DE1159460B - Process for the manufacture of antihypertensive urazoles - Google Patents

Description

Process for the production of antihypertensive urazoles Addition to patent application F 31700 IVd / 12p (Auslegeschrift 1 153 759) The subject of patent application F 31700 IVd / 12p (German Auslegeschrift 1153 759) is a process for the production of antihypertensive urazoles of the general formula 1 where R is an aryl radical in which 1 or 2 hydrogen atoms can optionally be substituted by a halogen atom, a low molecular weight alkyl or alkoxy radical, Rl a halogen atom, a low molecular weight alkyl, alkoxy, aralkoxy or an aryloxy radical, R2 a halogen atom, a trifluoromethyl radical, an alkyl radical having 1 to 8 carbon atoms, a cycloalkyl radical having 3 to 6 carbon atoms, an aralkyl radical whose alkylene group is low molecular weight, an aryl radical, an alkoxy or alkyl mercapto radical having 1 to 6 carbon atoms, an aralkoxy radical whose alkoxy group is low molecular weight, an aryloxy or Aryl mercapto radical or a low molecular weight acyl radical, R3 a halogen atom, a low molecular weight alkyl, alkoxy or carbalkoxy radical, a nitro group, an aliphatic or cycloaliphatic acyl radical with up to 8 carbon atoms, a low molecular weight araliphatic or an aromatic acyl radical, an alkyl radical Sulphone, alkenylsulphone or an arylsulphone radical, R4 a low molecular weight alkyl or alkoxy radical and R5 a low molecular weight alkyl or alkoxy radical or a cycloalkyl radical with 5 to 6 carbon atoms, three of the radicals R2, R3, R4 and R5 also being hydrogen and where any alkyl or alkylene radicals present in the substituents R1 to R5, optionally substituted by a hydroxy or low molecular weight alkoxy group or a halogen atom, and two adjacent radicals can also be members of a ring system, or their salts, by a ) reactive derivatives of semicarbazidecarboxylic acids of the general formula II and IIa treated with alkaline agents or heated in the absence of alkaline agents, or b) semicarbazides of formulas III and IIIa with reactive derivatives of carbonic acid or c) reactive derivatives of phenylhydrazine-N1, N2-dicarboxylic acids of the formula IV with amines of the Fornei V converts or d) reactive derivatives of phenylhydrazine-N1- or N2-monocarboxylic acids of the formulas VI and VIa with reactive N-carboxylic acid derivatives of amines of the formula V or e) phenylhydrazines of the formula R - NH - NH2 in the presence of reactive derivatives of carbonic acid with amines of the formula V or f) in thiotriazolidines of the general formula VII the sulfur atom is replaced by an oxygen atom or g) triazolidines of the general formula VIII with amines of the formula V or h) oxdiazolone derivatives of the general formula reacts with amines of the formula V and, if appropriate, converts the compounds obtained into the corresponding salts with the aid of inorganic or organic bases.

In the further processing of this field of work it has now been found that the. Urazoles of the general formula I are also obtained when phenylhydrazines of the formula R - NH - NH2 are combined in a manner known per se with reactive derivatives of aniline-N, N-dicarboxylic acids of the general formula X heated.

As starting materials for the method according to the invention, for. B. following the given formula R - NH - NR2 corresponding phenylhydrazines in Consideration: phenylhydrazine, 2-, 3- or 4-chlorophenylhydrazine, 2-, 3- or 4-bromophenylhydrazine, 4-fluorophenyl hydrazine, 3-iodophenyl hydrazine, 4-methoxyphenyl hydrazine, 2-, 3- or 4-methylphenylhydrazine, 4-n-butoxyphenylhydrazine, 2-, 3- or 4-propylphenylhydrazine, 4-tert. Butylphenylhydrazine, 2-methoxy-4-methylphenylhydrazine, 2-ethoxy-4-methylphenylhydrazine, 2 - ethoxy - 4 - ethylphenylhydrazine, 2-methoxy-4-ethylphenylhydrazine, 3,4-dichlorophenylhydrazine, 2 - chloro - 4 - butylphenylhydrazine, 2,6-dimethoxyphenylhydrazine.

