NZ204153A

NZ204153A - 3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridazine derivatives and pharmaceutical compositions

Info

Publication number: NZ204153A
Application number: NZ204153A
Authority: NZ
Inventors: M Roesner; F Hock
Original assignee: Hoechst Ag
Priority date: 1982-05-08
Filing date: 1983-05-06
Publication date: 1985-04-30
Also published as: CA1201122A; DE3217325A1; FI831548A0; MA19791A1; ES8501400A1; IE55096B1; ATE24728T1; IL68611A0; GR79281B; JPS58203992A; NO831614L; ZA833239B; PT76654B; IE831043L; EP0094038A1; FI831548A7; EP0094038B1; KR840004753A; DK204783D0; ES530640A0

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines of the general formula I see diagramm : EP0094038,P8,F2 and their salts with a physiologically tolerated acid, wherein R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphtyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which radicals can optionally be substituted by one, two, three, four or five fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluormethyl, carboxyl groups, their esters with C1 -C6 -alcohols, aminocarbonyl, amino, acetamino or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical. 1. Claims for the Contracting State : AT Processes for the preparation of 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines of the general formula I see diagramm : EP0094038,P9,F1 and of their salts with a physiologically tolerated acid, wherein R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphtyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which radicals can optionally be substituted by one, two, three, four or five fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluormethyl, carboxyl groups, their esters with C1 -C6 -alcohols, aminocarbonyl, amino, acetamino or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical which comprise a) reacting an arylhydrazinopyridazine of the formula II see diagramm : EP0094038,P9,F4 wherein R**1 , R**2 and Ar have the meanings indicated for formula I, with cyanogen chloride, cyanogen bromide, O-methylisourea or S-methylisothiourea, guanidine or their salts, chloroformamidine hydrochloride or cyanamide as cyclization reagent, or b) reacting an arylhydrazinopyridazine of the formula II with a N-(R**3 -oxy)carbonyl-O-methylisourea, to give a compound of the formula III see diagramm : EP0094038,P9,F6 wherein Ar, R**1 and R**2 have the meanings indicated for formula I and R**3 denotes alkyl having 1-10 carbon atoms, benzyl or phenyl, and then hydrolyzing the compound thus obtained, or c) reacting a compound of the formula IV see diagramm : EP0094038,P9,F2 wherein R**4 denotes chlorine, bromine or methylthio, and Ar, R**1 and R**2 have the meanings indicated for formula I, with ammonia or d) cyclizing a compound of the formula V see diagramm : EP0094038,P9,F3 wherein Ar, R**1 and R**2 have the meanings indicated for formula I and Z represents O, S or NH, by heating, optionally with the addition of a condensing agent, to give a compound of the formula I, and optionally converting the compound thus obtained into the salt with a physiologically tolerated acid.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £04153 2041 | Priority Dato|s): .."? Compiiii® Opacification Filed: b. Class: fP.19.^7.. ./&! f&\ . 5 0 APR 1985^ \2JcP( Piifc-Iicstlon Date: P.O. Journal, fS!o: r2" °^n [* 6MAYl98$ ~ ? * N.Z. No. new zealand Patents Act 1953 complete specification "3-AMINO-6-ARYL-1,2,4-TRIAZOLO/4,3-B/PYRIDAZINES, THEIR PREPARATION AND THEIR USE". We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany,QE d-6230 Frarikfurt/Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the ;method by which it is to be performed,to be particularly described in and by the following statement -1- - 2 - 20.4153 The invention relates to new 3-amino-6-ary1-1,2,A-triazo loC4,3-bDpyridazines of the general formula I and their salts with a physiologically tolerated acid, 1 2 5 wherein R and R are identical or different and represent hydrogen/ alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents c~ - phenyl, biphenylyl, phenoxyphenyI, phenylthio-phenyl, phenylsulfiny Ipheny I, phenyIsuIfonyIphenyI, 1- or 10 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which can optionally be substituted by one, two, three, four or five radicals chosen from T- fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon 15 atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trif luoromethyI, carboxyl groups, their esters with C-j-C^-a Icohols, ami noca rbony I, amino, acetamido or a Ikoxycarbonylamino having 1-6 carbon 20 atoms in the alkyl radical. Among the compounds of the general formula I, t'ho.s*e; are preferred in which R1 and R2 are identical or J J 2 04153 different and denote hydrogen, methyl, ethyl, phenyl or chlorine and in which Ar denotes phenyl, biphenylyl, 2-or 3-thienyl, 2-furyl, 2-, 3- or 4-pyridyl which can optionally be substituted by one, two or three fluorine, 5 chlorine, bromine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-6 carbon atoms or trifluoro-methyl. 1 Those compounds of the formula I in which R and 2 R are identical or different and denote hydrogen, 10 methyl or ethyl and Ar denotes phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, optionally substituted by one or two fluorine, chlorine, methyl, ethyl or trifluoromethyl are particularly preferred. The invention also relates to processes for the 15 preparation of these compounds and pharmaceutical formulations of these compounds and their use as medicaments. The process for the preparation of the compounds of the formula I comprises reacting an ary I hydrazinopyri-dazine of the formula II 1 2 wherein R , R and Ar have the meanings indicated for formula I, a) with a cyclization reagent such as cyanogen chlo ride, cyanogen bromide, O-methylisourea or S-methyliso-25 thiourea, guanidine or their salts, ch loroformamidine hydrochloride or cyanamide, or - 4 - • ■'? b) with a N-(R^-oxy)carbonyl-0-methylisourea, to give a compound of the formula III Ar III NHCOOR* 1 P wherein Ar, R and R have the meanings indicated for formula I and R^ denotes alkyl having 1-10 carbon atoms, benzyl or phenyl, and then hydrolyzing the compound thus obtai ned, or c) comprises reacting a compound of the formula IV Ar IV 10 wherein R denotes chlorine, bromine or methylthio, and Ar, R^ and R^ have the meanings indicated for formula I, with ammoni a, or d) comprises cyclizing a compound of the formula V 1 Ar -Q- z y nh-nh-c-nh2 15 1 2 wherein Ar, R and R have the meanings indicated for formula I and Z represents 0, S or NH, by heating, optionally with the addition of a condensing agent, to X 04-1 5! - 5 - give a compound of the formula I. Compounds of the formula II are known, for example, from J. Heretocyclic Chem. 1^5, 881 (1978) and can be prepared from chlorine compounds of the formula VI R1 ,R "If1 • VT with hydrazine hydrate by processes known from the literature (The Chemistry of Heterocyclic Compounds, Vol. 28, Pyridazines, Editors A. Weissberger and E.C. Taylor, John Wiley, New York 1973). Both literature citations also 10 describe the synthesis of the chlorine compounds VI and their precursors. The process a) is carried out in a suitable solvent in a temperature range from 0°C to the boiling point of the solvent used, preferably at 50 to 100°C. 15 Examples of suitable solvents for the process a) are water, acetic acid, aliphatic alcohols, such as methanol, ethanol and isopropanol, dioxane, DMF, toluene and chlorinated hydrocarbons, such as methylene chloride, chloroform, dich loroethane and carbon tetrachloride. 