GB1579270A - 1-methyl-2-substituted-methyl-k-nitroimidazoles - Google Patents
1-methyl-2-substituted-methyl-k-nitroimidazoles Download PDFInfo
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- GB1579270A GB1579270A GB2366177A GB2366177A GB1579270A GB 1579270 A GB1579270 A GB 1579270A GB 2366177 A GB2366177 A GB 2366177A GB 2366177 A GB2366177 A GB 2366177A GB 1579270 A GB1579270 A GB 1579270A
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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-SUBSTITUTED-METHYL-5-NITROIMIDAZOLES (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany of 6230 Frankfurt/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:
This invention relates to 1-methyl-2-substituted methyl-5-nitroimidazoles and à process for their manufacture.
The invention provides a compound of the general formula I
in which Z represents an oxygen or sulphur atom, Rl represents a hydrogen atom or a methyl group, R2 and R3, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group, or R2 and R3 together with the nitrogen atom carrying them, represent a pyrrolidine, piperidine or morpholine ring and n is zero or one. The invention also provides physiologically tolerable addition salts of the compounds of the general formula I.
Compounds of the general formula I as defined above may be manufactured (a): a process which comprises reacting a compound of the general formula II
in which Z is as defined above, with a compound of the general formula III
in which Rl and n are as defined above, X represents a halogen atom, such as chlorine, bromine or iodine, and m is zero or one, to form a compound of the general formula IV
in which Z, X R1 and n are as defined above, and reacting the compound of the general formula IV with a compound of the general formula V.
in which R2 and R3 are as defined above, and optionally reacting the reaction product with an acid to form a physiologically tolerable salt.
Compounds of the general formula I as defined above may instead be prepared by (b) reacting a compound of the general formula VI
in which Y represents a halogen atom, such as fluorine, chlorine, bromine, iodine atom, or an acyloxy group, such as an acetyloxy, benzoyloxy, nitrobenzoyloxy group or an aryl-sulphonyloxy group, such as a benzenesulpnonyloxy, toluenesulphonyloxy or mtrobenzenesulphonyloxy group, with a phenol or thiophenol of the general formula VII
in which Z, RJ, R2, R3 and n are as defined above and A represents a hydrogen atom, an ammonium ion or an alkali metal, especially sodium or potassium, and optionally reacting the compound of the general formula I as defined above with an acid to convert it to a physiologically tolerable salt.
Examples of compounds of the general formula II which may be used include 1-methyl-2-(4-aminophenoxymethyl)-5-nitroimidazole and 1-methyl-2-(4 aminophenylthiomethyl).5-nitroimidazole. Their manufacture is described in the Examples.
The following compounds are examples of halocarboxylic acid derivatives of the formula III:
chloroacetic acid chloride or bromide,
bromoacetic acid chloride or bromide,
iodoacetic acid chloride or bromide, o-chloropropionic acid chloride or bromide,
a-bromopropionic acid chloride or bromide,
a-iodopropionic acid chloride or bromide, ss-chloropropionic acid chloride or bromide, ss-bromopropionic acid chloride or bromide, ss-iodopropionic acid chloride or bromide, chloroacetic acid anhydride,
bromoacetic acid anhydride, iodoacetic acid anhydride,
a-chloropropionic acid anhydride,
a-bromopropionic acid anhydride,
a-iodopropionic acid anhydride, ss-chloropropionic acid anhydride, ss-bromopropionic acid anhydride, and P-iodopropionic acid anhydride
Examples of compounds of the general formula IV include:
1-methyl-2- 4-(chloroacetylamino)-phenoxymethyll-5-nitro-imidazole
1-methyl-2- 4-(bromoacetylamino)-phenoxymethyl]-5-nitro-imidazole
1-methyl-2- 4- iodoacetylamino)-phenoxymethyl -5-nitro-imidazole
1-methyl-2- 4- a-chloropropionylamino)-phenoxymethyl -5-nitro-imidazole 1-methyl-2- 4- a-bromopropionylamino)-phenoxymeth I -5-nitro-imidazole 1-methyl-2- 4- (a-iodopropionylamino) henoxymethyl-S-nitro-imidazole 1-methyl-2- 4-bss-chloropropionylamino)-phenoxymethyll-5-nitro-imidazole 1-methyl-2- 4- t3-bromopropionylamino)-phenoxymethyl -5-nitro-imidazole 1-methyl-2- 4-(ss-iodopropionylamino)-phenoxymethyl]-5-nitro-imidazole 1-methyl-2- 4-(chloroacetylamino)-phenylthlomethyll-5-nitro-imidazole I-methyl-2- 4- bromoacetylamino)-phenylthiometh 1 -5-nitro-imidazole 1-methyl-2- 4- (iodoacetylamino)-phenylthiomethyl (5-nitro-imidazole
1-methyl-2-4- (a-chloropropionylamino) -phenylthiomethyl] 5-nitro-imidazole 1-methyl-2- 4- a-bromopropionylamino)-phenylthiometh I -5-nitro-imidazole 1-methyl-2- 4-(a-iodopropionylamino)-phenylthiomethyl-5-nitro-imidazole 1-methyl-2- 4- P-chlornpropionylamino -phenyithiomethyl -5-nitro-imidazole 1-methyl-2- 4- (3-bromopropionylamino)-phenylthiomethyl -5-nitro-imidazole 1-methyl-2- 4- (piodopropionylamino)-phenylthiomethylJ- .
Compounds ot the general formula V, which may be used include, for example:
ammonia, dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine.
Starting substances of the formula VI which may be used include for example: 1-methyl-2-chloro-, -2-bromo-, or -2-iodo-methyl-5-nitroimidazole, 1-methyl-2-acetoxy-, -2-benzoyloxy-, or -2-(4-nitrobenzoyloxy)-methyl-5-nitroimidazole, 1-methyl-2benzenesulphonyloxy-, or -2-(4-toluenesulphonyloxy)-methyl-5-nitroimidazole.
Starting substances of the formula VII, which may be used include for example:
4-(amino-, dimethylamino-, diethylamino-, pyrrolidino-, piperidino-, or morpholinoacetylamino)-phenol or -thiophenol, 4-(a or P-amino-, -dimethylamino-, -diethylamino-, pyrrolidino-, -piperidino-, or -morpholino-propionylamino)-phenol or -thiophenol.
Instead of the free phenols or thiophenols of the formula VII, it is possible to use their alkali metal salts, such as sodium or potassium salts, or their ammonium salts.
The starting substances of the general formula VII may be obtained for example, by reacting 4-aminothiophenol or 4-aminophenol, protected at the oxygen or sulphur atom with a halocarboxylic acid derivative of the formula III, and reacting the corresponding haloacyl compound so formed with a compound of the general formula V, and subsequently splitting off the protective groups. Examples of protecting groups for the oxygen atom in 4-aminophenol inlude acetyl or pyranyl groups. Bis-(4-aminophenyl)-disulphide can advantageously be used as starting substance instead of providing a protective group for the sulphur atom in 4-aminothiophenol. The disulphide is reduced to free thiophenol at the end of the reactions. Metal hydrides, such as lithium-aluminium hydride or sodium in liquid ammonia or triphenylphosphine may be used as reducing agents.
The two reaction stages of the method variant (a) are advantageously carried out with equivalent amounts of the particular starting materials, but it is advisable to use an excess of any volatile reactant.
The reactions are advantageously carried out in a solvent or dispersing agent, but it is also possible to carry them out without solvents or dispersing agents.
The solvents and dispersing agents which are to be used for both reaction stages are preferably aprotic solvents, such as ketones, for example acetone, methyl ethyl ketone, diethyl ketone, or methyl butyl ketone, ethers, for example diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tetrahydrofuran, or dioxane, amides, for example, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, or hexamethylphosphoric acid triamide, or halogenated hydrocarbons, for example, chloroform, 1,2-dichloroethane, cflloro-I,enzene or 1,Z-dichlorobenzene.
The hydrogen halide produced in the first reaction stage can be removed by adding a base, for example, a tertiary organic base, such as, for instance, triethylamine or pyridine, or an inorganic base such as, for instance, an alkali or alkaline earth metal carbonate or bicarbonate.
The hydrogen halide produced in the second reaction stage of the process (a) is bonded by using an excess of the compound of the general formula V. If equivalent quantities of the compound of the general formula V are used in the reaction, the end product of the general formula I is in the form of a salt of the hydrohalic acid and can, if desired, be converted by alkaline adjustment into the free base of the general formula I.
In the process (a), the compounds of general formula II and III may be reacted at a temperature in the range of from 0 to 1200C, preferably 60 to 800C when using a solvent or diluent, or if they are reacted without the use of solvent or diluent, the process may be conducted at a temperature of from 0 to 15û C, preferably 100 to 1300C.
The temperatures of the second reaction stage of the process (a) i.e. the reaction of the compound of the general formula IV with a compound of the general formula V are preferably between 0 and 1200C, especially 60 and 80"C.
The reaction times may range from a few minutes to a few hours, depending on the temperature range.
The process (bis advantageously carried out using equivalent amounts of the particular starting substances, although it is advisable to use any volatile reactant in excess.
The reactions are advantageously carried out in a solvent or dispersing agent. The solvents or dispersing agents which may be used in the reaction may be aprotic. Examples of solvents and dispersing agents include ketones, such as acetone, methyl ethyl ketone, diethyl ketone, or methyl butyl ketone; ethers, such as diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide,
dimethylacetamide, N-methyl-pyrrolidone, or hexamethylphosphoric acid triamide, or halogenated hydrocarbons, such as chloroform, 1,2-dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene.
The hydrogen halide produced can be removed by adding a base, for example, a tertiary
organic base such as, for example, triethylamine or pyridine, or an inorganic base such as,
for example an alkali or an alkaline earth metal carbonate or bicarbonate.
The process (b) may be conducted at a temperature in the range, of from 0 to 1200C,
preferably 40 to 800C.
The reaction times may range from a few minutes to a few hours depending on the
temperature range.
The compounds of the general formula I may optionally be converted into the
corresponding physiologically tolerable salts in the usual manner by adding an acid.
Examples of acids which may be used include hydrohalic acids, especially hydrochloric acid,
sulphuric acid, phosphoric acid, acetic acid, lactic acid, and tartaric acid.
If necessary, the products of the process can be purified by recrystallising from an
appropriate solvent or solvent mixture.
The compounds of the general formula I are physiologically tolerable and are generally
suitable for combating protozoal illnesses in humans and animals, as caused by infections
with trypanasomes such as Trypanasoma brucei, Trypanosoma rhodesiense, Trypanosoma gambiense and trichomonades, such as Trichomonas foetus, Trichomonas vaginalis.
The present invention also provides a pharmaceutical preparation which comprises one
or more compounds of the general formula I in admixture or conjunction with a
pharmaceutically suitable carrier or other constitutent or constitutents.
The compounds of the invention or pharmaceutical preparations may be administered
either enterally, for example, orally, or parenterally and may be used to treat both human
and non-human animals.
For oral administration the preparation may be in unit dosage form, for example in the
form of tablets or capsules, and may contain 10 to 1,000 mg of the compound of the
invention per unit per daily dose. The parenteral administration may be effected in the form
of solutions, especially in water, and optionally with the addition of physiologically
tolerable additives for the purpose of stabilization.
The following examples illustrate the invention.