As aniline-N, N-dicarboxylic acids of the given formula X, which are in the form reactive derivatives with the relevant -Phenylhydrazinen to the urazoles Formula 1 can be implemented, come z. B. possible: 2-methyl-4-methoxyaniline-N, N-dicarboxylic acid, 2-chloro-4-methoxyaniline-N, N-dicarboxylic acid, 2-chloro-4-ethoxyaniline-N, N-dicarboxylic acid, 2-methyl-4-ethoxyaniline-N, N-dicarboxylic acid, 2-methoxy-4-phenoxyaniline-N, N-dicarboxylic acid, 2-methyl-4-phenoxyaniline-N, N-dicarboxylic acid, 2,5-dimethoxy - 4 - phenoxyaniline - N, N - dicarboxylic acid, 2,4,6 - trimethylaniline - N, N - dicarboxylic acid, 2,4-dimethoxy-5 - isopropylaniline - N, N - dicarboxylic acid, 2- ethoxy-4-phenylmercaptoaniline - N, N - dicarboxylic acid, 2 - isopropyl - 4- (2 - methoxyphenoxy) - aniline - N, N - dicarboxylic acid, 2,4-diethoxy- 4-phenoxyaniline - N, N - dicarboxylic acid, 2-bromo - 4 - octyloxyaniline - N, N - dicarboxylic acid, 2,5 - dimethyl - 4 - phenoxyaniline - N, N - dicarboxylic acid, 2,4,6-Trimethyl-3-methoxyaniline-N, N-dicarboxylic acid, 2-methyl-4-cyclohexylaniline - N, N - dicarboxylic acid, 2-methoxy-S-t2,4,4-trimethyl-pentyl- (2)] - aniline-N, -aicarboxylic acid, 2 - chloro - 5 - trifluoromethylaniline - N, N - dicarboxylic acid, 2-tert-butyl-4-ethylmercaptoaniline-N, N-dicarboxylic acid.

As reactive derivatives of the aniline-N, N-dicarboxylic acids come mainly the esters of low molecular weight alcohols such as methanol, ethanol, propanol, Isopropanol, butanol, tert-butanol, in question, but can also, for. B. phenol esters, Esteramides or Diamides are used. Instead of the free phenylhydrazines can one use those derivatives that are in the reaction mixture like the free compounds react.

The reaction is expediently carried out in the presence of a suitable solvent, for example benzene, toluene, xylene or dioxane, and using an alkaline one Condensation agent carried out.

Suitable alkaline condensing agents are, for. B.

Alkali or alkaline earth metals, hydroxides, carbonates, alcoholates, hydrides or amides, in catalytic or stoichiometric amounts or in Excess can be applied. Since the urazoles have acidic properties, they can easily be separated as salts. From the alkali salts found in water are mostly easily soluble, the acidification results in the free urazoles; these fall generally in crystalline form and can in a conventional manner, for. B. by Recrystallize from alcohol, be purified.

The 3,5-dioxo-1,2,4-triazolidines obtainable by the process according to the invention are compounds with acidic properties made with the help of inorganic and organic bases can be converted into corresponding salts. in the Regard Alkali and alkaline earth salts are particularly important for their use as medicinal products, which in most cases are soluble in water and their solutions are physiological have pu value.

The products of the process are valuable remedies because they are invariably Have antihypertensive properties. Sometimes they also show anti-inflammatory, analgesic or (coronary) vasodilator effectiveness and are generally characterized characterized by their good physiological tolerance. So z. B. the l-phenyl-4- (2,4-dimethoxy-5-isopropylphenyl) -3,5-dioxo- 1,2,4-triazolidine on the anesthetized cat at a dose of 5 to 10 mg / kg i. v. a drop in blood pressure of 60 to 80 mm Hg, depending on the starting blood pressure.

The lowering of blood pressure lasts for several hours. With subcutaneous (10 mg / kg) and oral administration, there is also a long-lasting decrease in blood pressure.

In the anesthetized rabbit, 2 mg / kg i. v. a decrease in blood pressure by at least 20 mm Hg, which lasts for several hours. 10 mg of the named compound, the daily i. v. given to rabbits over 4 weeks were well tolerated.

There was no getting used to; the blood pressure measurement showed at the end of the 4 weeks of application after 10 mg / kg i.v. v. a decrease in blood pressure of 60mm Hg, which lasted for several hours.

The white mouse shows the connection when administered intravenously an LD50 of 500mg / kg and thus has a surprisingly favorable therapeutic Index.

