DE2625195A1 - 1-METHYL-2- (4-AMINOPHENYL-SUBSTIT.- METHYL) -5-NITRO-IMIDAZOLES AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT »

File number: HOE 76 / F 131

Date: O3.O6.1976 Dr.Km/hs

i-Methyl-2- (4-aminophenyl-substit.-methyl) -5-nitro-imidazoles and process for their preparation

The invention relates to 1-methyl-2- (4-aminophenyl substit. methyl) -5-nitro-imidazole of the formula I

R ² NH-C-CH- (CH-) _ -N _v (D

111 \ 3

OR ¹ R ^J

where Z is oxygen or sulfur, R is hydrogen or methyl, η zero or one (i.e. no or one additional methylene group)

2 3

and R and R, which can be the same or different, water

2 3

substance, methyl or ethyl or in which R and R together

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together with the nitrogen atom carrying them a pyrrolidine, Form piperidine or morpholine ring, as well as addition salts of these Compounds (I) with a physiologically acceptable acid.

The invention also relates to a process for the preparation of 1-methyl-2- (4-aminophenyl-substit.-methyl) -5-nitro-imidazoles of formula I, as well as their addition salts with a physiologically acceptable acid, which is characterized in that one

a) an i-methyl-2- (4-aminophenyl-substit.-methyl) -5-nitro-imidazole of formula II

-NH,

ON

(ID

I

wherein Z has the meaning given, with a halocarboxylic acid derivative of the formula III

X- (CH ^) -CH-CO-

.1

O-CO-CH- (CH ₂ ) _n -

(III)

where R has the meaning given and X is a halogen atom, such as chlorine, bromine or iodine and η and m are zero or one,

implements,

and the haloacylamino compounds of the formula thus obtained

NH-C-CH- (CH ₀ ) -X HM ^{2 n} OR

(IV)

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wherein Z, X, R and η have the meanings given, with ammonia or an amine of the formula V

/ ^r2

HN (V)

2 3
wherein R and R have the meanings given, or converts

b) mono-methyl-2-substit.-methyl-5-nitro-imidazole of the formula VI

(VI)

wherein Y is a halogen atom such as fluorine, chlorine, bromine, iodine or an acyloxy group such as acetyloxy, benzoyloxy, nitrobenzoyloxy or an arylsulfonyloxy group, such as benzenesulfonyloxy, toluenesulfonyloxy, Nitrobenzenesulfonyloxy means with a phenol or thiophenol of the formula VII

R ² AZ- / V "NH-C-CH- (CH") -N (VII)

HI ₁ ⁿ \

OR

12 3
in which Z, R, R, R and η have the meanings given and A is hydrogen or an alkali metal, in particular sodium or potassium, or ammonium

and optionally the compound of the formula I thus obtained by adding a physiologically acceptable acid to the corresponding one Salt transferred.

The starting materials of the formula II are 1-methyl-2- (4-aminophenyl-oxymethyl-5-nitroimidazole and 1-methyl-2- (4-aminophenyl-thiomethyl) -5-nitro-imidazole into consideration. Their production is described in the context of the examples.

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Examples of halogenated carboxylic acid derivatives of the formula III are in question

Chloroacetic acid chloride or bromide, bromoacetic acid chloride or bromide, iodoacetic acid chloride or bromide, tfC-chloropropionic acid chloride or bromide, oC-bromopropionic acid chloride or bromide, δ ^ -iodopropionic acid chloride or bromide, β -Chloropropionic acid chloride or bromide, ß-bromopropionic acid chloride or bromide, / 3-iodopropionic acid chloride or bromide, chloroacetic anhydride, bromoacetic anhydride, iodoacetic anhydride , cL -chloropropionic anhydride, ei -bromopropionic anhydride , et-iodopropionic anhydride,

β -chloropropionic anhydride β- bromo-propionic anhydride β- iodopropionic anhydride »

As haloacylamino compounds of the formula IV, for example in question

1-methyl-2- / 4- (chloracetylamino) -phenyl-oxymethylZ-S-nitro-imide-

1 -Methyl-2 - / [4- (bromoacetylamino) -phenyl-oxymethylZ-S-nitro-imidazole 1-methyl-2- / 4- (iodoacetylamino) phenyl-oxymethylZ-S-nitro-imidazole 1-methyl-2- / 4- (o6-chloropropionylamino) -phenyl-oxymethylZ-S-nitroimidazole

1-methyl-2- / 4- (oO -bromopropionylamino) -phenyl-oxymethylZ-S-nitro- imidazole

1-methyl-2- / 4- (CO -iodopropionylamino) -phenyl-oxymethylZ-S-nitroimidazole

1-Methy1-2- / 4- (β- chloropropionylamino) -phenyl-oxymethylZ-S-nitroimidazole

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1-methyl-2- / 4- (β- bromopropionylamino) -phenyl-oxymethylZ-5-nitroimidazole 1-methyl-2 - / _ 4 - (/ 3 -iodopropionylamino) -phenyl-oxymethyl7-5-nitroimidazole 1-methyl -2 - / _ 4- (chloracetylamino) -phenyl-thiomethy ^ -S-nitro-imide-

1-methyl-2- / 4- (bromoacetylamino) -phenyl-thiomethylZ-5-nitro-imidazole 1-methyl-2- / 4- (iodacetylaraino) -phenyl-thiomethyl-S-nitro-iniidazole 1-methyl-2- / 4- ( ού -chlorpropionylamino) -phenyl-thiomethylZ-5-nitroimidazole 1-methyl-2- / 4- ( ob -bromopropiony! Amino) -phenyl-thiomethylZ-S-nitroimidazole 1 -methyl-2 - / _ 4- ( oC -iodopropionylamino) -phenyl-thiometh.yl7-5-nitroimidazole

1-methyl-2 - / _ 4- (A -chlorpropionylamino) -phenyl-thiomethylZ-S-nitroimidazole 1-methyl-2- / 4- (/ 2> -bromopropionylamino) -phenyl-thiomethylZ-S-nitroimidazole 1-methyl- 2- / _ 4- ( β- iodopropionylamino) -phenyl-thiomethyl7-5-nitroimidazole.

As amines of the formula V, for example, come into question

Ammonia, dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine.

As starting materials of the formula VI, for example, come into question

1-methyl-2-chloro-, -2-bron-, ^ -iodomethyl-S-nitro-imidazole, 1-methyl-2-acetoxy-, -2-benzoyloxy-, -2- (4-nitrobenzoyloxy) -methyl-5- " nitro-imidazole, i-methyl-2-benzenesulfonyloxy-, -2- (4-toluenesulfonyloxy) -methyl-5-nitro-imidazole.

As starting materials of the formula VII, for example, come into question

4- (amino, dimethylamino, diethylamino, pyrrolidino, piperidino,

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Morpholino-acetylamino) -phenol or -thiophenol, 4- (ce-- or / 2-amino-, -dimethylamine) -, -diethylamino-, pyrrolidino-, -Piperidino-, -Morpholino-propionylamino) -phenol or. -thiophenol .

Instead of the free phenols or thiophenols of the formula VII can their alkali metal salts, such as sodium or potassium salts, and their ammonium salts can also be used.

The starting materials of the formula VII can be obtained, for example are obtained by reacting 4-aminophenol or 4-aminothiophenol with halocarboxylic acid derivatives which are protected on the oxygen or sulfur atom of the formula III to the corresponding halo-acyl compounds and subsequent reaction with ammonia or amines of the Formula V and subsequent splitting off of the protective groups. As a protective group for the oxygen atom on the 4-aminophenol, for example in question the acetyl and pyranyl groups. Instead of these protective groups for the sulfur atom on the 4-aminothiophenol can advantageously bis (4-aminophenyl) disulfide as the starting material be used. The disulfide is reduced to the free thiophenol at the end of the reaction. As reducing agents, for example Metal hydrides such as lithium aluminum hydride or sodium in liquid ammonia or triphenylphosphine are possible.

The two reaction steps of process variant a) are generally expedient with equivalent amounts of the respective Starting materials carried out. In the case of volatile reaction partners, we recommend the application of an excess.

