SE204642C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C07 d12 p: 10/0 PATENT AND REGISTRATION AGENCY Ans. 5411/1964 was received on 30/4 1964 issued on 27/9 196 FARBWERKE HOECHST AG VORMALS MEISTER LUCIUS & BRVNING, FRANKFURT AM, FEDERAL REPUBLICEN GERMANY Set for the production of triazolidines Inventors: H Ruschig, V it Pgetard, L Therf, L Ther The present invention relates to a process for the preparation of new triazolidines of the form I: I: NH - C = O I \ A (I), 111R, 0 in which R or halogen atom, an alkyl or alkoxy group having 1-4 carbon atoms and R, a hydroxy group, a halogen atom, an alkoxy group having 1-4 carbon atoms, a haloalkoxy or hydroxyalkoxy group having up to 4 carbon atoms, a phenoxy or benzyloxy group, in which a hydrogen atom in any position of the phenyl nucleus may be substituted by a halogen atom or by an alkyl or alkoxy group having up to 4 carbon atoms, or an aliphatic acylamino group having up to 4 carbon atoms, and their salts, which may be characterized by solids of general formula II // \ / - 11 \ I A / \\ / \ / R replace the sulfur atom with an oxygen atom and possibly with the help of inorganic or organic bases jived & the obtained compounds to the corresponding salts.

The new triazolidines, while being physiologically tolerable, are valuable drugs with particularly antiphlogistic properties.

As substituents R 1 and R 2 in the general formula I for the process products, the following may be mentioned, for example: 11.1: Hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy; R2: fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-propamide, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, fl-hydroxyethoxy, benzyloxy, o-, m- or p-methoxybenzyloxy, phenoxy, o-, in- or p-methoxyphenoxy, p-chloro-phenoid, o-methyl-phenoxy, formylamino, acetamino, butyrylamino, f3-chloro-ethoxy.

The substituents may be in any position of the phenyl nucleus.

Examples of starting materials for the process according to the invention are: 1-phenyl-4- (p-ethoxy-phenyl) -3-oxo-5-thio-1,2,4-triazolidine, 1-phenyl-4- (2,3 or 4-methoxy-phenyl) -3-oxo-5-thio1,2,4-triazolidine, 1-phenyl-4- (2- or 3-ethoxy-phenyl) -3-oxo-5-thio-1, 2,4-triazolidine, 1-phenyl- 4- (4-hydroxy-phenyl) -3-oxo-5-thio-1,2,4-triazolidine, CX R2 2 1- (4-methoxy-phenyl) -4 - (4-Methodec-phenyl) -3-oxo-5-thio-1,2,4-triazolidine, 1- (2,3- or 4-methyl-phenyl) -4- (2,3- or 4- (4-oxo-5-thio-1,2,4-triazolidine), 1-phenyl-4- (4-acetylamino-phenyl) -3-oxo-5-thio-1,2,4-triazolidine , 1-phenyl- 4- (4-chloro-phenyl) -3-oxo-5-thio-1,2,4-triazolidine, 1-phenyl- 4- (4-n-propoxy-phenyl) -3 -oxo-5-thio-1,2,4-triazolidine, 1-phenyl-4- (4-benzylcod-phenyl) -3-oxo-5-thio-1,2,4-triazolidine, 1-phenyl-4 - (4-phenoxy-phenyl) -3-oxo-5-thio-1,2,4-triazo-11-dine, 1- (4-chloro-phenyl) -4- (4-ethoxy-phenyl) -3-oxo -5-thio-1,2,4-triazolidine, 1- (2,3- or 4-n-propyl-phenyl) -4- (4-isopropoxyphenyl) -3-oxo-5-thio-1,2, 4-triazolidine.

The exchange of the sulfur atom in the thiotriazolidines of the formula II for oxygen is a reaction known in principle to the application to other starting materials. An oxidizing agent such as potassium permanganate is suitably used, which in the cold quickly acts on a e.g. in aqueous alkali dissolved thiotriazolidine. The reaction is finally led by slow heating and the reaction solution is sucked off from the manganese dioxide formed. When acidifying the filtrate, Mies is the triazolidine. You can then replace the sulfur with the help of a heavy metal oxide, e.g. mercury oxide, with oxygen and working therein suitably in an inert organic solvent such as benzene, toluene, cinnamon or cymene using temperatures above 100 ° C, preferably about 150 ° C, the reaction having to be carried out in an autoclave. Purification of the process products takes place by recrystallization or precipitation with acids from alkaline solution.

