DE1172264B - Process for the preparation of N-(ª-chloroethyl)-N'-[5-nitrothiazolyl-(2)]-urea - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

Number:
File number:
Registration date:
Display day:

German KL: 12 ρ - 4/01

C 28241 IVd / 12 ρ
October 22, 1962
June 18, 1964

The invention relates to procedures for the preparation of the new N - (/? - chloroethyl) -N '- [5-nitrothiazolyl- (2)] - urea and its salts.

Salts of the new compound are metal salts, in particular alkali and alkaline earth metal salts, such as sodium, Potassium or calcium salts, ammonium salts or salts of organic amines.

The new compound and its salts have anti-parasitic properties, especially against protozoa, such as entamöba, flagellates such as trichomonads, and Eimeria tenella, and against schistosomes. They are suitable for the treatment of the diseases caused by the parasites mentioned Animals and especially humans, e.g. B. for the treatment of schistosomiasis, the amoebic dysentery or human amoebic hepatitis or that caused by Histomonas meleagridis or by Eimeria tenella caused infection of animals, e.g. B. for the treatment of enterohepatitis or coccidiosis in poultry or rabbits. The new connection can, however, also be used together with conventional feed or Carriers in veterinary medicine in the form of preparations or as feed additives for Raising animals find use. Preferably they are intended as additives for animal feed the rearing and keeping of poultry or rabbits are used.

From British patents 771 147 and 877 106 similar compounds are already known as in effectively known in the same direction. Although in the latter patent also in principle Possibility is mentioned that the salts of N-substituted N '- [5 - nitrothiazolyl - (2)] - urea compounds can also be halogenated on the N-substituent is the compound obtained according to the invention therein not specifically mentioned. The chemotherapeutic effectiveness of the obtained according to the method N - (^ - chloroethyl) -N '- [5-nitrothiazolyl- (2)] - urea (A) and the known commercial product N-ethyl-N' - [5-nitrothiazolyl- (2)] - urea (B) was tested comparatively on hamsters infected with amoeba.

The animals were injected into a lobe of the liver with a virulent strain of Entamoeba histolytica so infected that by the 5th day they had an amoebic abscess covering most of the liver developed. By treating these animals daily, beginning 2 days before infection and ending with it on the 4th day after infection, this process can be clearly inhibited, so that on the 5th day after infection the extent of the abscess is limited to the size of a pea in the absence of amoeba. the Process for the preparation of N - (/? - chloroethyl) -N '- [5-nitrothiazolyl- (2) j -urea

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-Ing. Dr. jur. F. Redies, Dr. rer. nat. B. Redies and Dr. rer. nat. D. Türk, patent attorneys,

Opladen, Rennbaumsir. 27

Named as inventor:

Dr. Paul Schmidt, Therwil,

Dr. Max Wilhelm

Dr. Kurt Eichenberger, Basel (Switzerland)

Claimed priority:

Switzerland of October 25, 1961 (12 334)

Test results are summarized in the following table.

number treatment Autopsy
Number of animals without Amoebas 0 14th infected animals 100 mg / kg with 5 5 10 8th 14th A. 10 B. 18th Φ

With the same dose, the product of the process is the known substance as an amoebicide think.

The new compound is produced by methods known per se by either
a) Compounds of the general formulas

N,

L- NO ₂

Cl-C ₂ H ₄ -Y and

or their salts are reacted with one another, one of the radicals Y and Z, in particular Z, being one free amino group and the other, in particular Y, for an esterified, halogenated, dehydrated, amidated or O-acylated carboxyamino radical of the formula —NH — COOH stands, or

409 600/391

b) N ~ (ß- chloroethyl) -N'-thiazolyl- (2) -urea in the 5-position of the thiazole radical or nitrated

c) in N-05-hydroxyethyl) -N '- [5-nitrothiazolyI-2)] - ureas the hydroxyl group by treatment with thionyl chloride against a chlorine atom from-> > exchanges or

d) in N - (β - sulfonyloxyethyl) - N '- [5 - nitrothiazolyl (2)] ureas, the sulfonyloxy group is exchanged for a chlorine atom by treatment with lithium chloride.

Esters of the carboxyamino radical are, for. B. be alkyl or phenyl esters, halides, e.g. B. the carbamyl chloride or bromide radical, amides, e.g. B. the diphenylamide of the carboxyamino residue. A dehydrated carboxyamino radical is understood to mean the group - N = C = O and under an acylated die Group - NH - COOR, in which R represents an acyl radical, primarily that of a carboxylic acid. as The sulfonyloxy group is particularly suitable, the methane or p-toluenesulfonyloxy group.

A preferred method of making the new one Urea consists in reacting 2-amino-5-nitrothiazole with / S-chloroethyl isocyanate.

The reactions mentioned are carried out in the usual manner, in the presence or absence of diluents, Condensing agents and / or catalysts, at reduced, normal or elevated temperature, carried out at normal or elevated pressure and / or under an inert gas atmosphere.

The starting materials used are known or, if new, are produced in a manner known per se.

The N-Oe-hydroxyethyl) -N '- [5-nitrothiazolyl- (2)] - urea is new. It is not claimed by saponification of N-Q3-bromoethyl) -N '- [5-nitrothiazolyl- (2)] - urea won.

Depending on the method of operation, the new compound is obtained in free form or in the form of its salts. The latter can be converted into the free solution in the usual way by acidifying a solution containing these salts Transfer connection. This in turn can be reacted with basic agents such. B. metal hydroxides or basic salts, especially alkali or alkaline earth metal hydroxides, such as sodium, potassium or calcium hydroxide, alkali metal carbonates, such as sodium or potassium carbonate, ammonia or organic amines, converted into the corresponding salts.

The invention is further described in the following example.

example

A solution of 25 g of 2-amino-5-nitrothiazole and 50 g of .beta.-chloroethylisocyanate in 250 cm ³ of tetrahydrofuran is heated in a sealed vessel for 16 hours at 80 to 9O ⁰ C. After cooling, 150 cm ^{3 of} tetrahydrofuran are evaporated, the precipitated product is suction filtered and it is washed thoroughly with warm isopropyl ether. This gives 34 g of N - (, e-chloroethyl) -N '- [5-nitrothiazolyl- (2)] - urea in yellow crystals; F. 155 to 16O ⁰ C (decomposition).

- The same compound is obtained by chlorination using thionyl chloride from N - (/ 9-hydroxyethyl) -N '- [5-nitrothiazolyl- (2)] - urea obtain. The N - (/? - Hydroxyethyl) -N '- [5-nitrothiazolyl- (2)] - urea used here as starting material (F. 187 to 189 ° C) can be obtained from N - (/ S-bromoethyl) -N '- [5-nitrothiazolyl- (2)} - urea can be obtained by heating in water for several hours.

The bromine compound can in turn by reacting ß-bromoisocyanate and 2-amino-5-nitrothiazole can be obtained.

Claims (2)

Patent claims: 1. A process for the preparation of N - (/? - chloroethyl) -N '- [5-nitrothiazolyl- (2)] - urea and its salts, characterized in that either in a manner known per se
a) Compounds of the general formulas Cl-C ₂ H ₄ -Y and Z NO ₂ or reacting their salts with one another, in which one of the radicals Y and Z is a free one Amino group and the other for one esterified, halogenated, dehydrated, amidated or O-acylated carboxyamino radical, or b) N-Ge-chloroethyl) -N'-thiazolyl- (2) -urea in 5-position of the thiazole radical or nitrated c) in N - (ß - hydroxyethyl) - N '- [5 - nitrothiazolyl- (2)] - urea the hydroxyl group is exchanged for a chlorine atom by treatment with thionyl chloride or d) in N-09-sulfonyloxyethyl) -N '- [5-nitrothiazolyl- (2)] - ureas the sulfonyloxy group is exchanged for a chlorine atom by treatment with lithium chloride and, if desired, the free compound obtained by adding a base to its salts or obtained salts Acidification converted into the free compound. 2. The method according to claim 1, characterized in that in the mode of operation a) compounds of the general formulas given are used as starting materials, in which Y is an isocyanate group and Z is an amino group. Considered publications:
British Patent Nos. 771 147, 877 106. 409 600/391 6.64 © Bundesdruckerei Berlin