Example 1 10.8 g of phenylhydrazine and 23.7 g of 2,4-dimethylaniline-N, N-dicarboxylic acid dimethyl ester with a melting point of 121 to 123 "C are mixed with 9.5 g of sodium methylate in 150 ccm of xylene heated to boiling until the elimination of methanol has ended. The reaction mixture is mixed with excess dilute sodium hydroxide solution, the aqueous solution under Addition of charcoal sucked off and acidified. 13.8 g of l-phenyl-4- (2,4-dimethylphenyl) -3,5-dioxo-1,2,4-triazolidine are obtained, which melts at 187 to 189 "C after recrystallization from ethanol.

Example 2 Is used for the reaction described in Example 1 instead of the stated amount of sodium methylate, 0.3 g of sodium amide is obtained with an analogous procedure 7.7 g of 1-phenyl-4- (2,4-dimethylphenyl) -3,5-dioxo-1 2,4-triazolidine from a melting point of 187 to 189 "C. The sodium salt is obtained in crystalline form, if you take the triazolidine derivative together with the calculated amount of sodium methylate Dissolve in isopropanol in the heat and cool the filtered solution in ice.

Example 3 The procedure given in Example 1 is used 24.5 g of o-methylphenylhydrazine and 47.5 g of 2,4-dimethylaniline-N, N-dicarboxylic acid dimethyl ester with 6 g of powdered potassium hydroxide, 18.3 g of l- (o-methylphenyl) are obtained - 4- (2,4-dimethylphenyl) - 3,5 - dioxo - 1,2,4 - triazolidine of melting point 134 to 136 "C (from ether-petroleum ether).

Example 4 A mixture of 13.6 g of 2,4-dimethylphenyl hydrazine, 23.8 g of 2,4-dimethylaniline-N, N-dicarboxylic acid dimethyl ester and 12.4 g of sodium methylate Boiled in 300 cc of benzene until no more methanol distills off, whereby one the liquid volume of the reaction mixture by the occasional addition of Benzene keeps constant. The mixture is then heated to the boil for a further 11/2 hours. To After cooling, the solid product is suctioned off and washed on the filter with ether. The crude sodium salt thus obtained is dissolved in 80% methanol, the solution heavily diluted with water and sucked off with the addition of charcoal. From the filtrate acidification gives 10.5 g of 1,4-bis (2,4-dimethylphenyl) -3,5-dioxo-l 2,4-triazolidine, which melts at 127 to 129 "C after recrystallization from ethyl acetate-petroleum ether.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of antihypertensive urazoles of the general formula 1 wherein R is an aryl radical in which 1 or 2 hydrogen atoms, optionally by a halogen atom, a low molecular weight alkyl or alkoxy radical can be substituted, R2 a halogen atom, a low molecular weight alkyl, alkoxy, aralkoxy or an aryloxy radical, R2 a halogen atom, a Trifluoromethyl radical, an alkyl radical with 1 to 8 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, an aralkyl radical whose alkylene group is low molecular weight, an aryl radical, an alkoxy or alkyl mercapto radical having 1 to 6 carbon atoms, an aralkoxy radical whose alkoxy group is low molecular weight, an aryloxy - Or aryl mercapto radical or a low molecular weight acyl radical, R3 a halogen atom, a low molecular weight alkyl, alkoxy or carbalkoxy radical, a nitro group, an aliphatic or cycloaliphatic acyl radical with up to 8 carbon atoms, a low molecular weight araliphatic or an aromatic acyl radical, a low molecular weight alkylene radical ylsulfone, alkenylsulfone or an arylsulfone radical, R4 a low molecular weight alkyl or alkoxy radical and R5 a low molecular weight alkyl or alkoxy radical or a cycloalkyl radical with 5 to 6 carbon atoms, three of the radicals R2, R3, R4 and R5 also being hydrogen and where any alkyl or alkylene radicals present in the substituents R1 to R5 are optionally substituted by a hydroxy or low molecular weight alkoxy group or a halogen atom and two adjacent radicals can also be members of a ring system, or salts thereof, characterized in that, in a further embodiment of the Process according to patent application F 31700 IVd / 12 p (German Auslegeschrift 1153 759) phenylhydrazines of the formula R - NH - NH2 in a manner known per se with reactive derivatives of aniline-N, N-dicarboxylic acids of the general formula heated and, if appropriate, the compounds obtained are converted into the corresponding salts with the aid of inorganic or organic bases. 2. The method according to claim 1, characterized in that the implementation carried out in the presence of an alkaline condensing agent and a solvent will. Documents considered: German Auslegeschrift No. 1104 965.