The 3,5-dioxo-1,2,4-triazolidines obtained in the process according to the invention constitute compounds of acidic character, which p5. usually sat with the help of inorganic and organic bases can be Transferred to the corresponding salts. Examples of inorganic bases are; alkali or alkaline earth metal hydroxides, alcohols or hydrides, respectively sodium hydroxide, methylate, ethylate, hydride, magnesium hydrocode and calcium hydroxide. Particularly suitable organic bases are aliphatically substituted amines, such as 13-dimethylaminoethanol, β-diethylaminoethanol, diethanolamine, triethanolamine, diethanolomethylamine and others. With regard to their use as medicaments, the corresponding alkali and alkaline earth salts are particularly important, which in most cases are soluble in water and whose solutions have a physiologically acceptable pH value.

The process products constitute valuable drugs. They have particularly anti-phlogistic properties, but also exhibit. e.g. antihypertensive, analgesic avensom (coronary) vasodilator effect and stand out in general for its good physiological tolerability. Salunda, for example, 1-phenyl4- (4-encod-phenyl)-3,5-dioxo-1,2,4-triazolidine sodium salt in aerosil test ph shows a steering wheel at a dose of 500 mg / kg subcutaneously a strong, long-lasting antiflogistic effect. LD 'in moss during intravenous application is about 800 mg / kg, from which it appears that the preparation has a considerable therapeutic breadth. The strong antiphlogistic effect of the process products is surprising, since when testing canda triazolidines, e.g. 1,4-diphenyl-, 1- (p-methyl-phenyl) -4-phenyl avensom 1-phenyl- 4- (p-methyl-phenyl) -3,5-dioxo-1,2,4-triazolidine, found , that these associations have no antiphlogistic effect.

The process products can be applied as such or in the form of their corresponding salts, optionally with admixture of pharmaceutically acceptable solid or liquid bar materials, such as water, vegetable oils, starches or excipients, for example stabilizers, preservatives, aqueous or emulsifying agents, orally or parenterally in in the form of tablets, dragees, capsules, capsules, suspensions, etc. Concerning the oral administration may be used as administration forms, preferably tablets or dragees, to which the process ingredients as active substances are processed with the usual bar materials, such as milk sugar, starch, gum, magnesium, tragacanth. The dosage ph people Jigger is generally between 50 and 200 mg per administration unit.

Example. 1-phenyl- 4- (p-ethoxy-phenyl) -3,5-dioxo-1,2,4-triazolidine.

An alkaline solution of 6 g of 1-phenyl- 4- (p-ethoxyphenyl) -3-oxo-5-thio-1,2,4-triazolidine, m.p. 240-243 ° C (prepared by condensation of phenylhydrazine-p-carboxylic acid -ethyl ester-α-thiocarboxylic acid chloride with p-phenetidine and subsequent treatment with sodium hydroxide solution) are treated with potassium permanganate in small excess and the reaction is completed by gentle heating. Any remaining spruce staining is removed by adding a few drops of methanol, aspirating from the manganese dioxide and acidifying the filtrate. After recrystallization from alcohol, 1-phenyl- 4- (petoxy-phenyl) -3,5-dioxo-1,2,4-triazolidine melts at 193195 ° C.

The sodium salt of 1-phenyl- 4- (p-ethoxy-phenyl) -3,5-dioxo-1,2,4-triazolidine can e.g. from isopropanol by the addition of an estimated amount of sodium methylate is obtained in the form of selected pronounced crystals.

Analysis: C 161-124N 2 O 2 Na 1H 2 O Calculated: C 57.0 H 4.8 N 12, Found: C 56.9 H 4.8 N 12.6 Calculated: Na 6.8 11.0 5.3 Found: Na 6, 8 H 2 O 5.2

Claims (1)

1. Patent claim: \ / - NN - \ / A / c / RiR, 3 atoms, or an aliphatic acylamino group having up to 4 carbon atoms, and their salts, characterized in that thiotriazolidines of formula II are used for the preparation of new triazolidines of the formula I NH-C = O HN-C = .0 / CB, X R 2 which R 1 represents a free or halogen atom, an alkyl or alkoxy group having 1-4 carbon atoms and R, a hydroxy group, a halogen atom , an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy or hydroxyalkoxy group having up to 4 carbon atoms, a phenoxy or benzyloxy group in which a hydrogen atom in any position of the phenyl nucleus may be substituted by a halogen atom or by an alkyl or alkoxy group with up to 4 carbon replaces the sulfur atom with an oxygen atom and possibly with the help of inorganic or organic bases transfer the compounds of formula I to the corresponding salts. Request publications: