IE55096B1 - 3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridazines,their preparation and their use - Google Patents
3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridazines,their preparation and their useInfo
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- IE55096B1 IE55096B1 IE1043/83A IE104383A IE55096B1 IE 55096 B1 IE55096 B1 IE 55096B1 IE 1043/83 A IE1043/83 A IE 1043/83A IE 104383 A IE104383 A IE 104383A IE 55096 B1 IE55096 B1 IE 55096B1
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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
-2 - -2 - S 5 0 8 6 The invention relates to new 3-amino-6~aryl-1,2,4-triazoloC4,3-blpyridazines of the general formula I and their salts with a physiologically tolerated acid, 5 wherein R^ and R^ are identical or different and each represents hydrogen, an alkyl group having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthio-phenyl, phenylsulfinylphenyl, phenylsulfonyIphenyl, 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 substituents selected frcm fluorine, chlorine, branine, iodine, alkyl groups having 1-6 carbon atoms, cyeloalkyl 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, trifluoromethyl, carboxyl groups, their esters with C^-C^-alcohols, ami nocarbonyl, amino, acetamido or aIkoxycarbonylamino having 1-6 carbon 20 atoms in the alkyl radical.
Among the compounds of the general formula X, those are preferred in which R1 and R2 are identical or - 3 - different and denote hydrogen, methyl, ethyl, phenyl or chlorine and in which Λγ denotes phenyl, biphenyl, 2-or 3-thienyl, 2-furyl, 2-, 3- or 4-pyridyl which can optionally be substituted by one, two or three fluorine, chlorine or branine atatis, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-6 carbon atoms or trifluoro-methyl.
A Those compounds of the formula I in which R and are identical or different and denote hydrogen, 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 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 a) reacting an arylhydrazinop^ri dazine of the formula II II - 4 - b) reacting an arylhydrazinopyridazine of the formula 3 II with an N-(R -oxy)carbonyl-O-methylisourea, to give a compound of the formula III 1 7 wherein Ar, R1 and R have the meanings indicated for 5 formula I and R^ 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 R wherein R^ denotes chlorine, bromine or methylthio, and Ar, R^ and R^ have the meanings indicated for formula I, with ammonia, or d) cyclizing a compound of the formula V 7 15 wherein Ar, R1 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 - 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 VI Ar 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.
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, dichloroethane and carbon tetrachloride.
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 example, NaOH, KOH, Ca(0H>2 or Ba(OH>2 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-nethoxyethanol 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, Cl or SCHj 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.
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, isopropanol, DMF, tetrahydrofuran, toluene, chloroform or di- 7 chloroethane, 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-carbodiimide or 1-hydroxybenzotriazole.
When the compounds of the formula X are obtained as salts by the processes described, then the corresponding base can be liberated from these using ammonia, amines or hydroxides.
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, maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, or acetylglycine. The hydrochlorides of the formula I are preferred.
The compounds of the formula I according to the invention are suitable for the preparation of medicaments. The medicaments can contain one or more of the compounds according to the invention or mixtures of them with other pharmaceutically active substances. In order to prepare the medicaments, the customary pharmaceutical vehicles and auxiliaries and known formulating processes can be used. The medicaments can be used enterally, parenterally, orally or perlingually. 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 - 8 - 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 following may be mentioned as compounds according to the invention: 3-amino-6-(2-bromophenyl)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(2-trifluoromethyl-phenyl)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(4-10 chloro-3-trifluoromethyIphenyl)-1,2,4-triazoloC4,3-b3- pyridazine, 3-ami no-6-(3-ethy Ipheny 1)-1 ,2,4-triazoloC4,3-b3 pyridazine, 3-ami no-6-(2-methyIphenyl)-1,2,4-triazolo-C4,3-b3pyri dazine, 3-ami no-6-(2-ethyIpheny1)-1,2,4-tri-azo loC4,3-b!l pyridazine, 3-ami no-6- (3-methoxypheny 0-1 ,2,4-15 tri azoloC4,3-bDpyridazine, 3-ami no-6-(4-propyIthiopheny1)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(4-acetamido-phenyl )-1 ,2,4-tri azolot4,3-b3pyri dazine, 3-ami no-6-¢4-aminophenyl)-1,2,4-triazo loC4,3-b3pyridazine, 3-amino-6-(4-methoxycarbonylaminopheny1)-1,2,4-triazolo E4,3-b3pyri- ' 20 dazine, 3-ami no-6-(4~nitropheny1)-1,2,4-tr1azoloC4,3-b3-pyridazine, 3-ami no-6-(3-nitropheny1)-1,2,4-triazolo-E4,3-b3pyridazine, 3-ami no-6-(2-nitrophenyl)-1,2,4-tri-azoloC4,3-b3pyridazine, 3-amino-6-¢4-cyanopheny1)-1,2,4-tria2olot4,3-b3pyridazine, 3-amino-6-C3-cyanopheny1)-1,2,4-25 triazoloC4,3-b3pyridazine, 3-amino-6-(2-cyanophenyl)-1,2,4-triazolo C4,3 -b3 pyridazine, 3-amino-6-(4-phenyIsulfinyl-phenyl)-1,2,4-triazolo/4,3-b7pyridazine, 3-ami no-6-(4-phenyIsuIfonyIpheny1)-1,2,4-triazoloE4,3-b3pyridazine, 3-ami no-6-C4-hydroxyphenyl)-1,2,4-tri azoloE4,3-bDpyrida- - 9 - zine, 3-ami no-6-(3-hydroxypheny1)-1,2,4-tri azoloC4,3-b3-pyridazine, 3-amino-6-<3/4-dihydroxypheny0-1,2,4-triazolo C4,3-b)pyridazine, 3-ami no-6-(1-naphthy 0-1,2,4-triazolo-C4,3-b3pyridazine, 3-amino-6-(2-naphthyl)-1,2,4-triazolo-C4,3-b3pyri dazine, 3-amino-6-(3-thienyl)-1,2,4-triazolo-C4,3-b3pyridazine, 3-anino-6-(4-chloro-2-thieny0-1,2,4-triazoloC4,3-b3pyridazine, 3-ami no-6- (3-methy 1-2-thi eny ΟΙ,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(4-methyl-2-thienyl)-1,2,4-ΐriazoloC4,3-b3pyridazine, 3-amino-6-(2-furyO-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(5-methyl-2-furyl)-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(4-pyridyO-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(3-pyri dyl)-1,2,4-triazoloC4,3-b3pyridazine, 3-amino-6-(2-pyridyO-1,2,4-triazoloC4,3-bDpyridazine, 3-amino-6-(2-pyrrolyl)-1,2,4-triazoloC4,3-b!Jpyridazine and 3-amino-6-(1 -methyt-2-pyrroly 0-1,2,4-triazoloC4,3-b3pyri-dazine.
The compounds of the formula I according to the invention have pharmacological properties; in particular, 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) according to the invention.
The anxiolytic effect of the compounds of the formula I is accompanied by a very slight sedation and good tolerance (LD50 inter alia J>300 mg/kg i.p. in the mouse). This is clear from investigations in which the - 10 effect of the compounds according to the invention on motor activity, hexobarbitat-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 abovei 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 adminis tered once to thrice daily.
Example 1: Process a) 3-Amino-6-pheny1-1,2,4-triazoloC4,3-b3pyridazine hydrochloride 20 25 g of 3-hydrazino-6-phenylpyridazine 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 11 point 280°C (decomposition).
Example 2; Process a) 3-Ami no-6-(4-fluoropheny1)-1,2,4-t ri azoloE4,3-bDpyri da-zine hydrochloride A slight excess of cyanogen chloride is passed into a solution of 5 g of 3 — (4—fluorophenyl)-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).
The precipitated hydrochloride is filtered off with suction, washed with isopropanol and dried, melting point 284°C (decomposition).
Example 3: Process b) 3-Amino-6-(3,4-di chloropheny1)-1,2,4-triazoloC4,3-b3pyri-dazine. 3 g of 6-(3,4,-dichlorophenyl)-3-methoxycarbonyl-amino-1,2,4-triazoloC4,3-b]pyridazine 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.
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-Hethylphenyl)-1,2,4-triazolo[4,3-b]]pyridazine 5 g of 3-hydrazino-6-(4-methylphenyl)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 186°C. 3-Bromo-6-(4-methyIpheny 1)-1 ,2,4-triazoLot4,3-blpyrida-zine 4 g of 6-(4-methyIpheny0-1,2,4-triazoloC4,3-b3-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 dryness, water is added and the product is filtered off with suction. After recrystallization from isopropanol and drying, the melting point is 211°C, 3-Ami no-6-(4-mcthyIpheny1)-1,2,4-triazoloC4,3-bDpyridazine 3 g of 3-bromo-6-(4-methylphenyl)-1,2,4-triazolo-C4,3-b3pyridazine 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 neutrality and dried, melting point 261°C.
Example 5i Process d) 3-Phenyl-6-th iosemi ca rbazidopyridazine 6 g of 3-chloro-6-phenylpyridazine and 6 g of thiosemicarbazide in 60 ml of ethanol are heated to reflux 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). 3-Amino-6-phenyl-1,2,4-triazoloC4,3-b3pyridazine 13 2 g of 3-phenyl-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 recrystallized from isopropanol, melting point 212°C.
The following compounds can be prepared in analogy to Examples 1 - 5: Example Compound Melting point Salt Process 6. 3-Amino-6-(4-bromopheny1)-1,2,4-triazolo[4,3-b]pyridazine 317°C (decomp.) HBr b 7. 3-Amino-6-(4-chlorophenyl)- 1,2,4-triazolo[4,3-b]pyridazine 264°C - c 8. 3-Am i no-6-(4-i odoph enyl)-1,2,4-triazolo[4,3-b]pyridazine a 9. 3-Amino-6-(4-tri fluoromethyl- phenyl)-1,2,4-triazolo[4,3-b]- pyridazine 289°C (decomp.) HCl a 10.. 3-Ami no-6-(3-bromopheny1)-1,2,4-triazolo[4,3-b]pyridazine 273°C (decomp.) HCl d 11. 3-Ami no-6-(3-chlorophenyl)-1,2,4-triazolo[4,3-b1pyridazine 288°C (decomp.) HCl a 12 . 3-Amino-6-(3-fluorophenyl)-1,2,4-triazolor4,3-b3pyridazine 266°C (decomp.) HCl a 13 . 3-Ami no-6-(3-t r i fluoromethyl- phenyl)-1,2,4-triazolo£4,3-bJ- pyridazine 276°C (decomp.) HCl a 14 . 3-Ami no-6-(2-chloropheny1)-1,2,4-triazolo[4,3-b3pyridazine 258°C (deccmp.) HCl a 15. 3-Ami no-6- (2-f luoropheny ΟΙ, 2,4-triazolo[4,3-¾ pyridazine 234°C (decomp.) HCl a - 14 - Example Compound Melting point Salt Process 16. 3-Ami no-6-C4~ethyIphenyl)-1,2,4-triazolo[4,3-b3pyridazine 263°C ! (decoap.) HCL b 17. 3-Ami no-6-¢4-isopropyLphenyl)-1,2,4-triazolo£4,3-b3pyridazine 253°C (decomp.) HCl d 18 . 3-Ami no-6-(4-tert,butyLphenyl)-1,2,4-triazolo£4,3-b0pyridazine 272°C (decomp.) HCl d 19 . 3-Amino-6- (4-cyclohexylpheny1)-1,2,4-triazolo£4,3-bJpyridazine 259°C (decomp.) HCl a 20. 3-Amino-6-(4-biphenylyl)-1,2,4-triazolo|4,3-b]pyridazine 274°C (decomp.) HCl a 21. 3-Ami no-6-(4-benzylphenyl)-1,2,4-t ri azo t o [4,3-bT py ri dazi ne 297°C (decomp.) HBr c 22. 3-Amino-6-(3-methy Lpheny1)-1,2,4-triazolol4,3-b3pyridazine 290°C (decomp.) HCl c 23. 3-Amino-6-(4-methoxypheny ΟΙ,2,4-triazolof4,3-10 pyridazine 275°C (decomp.) HCl d 24. 3-Amino-6-(3,4-dimethoxyphenyl)- 1,2,4-triazolo[4,3-b0pyridazine 259°C (decomp.) HBr a 25.' 3-Amino-6-(4-methylthiophenyl)- 1,2,4-triazolo£4,3-bJpyridazine 316°C (decomp.) HCl a 26- 3-Ami no-6-(4-phenoxyphenyl)-1,2,4-triazolo£4,3-b3pyridazine 236°C HCl a 27. 3-Amino-6-(4-phenylthiophenyl)~ 1,2,4-triazolo£4,3-b3pyridazine 274°C HCl a: 28. 3-Ami no-6- (2-th i enyD-1,2,4-triazolo£4,3-b3pyridazine 280°C HCl a 29. 3-Ami no-6-(5-met hyl-2-thi enyl)-1,2,4-t riazolo [4,3-bJ pyri dazine 318°C (decomp.) HCl a 30. 3-Amino-6-(5-chloro-2-thienyl)-1,2,4-tri azolo£4,3-bJ pyri dazine 306°C (decomp.) HCl a 31. 3-Ami no-6-(5-bromo-2-thi eny1)-1,2,4-triazolor4,3-b]pyridazine 316°C (decomp.) HCl b
Claims (9)
1. A 3-amino-6-aryl-1,2,4-tria2oloC4,3-blpyridazine of the formula I or a salt thereof with a physiologically tolerated acid, 5 wherein R^ and R^ are identical or different and each represents hydrogen, an alkyl group having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthio-phenyl, phenylsulfinylphenyl, phenyIsulfonyIphenyl, 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 substituents selected fran fluorine, chlorine, branine, 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, trifluoromethyl, carboxyl groups, their esters with C^-C^-a Icohols, aminocarbonyl, amino, acetamido or a Ikoxycarbony lamino having 1-6 carbon 20 atoms in the alkyl radical. A
2. A compound, as claimed in claim 1, wherein R and R^ are identical or different and each denotes hydrogen, methyl, ethyl, phenyl or chlorine and in which Ar denotes phenyl, biphenyl, 2- or 3-thienyl, 2-furyl, 2-, 3- or 16 - 4-pyridyl which can optionally be substituted by one, two or three fluorine, chlorine or bromine atoms, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-6 carbon atoms or trifluromethyl.
3. A process for the preparation of a compound of the formula X in claim 1, which comprises a) reacting an arylhydrazinopyridazine of the formula II Ar- N—N \\ /)-nhnh2 II 1 2 10 wherein R , R and Ar have the meanings indicated for formula I in claim 1 with cyanogen chloride, cyanogen bromide, O-methylisourea or 5-methylisothiourea, guanidine or a salt thereof, chloroformamidine hydrochloride or cyanamide as cyclization agent, or 15 b) reacting an arylhydrazinopyridazine of the formula II given and defined above with an N-(R -oxy)carbonyl-0-methylisourea, to give a compound of the formula III III 17' - 1 2 wherein Ar, R and R have the meanings indicated for 3 formula I in claim 1 and R denotes alkyl having 1-10 carbon atoms, benzyl or phenyl, and then hydrolyzing the compound thus obtained, or 5 c) reacting a compound of the formula IV
4. A pharmaceutical preparation with anxiolytic and 5 anticonvulsive effects containing a compound of the formula I in claim 1 in association with a pharmaceutically acceptable carrier or diluent therefor.
5. A compound of the formula X in claim 1 or a salt thereof for use in the treatment of states of agitation, 10 insomnia, convulsive states and neurodystonia.
