, methyl or halogen, and to a process for preparing these compounds.
The compounds of the invention are suitable for the treatment of protozoal diseases caused in humans and animals and of bacteria and fungi.
Description
735~i The present invention relates to 1-ethyl-2-(phenyl-oxy-methyl)-5-nitro-imidazoles and to a process for preparing them.
1-(2-~ydroxyethyl)-2-methyl-5-nitro-imidazole (Metro-nidazol) is used for the treatment of protozoal diseases, such as trichomoniasis and amoebiasis.
The subject matter of Applicants' Canadian Patent 1,069,910 issued January 5, 1980 relates -to 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of the formula ~ ~ CH2- O ~ -A - R
O2N ~H3 2 in which A is a sulfur atom or a sulfoxide group (-SO-) and is methyl or ethyl and R2 is hydrogen, methyl or halogen, as well as processes for the preparation of these compounds, pharmaceutical compositions containing the same, and their use.
This subject matter has been further developed.
1-(2-~ydroxyethyl)-2-methyl-5-nitro-imidazole (Metro-nidazol) is used for the treatment of protozoal diseases, such as trichomoniasis and amoebiasis.
The subject matter of Applicants' Canadian Patent 1,069,910 issued January 5, 1980 relates -to 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of the formula ~ ~ CH2- O ~ -A - R
O2N ~H3 2 in which A is a sulfur atom or a sulfoxide group (-SO-) and is methyl or ethyl and R2 is hydrogen, methyl or halogen, as well as processes for the preparation of these compounds, pharmaceutical compositions containing the same, and their use.
This subject matter has been further developed.
- 2 --i""' ...."~, . ..
~ .
~L~
~973~5 Subject-matter of the further developm~nt of the in-~ention are l-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazo~es of the formula I
~ ~ ~12- ~ ~ - R1 ~I) 02N C2~5 R
in which A is a suLfur atom or a sulfoxide group (-SO-) and Rl is methyl or ethyl and R2 is hydrogen, methyl or halogen, Subject-matter of the further deYelopment of the in-vention is also a process for the preparation of l-ethyl-2-(phenyl-oxymethyl)-5-nitro-imida~oles of the formula I, which comprises a~ reacting nitroimida~oles o~ the formula II
N (II) 02N C2~.-5 in which X is a halogen atom, such as fluorine, ohlor-ne, bromine, iodine or an acyloxy group, such as acetoxy, pro-- pionyloxy, butyryloxy, benzoyloxy, toloyloxy, nitrobenzoyl-oxy, or an arylsulfonyloxy group, such as benzeJIesuli`onyl-oxy, toluene-sulfonyloxy or nitrobenæene~sulfonyloxy, ~-ith phenols or the alkali metal or an~lonium salts thereof corresponding to the formula III
Y-C ~ R1 ~IXI) ~ ;~ ' . .
R
in which Y is hydrogen, an alkali metal, especially so,-liu~
or potassium, or ammonium and A, R1 and R aro derilled as in formula 1, or - .
~ 3 -~' ~
~7~35~
b) alkylating nitroimidazoles of the ~ormula IV
~ C (~
in which Y and R are defined as above, and optionallv oxidizing the sulfide compound thus obtained of the for~ula I to give a sulfoxide.
As starting compounds o~ th~ ~ormula II there may be mentioned, for example, 1-ethyl-2-chloro-, -2-bromo-, -2-iodo-~nethyl 5-nitro-imidazole, 1-ethyl-2-acetyloxy-, -2-benzoyloxy-, -2-~4-nitrobenzoyloxy)-, -2-(ll-toluene-sulfonyloxy)-methyl-5-nitro-imidazole.
