DE1001683B - Process for the production of a new tuberculostatic - Google Patents

Description

GERMAN

The invention relates to a method for producing a new tuberculostatic.

In recent years, many researches have been conducted leading to the discovery of new chemotherapy drugs with an inhibiting effect on that which causes tuberculosis in humans and animals Microorganism, M. tuberculosis. These investigations resulted in a number Tuberculostatics, the most important of which are streptomycin, p-aminosalicylic acid and isonicotinic acid hydrazide and derivatives thereof.

However, various applications of these compounds in the treatment of tuberculosis have been made Disadvantages clearly. For example, streptomycin and p-aminosalicylic acid are often undesirable Side effects. Also, most of the known anti-tuberculosis drugs have included Isonicotinic hydrazide has the major disadvantage that its use over chemotherapeutic agents resistant strains of the tubercle bacillus are produced. Such resistance can occur very soon after onset the treatment will occur and · then creates a condition in which successful treatment is significant is more difficult to carry out than in the original condition of the sick person.

Therefore, among others, the following requirements must be made of a good tuberculostatic agent will:

It should have a low toxicity and practically no side effects such as nausea, vomiting, Cause dizziness and the like.

It is said to have a strong inhibition of the development of the tubercle bacillus in vivo.

It is said not to produce resistant strains of the bacillus and also with strains which, due to the use of known tuberculostatics, are already against these have become resistant to be effective.

It should be stable and easy to administer, preferably orally.

It has now been found that a new tuberculostatic agent which meets the conditions listed above can be obtained fulfilled to a surprisingly high extent, if you get 2-pyridyl- (4) -l, 3, 4-oxdiazolon- (5) or a salt thereof with p-aminosalicylic acid or a salt of the same.

The new 2-pyridyl- (4) -l, 3, 4-oxdiazolon- (5) used as starting material (for the sake of simplicity hereinafter referred to as oxdiazolone) can, for example be prepared by adding isonicotinic acid hydrazide in anhydrous or water-containing reaction medium reacted with phosgene in a manner known per se (cf. French patent specification 865 155) will. This reaction can, for example, by dissolving isonicotinic acid hydrazide in dioxane and

Process for the production of a new tuberculostatic

Applicant:

Ed. Geistlich Sons AG for chemical
Industry, Wolhusen (Switzerland)

Representative: Dr. F. Zumstein, patent attorney,
Munich 2, Bräuhausstr. 4th

Claimed priority:
Switzerland from 7 December 1953

Dr. Arthur Ernest Wilder Smith, Wolhusen (Switzerland), has been named as the inventor

Introducing phosgene into the solution thus obtained or by introducing excess phosgene into a solution of isonicotinic acid hydrazide hydrochloride in water can be carried out. That is what forms Hydrochloride of Oxdiazolons, which converted into the free base or as such for the reaction with p-aminosalicylic acid can be used.

The preparation of the p-aminosalicylic acid derivative according to the invention of the oxdiazolone obtained as described above can be carried out in several ways. For example, you can use the free base with a salt of p-aminosalicylic acid, e.g. B. the sodium salt, implement in aqueous solution. However, it is also possible to use an acid addition salt of the phosgenation product as a starting material

turn around. The p-aminosalicylic acid derivative of oxdiazolone represents an orange connection and is assumed not to be a is real salt, since the two components are colorless and the derivative is relatively low Melting point, namely 165 ° (decomposition) possesses.

The new compound prepared according to the invention has a surprisingly low toxicity. The LD ₅₀ for subcutaneous use in mice

about one tenth and when administered orally to rabbits about one third that of isonicotinic hydrazide. The tendency of the new compound to produce resistant strains of M. tuberculosis is much lower than that of the usual ones up to now

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Tuberculostatics. Laboratory tests have also shown that the inventively produced Compound still in large dilutions the development of versus isonicotinic hydrazide able to inhibit strains that are already resistant. In the case of successful tuberculosis treatment The new derivative does not cause any of the unpleasant doses associated with the known tuberculostatics Side effects.

The following example is intended to explain the invention in more detail without restricting it.

example

A. Preparation of 2-pyridyl- (4) -l, 3, 4-ox-

diazolon- (5)

a) 5 g of isonicotinic acid hydrazide are dissolved in 300 cm ^{3 of} dioxane (absolute) while hot. At 44 °, 80 g of phosgene are introduced in gaseous form over a period of 35 minutes. The new compound precipitates as salt and is sucked off. Yield 8g.

14 g of the above-mentioned salt are dissolved in 100 cm ² 2 η-aqueous sodium hydroxide solution, treated with charcoal and filtered, then treated with 2-η hydrochloric acid to p _H neutralized. 7 The precipitated substance is suction filtered and dried, yield 9 g. It can be recrystallized from water or ethanol; F. = 257 °.

C ₇ H ₅ N ₃ O ₂

calculated in C 51.5%, H 3.06%, N 25.75 «/»,
found in C 51.35%, H 2.95%, N 25.36%;

b) 500 g of isonicotinic acid hydrazide are dissolved in 800 cm ^{3 of} water and 170 cm ^{3 of} concentrated hydrochloric acid and cooled to room temperature. The solution is placed in a flask (2 1) which is provided with a wide inlet tube. 1.2 kg of phosgene

30 are introduced with cooling for 3 hours. A precipitate forms. The contents of the flask .If in a beaker (41) poured and bringing the p _H of 25% ammonia with cooling to. 6 After cooling (1 hour to 5 °) it is filtered off with suction, washed with water and dried. Yield 340g, mp = 240 ° (decomposition).

The product is further purified by dissolving in dilute ammonia and precipitating by addition of dilute nitric acid to p _H. 6 However, it can also be recrystallized directly from water or alcohol or other solvents. M.p. = 265 ° (decomposition).

No protection is claimed for the manufacturing process described above.

B. Preparation of the p-atninosalicylic acid derivative of 2-pyridyl- (4) -l, 3, 4-oxdiazolotis- (5)

4.4 parts of sodium p-aminosalicylic acid are used in Dissolved 7.5 parts of water and at 20 to 40 ° with the solution of 4.1 parts of the base described above of the phosgenation product in 12.5 parts of 2N hydrochloric acid. The new orange connection fails immediately; Yield 6.2 parts, mp = 165 ° (decomposition).

Claims (1)

PATENT CLAIM: Process for the production of a new tuberculostatic, characterized in that one 2-pyridyl- (4) -1, 3, 4-oxdiazolon- (5) or a salt thereof with p-aminosalicylic acid or a salt the same implements. Considered publications:
French patent specification No. 865 155. © 609 768/281 1.57