6. A 3-amino-6-aryl-l,2,4-triazolo[4,3-b]pyridazine of the formula I given and defined in Claim 1 or a salt thereof with a physiologically tolerated acid, which is any one of those specifically hereinbefore mentioned. 15
7. A process for the preparation of a 3-amino-6-aryl- l,2,4-triazolo[4,3-b]pyridazine of the formula I given and defined in claim 1 or a salt thereof with a physiologically tolerated acid, substantially as hereinbefore described with particular reference to the 20 accompanying Examples. 19
8. A 3-amino-6-aryl-l,2,4-triazolo[4,3-b]pyridazine of the formula I given and defined in claim 1 or a salt thereof with a physiologically tolerated acid, whenever prepared by a process claimed in a preceding claim. 5
9. A pharmaceutical preparation according to claim 4, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823217325 DE3217325A1 (en) | 1982-05-08 | 1982-05-08 | 3-AMINO-6-ARYL-1,2,4-TRIAZOLO (4,3-B) -PYRIDAZINE, THEIR PRODUCTION AND USE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE831043L IE831043L (en) | 1983-11-08 |
| IE55096B1 true IE55096B1 (en) | 1990-05-23 |
Family
ID=6163075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1043/83A IE55096B1 (en) | 1982-05-08 | 1983-05-06 | 3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridazines,their preparation and their use |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0094038B1 (en) |
| JP (1) | JPS58203992A (en) |
| KR (1) | KR840004753A (en) |
| AT (1) | ATE24728T1 (en) |
| AU (1) | AU1434383A (en) |
| CA (1) | CA1201122A (en) |
| DE (2) | DE3217325A1 (en) |
| DK (1) | DK204783A (en) |
| ES (4) | ES8405800A1 (en) |
| FI (1) | FI831548L (en) |
| GR (1) | GR79281B (en) |
| HU (1) | HU189277B (en) |
| IE (1) | IE55096B1 (en) |
| IL (1) | IL68611A0 (en) |
| MA (1) | MA19791A1 (en) |
| NO (1) | NO831614L (en) |
| NZ (1) | NZ204153A (en) |
| PT (1) | PT76654B (en) |
| ZA (1) | ZA833239B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3311753A1 (en) * | 1983-03-31 | 1984-10-04 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINE - THEIR PRODUCTION AND USE - |
| FR2562071B1 (en) * | 1984-03-30 | 1986-12-19 | Sanofi Sa | TRIAZOLO (4,3-B) PYRIDAZINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4654343A (en) * | 1985-10-31 | 1987-03-31 | American Cyanamid Company | N-substituted-N[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas |
| ATE523199T1 (en) | 2004-11-02 | 2011-09-15 | Univ Northwestern | PYRIDAZINE COMPOUNDS AND METHODS |
| EP1812408B1 (en) | 2004-11-02 | 2013-10-09 | Northwestern University | Pyridazine compounds, compositions and methods |
| CA2650711A1 (en) | 2006-04-28 | 2007-11-08 | Northwestern University | Compositions and treatments using pyridazine compounds and cholinesterase inhibitors |
| CA2650625A1 (en) | 2006-04-28 | 2007-11-08 | Northwestern University | Formulations containing pyridazine compounds for treating neuroinflammatory diseases |
| AU2008223066A1 (en) * | 2007-03-02 | 2008-09-12 | Northwestern University | Compositions comprising derivatives of 3 -phenylpyridazine for treating seizure-related disorders |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL128809C (en) * | 1966-06-18 | |||