The starting compounds of the formula II may be prepared according to German Of~enlegungsschrift No. 1 595 929 by reacting 1-ethyl~2 hydroxymethyl-5-nitro-imidazole (cf. Ger~an Offenlegungsschrift No. 1 470 102) ~ith thionyl halides or by reacting acetyl-, benzoyl-, 4-nitrobenzoyl- or 4-toluene-sulfonyl halides or -anhydrides~
As startin~ compounds of the formula III there may be mentioned, for example, 3-methyl-, 3-fluoro-, 3-chloro-,
~ .
~L~
~973~5 Subject-matter of the further developm~nt of the in-~ention are l-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazo~es of the formula I
~ ~ ~12- ~ ~ - R1 ~I) 02N C2~5 R
in which A is a suLfur atom or a sulfoxide group (-SO-) and Rl is methyl or ethyl and R2 is hydrogen, methyl or halogen, Subject-matter of the further deYelopment of the in-vention is also a process for the preparation of l-ethyl-2-(phenyl-oxymethyl)-5-nitro-imida~oles of the formula I, which comprises a~ reacting nitroimida~oles o~ the formula II
N (II) 02N C2~.-5 in which X is a halogen atom, such as fluorine, ohlor-ne, bromine, iodine or an acyloxy group, such as acetoxy, pro-- pionyloxy, butyryloxy, benzoyloxy, toloyloxy, nitrobenzoyl-oxy, or an arylsulfonyloxy group, such as benzeJIesuli`onyl-oxy, toluene-sulfonyloxy or nitrobenæene~sulfonyloxy, ~-ith phenols or the alkali metal or an~lonium salts thereof corresponding to the formula III
Y-C ~ R1 ~IXI) ~ ;~ ' . .
R
in which Y is hydrogen, an alkali metal, especially so,-liu~
or potassium, or ammonium and A, R1 and R aro derilled as in formula 1, or - .
~ 3 -~' ~
~7~35~
b) alkylating nitroimidazoles of the ~ormula IV
~ C (~
in which Y and R are defined as above, and optionallv oxidizing the sulfide compound thus obtained of the for~ula I to give a sulfoxide.
As starting compounds o~ th~ ~ormula II there may be mentioned, for example, 1-ethyl-2-chloro-, -2-bromo-, -2-iodo-~nethyl 5-nitro-imidazole, 1-ethyl-2-acetyloxy-, -2-benzoyloxy-, -2-~4-nitrobenzoyloxy)-, -2-(ll-toluene-sulfonyloxy)-methyl-5-nitro-imidazole.
The starting compounds of the formula II may be prepared according to German Of~enlegungsschrift No. 1 595 929 by reacting 1-ethyl~2 hydroxymethyl-5-nitro-imidazole (cf. Ger~an Offenlegungsschrift No. 1 470 102) ~ith thionyl halides or by reacting acetyl-, benzoyl-, 4-nitrobenzoyl- or 4-toluene-sulfonyl halides or -anhydrides~
As startin~ compounds of the formula III there may be mentioned, for example, 3-methyl-, 3-fluoro-, 3-chloro-,
3-bromo-, 3-iodo-4~methyl-, -4-ethyl-mercapto-phenol and 4~
methyl~, 4-~thyl-mercapto-ph~nol, 3-methyl-, 3-fluoro-, 3-chlo-ro-, 3-bromo-, 3-iodo-4-~ethyl-, -4-~thyl-sulfinyl-phenol and
methyl~, 4-~thyl-mercapto-ph~nol, 3-methyl-, 3-fluoro-, 3-chlo-ro-, 3-bromo-, 3-iodo-4-~ethyl-, -4-~thyl-sulfinyl-phenol and
4-methyl-, 4-ethyl-sulfinyl-phenol. Instead of the free phe-nols there may also be used the alkali metal salts or ammonium salts thereo~.
The starting u~aterials of the formula III may be preparcd by reacti~g 4-mercaptophenols optionally substituted in the - 4 - .
~
1.~3~7'3~
3-position with one molar equivalent of dialkylsulfate in the presence of one molar equivalent Or alkali metal.
Aq dialkylsulfates there may be mentioned di-methyl-, -ethyl-~ulfate.