MANUFACTURING EXAMPLES:
Example 1 (Method a) 1.1) 1 -Methyl-2-(4-dimethylaminoacetylaminophenoxymethyl)-5-nitroimidazole dihydroch bride 36.1 g (0.1 mole) of 1.methyl-2-(4-chloroacetylaminophenoxy-methyl)-S-nitroimidazole monohydrochloride are suspended in 500 ml of ethylene glycol dimethyl ether, and dimethylamine gas is introduced while stirring well. After the slightly exothermic reaction (up to about 35"C) has died down, the mixture is heated to 750C and dimethylamine gas is introduced for a further hour. The precipitated dimethylamine hydrochloride is suctionfiltered from the cooled reaction solution, the filtrate is concentrated by evaporation, the residue is taken up in ethyl acetate., extracted by shaking with water, and the organic phase is dried over sodium sulphate and concentrated by evaporation. The end product that remains is an oil, which is dissolved in ethanol and converted into the dihydrochloride by adding 2 mole equivalents of ethanolic hydrochloric acid. 35 Grams (86 % of the theoretical yield) of 1-methyl-2-(4-dimethyl-aminoacetylaminophenoxymethyl)-5-nitroimidazole dihydrochloride in the form of white crystals, melting at 1940C, are obtained.
The 1methyl-2(4-chloroacetylaminophenoxymethyl-S-mtroimidaWle monohydrochloride (melting point 203"C with decomposition) used as starting substances is obtained by reacting 24.8 grams (0.1 mole) of 1-methyl-2-(4-amino-phenoxymethyl)-5-nitroimidazole with 11.3 grams (0.1 mole) of chloroacetyl chloride in ethylene glycol dimethyl ether at 30"C (while cooling with ice) and subsequently boiling for 2 hours under reflux.
The 1-methyl-2-(4-aminophenoxymethyl)-5-nitroimidazole (orange-red crystals, melting point 152"C) used as starting substance is obtained in an 85 % yield by hydrolysing 1-methyl-2-(4-acetaminophenoxymethyl)-5-nitroimidazole using 40 % strength sulphuric acid (2 hours, 80 - 90"C).
The 1-methyl-2-(4-acetaminophenoxymethyl)-5-nitro-imidazole (pale yellow crystals, melting point 163"C) used for preparing the starting substance is obtained in a 95% yield by reacting molar amounts of 4-acetoamino-phenol with 1-methyl-2-chloromethyl-5nitroimidazole in dimethylformamide (1 hour, 30 - 40 "C) in the presence of potassium carbonate.
The preparation of 1-methyl-2-chloromethyl-5-nitro-imidazole is described in German
Offenlegungsschrift No. 1 595 929; it is effected by reacting the 1-methyl-2-hydroxymethyl compound with thionyl chloride.
The following are obtained according to the method described in Example 1.1: 1.2) 1.Methyl-2-(4-aminoacetylaminophenoxymethyl)-S-nitroimidazole hydrochloride, m.p. 268"C, from 1-methyl-2-(4-chloroacetylaminophenoxymethyl)-5-nitroimidazole monohydrochloride (A) and ammonia.
1.3) 1-Methyl-2- (4-diethylaminoacetylaminophenoxymethyl)-5-nitroimidazole dihydrochloride, m.p. 1700C, from A and diethylamine.
1.4) 1-Methyl-2-(4-pyrrolidinoacetylaminophenoxymethyl)-5-nitroimidazole dihydrochloride, m.p. 185"C, from A and pyrrolidine.
1.5) 1-Methyl-2-(4-piperidinoacetylaminophenoxymethyl)-5-nitroimidazole dihydroch bride, m.p. 188"C, from A and piperidine.
1.6) 1-Methyl-2-(4-morpholinoacetylaminophenoxymethyl)-5-nitroimidazole dihydrochloride,m.p. 200"C, from A and morpholine.
2.1) 1-Methyl-2-[4-(a-aminopropionylamino)-phenoxymethyl]-s-nitroimidazole dihydrochloride from 1-methyl-2-[4-(a-chloropropionylamino)-phenoxymethyl]-5-nitroimidazole monohydrochloride (B) and ammonia.