| US3708484A (en) * | 1970-10-16 | 1973-01-02 | Sandoz Ag | Amino and substituted amino-s-triazolo-(4,3-b)-pyridazines |
| DE2113438A1 (en) * | 1971-03-19 | 1972-09-21 | Boehringer Mannheim Gmbh | Anti-microbial nitrofuryl-triazolo -(4,3-b) - pyridazine derivs - used for treating urinary system infections |
| CA1080712A (en) * | 1976-09-22 | 1980-07-01 | Jay D. Albright | Hypotensive agents |
| US4260756A (en) * | 1979-11-15 | 1981-04-07 | American Cyanamid Company | 6- And 8-heteroaryl-1,2,4-triazolo[4,3-b]pyridazines |
-
1982
- 1982-05-08 DE DE19823217325 patent/DE3217325A1/en not_active Withdrawn
-
1983
- 1983-05-04 GR GR71294A patent/GR79281B/el unknown
- 1983-05-05 FI FI831548A patent/FI831548L/en not_active Application Discontinuation
- 1983-05-05 DE DE8383104427T patent/DE3368931D1/en not_active Expired
- 1983-05-05 AT AT83104427T patent/ATE24728T1/en not_active IP Right Cessation
- 1983-05-05 EP EP83104427A patent/EP0094038B1/en not_active Expired
- 1983-05-06 ZA ZA833239A patent/ZA833239B/en unknown
- 1983-05-06 CA CA000427630A patent/CA1201122A/en not_active Expired
- 1983-05-06 DK DK204783A patent/DK204783A/en not_active Application Discontinuation
- 1983-05-06 IL IL68611A patent/IL68611A0/en unknown
- 1983-05-06 KR KR1019830001924A patent/KR840004753A/en not_active Application Discontinuation
- 1983-05-06 IE IE1043/83A patent/IE55096B1/en unknown
- 1983-05-06 NO NO831614A patent/NO831614L/en unknown
- 1983-05-06 ES ES522144A patent/ES8405800A1/en not_active Expired
- 1983-05-06 AU AU14343/83A patent/AU1434383A/en not_active Abandoned
- 1983-05-06 PT PT76654A patent/PT76654B/en unknown
- 1983-05-06 JP JP58078423A patent/JPS58203992A/en active Pending
- 1983-05-06 MA MA20012A patent/MA19791A1/en unknown
- 1983-05-06 NZ NZ204153A patent/NZ204153A/en unknown
- 1983-05-06 HU HU831579A patent/HU189277B/en unknown
-
1984
- 1984-03-15 ES ES530639A patent/ES8501399A1/en not_active Expired
- 1984-03-15 ES ES530640A patent/ES530640A0/en active Granted
- 1984-03-15 ES ES530638A patent/ES530638A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| EP0094038A1 (en) | 1983-11-16 |
| ES8501400A1 (en) | 1984-11-16 |
| DE3368931D1 (en) | 1987-02-12 |
| ES530639A0 (en) | 1984-11-16 |
| ES8501398A1 (en) | 1984-11-16 |
| FI831548L (en) | 1983-11-09 |
| ES522144A0 (en) | 1984-06-16 |
| JPS58203992A (en) | 1983-11-28 |
| HU189277B (en) | 1986-06-30 |
| GR79281B (en) | 1984-10-22 |
| PT76654B (en) | 1986-01-28 |
| ES530638A0 (en) | 1984-11-16 |
| IL68611A0 (en) | 1983-09-30 |
| FI831548A0 (en) | 1983-05-05 |
| PT76654A (en) | 1983-06-01 |
| ES8405800A1 (en) | 1984-06-16 |
| ZA833239B (en) | 1984-01-25 |
| ATE24728T1 (en) | 1987-01-15 |
| AU1434383A (en) | 1983-11-10 |
| EP0094038B1 (en) | 1987-01-07 |
| IE831043L (en) | 1983-11-08 |
| CA1201122A (en) | 1986-02-25 |
| NZ204153A (en) | 1985-04-30 |
| ES8501399A1 (en) | 1984-11-16 |
| DE3217325A1 (en) | 1983-11-10 |
| DK204783D0 (en) | 1983-05-06 |
| ES530640A0 (en) | 1984-11-16 |
| NO831614L (en) | 1983-11-09 |
| MA19791A1 (en) | 1983-12-31 |
| DK204783A (en) | 1983-11-09 |
| KR840004753A (en) | 1984-10-24 |
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