The alkylsulfinylphenols are prepared from the alkylmer-captophenols by the action of one molar equivalent of an ox-d-izing agent. As oxidi.zing agents there may be mentioned, ~or example, hydrogen p~ro~ide or per-acids, such as perac~tic acid, perbenzoic acid, m-chloroperbenzoic acids, as well as 10 nitric acid or chrotnic acid.
As starting compounds of the formula IV there mzy be mentioned, for example, 1-ethyl-2-~3-methyl-4-mercaptophenyl -oxymethyl)-5-nitro-imidazole, 1-ethyl-2-(4-mercaptophenyl-oxy-m~thyl~-5-nitro-imidazol0, 1-ethyl-2-(3-~luoro-4-mercapto-15 phenyl-oxymethyl)-5-nitro-imidazole, 1-ethyl-Z-(3-chloro-4-mercaptophenyl-oxymethyl)-5-nitro-imida~.ole, 1-ethyl-2-(3-bro-mo~4-mercaptophenyl-oxymethyl)-5-nitro imidazole, 1-ethyl-2~
~3-iodo-4-mercaptophenyl-oxymethyl)-5~nitro-imidazole and the alkali mstal salts thereof. The above-mentloned compounds may 20 be prepared by diazotizin~ the corresponding 1~ethyl-2- ~3-methyl- or 3-halogeno)-~-aminophenyl-oxymethy~ -5-nitro-imi-dazoles, reacting the same with alkali metal xanthogenate and sub,jecting them subsequently to a hydrolytic cleavage. The 1-ethyl-2- ~ 3-methyl- or 3-halogeno)-4-aminophenyl-oxymet}ly~ -
The starting u~aterials of the formula III may be preparcd by reacti~g 4-mercaptophenols optionally substituted in the - 4 - .
~
1.~3~7'3~
3-position with one molar equivalent of dialkylsulfate in the presence of one molar equivalent Or alkali metal.
Aq dialkylsulfates there may be mentioned di-methyl-, -ethyl-~ulfate.
The alkylsulfinylphenols are prepared from the alkylmer-captophenols by the action of one molar equivalent of an ox-d-izing agent. As oxidi.zing agents there may be mentioned, ~or example, hydrogen p~ro~ide or per-acids, such as perac~tic acid, perbenzoic acid, m-chloroperbenzoic acids, as well as 10 nitric acid or chrotnic acid.
As starting compounds of the formula IV there mzy be mentioned, for example, 1-ethyl-2-~3-methyl-4-mercaptophenyl -oxymethyl)-5-nitro-imidazole, 1-ethyl-2-(4-mercaptophenyl-oxy-m~thyl~-5-nitro-imidazol0, 1-ethyl-2-(3-~luoro-4-mercapto-15 phenyl-oxymethyl)-5-nitro-imidazole, 1-ethyl-Z-(3-chloro-4-mercaptophenyl-oxymethyl)-5-nitro-imida~.ole, 1-ethyl-2-(3-bro-mo~4-mercaptophenyl-oxymethyl)-5-nitro imidazole, 1-ethyl-2~
~3-iodo-4-mercaptophenyl-oxymethyl)-5~nitro-imidazole and the alkali mstal salts thereof. The above-mentloned compounds may 20 be prepared by diazotizin~ the corresponding 1~ethyl-2- ~3-methyl- or 3-halogeno)-~-aminophenyl-oxymethy~ -5-nitro-imi-dazoles, reacting the same with alkali metal xanthogenate and sub,jecting them subsequently to a hydrolytic cleavage. The 1-ethyl-2- ~ 3-methyl- or 3-halogeno)-4-aminophenyl-oxymet}ly~ -
5-nitro-imidazoles ara o~tained by reacting compoun~s of the ~ormula II with the corresponding (3-methyl- or 3-halogeno~-4-acetamino-phenols and splitting o~f the acetyl radical by saponification.