20 The process b) is carried out in a suitable sol vent in the presence of an acid. For example, it is carried out in a mixture of methanol and glacial acetic acid in a volume ratio of, for example, 10:1 at the reflux temperature. The hydrolysis of the carbaminate III takes 25 place under alkaline conditions by heating with an alkali metal or alkaline earth metal hydroxide such as, for - 6 - X04r 1 example, N a 0 H , K 0 H , C a ( 0 H ) 2 or B a ( 0 H ) 2 in a solvent or mixture of solvents at 60-180°C, preferably at 100-140°C. Particularly suitable solvents are water and aliphatic alcohols and diols such as ethanol, propanol, 5 isopropanol, butanol, 2-methoxyethanol and glycol. For process c) , the starting materials of the formula IV are converted, by heating arylhydrazinopyridazines II with formic acid or its esters (when R ^ = H), chloro-formic esters or a dialkyl carbonate (when R^ = OH) or 10 with carbon disulfide and alkali (when R^ = SH), optionally with the addition of a solvent or diluent, such as chloroform, toluene, dioxane, water or ethanol, to give a compound of the formula IV" in which R^ denotes H, OH or SH. From this the corresponding compounds IV with 15 R^ = Br, CI or S CHj are obtained by heating with bromine in glacial acetic acid/sodium acetate (when R^ = H), phosphorus oxychloride (when R ^ = OH) or methyl iodide or dimethyl sulfate (when R^ = SH). According to process c), the reaction of the com-20 pounds of the formula IV takes place with liquid, aqueous or alcoholic ammonia, or with gaseous ammonia by passing in, or under pressure, in an inert solvent such as methanol, dioxane or toluene. The temperature range extends from the temperature of liquid ammonia up to 200°C. 25 According to process d), the compounds V obtained, for example, by reaction of chlorine compounds VI with semicarbazide, thiosemicarbazide or aminoguanidine in a solvent such as, for example, methanol, ethanol, isopro-panol, DMF, tetrahydrofuran, toluene, chloroform or di- - 7 - ch loroethane, are converted into compounds of the formula I by heating, for example in one of the solvents mentioned, to 40-150°C, optionally with the addition of a condensing agent such as glacial acetic acid, cyclohexyl-5 carbodiimide or 1-hydroxybenzotriazoIe. When the compounds of the formula I are obtained as salts by the processes described, then the corresponding base can be liberated from these using ammonia, amines or hydroxides. 10 The free bases of the formula I are converted into the corresponding salts with physiologically tolerated acids. Suitable acids are inorganic or organic acids such as hydrochloric or hydrobromic acid, phosphoric acid, acetic acid, benzoic acid, citric acid, ma lei c' acid, 15 fumaric acid, lactic acid, tartaric acid, succinic acid, or acetylglycine. The hydrochlorides of the formula I a re prefe rred. The compounds of the formula I according to the invention are suitable for the preparation of medicaments. 20 The medicaments can contain one or more of the compounds according to the invention or mixtures of them with other pharmaceutica I ly active substances. In order to prepare the medicaments, the customary pharmaceutical vehicles and auxiliaries and known formulating processes can be 25 used. The medicaments can be u-sed enterally, pa rente ra I ly, orally or per I ingua I ly . For example, administration can take place in the form of tablets, capsules, pills, coated tablets, suppositories, gels, creams, powders, liquids, dusting powders or aerosols. Examples of suitable liquids ^-O/f/5 b are: oily or aqueous solutions or suspensions, emulsions, injectible aqueous solutions or suspensions. Moreover, the compounds according to the invention can be used as intermediate products for the prepara-5 tion of other medicaments. The foliowing may be mentioned as compounds according to the invention: 3-amino-6-(2-bromopheny I)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(2-trifluoromethyl-phenyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-10 chloro-3-tri fluoromethylphenyl)-1,2,4-triazoloC4,3-b3- pyridazine, 3-amino-6-(3-ethylphe-nyl)-1,2,4-triazoloC4,3-b3 pyridazine, 3-amino-6-(2-methylphenyl)-1,2,4-triazolo-C4,3-b3pyridazine, 3-amino-6-(2-ethylphenyl)-1,2,4-tri-azolot4,3-b3pyridazine, 3-amino-6-(3-methoxyphenyl)-1,2,4-15 tri azoloC4,3-b]pyridazine, 