DE1136705B - Process for the preparation of 2- (4'-acetylpiperazino) -5-nitrothiazole - Google Patents

Description

GERMAN

PATENT OFFICE

W 27247 IVd / 12 ρ

REGISTRATION DATE: F E B RUARY 15, 1960

NOTICE
THE REGISTRATION
AND ISSUE OF
A1JSLEGESGHRIFT: SEPTEMBER 20, 1962

The invention relates to processes for the preparation of 2- (4'-acetylpiperazino) -5-nitrothiazole and its Acid addition salts.

These new compounds are useful in the treatment of certain protozoal infections. they seem especially as a trichomonacid, especially in such a way that it stimulates the growth of Trichomonas vaginalis organisms prevent and kill these organisms, as will be explained in more detail below. The new compounds are also effective against Trichomonas fetus organisms.

The 2- (4'-acetylpiperazino) -5-nitrothiazole is prepared in a manner known per se either a) by Condensation of a 2-halo-5-nitrothiazole with N-acetylpiperazine in the presence of an acid binding agent or b) by treating 2-piperazino-5-nitrothiazole with an acetylating agent. If if desired, the reaction product obtained can be converted into an acid addition salt.

The following example illustrates the invention.

example

A mixture of 103.5 g of 2-bromo-5-nitrothiazole, 90 g of N-acetylpiperazine hydrochloride, 125 g of sodium bicarbonate and 800 ml of ethanol is refluxed with stirring for 30 minutes. then is cooled to 20 ° C, filtered and successively with 350 ml of ethanol, a solution of 300 ml of water and 30 ml of glacial acetic acid and finally washed with 200 ml of water.

The crude 2- (4'-acetylpiperazino) -5-nitrothiazole is triturated with 250 ml of acetone, washed with 150 ml of ether and dried at 80 ° C. to constant weight. M.p. = 183 to 187 ° C, yield 97.8 ° / ₀ . After recrystallization from aqueous acetic acid, alcohol or nitromethane, the melting point rises to 189 to 190 ° C.

A solution of 25 g of the 2- (4'-acetylpiperazino) -5-nitrothiazole obtained as described above in 150 ml of water and 45 ml of concentrated sulfuric acid is refluxed for 39 minutes and filtered off. The pH of the filtrate is _{adjusted to 8 with 110 ml of concentrated NH 4} OH, the temperature being kept below 40 ° C. The solid substance is filtered off and washed well with water. After drying in vacuo over anhydrous phosphorus pentoxide, the sulfate of 2- (4'-acetylpiperazino) -5-nitrothiazole is recrystallized from ethanol. M.p. = 158.5-159.5 ° C, yield 61%.

The trichomonacidal effectiveness of the process product was determined by a series of tests, the minimum inhibiting concentration method of manufacture
of 2- (4 ^/ -acetylpiperazino) -5-nitrothiazole

Applicant:

Wallace & Tiernan Incorporated,
Belleville, NJ (V. St. A.)

Representative: Dipl.-Chem. Dr. I. M. Maas, patent attorney, Munich 23, Ungererstr. 25th

Claimed priority:

V. St. v. America February 20, 1959

and January 13, 1960 (No. 794 499 and No. 2137)

David Bernard Reisner, Cedar Grove, N.J.,

and John Vincent Scudi, Springfield, N. J. (V. St. Α.),

have been named as inventors

tration of this connection was determined. The expression "minimal inhibiting concentration" used here means the lowest concentration of an agent that is sufficient for growth on contact to prevent and kill Trichomonas vaginalis organisms.

In these experiments 0.1 ml of a 48-hour culture of a virulent strain of Trichomonas vaginalis was left on a simplified "trypticase serum medium" (described by Kupferberg in "International Record of Medicine and General Practice Clinisc", vol. 168, 1955 p . 709 to 717) in the presence of increasing amounts of the compound under investigation at 37 ° C for 48 hours. In the absence of an inhibiting compound, the organism continued to grow, but if the organisms ^{were brought into contact with the process product in a concentration of 1 μg / cm 3} , then the Trichomonas vaginalis organisms were killed.

The 2- (4'-methylpiperazino) -thiazole known from US Pat. No. 2,543,972 was tested in the same manner as the compound obtained according to the method, whereby an abundant growth of the Trichomonas vaginalis organisms was still observed even if a high concentration of 1000 7 / cm ^{3 of} this test compound was used. There was no visible inhibition of life

209 657/258

or growth of the organisms. This experimental result was used as a sign of the importance of the Nitro group in the 5 control of the thiazolyl ring.

When treating mice infected with Trichomonas fetalis, this was shown to be in accordance with the procedure 2- (4'-Acetylpiperazino) -5-nitrothiazole obtained also the known 2-acetylamino-5-nitrothiazole (USA.Patent 2 735 798) as superior, as the following experiments show:

A number of mice were infected with Trichomonas foetalis in an amount sufficient to to kill all infected mice. A group of these mice was treated with 2- (4'-acetylpiperazino) -5-nitrothiazole- (I), another group with the well-known 2-acetylamine-4-nitrothiazole- (II) in different Cans handled. The substances were introduced with the hooves of a gastric tube in the manner that the administration of the desired dose to the animal was guaranteed. The received The results are given in the following table:

Dose of I. II Test substance Surviving animals Surviving animals mg / kg in% in ° / o 60 100 100 50 75 65 40 40 0 25th 20th 0

The table shows that the new compound is a good one even in small doses Protective effect results, while the known substance has no effect on the host as long as the dosage does not reach a comparatively high lower limit value. This is with oral administration therefore of great importance, because it must always be expected that not the entire gift is absorbed.

ίο With the results of the pharmacological test the clinical observations to date also agree. It has been shown that with the local Application of the new compounds reduced the number of patients treated for relapse suffers than with the local application of II or other closely related and in trade Remedies.

In the clinical treatment of 30 people with I, not a single relapse was observed.

Claims (1)

PATENT CLAIM: Process for the preparation of 2- (4'-acetylpiperazino) -5-nitrothiazole and its acid addition salts, characterized in that either a) a 2-halo-5-nitrothiazole is condensed with N-acetylpiperazine in the presence of an acid-binding agent in a manner known per se or b) treating 2-piperazino-5-nitrothiazole with an acetylating agent and optionally converting the reaction product into an acid addition salt. Each test was performed on six, eight, or ten mice, and the results represent those obtained Mean values. Considered publications:
U.S. Patent Nos. 2,543,972, 2,735,798.