The reactions are advantageous in a solution or distribution They are also used as solvents or distributing agents feasible.

Aprotic solvents are preferably used as solvents or distributing agents in both reaction steps, for example

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AO

wise ketones, such as acetone, methyl ethyl ketone, diethyl ketone, methyl butyl ketone, Ethers, such as diisopropyl ether, ethylene glycol dimethyl ether, diethyl ether, diethylene glycol dimethyl ether, diethyl ether, Tetrahydrofuran, dioxane, amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric acid triamide, or halogenated hydrocarbons, such as chloroform, 1,2-dichloroethane, Chlorobenzene or 1,2-dichlorobenzene.

The hydrogen halide obtained in the first reaction step can be intercepted by adding a base. Suitable bases are, for example, tertiary organic bases, such as triethylamine or pyridine, or inorganic bases such as alkali and alkaline earth carbonates and bicarbonates.

The one obtained in the second reaction step of process variant a) Hydrogen halide is bound when using an excess of the amine of the formula V used. In implementation equivalent amounts of the amine of the formula V, the end product of the formula I is obtained as a hydrohalic acid salt and can optionally be converted into the free base of the formula I by making them alkaline.

The temperatures of the first reaction step of the process variant a) are held by the use of a solvent or diluent between 0 and 120 ⁰ C, preferably at 60 to 80 ⁰ C without solvents or diluents between 0 and 150 ⁰ C, preferably at 100-130 ⁰ C.

The temperatures of the second reaction step of the process variant a) are between 0 and 120 ⁰ C, preferably at 60-80 ⁰ C.

The reaction times are a few minutes depending on the temperature range until a few hours.

Process variant b) is generally expedient with equivalents Quantities of the respective starting materials carried out. at

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For volatile reactants, it is advisable to use an excess.

The reactions are advantageously carried out in a solvent or spreading agent carried out. Come as a solution or a means of distribution preferably aprotic solvents in question, for example ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl butyl ketone, Ethers, such as diisopropyl ether, ethylene glycol dimethyl ether, diethyl ether, diethylene glycol dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, or Halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, chlorobenzene or 1,2-dichlorobenzene.

The resulting hydrogen halide can be obtained by adding a base be intercepted. Suitable bases are, for example, tertiary bases such as triethylamine or pyridine, or inorganic bases such as alkali and alkaline earth carbonates and bicarbonates, ♦ organic

The temperatures of the process variant b) are between 0 and 120 ⁰ C, preferably at 40 - 80 ⁰ C.

The reaction times are a few minutes to a few hours, depending on the temperature range.

The new compounds of the formula I can optionally be used in customary Way can be converted into the corresponding salts by adding a physiologically acceptable acid. As physiological Compatible acids are, for example, hydrohalic acids, in particular hydrochloric acid, also sulfuric acid, phosphoric acid, Acetic acid, lactic acid, tartaric acid.

If necessary, the products of the process can be cleaned by recrystallization from a suitable solvent or Solvent mixture take place.

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The new compounds of .Formel.1 are well tolerated and are suitable for combating protozoal diseases in humans and animals, such as those caused by infections with trypanosomes such as Trypanosoma brucei _f Trypanosoma rhodiense, Trypanosoma gambiense and Tricholacnadcn, v / Ig Trichimonas fetus, Trichomonas vaginal will.

The new compounds can be used orally or parenterally.

Oral use takes place in the form of conventional pharmaceutical preparations, e.g. tablets or capsules, which per daily dose contain about 10 to 1,000 mg of the active ingredient mixed with a common carrier and / or constituent. Parenteral use takes place in the form of solutions, in particular in water, optionally with the addition of physiologically compatible Additives for stabilization.