373~5 The variants a) and ~) of the preparation pr~ces~ are suitably carried out with equimolar amounts of th~ respecti-~-e ~tarting compounds, preferably in a solvent or dispersing a~ent.
The variant b) Or the preparation process ~ay also be carried out without the use of a solvent or dispersing a~ent.
In this case the alkylating agent used as reaction partner ser~es in an excess amount as reaction medium.
For the reactions accordinF to process ~ariant aj there are mentioned preferably polar solvents, such as alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, 2-methoxy-, 2-ethoxy-ethanol, ketones, such as acetone, di-ethylketone, methylethylketone, methylisobutylketone, amides, such as dimethylformamide, dimethylacetamide, N~methylpyrroli-done, tetramethylurea, hexamethyl-phosphoric acid-triamide, dimethylsulfoxide, heterocyclic bases, such as pyridine, picoline and quinolin~.
If the free phenols of the formula III are used, an acid~
binding agent is suitably applied.
As acid-bindlng agents there may be mentioned, for example, bases, such as tl-iethylamine or pyridine, as welI as alkali metal and alkaline earth metal carbonates and -bicarbonatest -hydroxides and -alkoxides, for example, -methoxides, -ethox-ides and -butoxides.
The reaction temperatures for process ~ariant a) are in the range of from 0 to 80C, the reaction being carried out preferably at room temperature. The reaction time is from a few minutes to ~ome hours.
For the reactions according to proces~ Yariant b) there 29 may be used preferably aprotic solvents, fF example, et~ers.
_ 6 -~373~
such as tetrahydrofurane, dloxane, ethylene~glycol-dirnethyi-ether, ethylene-glycol-diethylether, aromatic hydr~carbon~, such as benzene, toluene, xylene. However, the alkylation reaction may also be carried out without solvent. In this case ? excess alkylating agent is used as diluent.
The alkylation temperatures are in the range of from 20 to 100 C, preferably from 20 to 60 C. The reaction time is from a few minutes to som~ hours.
As alkylating agents there may be mentioned, for examplc, methyl halides, ethyl halides, especially -iodides, dimethyl sulfate, diethyl sulfate, arylsulfonic acid esters, especial]y 4-toluene-sulfonic acid methylester and 4-toluene-sulfoni~
acid ethylester.
The sulfides o~ the formula I (A equals -S-) obtained accordin~ to the process ~ariants a) and b) described abo~e may be con~erted by way of oxidation into corresponding sulf-oxides (A equals -S0-). The oxidation is carried out by the ~ctio~ of suitably one molar equivalent of an oxidizing agent.
As oxidizing agents there are mentionedl ~or example, hydrogen peroxide or per-acids, such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, as well as nitric acid or chromic acid. The oxidation reaction is gellerally carried out at a temperature in the range of from 0 to 30C.
The products Or the process are isolated according to common methods by eliminating the sol~ents used by distillation or diluting the reaction solution with water. They may option-ally be purified by recrystallization from an appropriate sol~snt or mixture of solvents.
29 The novel 1~ethyl-2-~phenyl-oxymethyl~5-nitro-imidazoles - 7 ~
~ -,, ' ', - ~ , , of the formula I according to the further ds~elopment of the in~ention are suitabls for the treatment of protozoal d~-eases in humans and animals as caused, for example, by i~-fections with Trichomonas vaginalis and Entamoeba histo~tica.
Moreo~er, they are effective against bacteria and fungi.
The new compounds of the invention may be administered orall~-or locallyO ~or oral administration, the products are used normally in the form of tablets or capsules containing, per daily dosage unit, from about 10 to 750 mg of the active in-gredient, in admixture with a pharmaceutically suitable carrier or constituent. ~or local application, gels, creams, ~intments or suppositories may be used.
EXAI~IPL~S 0~ PREP~RATION
E X ~ M P L E ? ~pro-ces5 a)):
1~ i.1 1-Ethyl-2 (4-methylthiophenyl-oxymethyl~-5-nitro-imida-zole 13.8 Grams (0.1 mole) of powdered potassium carbonate are added to a solution of 1470 g (0.1 mole) of 4 methyl-mercaptophenol in 30 ml of dimethylformamide7 subsequent-ly a solution vf 19.0 g (0.1 mole~ of 1~ethyl-2-ch1oro-methyl-5-nitro-imidazole in 40 ml of dimethylforma~ide is added dropwise at 25C, while stirrin~. The slightly exothermic reaction is adjusted to a maximum o~ 35C, ~hile cooling with ice water. When everything has been introduced, the mixture is continued to be stirred for 1 hour at 25C; the reaction mixture is poured onto a ~ixture of ice and water, the precipitate is f;ltered off with suction7 is washcd with water and recrystalli~ed 29 from methanol wlth the addition of charcoal.
~3~73~ f~
In this manner, 17.0 g (58 ~ Or the theory) of 1 ethyl_ 2~(4-methyl-thiophenyl-oxymethyl)-5-nitro-imidazole are c~_ tained in the form of light yellow crystals, m.p. 76 C.
According to the process described in Exarnple 1, b~e following compounds are obtained:
1.2 1-Ethyl-2-(4-ethylthiophenyl-oxymethyl)-5-nitro-imiciazole from 1-ethyl-2~chloromethyl-5-nitro-imidazole (EC~I) and 4-ethyl-m~rcaptophenyl;
1.3 1-ethyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 68C, from ~CNI and 3-methyl-4-methyl-mercaptophenol;
1.4 1-ethyl-2-(3-chloro-4~methylthiophenyl-oxymethyl) 5 nitro-imidazole from ECNI and 3-chloro-4-methylmercaptophenol.
X A M P_L E 2 2.1 1-Ethyl-2~t4-methylsulfinylphenyl-oxymethyl)-5-nitro-i 29.3 Grams (0.1 mole) of 1-ethyl-2-(4-methylsulfinyl-phenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and 17.25 g (0.1 mole) of m-chloroper-benzoic acid dissolved in 70 ml of chloroform are added dropwise at 25~C, while stirrin~. The reaction mixture is continued to be stirred for 1 ~our at 25C, then it is shaken out witn diluted soda solution, the chloroform phase is separated, is dried over sodium sulfate and eva-porated. The residue is dissolved and recrystallized from alcohol with the addition of charcoal.
In this manner, 23.5 g (76 ~ of the theory) of 1-ethyl~2 (4-methylsulfinylphenyl oxymethyl)-5-nitro-imidazole are 29 obtained in the form of yellowish crystals, m.p. 90C.
_ g _ ~973~iS J~ G~ ~, hecording to the process described in ~xample 2, the f'ollowir,~, compounds are obtained:
2.2 1-Ethyl-2~(4~ethylsulfinylphenyl-oxymethyl)-5-nitro-imidazole from l-ethyl-2-(4-ethylthiophenyl-oxymethyl)-5-nitro-imidazole;
2.3 1~ethyl-2-(3-methyl-4-methylsulfinylphenyl-oxymethyl)-5-nitro-imidazole, m.p. 80 C~ from 1-ethyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole;
2.4 1-ethyl-2-~3-chloro-4-methylsulfinylphenyl-oxymethyl)-5 nitro-imidazole from l-ethyl-2-(3 chloro-4-methylthio-phenyl-oxymethyl)-5-nitro-imidazole.
373~5 The variants a) and ~) of the preparation pr~ces~ are suitably carried out with equimolar amounts of th~ respecti-~-e ~tarting compounds, preferably in a solvent or dispersing a~ent.
The variant b) Or the preparation process ~ay also be carried out without the use of a solvent or dispersing a~ent.
In this case the alkylating agent used as reaction partner ser~es in an excess amount as reaction medium.
For the reactions accordinF to process ~ariant aj there are mentioned preferably polar solvents, such as alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, 2-methoxy-, 2-ethoxy-ethanol, ketones, such as acetone, di-ethylketone, methylethylketone, methylisobutylketone, amides, such as dimethylformamide, dimethylacetamide, N~methylpyrroli-done, tetramethylurea, hexamethyl-phosphoric acid-triamide, dimethylsulfoxide, heterocyclic bases, such as pyridine, picoline and quinolin~.
If the free phenols of the formula III are used, an acid~
binding agent is suitably applied.
As acid-bindlng agents there may be mentioned, for example, bases, such as tl-iethylamine or pyridine, as welI as alkali metal and alkaline earth metal carbonates and -bicarbonatest -hydroxides and -alkoxides, for example, -methoxides, -ethox-ides and -butoxides.
The reaction temperatures for process ~ariant a) are in the range of from 0 to 80C, the reaction being carried out preferably at room temperature. The reaction time is from a few minutes to ~ome hours.
For the reactions according to proces~ Yariant b) there 29 may be used preferably aprotic solvents, fF example, et~ers.
_ 6 -~373~
such as tetrahydrofurane, dloxane, ethylene~glycol-dirnethyi-ether, ethylene-glycol-diethylether, aromatic hydr~carbon~, such as benzene, toluene, xylene. However, the alkylation reaction may also be carried out without solvent. In this case ? excess alkylating agent is used as diluent.
The alkylation temperatures are in the range of from 20 to 100 C, preferably from 20 to 60 C. The reaction time is from a few minutes to som~ hours.
As alkylating agents there may be mentioned, for examplc, methyl halides, ethyl halides, especially -iodides, dimethyl sulfate, diethyl sulfate, arylsulfonic acid esters, especial]y 4-toluene-sulfonic acid methylester and 4-toluene-sulfoni~
acid ethylester.
The sulfides o~ the formula I (A equals -S-) obtained accordin~ to the process ~ariants a) and b) described abo~e may be con~erted by way of oxidation into corresponding sulf-oxides (A equals -S0-). The oxidation is carried out by the ~ctio~ of suitably one molar equivalent of an oxidizing agent.
As oxidizing agents there are mentionedl ~or example, hydrogen peroxide or per-acids, such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, as well as nitric acid or chromic acid. The oxidation reaction is gellerally carried out at a temperature in the range of from 0 to 30C.
The products Or the process are isolated according to common methods by eliminating the sol~ents used by distillation or diluting the reaction solution with water. They may option-ally be purified by recrystallization from an appropriate sol~snt or mixture of solvents.
29 The novel 1~ethyl-2-~phenyl-oxymethyl~5-nitro-imidazoles - 7 ~
~ -,, ' ', - ~ , , of the formula I according to the further ds~elopment of the in~ention are suitabls for the treatment of protozoal d~-eases in humans and animals as caused, for example, by i~-fections with Trichomonas vaginalis and Entamoeba histo~tica.
Moreo~er, they are effective against bacteria and fungi.
The new compounds of the invention may be administered orall~-or locallyO ~or oral administration, the products are used normally in the form of tablets or capsules containing, per daily dosage unit, from about 10 to 750 mg of the active in-gredient, in admixture with a pharmaceutically suitable carrier or constituent. ~or local application, gels, creams, ~intments or suppositories may be used.
EXAI~IPL~S 0~ PREP~RATION
E X ~ M P L E ? ~pro-ces5 a)):
1~ i.1 1-Ethyl-2 (4-methylthiophenyl-oxymethyl~-5-nitro-imida-zole 13.8 Grams (0.1 mole) of powdered potassium carbonate are added to a solution of 1470 g (0.1 mole) of 4 methyl-mercaptophenol in 30 ml of dimethylformamide7 subsequent-ly a solution vf 19.0 g (0.1 mole~ of 1~ethyl-2-ch1oro-methyl-5-nitro-imidazole in 40 ml of dimethylforma~ide is added dropwise at 25C, while stirrin~. The slightly exothermic reaction is adjusted to a maximum o~ 35C, ~hile cooling with ice water. When everything has been introduced, the mixture is continued to be stirred for 1 hour at 25C; the reaction mixture is poured onto a ~ixture of ice and water, the precipitate is f;ltered off with suction7 is washcd with water and recrystalli~ed 29 from methanol wlth the addition of charcoal.
