DE1001683C2 - Process for the production of a new tuberculostatic - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT LETTER 1001683

ON REPORTING DAY:

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL:

ISSUE OF
PATENT LETTERING:

kl. 12 ρ 9

INTERNAT. KL. C 07 d 2 3 MARCH 1954

JANUARY 31, 1957 JULY 11, 1957

agrees with the exposition

1 001 683 (G 14043 IV b / 12 p)

The invention relates to a method for producing a new tuberculosis disease.

In the past few 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 uses have been made of these compounds in the treatment of tuberculosis Disadvantages clearly. For example, streptomycin and p-aminosalic acid are often undesirable Side effects. Also possess most of the known tuberculostatics including Isonicotinic hydrazide has the major disadvantage that its use over chemotherapeutic agents resistant strains of the tubercle bacillus produced. One such resistance can set in very soon after starting treatment, and then creates a condition in which successful treatment is considerably more difficult to carry out than in the original Condition of the sick.

A good tuberculostatic agent must therefore meet the following requirements, among others 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 not supposed to produce resistant strains of the bacillus and also in strains that are due to the application known anti-tuberculosis drugs have already become resistant to them.

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 met to a surprisingly high extent, if you get 2-pyridyl- (4) -l, 3, 4-oxdiazolon- (5) or a. Salt the same with p-amino salicylic acid or a salt of the same converts.

The new 2-pyridyl- (4) -l, 3, 4-oxdiazolon- (5) used as starting material (for the sake of simplicity hereinafter referred to as ate 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 865 155) will. This reaction can, for example, by dissolving isonicotinic acid hydrazide in dioxane and Process for the production of a new tuberculostatic

Patented for:

Ed. Geistlich Sons A.G. for the chemical industry, Wolhusen (Switzerland)

Claimed priority: Switzerland of December 7, 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 of the invention obtained as described above Oxdiazolons can be done 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. The p-aminosalicylic acid derivative of oxdiazolone represents an orange compound and is believed not to be a real salt, since the two components are colorless and the derivative is relatively low Melting point, namely 165 ° (decomposition) possesses.

The new compound produced according to the invention

has a surprisingly low toxicity. the

. LD ₅₀ when administered subcutaneously to the mouse

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

709 583/235

Tuberculostatics. Laboratory tests have also shown that the manufactured according to the invention 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-oxdiazolone- (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 are introduced over 3 hours with cooling.

A precipitate forms. The contents of the flask are poured into a glass beaker (4 1) 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 340 g, mp = 240 ° (decomposition).

The product is diluted by dissolving in

Ammonia and precipitating by addition of dilute nitric acid ίο to p _H 6 further purified. 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-aminosalicylic acid derivative des 2-pyridyl- (4) -l, 3, 4-oxdiazolons- (5)

4.4 parts of sodium p-aminosalicylic acid are used in 7.5 parts of water and dissolved 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 No. 865 155. θ 609 768/281 1.57 (709 583 / 2Ϊ5 7.57)