3-amino-6-(4-propylthiophenyl)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(4-acetamido-phenyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-aminophenyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-methoxycarbonylaminophenyl)-1,2,4-triazolo-C4,3-b]pyri-20 dazine, 3-amino-6-(4-nitropheny I >-1,2,4-1riazoIoC4,3-bD-pyridazine, 3-amino-6-(3-nitrophenyl)-1 ,2,4-triazolo-C4,3-bDpyridazine, 3-amino-6-(2-nitrophenyl)-1,2,4-tri-azoloC4,3-bUpyridazine, 3-amino-6-(4-cyanophenyl)-1,2,4-triazoloC4,3-b!]pyri dazine, 3-amino-6-(3-cyanophenyl)-1,2,4-25 triazoloC4,3-b]pyri dazine, 3-amino-6-(2-cyanophenyl)-1,2,4-triazoloC4,3-bUpyridazine, 3-amino-6-(4-phenylsulfinyl-phenyl)-1 ,2,4-tri azoIo/4,3-b7pyridazine, 3-amino-6-(4-phenylsulfonylphenyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-hydroxyphenyl)-1,2,4-triazoloC4,3-bIIpyrida- 1041! - 9 - z ine, 3-amino-6-(3-hydroxyphenyl)-1,2,4-triazoloC4,3-b3-pyri dazine, 3-amino-6-(3,4-dihydroxyphenyl)-1,2,4-triazolo-C4,3-bUpyridazine, 3-amino-6-(1-naphthyl)-1,2,4-triazolo-C4,3-b!]pyridazine, 3-amino-6-(2-naphthyl)-1,2,4-triazolo-5 C4,3-bDpyridazine, 3-amino-6-(3-thienyl)-1,2,4-triazolo-C4,3-bDpyridazine, 3-amino~6-(4-chloro-2-thienyl)-1,2,4-triazoloC4,3-b!lpyridazine, 3-amino-6-(3-methyl-2-thienyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-methyl-2-thienyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(2-10 furyl)-1,2/4-triazoloC4,3-b3pyridazine, 3-amino-6-(5- methyl-2-furyl)-1,2,4-triazoloC4,3-bIlpyridazine, 3-amino-6-(4-pyridyl)-1,2,4-triazoloC4,3-bI]pyridazine, 3-amino-6-(3-pyridyl)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(2-pyridyl)-1,2,4-triazolo£4,3-bDpyridazine, 3-amino-15 6-(2-pyrro Iy I )-1,2,4-1riazo I oC4,3-bDpyridazine and 3- amino-6-(1-methyl-2-pyrrolyl)-1,2,4-triazoloC4,3-bIlpyri-dazi ne. The compounds of the formula I according to the invention have pharmacological properties; in particular, 20 they have anxiolytic and anticonvulsive effects. Thus, suitable indications are insomnia, agitation and autonomic depression. In general, the pharmaceutical formulations contain between 1 and 10% of the active component(s) accor-25 ding to the invention. The anxiolytic effect of the compounds of the formula I is accompanied by a very slight sedation and good tolerance (LDjg inter alia ^>300 mg/kg i.p. in the mouse). This is clear from investigations in which the 2 041 5: effect of the compounds according to the invention on motor activity, hexobarbital-induced narcosis and cardia-zole-induced spasms in mice was measured. In addition, the Geller anxiolysis test and the lick shock test were 5 employed on rats. In the tests indicated above, examples of the lowest dose which still has activity are 5 mg/kg oral, 2.5 mg/kg sublingual and 1 mg/kg intravenous. Examples of generally suitable dose ranges for an effect (tests on 10 animals as above) are: 5 to 50 mg/kg oral, 2.5 to 25 mg/ kg sublingual and 1 to 10 mg/kg intravenous. For example, 1 to 3 tablets containing 10 to 100mg of active substance can be administered thrice daily or, for example for intravenous injection, a vial containing 15 2 to 4 ml with 0.5 to 5 mg of substance can be administered once to thrice daily. Example 1: Process a) 3-Amino~6-phenyl-1,2,4-triazoloC4,3-bHpyridazine hydrochloride 20 25 g of 3-hydrazino-6-pheny Ipyridazine and 17.1 g of cyanogen bromide in 150 ml of ethanol are stirred under reflux for 3 hours and then evaporated in a vacuum rotary evaporator. The residue is dissolved in hot water, filtered and made alkaline with excess ammonia. The free 25 base is filtered off with suction, washed to neutrality and dried, then suspended in ethanol, ethanolic hydrochloric acid is added, and evaporated in vacuo. The precipitated hydrochloride is filtered off with suction, washed with ethanol and dried, melting 2 0415 3 - 11 - point 280°C (decomposition). Examp le 2 : Process a) 3-Amino-6-(4-fLuorophenyl)-1/2/.4-triazolo[I4/3-bDpyri dazine hydrochloride 5 A slight excess of cyanogen chloride is passed into a solution of 5 g of 3-(4-fluorophenyI)-6-hydrazino-pyridazine in 50 ml of ethanol at 0 - 10°C and stirring is continued at room temperature until reaction is complete (checked by TLC). 