~3~73~ f~
In this manner, 17.0 g (58 ~ Or the theory) of 1 ethyl_ 2~(4-methyl-thiophenyl-oxymethyl)-5-nitro-imidazole are c~_ tained in the form of light yellow crystals, m.p. 76 C.
According to the process described in Exarnple 1, b~e following compounds are obtained:
1.2 1-Ethyl-2-(4-ethylthiophenyl-oxymethyl)-5-nitro-imiciazole from 1-ethyl-2~chloromethyl-5-nitro-imidazole (EC~I) and 4-ethyl-m~rcaptophenyl;
1.3 1-ethyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 68C, from ~CNI and 3-methyl-4-methyl-mercaptophenol;
1.4 1-ethyl-2-(3-chloro-4~methylthiophenyl-oxymethyl) 5 nitro-imidazole from ECNI and 3-chloro-4-methylmercaptophenol.
X A M P_L E 2 2.1 1-Ethyl-2~t4-methylsulfinylphenyl-oxymethyl)-5-nitro-i 29.3 Grams (0.1 mole) of 1-ethyl-2-(4-methylsulfinyl-phenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and 17.25 g (0.1 mole) of m-chloroper-benzoic acid dissolved in 70 ml of chloroform are added dropwise at 25~C, while stirrin~. The reaction mixture is continued to be stirred for 1 ~our at 25C, then it is shaken out witn diluted soda solution, the chloroform phase is separated, is dried over sodium sulfate and eva-porated. The residue is dissolved and recrystallized from alcohol with the addition of charcoal.
In this manner, 23.5 g (76 ~ of the theory) of 1-ethyl~2 (4-methylsulfinylphenyl oxymethyl)-5-nitro-imidazole are 29 obtained in the form of yellowish crystals, m.p. 90C.
_ g _ ~973~iS J~ G~ ~, hecording to the process described in ~xample 2, the f'ollowir,~, compounds are obtained:
2.2 1-Ethyl-2~(4~ethylsulfinylphenyl-oxymethyl)-5-nitro-imidazole from l-ethyl-2-(4-ethylthiophenyl-oxymethyl)-5-nitro-imidazole;
2.3 1~ethyl-2-(3-methyl-4-methylsulfinylphenyl-oxymethyl)-5-nitro-imidazole, m.p. 80 C~ from 1-ethyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole;
2.4 1-ethyl-2-~3-chloro-4-methylsulfinylphenyl-oxymethyl)-5 nitro-imidazole from l-ethyl-2-(3 chloro-4-methylthio-phenyl-oxymethyl)-5-nitro-imidazole.
Claims (4)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 1-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazole of the formula I
(I) wherein A represents a sulfur atom or a sulfoxide group (-SO-) and R1 represents methyl or ethyl and R2 represents hydrogen, methyl or halogen, in which (a) a nitroimidazole of the formula II
(II) wherein X represents a halogen atom, an acyloxy group or an arylsulfonyloxy group, is reacted with a phenol or the alkali metal or ammonium salt thereof of the formula III
(III) wherein Y represents hydrogen, an alkali metal or ammonium and A, R1 and R2 are as defined in the formula I, or (b) a nitroimidazole of the formula IV
(IV) wherein Y and R2 are as defined above is alkylated, and the sulfide compound thus obtained of the formula I wherein A represents a sulfur atom may be oxidized to give a sulfoxide.
