DK144524B - ANALOGY PROCEDURE FOR THE PREPARATION OF 1-METHYL-2- (ALKYL SULPHONYLPHENOXYMETHYL) -5-NITRO-IMIDAZOLES - Google Patents

Description

in U4524 o

Danish Patent Application No. 5692/75 discloses an analogous process for the preparation of 1-alkyl-2- (phenoxymethyl) -5-nitro-imidazoles of the formula R2 5, -L

I ^ cV ° - (W.

Wherein R is methyl or ethyl, R is trifluoromethyl, trichloromethyl, nitro, cyano, methylsulfonyl or ethylsulfonyl, 3 and R is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, trichloromethyl, nitro or cyan, which are active against various protozoa, especially trichomonads, amoebas and trypanosomes. By this analogous process, the 15 desired compounds are prepared by reacting 1-alkyl-2-methyl-5-nitroimidazoles substituted in the 2-methyl group with halogen, acyloxy or arylsulfonyloxy or hydroxy, with 2 3 2 3 and R 3, respectively. and R -substituted phenol or R- and R -substituted 1-halo, 1-acyloxy or 1-arylsulfonyloxy-2-benzene or by alkylation of R- and R -substituted 2-phenoxymethyl-5- nitroimidazoles.

It has now been found that the novel 1-methyl-2 - (alkylsulfonylphenoxymethyl-5-nitro-1-imidazoles of formula 25 f-cH9-O-f1 -R2 1 ° 2N. R is methylsulfonyl or ethylsulfonyl and R is hydrogen, methyl or halogen as fluorine, chlorine, bromine or iodine, has similar activity, and the present invention therefore relates to an analogous process for the preparation of these compounds, the process of the invention being characterized by oxidizing a 1-methyl-2-phenoxymethyl-5-nitro-35-imidazole of Formula 2 14452Λ

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. ^ N

I - —CB2-0 / '\ A - R II

/ '' ΐ '' H 3

o2n ^ R

Wherein A is a sulfur atom or a sulfoxide group (-SO-), R is 3 methyl or ethyl, and R is hydrogen, methyl or halogen such as fluorine, chlorine, bromine or iodine.

The 1-methyl-2-phen-oxymethyl-5-nitro-imidazoles of formula II used as starting compounds are disclosed in Danish Patent Application No. 3135/76 and can be obtained from 1-methyl-2-chloromethyl-5 nitro-imidazole (available as described in German Publication Nos. 1,595,929 and 1,470,102) and optionally substituted alkyl mercaptophenols or alkylsulfinylphenols (which can be obtained from the corresponding mercaptophenols and dialkylsulfate and an optionally the following oxidation with perbenzoic acid) in dimethylformamide and in the presence of potassium carbonate.

Suitably, equal or twice the molar amounts of an oxidizing agent are used for the oxidation, but often an excess of the oxidizing agent may be used. When the corresponding sulfides (A = -S- in formula II) are used as starting material, at least two molar equivalents of oxidant are required, but if the corresponding sulfoxides (A = -SO- in formula II) are used as starting material, only one molar equivalent is required. oxidizer. As an oxidizing agent, e.g. hydrogen peroxide and peracids such as peracetic acid, pertrifluoroacetic acid and chlorperbenzoic acid, especially 3-chloroperbenzoic acid, as well as nitric acid, chromic acid and their salts, as well as chromic anhydride, permanganates, hypochlorites, chlorates, perchlorates, periodates and nitrous oxides, in particular dinitrogen oxides, are used.

The oxidation reactions are advantageously carried out in a solvent or distribution agent, and are particularly suitable for such solvents which are not attacked by the oxidizing agent, e.g. acetic acid or trifluoroacetic acid. Using perbenzoic acid, methylene chloride and chloroform are also suitable as solvents.

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3

The oxidation reactions are usually carried out at temperatures between 0 and 100 ° C, especially at 40-60 ° C, and the reaction times are, depending on the reaction conditions, from a few minutes to a few hours.

The isolation of the reaction products is done by diluting the reaction solution with water during simultaneous precipitation or by evaporation of the organic solvent in vacuo. Optionally, there may then be purified by recrystallization from suitable solvents or solvent mixtures.

The 1-methyl-2- (alkylsulfonylphenoxymethyl) -5-nitroimide azoles of formula I are suitable for the control of protozoan diseases in humans and animals such as those of e.g. are produced by infection with T. vag & ialis, E. histolytica and I. cruci, T. brucci and T. congolense and may be used orally or locally. For oral administration, pharmaceutical preparations are used as tablets or capsules containing, for the daily dose, between ca. 10 and approx. 750 mg of the active substance, preferably 30-300 mg, together with the usual additions of carriers, diluents and / or extenders. For local use, gels, creams, ointments or suppositories can be used.

The compounds of Formula I are distinguished by being well tolerated while having a significantly better effect on trichomonads and amoebas in vivo than the known comparative preparation Metronidazole.

The compounds of formula I are particularly suitable for the treatment of fluoro-genitalis, to which they are preferably prepared for topical treatment into vaginal suppositories (ovula) or vaginal tablets containing the active substance in an amount of 150-500 mg per day. dosage unit.

In a series of comparative experiments, the effect of two compounds of Formula I against Trichomonas fetus in mice was compared to the effect of four previously known, closely related compounds, giving the results set forth in the table below.

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U452A

The survival rate

Dose in mg / kg mice for Trichomonas fetus

Fprb._per os_ in 4 mice

Ex. (A) 2 x 25 0 0 0 0 5 2 X 12.5 0000 2 x 6.25 0 0 0 0 2 X 3.125 0111

Ex. (C) 2 X 25 0 0 0 0 10 2 x 12.5 0000 2 X 6.25 0 0 0 0 _2 X 3,125_0 12 1_ M 2x 25 0000 2 x 12.5 0000 15 2 x 6.25 1122 2 x 3,125 2333 N 2 x 100 0000 2 x 50 2 2 3 3 20 2 x 25 3 3 3 4 0 2 x 100 0 0 0 0 2 x 50 0 1 2 2 2 x 25 2 2 3 3 25 P 2x 25 0000 2 x 12.5 0000 2 x 6.25 1 2 2 1 _2 x 3,125_2 3 3 3 30 Infection Control _ -___ 3 4 4 4 _ M 1-Methyl-2- (2-pyridylsulfonylmethyl) -5-nitro imidazole DE Pat. 23 29 376, Example 1.

N 1-Methyl-2-hydroxymethyl-5-nitroimidazole Danish Patent 107,618, Example 1.

0 2-Methyl-5-nitro-1- [2- (3-pyridyloxy) -ethyl] -imidazole Danish Patent 135,166, Example 1.

P 1-Methyl-2- (pyridyl-2-thiomethyl) -5-nitro-imidazole DE Pat. Example 25.

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From these results it is clear that the two compounds of formula I are the far superior compounds, and similar activities have the other compounds of formula I.

The process of the invention is further illustrated by the following example.

Example (A) 1-Methyl-2- (4-methylsulfonyl-phenoxymethyl) -5-nitro-imidazole In 250 ml glacial acetic acid dissolve 27.9 g (0.1 mole) of 1-methyl-2- (4-methylthiophenoxymethyl) ) -5-nitro-imidazole (mp 116 ° C) and, while stirring, at room temperature, 24.3 g (0.25 mole) of 35% hydrogen peroxide are dropped, below which the temperature of the exothermic reaction rises to approx. 45 ° C. Then, stir for another 15 hours to 60 ° C with stirring, and after cooling to room temperature, the reaction mixture is poured onto 800 ml of an ice / water mixture, the precipitate is suctioned off, washed with water and recrystallized from isopropanol under addition. of activated carbon.

There are thus obtained 29 g (ie 93% of theory) of 1-methyl-2-20 - (4-methylsulfonylphenoxymethyl) -5-nitro-imidazole in the form of yellow crystals, m.p. 157 ° C.

Instead of the starting compound 1-methyl-2- (4-methylthiophenoxymethyl) -5-nitro-imidazole, the corresponding sulfoxide 1-methyl-2- (4-methylsulfinylphenoxymethyl) -25 -5-nitro-imidazole (m.p. 130 ° C) and it is then sufficient to use half the amount of hydrogen peroxide.

Similarly, the following compounds can be prepared: (B1-Methyl-2- (4-ethylsulfonylphenoxymethyl) -5-nitro-imidazole 30, mp 132 ° C by oxidation of 1-methyl-2- (4-ethylthiophenoxy-methyl) -5-nitro-imidazole (mp 90 ° C) or 1-methyl-2- (4-ethylsulfinylphenoxymethyl) -5-nitro-imidazole (mp 103 ° C).

(C) 1-Methyl-2- (3-methyl-4-methylsulfonylphenoxymethyl) -5-nitro-imidazole, m.p. 141 ° C by oxidation of 1-methyl-2- (3-methyl-4-methylthiophenoxymethyl) -5-nitro-imidazole (mp 108 ° C)

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Or 1-methyl-2- (3-methyl-4-methylsulfinylphenoxymethyl) -5-nitro-imidazole (mp 121 ° C.

(D} 1-Methyl-2- (3-methyl-4-ethylsulfonylphenoxymethyl) -5-nitro-5-imldazole, mp 115 ° C by oxidation of 1-methyl-2- (3-methyl-4-ethylthiophenoxymethyl) ) -5-nitro-imidazole (mp 80 ° C) or 1-methyl-2- (3-methyl-4-ethylsulfinylphenoxymethyll-5-nitro-imidazole (mp 95 ° C).

10 (E1-Methyl-2- (3-chloro-4-methylsulfonylphenoxymethyl-5-nitro-imidazole, mp 153 ° C by oxidation of 1-methyl-2- (3-chloro-4-methylthiophenoxymethyl) - 5-nitro-imidazole or 1-methyl-2- (3-chloro-4-methylsulfinylphenoxymethyl) -5-nitro-imidazole.

15 (FI 1-Methyl-2- (3-chloro-4-ethylsulfonylphenoxymethyl-5-nitro-imidazole, mp 98 ° C) by oxidation of 1-methyl-2- (3-chloro-4-ethylthiophenoxymethyl) - nitro-imidazole or 1-methyl-2- (3-chloro-4-ethylsulfinylphenoxymethyl-5-nitro-imidazole.