10 The precipitated hydrochloride is filtered off with suction, washed with isopropanol and dried, melting point 284°C (decomposition). Example 3: Process b) 3-Ami no-6-(3,4-di chlorophenyl)-1,2,4-triazoloC4,3-bDpyri-15 dazine. 3 g of 6-(3,4,-dichlorophenyI)-3-methoxycarbony l-amino-1,2,4-triazo IoC4,3-bDpyridazine and 3 g of potassium hydroxide in 10 ml of water and 20 ml of 2-methoxy-ethanol are heated to reflux for 16 hours. 20 The precipitated product is filtered off with suction, washed to neutrality and recrystallized from isopropanol, melting point 281°C. Example 4: Process c) 6-(4-Methylphenyl)-1,2,4-triazoloQ,3-b]pyridazine 25 5 g of 3-hydrazino-6-(4-methy Ipheny 1)pyridazine in 10 ml of formic acid are stirred under reflux for 2 hours. After cooling down, the mixture is diluted with water and the precipitated product is filtered off with suction, washed to neutrality and dried, melting point 2 04 1 5 - 12 - 186°C. Example 5 : Process c) 3-Bromo-6-(4-methylphenyl)-1,2,4-triazoloC4,3-b3pyrida-zi ne 5 4 g of 6-(4-methyIphenyI)-1,2,4-triazoloC4,3-bD- pyridazine and 3 g of sodium acetate are suspended in 20 ml of glacial acetic acid. 1 ml of bromine in 5 ml of glacial acetic acid are added dropwise and the solution is heated to reflux for 5 hours. It is then evaporated to 10 dryness, water is added and the product is filtered off with suction. After recrystallization from isopropanol and drying, the melting point is 211°C. Examp le 6 : Process c) 3-Amino-6-(4-methylphenyl)-1,2,4-triazoloC4,3-bDpyridazine 15 3 g of 3-bromo-6-(4-methy IphenyI)-1,2,4-1riazoLo- [4,3-bDpyridazine are treated with 25 ml of methanol and 25 ml of concentrated ammonia solution in an autoclave at 100°C. After cooling down, the mixture is diluted with water, filtered off wich suction, washed to neutra-20 lity and dried, melting point 261°C. Example 7: Process d) 3-Phenyl-6-thiosemicarbazidopyridazine 6 g of 3-ch loro-6-pheny Ipyridazine and 6 g of thiosemicarbazide in 60 ml of ethanol are heated to re-25 flux for 3 hours. The precipitate produced is filtered off with suction, washed with ethanol and water and dried in vacuo, melting point 213°C (decomposition). Example 8: Process d) 3-Amino-6-phenyl-1,2,4-triazoloC4,3-b3pyridazine 2-4153 - 13 - 2 g of 3-pheny1-6-thiosemicarbazidopyridazine in 20 ml of glacial acetic acid are heated to reflux for 6 hours. After evaporation of the reaction solution, the residue is thoroughly stirred with aqueous ammonia, fil-5 tered off with suction, washed with water to neutrality, dried and recrysta 11ized from isopropanol, melting point 212°C . The following compounds can be prepared in analogy to Examples 1 - 8: Example Compound Melting Salt Process point 9. 3-Amino-6-(4-bromophenyl)-1,2,4- 317°C HBr b triazolo [4,3-b_[ pyridazine (decomp.) 10. 3-Amino-6-(4-chlorophenyl)~ 264°C - c 1,2,4-triazolo[4,3-b]pyridazine 11. 3-Amino-6-(4-iodophenyl)-1,2,4- a triazolo[4,3-bJ pyridazine 12. 3-Amino-6-(4-trifluoromethyl- 289°C HCl a phenyl)-1,2,4-t riazolo [4,3-b].- (decomp.) pyridazine 13. 3-Amino-6-(3-bromophenyl)-1,2,4- 273°C HCl d triazolo[4,3-b] pyridazine (decomp.) 14. 3-Amino-6-(3-chlorophenyl)- 288°C HCl a 1,2,4-triazolo[4,3-bl pyridazine (decomp.) 15. 3-Amino-6-(3-f luorophenyO- 266°C HCl a 1,2,4-triazolof4,3-bl pyridazine (decomp.) 16. 3-Amino-6-(3-trifluoromethyl- 276°C HCl a phenyl)-1,2,4-triazolo[4,3-b] - (decomp.) pyridazine 17. 3-Amino-6-(2-chlorophenyl)- 258°C HCl a 1,2,4-t riazolo [4, 3-b^ pyridazine (decomp.) 3-Amino-6-(2-fluorophenyl)- 234°C 1,2,4-triazolo[4,3-b]pyridazine (decomp.) </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 14 - 2 04153 Example Compound Melting Salt Process point 19. 3-Amino~6-(4-ethylphenyl)- 1,2,4-triazolo j4,3-bj pyridazine 20. 3-Amino-6-(4-isopropylphenyl)-1,2,4-tri azolo£4,3-b3pyri dazine 263°C (deconp.) 253°C (decomp.) HCl HCl 21. 3-Amino-6-(4-tert.butylphenyl)-1,2,4-t riazoloL4,3-bJ pyridazine 22. 