(I) wherein A represents a sulfur atom or a sulfoxide group (-SO-) and R1 represents methyl or ethyl and R2 represents hydrogen, methyl or halogen, in which (a) a nitroimidazole of the formula II
(II) wherein X represents a halogen atom, an acyloxy group or an arylsulfonyloxy group, is reacted with a phenol or the alkali metal or ammonium salt thereof of the formula III
(III) wherein Y represents hydrogen, an alkali metal or ammonium and A, R1 and R2 are as defined in the formula I, or (b) a nitroimidazole of the formula IV
(IV) wherein Y and R2 are as defined above is alkylated, and the sulfide compound thus obtained of the formula I wherein A represents a sulfur atom may be oxidized to give a sulfoxide.
2. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a) in a solvent at a temperature of from 0 to 80°C and the reactants are present in equimolar amounts.
3. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b) in a solvent at a temperature of from 20 to 100°C.
4. A compound 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762650659 DE2650659A1 (en) | 1976-11-05 | 1976-11-05 | 1-AETHYL-2- (PHENYL-OXYMETHYL) -5-NITRO- IMIDAZOLE AND THE METHOD OF MANUFACTURING IT |
| DEP2650659.2 | 1976-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097355A true CA1097355A (en) | 1981-03-10 |
Family
ID=5992495
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA290,219A Expired CA1097355A (en) | 1976-11-05 | 1977-11-04 | 1-ethyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles and process for their manufacture |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5359667A (en) |
| BE (1) | BE860551A (en) |
| CA (1) | CA1097355A (en) |
| CH (1) | CH609688A5 (en) |
| DE (1) | DE2650659A1 (en) |
| ES (1) | ES463709A2 (en) |
| FR (1) | FR2370040A2 (en) |
| GB (1) | GB1590974A (en) |
| IL (1) | IL53302A (en) |
| NL (1) | NL7711943A (en) |
| SE (1) | SE7712417L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2517969B1 (en) * | 1981-08-21 | 1986-07-18 | May & Baker Ltd | METHOD FOR CONTROLLING THE ALTERATION OF TECHNICAL LIQUIDS USING NITROIMIDAZOLE DERIVATIVES |
| JP4723923B2 (en) * | 2005-06-15 | 2011-07-13 | 本田技研工業株式会社 | Shift device |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EG11928A (en) * | 1974-12-16 | 1979-03-31 | Hoechst Ag | Process for preparing of 1-alkyl-2-(phenoxy-methyl)-5-nitro-imidazoles |
-
1976
- 1976-11-05 DE DE19762650659 patent/DE2650659A1/en not_active Withdrawn
-
1977
- 1977-10-29 ES ES463709A patent/ES463709A2/en not_active Expired
- 1977-10-31 NL NL7711943A patent/NL7711943A/en not_active Application Discontinuation
- 1977-11-01 CH CH1331877A patent/CH609688A5/en not_active IP Right Cessation
- 1977-11-03 SE SE7712417A patent/SE7712417L/en unknown
- 1977-11-04 CA CA290,219A patent/CA1097355A/en not_active Expired
- 1977-11-04 JP JP13299477A patent/JPS5359667A/en active Pending
- 1977-11-04 GB GB45943/77A patent/GB1590974A/en not_active Expired
- 1977-11-04 IL IL53302A patent/IL53302A/en unknown
- 1977-11-07 BE BE182406A patent/BE860551A/en unknown
- 1977-11-07 FR FR7733391A patent/FR2370040A2/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2370040B2 (en) | 1980-06-20 |
| IL53302A0 (en) | 1978-01-31 |
| NL7711943A (en) | 1978-05-09 |
| ES463709A2 (en) | 1978-11-01 |
| IL53302A (en) | 1980-12-31 |
| DE2650659A1 (en) | 1978-05-18 |
| BE860551A (en) | 1978-05-08 |
| CH609688A5 (en) | 1979-03-15 |
| SE7712417L (en) | 1978-05-05 |
| JPS5359667A (en) | 1978-05-29 |
| FR2370040A2 (en) | 1978-06-02 |
| GB1590974A (en) | 1981-06-10 |
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