10 -

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A3

Manufacturing examples :

Example 1 (method a)

1.1) 1-Methyl-2- (4-dimethylamino-acetyiaminophenyi-oxyiuethyl) -5- nitro-imidazole dihydrochloride

36.1 g (0.1 mol) of 1-methyl-2- (4-chloroacetylaminophenyl-oxymethyl) -5-nitro-imidazole monohydrochloride are suspended in 500 ml of ethylene glycol dimethyl ether and dimethylamine gas is passed in with thorough stirring. After the weakly exothermic reaction has subsided (up to approx. 35 ^° C.), the ^{mixture is heated to 75 °} C. and dimethylamine gas is passed in for a further hour. The cooled reaction solution is filtered off with suction from the precipitated dimethylamine hydrochloride, evaporated, the residue taken up in ethyl acetate, extracted with water, the organic phase dried over sodium sulfate and evaporated. The end product that remains is an oil, it is dissolved in ethanol and converted into the dihydrochloride by adding 2 molar equivalents of ethanolic hydrochloric acid. As 35 g (86% of theory) of 1-methyl-2- (4-dimethylamino-acetylaminophenyl-oxymethyl) -5-nitro-imidazol-dihydrochloride in the form of white crystals, mp. 194 ⁰ C.

Used as a starting material 1-methyl-2- (4-chloracetylaminophenyl-oxymethyl) -5-nitro-imidazole monohydrochloride (mp. 203 ⁰ C u. Dec.) Is obtained by reacting 24.8 g (0.1 mole ) 1-methyl-2- (4-aminophenyl-oxymethyl) -5-nitro-imidazole 11.3 g (0.1 mole) of chloroacetyl chloride in Äthylenglycoldimethyläther at 30 ⁰ C (with ice cooling) followed by 2 hours of boiling under reflux.

Used as a starting material 1-methyl-2- (4-aminophenyloxymethyl) -5-nitro-imidazole (orängerote crystals, mp. 152 ⁰ C) is obtained by saponification of 1-methyl ~ 2- (4-acetaminophenyl-oxymethyl) -5 -nitro-imidazole using 40% sulfuric acid (2-

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IN THE

Vl -

Hours, 80-90 ^° C.) in 85% yield.

The used to represent the starting material 1-methyl-2- (4-acetaminophenyl-oxymethyl) -5-nitro-imidazole (pale yellow crystals, mp. 163 ⁰ C) is obtained by reacting molar amounts of 4-acetaminophenol with 1-methyl ^ (- 40 ⁰ C 1 hour 30) is in the presence of potassium carbonate in 95% yield -chloromethyl-S-nitro-imidazole in dimethylformamide.

The preparation of 1-Methy1-2-chloromethyl-5-nitro-imidazole is described in DOS 1,595,929; it takes place by reacting the 1-methyl-2-hydroxymethyl compound with thionyl chloride.

After the example 1.1. procedures described are obtained ^

1.2) From 1-methyl-2- (4-chloroacetylaminophenyl-oxymethyl) -5-nitroimidazole monohydrochloride (A) and ammonia 1-methyl-2- (4-aminoacetylaminophenyl-oxymethyl) -5-nitro-imidazole hydrochloride, Mp. 268 ° C.

1.3) From A and diethylamine, 1-methyl-2- (4-diethylamino-acetylaminophenyl-oxymethyl) -5-nitro-imidazol-dihydrochloride, mp. 170 ⁰ C.

1.4) From A and pyrrolidine, 1-methyl-2- (4-pyrrolidino-acetylamino-phenyl-oxymethyl) -S-nitro-imidazole dihydrochloride, Mp 185 ° C.

1.5) From A and piperidine 1-methyl-2- (4-piperidino-acetylaminophenyl-oxymethyl) -5-nitro-imidazole dihydrochloride, M.p. 188 ° C.

1.6) From the A and morpholine 1-methyl-2- (4-morpholino-acetylaminophenyl-oxymethyl) -5-nitro-imidazol-dihydrochloride, mp. 200 ⁰ C.

2.1) From 1-methyl-2- / 4- (ού -chlorpropionylamino) -phenyl-oxymethyl / -5-nitro-imidazole-monohydrochloride (B) and ammonia the 1-methyl-2- ^ 4- ( ού -aminopropionylamino) -phenyl-oxymethylZ-S-nitro-imidazole hydrochloride

- 12 -

- 12. -

2.2) From B and dimethylamine 1-methyl-2- / 4- ( CC -dimethylaminopropionylamino) -phenyl-oxymethyl-S-nitro-imidazole-dihydro-chloride, mp. 201 ⁰ C.

2.3) From B and diethylamine 1-methyl-2 - / _ 4- (<χ -diäthyiaminopropionylamino) -phenyl-oxymethyl-S-nitro-imidazole-dihydrochloride.

2.4) From B and pyrrolidine 1-methyl-2 - / _ 4- ( CL -pyrrolidino-proionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole dihydrochloride

2.5) From B and piperidine 1-methyl-2- / 4- ( OO -piperidino-propionyl-amino) -5-nitro-imidazole dihydrochloride

2.6) From B and morpholine 1-methyl-2- / 4- ( OC -morpholino-propionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole dihydrochloride

3.1) 1-Methyl-2- / 4- (/ 3 -aminopropionylamino) from 1-methyl-2- ^ 4- ( β- chloropropionylamino) -phenyl-oxymethyl-5-nitro-imidazole-monohydrochloride (C) and ammonia -phenyl-oxymethyl? - ^ - nitro-imidazole hydrochloride

3.2) 1-Methyl-2- / 4- ( fö -dimethylaminopropionylamino) -phenyl-oxymethyjV-S-nitro-imidazole dihydrochloride, melting point 196 ° C., from C and dimethylamine

3.3) From C and diethylamine 1-methyl-2- / 4- ( β- diethylaminopropionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole dihydrochloride

3.4) 1-Methyl-2- / 4- (/ o -pyrrolidino-propionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole dihydrochloride from C and pyrrolidine

3.5) 1-Methyl-2 - / _ 4- (/ J -piperidino-propionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole dihydrochloride from C and piperidine

3.6) From C and morpholine the 1-methyl-2 - / _ 4- ( β -morphplino-propionyl-amino) -phenyl-oxymethylZ-S-nitro-imidazole-dihydrochlo-

7098S1 / 0083

Mc

-VS-

rid

4.1) From i-methyl-2- (4-chloroacetylaminophenyl-thiomethyl) -5-nitro-imidazole-monohydrochloride (D) and ammonia the 1-methyl-2- (4-aminoacetylaminophenyl-thiomethyl) -5-nitro-imidazole hydrochloride

4.2) From D and dimethylamine 1-methyl-2- (4-dimethylamino-acetyl-aminophenyl-thiomethyl) -5-nitro-imidazole-dihydrochloride, Mp 177 ° C

4.3) From D and diethylamine 1-methyl-2- (4-diethylamino-acetylaminophenyl-thiomethyl) -5-nitro-imidazole dihydrochloride

4.4) 1-Methyl-2- (4-pyrrolidino-acetylamino-phenyl-thiomethyl) -5-nitro-imidazole-dihydrochloride from D and pyrrolidine

4.5) From D and piperidine 1-methyl-2- (4-piperidino-acetylamino-phenyl-thiomethyl) -5-nitro-imidazole-dihydrochloride

4.6) From D and morpholine 1-methyl-2- (4-morpholino-acetylaminophenyl-thiomethyl) -5-nitro-imidazole-dihydrochloride

5.1) From 1-methyl-2- / 4- ( CC -chlorpropionylamino) -phenyl-thiomethylZ-S-nitro-imidazole-monohydrochloride (E) and ammonia the 1-methyl-2- ^ 4- ( ού -aminopropxonylamino) - phenyl-thiomethyl? - 5-nitro-imidazole hydrochloride

5.2) From E and dimethylamine 1-methyl-2- ^ 4- (cO -dimethylaminopropionylamino) -phenyl-thiomethylZ-S-nitro-imidazole dihydrochloride

5.3) From E and diethylamine 1-methyl-2- / 4- {CO -diethylaminopropionylamino) -phenyl-thiomethyl-S-nitro-imidazole dihydrochloride

5.4) From E and pyrrolidine the 1-methyl-2- / 4- (Oi / -pyrrolidino-propionyl-amino) -phenyl-thiomethyl-S-nitro-imidazole-dihydro-

chloride

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-H-

5.5) From E and piperidine 1-methyl-2- / 4- (cC -piperidino-propionyl-amino) -phenyl-thiomethyl-7-5-nitro-imidazole dihydrochloride

5.6) From E and morpholine 1-methyl-2- / 4- { OC- -morpholino-propionyl-amino) -phenyl-thiomethyl / -5-nitro-imidazole dihydrochloride

6.1) From 1-methyl-2- / 4- ( β- chloropropionylamino) -phenyl-thiomethyl / S-nitro-imidazole-monohydrochloride (F) and ammonia the 1-

Methy 1-2- / 4- / 3-aminopropionylamino) phenyl-thiomethyl / -5-nitroimidazole hydrochloride

6.2) From F and dimethylamine 1-methyl-2- / 4- ( β -dimethylaminopropionylamino) -phenyl-thiomethyl / -5-nitro-imidazole dihydrochloride

6.3) From F and diethylamine 1-methyl-2- / 4- (ß- diethylamino-pro-

pionylamino) -phenyl-thiomethyl7-5-nitro-imidazole ~ dihydrochloride

6.4) From F and pyrrolidine 1-methyl-2- / 4- (ß -pyrrolidino-propionylamino) -phenyl-thiomethyl / -5-nitro-imidazole dihydrochloride

6.5) 1-Methyl-2- / 4 - (/ S-piperidino-propionyl-amino) from F and piperidine -phenyl-thiomethyl? -5-nitro-imidazole-dihydrochloride

6.6) From F and morpholine 1-methyl-2- / 4- (p -morpholino-propionyl-amino) -phenyl-thiomethyl7-5-nitro-imidazole dihydrochloride

The showing of the compounds 2.1 - 2.6 used as the starting material 1-methyl-2- / 4- (o6 -chlorpropionylamino) -phenyl-oxymethyl7-5-nitro-imidazole monohydrochloride (B), mp 200 ⁰ C u dec... ),

is obtained by reacting equimolar amounts of 1-methyl-2- (4-aminophenyl-oxymethyl) -5-nitro-imidazole mitoc-chloropropionylchlo-

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-Y Z-

The showing of the compounds 3.1 - 3.6 used as starting material 1-methyl-2- / 4 - (/ o-chloropropionylamino) -phenyl-oxymethyiy-5-nitro-imidazole monohydrochloride (C), mp 205 ⁰ C u dec.. .) is obtained by reacting equimolar amounts of 1-methyl-2- (4-aminophenyl-oxymethyl) -5-nitro-imidazole with β- chloropropionyl chloride.

That for the representation of the compounds 4.1 - 4.6 as starting material used 1-methyl-2- (4-chloroacetylaminophenyl-thiomethyl) -5-nitro-imidazole monohydrochloride (D) is obtained by reacting equimolar amounts of 1-methyl-2- (4-aminophenyl-thiomethyl) -5-nitroimidazole with chloroacetyl chloride.

The 1-methyl-2- / 4- (<X -chloropropionylamino) -phenyl-thiomethyl / -5-nitro-imidazole-monohydrochloride (E) used as starting material for the preparation of the compounds 5.1-5.6 is obtained by reacting equimolar amounts of 1 -Methyl-2- (4-aminophenyl-thiomethyl) -5-nitro-imidazole mito ^ -chloropropionyl chloride.

The 1-methyl-2- / 4- (ß- chloropropionylamino) -phenyl-thiomethylV-S-nitro-imidazole-monohydrochloride (F) used as starting material for the preparation of the compounds 6.1-6.6 is obtained by reacting equimolar amounts of 1-methyl -2- (4-aminophenyl-thiomethyl) -5-nitro-imidazole with / 3-chloropropionyl chloride.

That for the representation of the starting material for the connections
4.1-6.6 required 1-methyl-2- (4-aminophenyl-thiomethyl) -5-nitroimidazole (melting point 156 ° C.) is obtained by reacting 1-methyl-2-chloromethyl-5-nitro-imidazole (DOS 1.595. 929) with equimolar
Amounts of 4-aminothiophenol in dimethyl amide at room temperature
in the presence of potassium carbonate.