2.2) 1-Methyl-2-[4- a-dimethylaminopropionylamino)-phenoxymethylj-S-nitroimidazole dihydrochloride, m.p. 201"C, from B and dimethylamine.
2.3) 1-Methyl-2-[4-(α-diethylaminopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from B and diethylamine.
2.4) 1-Methyl-2-[4-(α-diethylaminopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from B and pyrrolidine.
2.5) 1-Methyl-2-[4-(a-piperidinopropionylamino)-5-nitroimidazole dihydrochloride, from B and piperidine.
2.6) 1-Methyl-2-[4- (a-morpholinopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from B and morpholine.
3.1) 1-Methyl-2-[4-(ss-aminopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from 1 -methyl-2-[-4-(ss-chloropropionylamino)-phenoxymethyl-5-nitroimidazole monohydrochloride (C) and ammonia.
3.2) 1-Methyl-2-[4-(ss-dimethylaminopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, m.p. 196 C, from C and dimethylamine.
3.3) 1-Methyl-2-[4-(ss-diethylaminopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from C and diethylamine.
3.4) 1-Methyl-2-[4-(ss-pyrrolidinopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from C and pyrrolidine.
3.5) 1-Methyl-2-[4-(fi-piperidinopropionylamino)-phenoxymethyl]-5-nitroimidazole dihydrochloride, from C and piperidine.
3.6) 1-Methyl-2-[4-(f3-rnorpholinopropionylamino)-phenoxymethyl]-5-nitroimidazole dih drochloride, from C and morpholine.
4.1 1-Methyl-2-(4-aminoacetylaminophenylthiomethyl).5-nitroimidazole hydrochloride, from 1-methyl-2-(4-chloroacetylaminophenylthiomethyl)-s-nitroimidazole monohydrochbride (D) and ammonia.
4.2) 1 -Methyl-2-(4-dimethylaminoacetylaminophenylthiomethyl)-5-nitroimidazole dihydrochloride, m.p. 177"C, from D and dimethylamine.
4.3) 1-Methyl-2-(4-dimethylaminoacetylaminophenylthiométhyl)-5-nitroimidazole dihydrochloride, from D and diethylamine.
4.4) 1-Methyl-2-(4-pyrrolidinoacetylaminophenylthiomethyl)-5-nitroimidazole dihydrochloride, from D and pyrrolidine.
4.5) 1-Methyl-2-(4-piperidinoacetylaminophenylthiomethyl)-5-nitroimidazole dihydroch bride, from D and piperidine.
4.6) 1-Methyl-2-(4-morpholinoacetylaminophenylthiomethyl)-5-nitroimidazole dihydrochloride, from D and morpholine.
5.1) 1-Methyl-2-4-(a-aminopropionylamino)-phenylthiomethyl]-S-nitroimidazole dihydrochloride, from 1-methyl-2-[4-(a-chloropropionylamino)-phenylthiomethyl]-5nitroimidazole monohydrochloride (E) and ammonia.
5.2) 1-Methyl-2-[4-(a-dimethylaminopropionylamino)-phenylthio-methyl]-5- nitroimidazole dihydrochloride, from E and dimethylamine.
5.3) 1-Methyl-2-[4-(a-doethylaminopropionylamino)-phenylthio-methyl]-5- nitroimidazole dihdrochloride, from E and diethylamine.
5.4) 4) 1 -Methyl-2-4-(ct-pyrrolidinopropionylamino -phenylthio-methyl]-S-nitroimidazole dih drochloride, from E and pyrrolidine.
5.5 1-Methyl-2-[4-(a-pipen.dinopropionylamino)-phenylthiomethyl] -5-nitroimidazole dih drochloride, from F and piperidine.
5.6) 1-Methyl-2-[4-(a-morpholinopropionylamino)-phenylthiomethyl]-5-nitroimidazole dihydrochloride, from E and morpholine.