3-Amino-6-(4-cyclohexy Iphenyl)-1,2,4-triazolo[4,3-b3 pyridazine 23. 3-Amino-6-(4-biphenylyl)-1,2,4-triazolo[4,3-bJ pyridazine 24. 3-Amino-6-(4-benzylphenyl)- 1,2,4-triazolo[4,3-blpyridazine 25. 3-Amino-6-(3-methylphenyl)- 1 /.2,4-triazolo£4,3-bl pyridazine 26. 3-Amino-6-(4-methoxyphenyl)- 1,2,4-triazolof4,3-bjpyridazine 27. 3-Ami no-6-(3,4-di met hoxyphenyI)-1,2,4-tri azolo[4,3-b3 pyridazine 28. 3-Amino-6-(4-methyIt hiopheny l)-1,2,4-triazolo[4,3-bJ pyridazine 29. 3-Amino-6-(4-phenoxyphenyl)~ 1 /2,4-tria2olo{4,3-b_| pyridazine 30. 3-Amino-6-(4-phenylthiophenyl)-1,2/4-triazolof4,3-b3 pyridazine 31. 3-Amino-6-(2-thienyl)-1,2x4-triazolo f4,3—b]pyridazine 32. 3-Amino-6-(5-methyl-2-thienyl)-1 ,2/.4-triazolo£4,3-blpyridazine 33. 3-Amino-6-(5~chloro-2-thienyl)-1,2,4-triazolof4,3-bJpyridazine 34. 3-Amino-6-(5-bromo-2-thienyD- 1,2,4-triazolof4,3-b]pyridazine 272°C (decomp.) 259°C (decomp.) 274°C (decomp.) 297°C (decomp.) 290°C (decomp.) 275°C (decomp.) 259°C (decomp.) 316°C (decomp.) 236°C 274°C 280°C 318°C (decomp.) 306°C (decomp.) 316°C (decomp.) HCl HCl HCl HBr HCl HCl HBr HCl HCl HCl HCl HCl HCl HCl WKAT %'WE CLAIM )§w - 15 - 204153 1. 3-Amino-6-aryl-1,2,4-triazoloC4,3-b3pyridazines of the formula I .1 ^2 and their salts with a physiologically tolerated acid, 1 2 5 wherein R and R are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenylyl, phenoxyphenyl, phenylthio-phenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 10 2-naphthyl, 2- or 3-thieny I, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which can optionally be substituted by one, two, three, four or five radicals chosen uorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon 15 atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trif luoromethyI, carboxyl groups, their esters with C-j-C^-a Icohols, aminocarbony I, amino, acetamido or a IkoxycarbonyI ami no having 1-6 carbon 20 atoms in the alkyl radical. 2. Compounds as claimed in claim 1, wherein R and R are identical or different and denote hydrogen, methyl, ethyl, phenyl or chlorine and in which Ar denotes phenyl, biphenylyl, 2- or 3-thienyl, 2-furyl, 2-, 3"-y, o/. 204153 - 16 - 4-pyridyl which can optionally be substituted by one, two radicals selected from or three[fluorine, chlorine, bromine, alkyl groups having

1-6 carbon atoms, cycloalkyl groups having 3-6 carbon atoms or trifluoromethyI. 5 3. Processes for the preparation of compounds of as claimed the formula l|in claim 1, which comprise reacting an aryl-hydrazinopyridazine of the formula II 1 2 wherein R , R and Ar have the meanings indicated 10 for formula I, a) with a cyclization reagent, or b) with a N-(R^-oxy)carbonyl-0-methylisourea, to give a compound of the formula III 1 2 15. wherein Ar, R and R have the meanings indicated for § formula I and r' denotes alkyl having 1-10 carbon atoms, benzyl or phenyl, and then hydrolyzing the compound thus obtained, or c) comprises reacting a compound of the formula IV - 17 - Ar, R^ and R^ have the meanings indicated for formula I, with ammoni a, or 5 .d).. comprises cyclizing a compound of the formula V 1 2 wherein Ar, R and R have the meanings indicated for formula I and Z represents 0, S or NH, by heating, optionally with the addition of a condensing agent, to 10 give a compound of the formula I, and optionally converting the compound thus obtained into the salt with a physiologically tolerated acid. i. 4. Pharmaceutical preparations with anxiolytic and anticonvulsive effects containing a compound of the formula I 15 as claimed in claim 1. as claimed 5. The use of a compound of the formula Iin;claim 1 for the treatment of states of agitation, insomnia, convulsive states and neurodystoni a in non-human animals. 17 JAN 1985 i 18" I ^ + 153 6. A compound according to claim 1 substantially as herein described with reference to the Examples. 7. A preparation according to claim 4 substantially as hereinbefore described. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED by= J, </div>