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Example 2 (method b)

1.1 1-methyl-2- (4-dimethylamino-acetylaminophenol-oxymethyl) -5-

17.6 g (0.1 mol) of i-methyl ^ -chloromethyl-S-nitro-imidazole and • 23.1 g (0.1 mol) of 4-dimethylaminoacetaminophenol hydrochloride are suspended in 150 ml of dimethylformamide, 27.6 g ( 0.2 mol) of powdered potassium carbonate was added and the reaction mixture was ^{heated to 50 °} C. for 1 hour. The dimethylformamide reaction medium is then completely distilled off in vacuo, the residue is treated with water and ethyl acetate, the ethyl acetate phase is separated off, dried over sodium sulfate and evaporated. The end product is thus obtained as an oily residue. As in process a), this is converted into the dihydrochloride with alcoholic hydrochloric acid. The compound is identical to the compound with a melting point of 194 ^° C. which is represented by method A, Example 1, 1.1.

The representation of 1-methyl ^ -chloromethyl-S-nitro-imidazole is described in DOS 1.595.929. It takes place by reacting 1-methyl-2-hydroxymethyl-5-nitro-imidazole with thionyl chloride.

4-dimethylaminoacetaminophenol hydrochloride is shown

by splitting off the pyranyl protective group in 4-dimethylaminoacetamino-O-pyranyl- (2) -phenol using hydrochloric acid. 4-Dimethylaminoacetamino-O-pyranyl- (2) -phenol is obtained by Reaction of 4-amino-O-pyranyl- (2) -phenol with chloroacetyl chloride and then with dimethylamine.

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Claims (1)

PATENT CLAIMS: 1. / i-Methyl-2- (4-aminophenyl-substit.-methyl) -5-nitro-imidazole of formula I. O, N. ^ CH ₂ -Z - / \ -NH-C-CH- (CH ₂ ) -N N ^XX = - ^/ (5 R ^ (I) where Z is oxygen or sulfur, R is hydrogen or methyl, 2 3
η zero or one and R and R, which can be identical or different, denote hydrogen, methyl or ethyl, or 2 3 where R and R together together with the one wearing them Nitrogen atom form a pyrrolidine, piperidine or morpholine ring, as well as addition salts of these compounds (I) with a physiologically compatible acid. Process for the preparation of 1-methyl-2- (4-aminophenyl-substit. Methyl) -5-nitro-imidazoles der.Formel I in claim 1, and of their addition salts with a physiologically acceptable acid, characterized in that one a) a 1-methyl-2- {4-aminophenyl-substit.-methyl) -5-nitroimidazole of formula II NH, (ID CH- where Z has the meaning given, with a halocarboxylic acid derivative of the formula III X- (CH ^) _n -CH-CO- O-CO-CH- (CH ₁ ) R1 (III) 709851/0083 iGiNAl IhJSPECTi = D ^ _ HOE 76 / P 131 where R has the meaning given /. * X is a halogen atom, and η and m are zero or one, and the thus obtained haloacylamino compounds of the formula IV NH-C-CH- (CH,) -X (IV) Il I 1 ^{2 n} 0 R wherein Z, X, R and η have the meanings given, with ammonia or an amine of the formula V. HN 2 3
wherein R and R have the meanings given, or converts b) a 1-methyl-2-substit.-methyl-5-nitro-imidazole of the formula VI % CH ₉ -Y O ₀ NN ² 1 CH ₃ wherein Y represents a halogen atom or an acyloxy group or an arylsulfonyloxy group with a phenol or thiophenol of formula VII r NH-C-CH- (CH ₉ ) -N (VII) h ^ ³ CH lh wherein Z, R ' _r r ² ^ _R 3 and η have the meanings given and A is hydrogen, * an alkali metal or ammonium, is converted
and optionally the compound of formula I thus obtained 709851/0083 J | HOE Το / Ρ 131 converted into the corresponding salt by adding a physiologically acceptable acid. 3. Agent against protozoal diseases, characterized by a content of a compound of the formula I in claim 1 with a pharmaceutically usual carrier. 4. Use of a compound of formula I in claim 1 for Treating protozoal diseases in humans and animals. 708851/0083