6.1) 1 -Methyl-2-[4-(I3-aminopropionylamino)-phenykhiomethylj-S-nitroimidawle dihydrochloride, from 1-methyl-2-[4- ( -chloropropionylamino)-phenylthiomethylj-S nitroimidazole monohydrochloride (F) and ammonia.
6.1) 1-Methyl-2-[4-(ss-dimethylaminopropionylamino)-phenylthiomethyl]-5- nitroimidazole dihydrochloride, from F and dimethylamine.
6.3) 1-Methyl-2-[4-(ss-diethylaminopropionylamino)-phenylthiomethyl]-5-nitroimidazole dihydrochloride, from F and diethylamine.
6.4) 1-Methyl-2-[4-(ss-pyrrolidinopropionylamino)-phenylthiomethyl]-5-nitroimidazole dihydrochloride, from F and pyrrolidine.
6.5) 1-Methyl-2-[4-(ss-piperidinopropionylamino)-phenylthiomethyl]-5-nitroimidazole dihydrochloride, from F and piperidine.
6.6 1-Methyl-2-[4-(ss-morpholinopropionylamino)-phenylthiomethyl]-5-nitroimidazole dihydrochloride, from F and morpholine.
The 1-methyl-2-[4-(α-chloropropionylamino)-phenoxymethyl]-5-nitroimidazole monohydrochloride (B), m.p. 200 C with decomposition, used as starting substance for preparing the compounds 2.1 - 2.6 is obtained by reacting equimolar amounts of 1-methyl-2-(4 aminophenoxymethyl)-5-nitroimidazole with a-chloropropionyl chloride.
The 1-methyl-2-[4-(ss-chloropropionylamino)-phenoxymethyl]-5-nitroimidazole monohydrochloride (C), m.p. 205 C with decomposition, used as starting substance for preparing the compounds 3.1 -3.6, is obtained by reacting equimolar amounts of 1-methyl-2-(4 aminophenoxymethyl)-5-nitroimidazole with ss-chloropropionyl chloride.
The 1 -methyl-2-(4-chloroacetylaminophenylthiomethyl)-S-nitroimidazole monohydroch bride (D) used as starting substance for the preparation of compounds 4.1 - 4.6 is obtained by reacting equimolar amounts of 1-methyl-2-(4-aminophenylthiomethyl)-S-nitroimidazole with chloroacetyl chloride.
The 1-methyl-2- 4-(α-chloropropionylamino)-phenylthiomethyl]-5-nitroimidazole monohydrochloride (E) used as starting substance for the preparation of the compounds 5.1 - 5.6, is obtained by reacting equirnolar amounts of 1-methyl-2-(4-aminophenylthiomethyl)5-nitroimidazole with a-chloropropionyl chloride.
The 1-methyl-2-[4-(ss-chloropropionylamino)-phenylthiomethyl]-5-nitroimidazole monohydrochloride F) used as starting substance for the preparation of the compounds 6.1 - 6.6 is obtained by reacting equimolar quantities of 1-methyl-2-(4-aminophenylthio methyl)-5-nitroimidazole with ss-chloropropionyl chloride.
The 1-methyl-2-(4-aminophenylthiomethyl)-5-nitroimidazole (m.p. 156"C) necessary for preparing the starting substance for the compounds 4.1 - 6.6. is obtained by reacting 1-methyl-2-chloromethyl-5-nitroimidazole (German Offenlegungsschrift No. 1 595 929) with equimolar amounts of 4-aminothiophenol in dimethylformamide at room temperature in the presence of potassium carbonate.
Example 2 (Method b) 1.1 1-Methyl-2-(4-dimethylaminoacetylaminophenoxymethyl)-5-nitroimidazole dihydroch bride 17.6 grams (0.1 mole) of 1-methyl-2-chloromethyl-5-nitroimidazole and 23.1 grams (0.1 mole) of 4-dimethylaminoacetamino-phenol hydrochloride are suspended in 150 ml of dimethylformamide, 27.6 grams (0.2 mole) of pulverised potassium carbonate are added and the reaction mixture is heated for one hour at 500C. The reaction medium dimethylformamide is then totally distilled off in vacuo, the residue is treated with water and ethyl acetate, the ethyl acetate phase is separated off, dried over sodium sulphate and concentrated by evaporation. The end product thus obtained is in the form of an oily residue. This is converted into the dihydrochloride as in method a) with alcoholic hydrochloric acid. The compound is identical to the compound with a melting point of 194"C prepared according to method a, Example 1, 1.1.
4-dimethylaminoacetaminophenol hydrochloride is prepared by splitting off the tetrahydropyranyl protective group in the 4-dimethyl-ammoacetamino-0-tetrahydropyranyl-2phenol by means of hydrochloric acid. 4-dimethylaminoacetamino-0-tetrahydropyranyl-2phenol is obtained by reacting 4-amino-0-tetrahydropyran-2-yl-phenol with chloroacetyl chloride and then with dimethylamine.
WHAT WE CLAIM IS;
1. A compound of the general formula I
in which Z represents an oxygen or sulphur atom, R1 represents a hydrogen atom or a methyl group, R2 and R3, which may be the same or different, each represents a hydrogen atom, or a methyl or ethyl group, or R2 and R3 together with the nitrogen atom carrying them represent a pyrrolidine, piperidine or morpholine ring, and n is zero or one; or a physiologically tolerable salt of a compound of the general formula I.
2. A salt of a compound of the general formula I as defined in claim 1 with a hydrohalic acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid or tartaric acid.
3. A hydrochloride addition salt of a compound of the general formula I as defined in
Claims (1)
- claim 1.4. Any compound as claimed in claim 1 which is specifically mentioned herein.5. 1-Methyl-2-(4-dimethylaminoacetylaminophenoxymethyl) -5-nitroimidazole dihydrochloride.6. 1:Methyl-2-(4- 1-Methyl-2-(4-diethylaminoacetylaminophenoxymethyl)-5-nitroimidazole dihyd- rochloride.7. 1-Methyl-2-(4-morpholinoacetylaminophenoxymethyl)-5.nitroimidazole dihydrochloride.8. 1-Methyl-2-[4-(a-dimethylaminopropionylamino)-phenoxy-methyl]-5-nitroimidazole dihydrochloride.9. 1-Methyl-2-[4-(ss-dimethylaminopropionylamino)-phenoxy-methyl]-5-nitroimidazole dihydrochloride.10. 1-Methyl-2-(4-dimethylaminoacetylaminophenylthiomethyl)-5-nitroimidazole dihydrochloride.il. A process for the manufacture of a compound as claimed in claim I, which comprises reacting a compound of the general formula IIin which Z is defined as in claim 1, with a compound of the general formula IIIin which R1 and n are as defined in claim 1, X represents a halogen atom and m is zero or one, to form a compound of the general formula IV.in which Z, R1 and n are as defined in claim 1, and reacting the compound of the general formula IV with a compound of the general formula Vin which R2 and R3 are as defined in claim 1; and optionally reacting the reaction product with an acid to form a physiologically tolerable salt.12. A process as claimed in claim 11, wherein X represents a chlorine, bromine or iodine atom.13. A process as claimed in claim 11, wherein the compound of the general formula III is any one of those specifically mentioned herein.14. A process as claimed in claim 11, wherein the compound of the general formula IV is any one of those specifically mentioned herein.15. A process as claimed in any one of claims 11 to 14, wherein the compound of the general formula IV is reacted with ammonia, dimethylamine, diethylamine, pyrrolidine, piperidine or morpholine.16. A process as claimed in any one of claims 11 to 15, wherein the compound of the general formula II is reacted with the compound of the general formula III in a solvent or diluent at a temperature in the range of from 0 to 1200C.17. A process as claimed in claim 16, wherein the temperature is in the range of from 60 to 80 C.18. A process as claimed in any one of claims 11 to 15, wherein the compound of the general formula II is reacted with the compound of the general formula III without a solvent or diluent, at a temperature in the range of from 0 to 1500C.19. A process as claimed in claim 18, wherein the temperature is in the range of from 100 to 1300C.20. A process as claimed in any one of claims 11 to 19, wherein the compound of the general formula IV is reacted with a compound of the general formula V at a temperature in the range of from 0 to 1200C.21. A process as claimed in claim 20, wherein the compound of the general formula IV is reacted with a compound of the general formula V at a temperature in the range of from 60 to 800C.22. A process for the manufacture of a compound as claimed in claim 1, which comprises reacting a compound of the general formula VIin which Y represents a halogen atom or an acyloxy group, with a compound of the general formula VIIin which Z, R1, R2, R3 and n are as defined in claim 1, and A represents a hydrogen atom, an ammonium ion or an alkali metal, and optionally reacting the reaction product with an acid to form a physiologically tolerable salt.23. A process as claimed in claim 22, wherein the compound of the general formula VI is any one of those specifically mentioned herein.24. A process as claimed in claim 22 or claim 23, wherein the compound of the general formula VII is any one of those specifically mentioned herein.25. A process as claimed in any one of claims 22 to 24, conducted at a temperature in the range of from 0 to 1200C.26. A process as claimed in claim 25, conducted at a temperature in the range from 40 to 800C.27. A process for the manufacture of a compound as claimed in claim 1 substantially as hereinbefore described in either of the Examples.28. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 11 to 27.29. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 10 or 28, in admixture or conjunction with one or more pharmaceutically suitable carriers.30. A pharmaceutical preparation as claimed in claim 29, which is in unit dosage form.A pharmaceutical preparation as claimed in claim 30, which comprises from 10 to 1000 mg. of a compound as claimed in any one of claims 1 to 10 or 28 per unit.31. A pharmaceutical preparation as claimed in claim 30, which comprises from 10 to 1000 mg. of a compound as claimed in any one of claims 1 to 10 or 28 per unit.32. A pharmaceutical preparation as claimed in any one of claims 29 to 31, in a form suitable for oral or parenteral administration.33. A process for the treatment of a protozoal infection in a non-human animal, which comprises administering a preparation as claimed in any one of claims 29 to 32.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762625195 DE2625195A1 (en) | 1976-06-04 | 1976-06-04 | 1-METHYL-2- (4-AMINOPHENYL-SUBSTIT.- METHYL) -5-NITRO-IMIDAZOLES AND THE METHOD FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1579270A true GB1579270A (en) | 1980-11-19 |
Family
ID=5979864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2366177A Expired GB1579270A (en) | 1976-06-04 | 1977-06-03 | 1-methyl-2-substituted-methyl-k-nitroimidazoles |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE2625195A1 (en) |
| GB (1) | GB1579270A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515790A (en) * | 1981-11-30 | 1985-05-07 | Hoffmann-La Roche Inc. | Antiprotozoal 2-nitroimidazole compounds |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3269449D1 (en) * | 1981-11-02 | 1986-04-03 | Cermol Sa | P-acylaminophenol derivatives with a therapeutical effect, process for their preparation, and compositions with a therapeutical effect containing these derivatives as pharmacologically active ingredients |
| CA2479071A1 (en) * | 2002-03-12 | 2003-09-18 | Hiroyuki Tawada | Process for producing optically active sulfoxide derivative |
-
1976
- 1976-06-04 DE DE19762625195 patent/DE2625195A1/en not_active Withdrawn
-
1977
- 1977-06-03 GB GB2366177A patent/GB1579270A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515790A (en) * | 1981-11-30 | 1985-05-07 | Hoffmann-La Roche Inc. | Antiprotozoal 2-nitroimidazole compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2625195A1 (en) | 1977-12-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |