NO841270L - SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, AND THEIR PREPARATION AND USE - Google Patents

SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, AND THEIR PREPARATION AND USE

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NO841270L
NO841270L NO841270A NO841270A NO841270L NO 841270 L NO841270 L NO 841270L NO 841270 A NO841270 A NO 841270A NO 841270 A NO841270 A NO 841270A NO 841270 L NO841270 L NO 841270L
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alkyl
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phenyl
chlorine
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Manfred Roesner
Franz Hock
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Hoechst Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

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Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. Compounds of the formula see diagramm : EP0121490,P11,F1 and salts thereof with a physiologically acceptable acid, in which formula R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine, R**3 denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, phenylalkyl which has 1-4 carbon atoms in the alkyl part and is optionally monosubstituted, disubstituted or trisubstituted in the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, alkylcarbonyl having 1-6 carbon atoms in the alkyl part, cycloalkylcarbonyl having 5-7 carbon atoms in the cycloalkyl part, or benzoyl which is optionally monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, or denotes Ar, and in which Ar represents phenyl, phenoxyphenyl, phenylthiophenyl, 2-thienyl or 2-furyl, these radicals being optionally monosubstituted or disubstituted by fluorine, chlorine, alkyl groups having 1-6 carbon atoms, cyano or trifluoromethyl, with the exception of compounds of the formula I in which R**1 and R**2 denote hydrogen, R**3 denotes phenyl and Ar denotes phenyl or 4-methylphenyl. For the Contracting State AT 1. A process for the preparation of compounds of the formula I see diagramm : EP0121490,P13,F1 and salts thereof with a physiologically acceptable acid, in which formula R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine, R**3 denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, phenylalkyl which has 1-4 carbon atoms in the alkyl part and is optionally monosubstituted, disubstituted or trisubstituted in the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, alkylcarbonyl having 1-6 carbon atoms in the alkyl part, cycloalkylcarbonyl having 5-7 carbon atoms in the cycloalkyl part, or benzoyl which is optionally monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, or denotes Ar, and in which Ar represents phenyl, phenoxyphenyl, phenylthiophenyl, 2-thienyl or 2-furyl, these radicals being optionally monosubstituted or disubstituted by fluorine, chlorine, alkyl groups having 1-6 carbon atoms, cyano or trifluoromethyl, with the exception of compounds of the formula I in which R**1 and R**2 denote hydrogen, R**3 denotes phenyl and Ar denotes phenyl or 4-methylphenyl, which comprises a) cyclizing a compound of the formula II see diagramm : EP0121490,P13,F2 in which Ar, R**1, R**2 and R**3 have the meanings indicated for formula I and Z represents O or S, by heating, if appropriate with the addition of a condensation agent, to give a compound of the formula I, or b) by reacting a compound of the formula III see diagramm : EP0121490,P13,F3 in which R**6 denotes chlorine, bromine or methylthio and Ar, R**1 and R**2 have the meanings indicated for formula I, with an amine of the formule IV see diagramm : EP0121490,P14,F4 in which R**3 has the meaning indicated for formula I, or c) reacting, if appropriate with the addition of a condensation agent or catalyst, a compound of the formula V see diagramm : EP0121490,P14,F5 or one of its salts in which Ar, R**1 and R**2 have the meanings indicated for formula I, with a compound of the formula VI R**3-Y in which R**3 has the meaning indicated for formula I and Y represents a leaving group, such as, for example, fluorine, chlorine, bromine, iodine, see diagramm : EP0121490,P14,F6 or the tosylate radical, and, if appropriate, converting a compound thus obtained into a salt thereof by adding a physiologically acceptable acid.

Description

Oppfinnelsens gjenstand er nye substituerte 6-aryl-l,2 , 4-triazolo/~4,3-b/pyridaziner, med den generelle formel I The object of the invention is new substituted 6-aryl-1,2,4-triazolo/~4,3-b/pyridazines, with the general formula I

og deres salter, med en fysiologisk tålbar syre, hvori R1 og R<2>er like eller forskjellige og betyr hydrogen, alkylgrupper med 1-6 C-atomer, fenyl eller klor, hvori R 3 betyr hydrogen, rettlinjet eller forgrenet alkyl med 1-6 C-atomer eller fenyl, som eventuelt er substituert med 1,2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, og R 4 betyr rettlinjet eller forgrenet alkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, fenylalkyl med 1-4 C-atomer i alkyldelen, og eventuelt i fenyldelen substituert med 1,2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, betyr videre alkylkarbonyl med 1-6 C-atomer i alkyldelen, cykloalkylkarbonyl med 5-7 C-atomer i cykloalkyldelen, eventuelt med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer substituert benzoyl eller Ar, og hvori Ar betyr aromatiske rester som fenyl, bifenyl, fenoksyfenyl, fenyltiofenyl, fenylsulfinylfenyl, fenylsulfonylfenyl, 1- eller 2-naftyl, 2- eller 3-tienyl, 2-furyl, 2-pyrrolyl, l-metyl-2-pyrrolyl, 2-, 3- eller 4-pyridyl, som eventuelt kan være substituert med 1,2, 3 eller 4 eller 5 rester som fluor, klor, brom, jod, alkylgrupper med 1-6 C-atomer, cykloalkylgruppen med 3-8 C-atomer, fenylalkylgruppe med 1-4 alkyl-C-atomer, alkoksy- eller alkyltiogrupper med hver gang 1-6 C-atomer, hydroksy, nitro, cyano, trifluormetyl, karboksygruppen, deres estere, med C-^-Cg-alkoholer, aminokarbonyl, amino, acetamido, alkoksykarbonylamino med 1-6 C-atomer i alkylresten, hvori videre kan bety en rest med den generelle formel II hvori and their salts, with a physiologically tolerable acid, in which R1 and R<2> are the same or different and mean hydrogen, alkyl groups with 1-6 C atoms, phenyl or chlorine, in which R 3 means hydrogen, straight or branched alkyl with 1 -6 C atoms or phenyl, which is optionally substituted with 1,2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms, and R 4 means straight or branched alkyl with 1-6 C -atoms, cycloalkyl with 3-8 C atoms, phenylalkyl with 1-4 C atoms in the alkyl part, and optionally in the phenyl part substituted with 1,2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C -atoms, further means alkylcarbonyl with 1-6 C atoms in the alkyl part, cycloalkylcarbonyl with 5-7 C atoms in the cycloalkyl part, optionally with 1, 2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C -atoms substituted by benzoyl or Ar, and in which Ar means aromatic residues such as phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which may optionally be substituted with 1,2, 3 or 4 or 5 residues which fluorine, chlorine, bromine, iodine, alkyl groups with 1-6 C atoms, the cycloalkyl group with 3-8 C atoms, phenylalkyl group with 1-4 alkyl C atoms, alkoxy or alkylthio groups with each 1-6 C atoms . II in which

X betyr CH2, CHR<5>, C=0, 0, S eller NR , hvori R betyr hydrogen, alkyl med 1-6 G-atomer, cykloalkyl med 3-8 C-atomer, alkylkarbonyl med 1-6 C-atomer i alkylresten, alkoksykarbonyl med X means CH2, CHR<5>, C=0, 0, S or NR, where R means hydrogen, alkyl with 1-6 G atoms, cycloalkyl with 3-8 C atoms, alkylcarbonyl with 1-6 C atoms in the alkyl residue, alkoxycarbonyl with

1-4 C-atomer i alkoksyresten, eventuelt substituert fenylalkyl med 1-4 C-atomer i alkylresten, eventuelt substituert fenyl eller eventuelt substituert benzoyl, hvori fenylringen hver gang kan være substituert med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl, eller alkyl med 1-6 C-atomer, 1-4 C atoms in the alkoxy residue, optionally substituted phenylalkyl with 1-4 C atoms in the alkyl residue, optionally substituted phenyl or optionally substituted benzoyl, in which the phenyl ring can each be substituted with 1, 2 or 3 fluorine, chlorine, bromine, iodine , trifluoromethyl, or alkyl with 1-6 C atoms,

og m betyr 1,2 eller 3.and m means 1,2 or 3.

Blant forbindelsene med den generelle formel I er slike fore-Among the compounds of the general formula I, such pre-

1 2 trukket hvori R dg R er like eller forskjellige og betyr hydrogen, metyl, etyl, fenyl eller klor, R 3 betyr hydrogen, eller alkyl med 1-6 C-atomer, og R 4 betyr rettlinjet eller forgrenet ilkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, fenylalkyl ned 1-4 C-atomer i alkyldelen og eventuelt i fenyldelen substituert med 1 eller 2 fluor, klor, brom, jod, trifluormetyl eller ilkyl med 1-4 C-atomer, eller betyr Ar, og hvori Ar betyr fenyl,Difenyl, fenoksyfenyl, fenyltiofenyl, 2- eller 3-tienyl, 2-iuryl, 2-, 3- eller 4-pyridyl som eventuelt kan være substituert ned 1, 2 eller 3 fluor, klor, brom, trifluormetyl, alkylgruppe ned 1-6 C-atomer eller cykloalkylgrupper med 3-6 C-atomer, eller slike hvori 1 2 drawn in which R dg R are the same or different and mean hydrogen, methyl, ethyl, phenyl or chlorine, R 3 means hydrogen, or alkyl of 1-6 C atoms, and R 4 means linear or branched alkyl of 1-6 C- atoms, cycloalkyl with 3-8 C atoms, phenylalkyl down 1-4 C atoms in the alkyl part and optionally in the phenyl part substituted with 1 or 2 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms, or means Ar, and in which Ar means phenyl, diphenyl, phenoxyphenyl, phenylthiophenyl, 2- or 3-thienyl, 2-iuryl, 2-, 3- or 4-pyridyl which may optionally be substituted down 1, 2 or 3 fluorine, chlorine, bromine, trifluoromethyl, alkyl group down to 1-6 C atoms or cycloalkyl groups with 3-6 C atoms, or those in which

iar den til formel II angitte betydning. iar the meaning given to formula II.

Spesielt foretrukket er slike forbindelser med formel I hvori Particularly preferred are such compounds of formula I in which

* 1 og R 2 er like eller forskjellige, og betyr hydrogen, metyl siler etyl, R<3>betyr hydrogen eller alkyl med 1-6 C-atomer, R<4>3e tyr rettlinjet eller forgrenet alkyl med 1-6 C-atomer, cyklo-ilkyl med 5 eller 6 C-atomer, benzyl eller fenyletyl, eventuelt ;i fenylringen substituert med 1 eller 2 fluor, klor, trifluormetyl, metyl eller etyl, eller betyr Ar, og Ar betyr fenyl, fenoksyfenyl, fenyltiofenyl, 2- eller 3- tienyl, 2-furyl eller 3-pyridyl, eventuelt substituert med 1 eller 2 fluor, klor, trifluormetyl, metyl eller etyl. ;Imidlertid omfattes ikke de forbindelser med formel I hvori ;12 3 4 ;R , R og R betyr hydrogen, R fenyl og Ar betyr fenyl, 4-metyl-r fenyl eller 4-bromfenyl. Disse forbindelser er omtalt i Rev. Roum. Chim. 10, 641, (1965) og Rev, Med. Chir. 81, 469 ;(1977) og skal virke delvis antihypertensive. Derimot virker forbindelsen ifølge oppfinnelsen med formel I anxiolytiske og antikonvulsive. ;Oppfinnelsens gjenstand er også fremgangsmåte til fremstilling;av disse forbindelser samt farmasøytiske tilberedninger av disse forbindelser, og deres anvendelse som legemiddel. Fremgangsmåten til fremstilling av forbindelsen med formel I ;erkarakterisert vedat;a) en forbindelse med formel III; ; 12 3 4 ;hvori Ar, R , R , R og R har de til formel I angitte betydning, og Z betyr 0 eller S, cykliseres ved oppvarming eventuelt under tilsetning av et kondensasjonsmiddel til en forbindelse med formel I eller ;b) en forbindelse med formel IV; ; hvori R betyr klor, brom, eller metyltio, Ar, R og R har den ;med formel I angitte betydning, omsettes med et amin med formel ;V ; ; hvori R<3>og R<4>eventuelt sammen med N-atomet har de til formel I angitte betydninger, eller ;c) en forbindelse med formel VI, eller av dens salter; ; hvori Ar, R 1 og R 2har de til formel-1 angitte betydninger, ;omsettes med en forbindelse med formel VII; ; hvori R 4 har den tinder formel I angitte betydning, og Y;betyr en avspaltbar gruppe som f. eks. fluor, klor, brom,;Dod, _0_c_R3;eller tosylatresten, eventuelt under tilsetning av et kondensasjonsmiddel eller katalysator. ;Ved fremgangsmåte a) fåes utgangsstoffer med formel III, f. eks. ved omsetning av aryl-hydrazinopyridaziner med formel VIII ; ; hvori R 1 , R 2 og Ar har den under formel I angitte betydning,;med isocyanater eller isotiocyanater med formel IX;R<4->N=C-Z (IX);hvori R 4 og Z har den under formel I resp. III angitte betydning, ved oppvarming ved 40-150°C, hensiktsmessig i et oppløsnings-middel som f. eks. metanol, etanol, isopropanol, diisopropyleter, dioksan, tetrahydrofuran, toluen, metylenklorid, kloro- ;form, eller dikloretan.;Forbindelsene med formel III overføres til forbindelser med formel I ved oppvarming, f. eks. i et av de nevnte oppløsnings-midler ved 4 0-150°C eventuelt under tilsetning av et kondensasjonsmiddel, som f. eks. iseddik, cykloheksylkarbodiimid, 1-hydroksybenztriazol, fosforoksyklorid, fosforoksyklorid/N,N-dimetylanilin, fosforoksybromid, fosforpentaklorid, tionylklorid, kvikksølvoksyd, blyoksyd. Forbindelsen med den generelle formel III kan også ved omsetning av klorpyridaziner med ; 1 2 hvori Ar, R og R har den til formel I angitte betydning, med substituerte semikarbaziner eller tiosemikarbaziner med formel XI ; 3 4 ;hvori R , R og Z har den til formel I angitte betydning, ved oppvarming, f. eks. i et av de nevnte oppløsningsmidler eller i DMF, DMSO eller acetonitril ved 40-150°C. ;For fremgangsmåte b) fåes utgangsstoffer med formel IV ved oppvarming av arylhydrazinopyridaziner VIII med maursyre eller deres estere (til R = H), fosgen, klormaursyreestere med dialkylpyrokarbonat eller en dialkylkarbonat (til R<6>= OH) eller med svovelkarbon og alkali (til R^ = SH), eventuelt under tilsetning av et oppløsnings-og fortynningsmiddel som kloroform, toluen, dioksan, eddikester, vann, etanol til en forbindelse med formel IV, hvori R<6>betyr H, OH eller SH. ;Ved oppvarming med brom i iseddik/natriumacetat (ved R<6>= H) fosforoksyklorid (ved R<6>OH) med metyljodid eller dimetyl-sulfat (ved R = SH) fåes herav de tilsvarende forbindelser IV med R6 = Br, Cl, SCH3. ;Ifølge fremgangsmåte b) foregår omsetningen av forbindelsene med formel IV med aminer med formel V uten oppløsningsmiddel eller i et inert<*>oppløsningsmiddel som metanol, isopropanol, 2-metoksyetanol, tetrahydrofuran, dioksan, toluen, kloroform, * 1 and R 2 are the same or different, and mean hydrogen, methyl siler ethyl, R<3> means hydrogen or alkyl with 1-6 C atoms, R<4>3e means straight or branched alkyl with 1-6 C- atoms, cycloalkyl with 5 or 6 C atoms, benzyl or phenylethyl, optionally substituted in the phenyl ring with 1 or 2 fluorine, chlorine, trifluoromethyl, methyl or ethyl, or means Ar, and Ar means phenyl, phenoxyphenyl, phenylthiophenyl, 2 - or 3-thienyl, 2-furyl or 3-pyridyl, optionally substituted with 1 or 2 fluorine, chlorine, trifluoromethyl, methyl or ethyl. However, the compounds of formula I in which ;12 3 4 ;R , R and R mean hydrogen, R phenyl and Ar means phenyl, 4-methyl-r phenyl or 4-bromophenyl are not included. These compounds are discussed in Rev. Rome. Chim. 10, 641, (1965) and Rev, Med. Chir. 81, 469 ; (1977) and is supposed to be partially antihypertensive. In contrast, the compound according to the invention with formula I has anxiolytic and anticonvulsant effects. The object of the invention is also a method for the production of these compounds as well as pharmaceutical preparations of these compounds, and their use as medicine. The method for preparing the compound of formula I is characterized by: a) a compound of formula III; ; 12 3 4 ; in which Ar, R , R , R and R have the meanings specified for formula I, and Z means 0 or S, is cyclized by heating, optionally with the addition of a condensing agent to a compound of formula I or ;b) a compound with formula IV; ; in which R means chlorine, bromine or methylthio, Ar, R and R have the meaning given in formula I, are reacted with an amine of formula V; ; in which R<3> and R<4>, optionally together with the N atom, have the meanings specified for formula I, or ;c) a compound of formula VI, or of its salts; ; in which Ar, R 1 and R 2 have the meanings given to formula-1, ; is reacted with a compound of formula VII; ; in which R 4 has the meaning given in formula I, and Y; means a leasable group such as e.g. fluorine, chlorine, bromine,; Dod, _O_c_R3; or the tosylate residue, optionally with the addition of a condensing agent or catalyst. ;In method a) starting substances with formula III are obtained, e.g. by reacting aryl-hydrazinopyridazines with formula VIII; ; in which R 1 , R 2 and Ar have the meaning given under formula I,; with isocyanates or isothiocyanates of formula IX; R<4->N=C-Z (IX); in which R 4 and Z have the meaning under formula I resp. III meaning, when heated at 40-150°C, suitably in a solvent such as, for example methanol, ethanol, isopropanol, diisopropyl ether, dioxane, tetrahydrofuran, toluene, methylene chloride, chloroform, or dichloroethane.;The compounds of formula III are transferred to compounds of formula I by heating, e.g. in one of the mentioned solvents at 40-150°C, possibly with the addition of a condensation agent, such as glacial acetic acid, cyclohexylcarbodiimide, 1-hydroxybenztriazole, phosphorus oxychloride, phosphorus oxychloride/N,N-dimethylaniline, phosphorus oxybromide, phosphorus pentachloride, thionyl chloride, mercury oxide, lead oxide. The compound with the general formula III can also by reacting chloropyridazines with ; 1 2 in which Ar, R and R have the meaning indicated for formula I, with substituted semicarbazines or thiosemicarbazines of formula XI; 3 4 ; in which R , R and Z have the meaning specified for formula I, upon heating, e.g. in one of the aforementioned solvents or in DMF, DMSO or acetonitrile at 40-150°C. For method b) starting materials of formula IV are obtained by heating arylhydrazinopyridazines VIII with formic acid or their esters (to R = H), phosgene, chloroformic acid esters with dialkyl pyrocarbonate or a dialkyl carbonate (to R<6>= OH) or with carbon disulfide and alkali ( to R^ = SH), optionally with the addition of a solvent and diluent such as chloroform, toluene, dioxane, acetate, water, ethanol to a compound of formula IV, in which R<6> means H, OH or SH. By heating with bromine in glacial acetic acid/sodium acetate (when R<6>= H) phosphorus oxychloride (when R<6>OH) with methyl iodide or dimethyl sulfate (when R = SH) the corresponding compounds IV with R6 = Br, Cl, SCH3. According to method b) the reaction of the compounds of formula IV with amines of formula V takes place without a solvent or in an inert solvent such as methanol, isopropanol, 2-methoxyethanol, tetrahydrofuran, dioxane, toluene, chloroform,

DMF, DMSO, acetonitril, aceton eller eddiksyreetylester, ved temperaturer på 20-200°C, fortrinnsvis 50-150°C ved normal- DMF, DMSO, acetonitrile, acetone or acetic acid ethyl ester, at temperatures of 20-200°C, preferably 50-150°C at normal

trykk eller i autoklav under trykk. Reaksjonen med gass-pressure or in an autoclave under pressure. The reaction with gas-

formede aminer kan gjennomføres ved normaltrykk ved innføringen eller likeledes under trykk. Eventuelt kan det tilsettes en katalysator som kobber (I)-klorid eller andre Cu (I)-salter til aksellerering av reaksjonen. formed amines can be carried out at normal pressure at the introduction or likewise under pressure. Optionally, a catalyst such as copper (I) chloride or other Cu (I) salts can be added to accelerate the reaction.

Ved fremgangsmåte c) foregår omsetningen av forbindelsene med formel VI som f, eks. fåes ved cyklisering av arylhydrazinopyridaziner med formel VIII med klorcyan eller bromcyan med forbindelser med formel VII uten eller i nærvær av et oppløsnings-eller fortynningsmiddel, som f. eks. aceton, metyletylketon, eddiksyreetylester, toluen, xylen, dioksan, tetrahydrofuran, In method c), the conversion of the compounds of formula VI takes place as f, e.g. are obtained by cyclization of arylhydrazinopyridazines of formula VIII with cyanogen chloride or cyanogen bromide with compounds of formula VII without or in the presence of a solvent or diluent, such as e.g. acetone, methyl ethyl ketone, acetic acid ethyl ester, toluene, xylene, dioxane, tetrahydrofuran,

DMF, DMSO, acetonitril, metylenklorid, kloroform eller dikloretan. DMF, DMSO, acetonitrile, methylene chloride, chloroform or dichloroethane.

Eventuelt kan uorganisk eller organisk base som f. eks. natrium-hydroksyd, trietylamin eller pyridin tilsettes til binding av eventuelt ved reaksjonen dannede syrer, eller også ved reaksjonen med syreanhydrider tilsettes katalytiske mengder av en sterk syre, som f. eks. saltsyre, svovelsyre eller trifluoreddiksyre. Optionally, inorganic or organic base such as e.g. sodium hydroxide, triethylamine or pyridine is added to bind any acids formed during the reaction, or catalytic amounts of a strong acid are added during the reaction with acid anhydrides, such as e.g. hydrochloric acid, sulfuric acid or trifluoroacetic acid.

Arylhydrazinopyridaziner med formel VIII er eksempelvis kjentArylhydrazinopyridazines of formula VIII are known, for example

fra J. Heterocyclic Chem. 15, 881 (1978) eller kan fremstilles av klorforbindelse med formel X med hydrazinhydrat eller littera-turkjente fremgangsmåter (The Chemistry of Heterocyclic Compounds, vol, 28 Pyridazines, Editors, A. Weissberger og E. C. Taylor, John Wiley, New York. 1973). Begge litteratursitater omtaler også fremstillingen av klorforbindelser X og dens fortrinn. from J. Heterocyclic Chem. 15, 881 (1978) or can be prepared from chlorine compound of formula X with hydrazine hydrate or methods known in 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 refer to the production of chlorine compounds X and its advantages.

Når forbindelsene med formel I etter de omtalte fremgangsmåter fåes som salter, så kan herav med ammoniakk, aminer eller hydroksyder den tilhørende base frigjøres. De for baser med formel I kan med fysiologisk tålbare syrer overføres i de til- When the compounds of formula I are obtained as salts according to the described methods, the corresponding base can be released from this with ammonia, amines or hydroxides. Those for bases of formula I can be transferred with physiologically tolerable acids in the

svarende salter. Som syrer kommer det i betraktning uorga-corresponding salts. As acids, inorganic

niske eller organiske syrer som klor- eller bromhydrogensyre, fosforsyre, eddiksyre, benzosyre, sitronsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, ravsyre, acetylglycin. basic or organic acids such as hydrochloric or bromic acid, phosphoric acid, acetic acid, benzoic acid, citric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, acetylglycine.

Forbindelsen ifølge oppfinnelsen med formel I er egnet til fremstilling av legemidler. Legemidlene kan inneholde en eller flere av forbindelsene ifølge oppfinnelsen eller blandinger herav, med andre farmasøytiske virksomme stoffer. Til fremstilling av legemidlene, kan det anvendes vanlige farmasøytiske bære- The compound according to the invention with formula I is suitable for the production of pharmaceuticals. The medicines may contain one or more of the compounds according to the invention or mixtures thereof, with other pharmaceutical active substances. For the production of the medicines, common pharmaceutical carriers can be used

og hjelpestoffer og kjente galeniske fremgangsmåter. Legemidlene kan anvendes enteralt, parenteralt, oralt eller per-lingualt. Eksempelvis kan administrering foregå i form av and excipients and known galenic procedures. The drugs can be used enterally, parenterally, orally or per-lingually. For example, administration can take place in the form of

tabletter, kapsler, piller, drageer, tapper, geleer, kremer, pudder, liquida, støvningspulvere eller a.erosoler. Som liquida kommer det eksempelvis på tale.: Oljeaktige eller vandige oppløsninger eller suspensjoner og emulsjoner, injiserbare oppløsninger eller suspensjoner. tablets, capsules, pills, dragees, drops, gels, creams, powders, liquids, dusting powders or a. aerosols. Liquids include, for example: Oily or aqueous solutions or suspensions and emulsions, injectable solutions or suspensions.

Forbindelsen ifølge oppfinnelsen kan dessuten finne anvendelse som mellomprodukter til fremstilling av andre legemidler. The compound according to the invention can also find use as intermediate products for the production of other medicinal products.

Som forbindelser ifølge oppfinnelsen skal det nevnes:As compounds according to the invention, the following should be mentioned:

(for stamnavnet "1, 2,4-triazolo /~4,3-b7pyridazin" anvendes(for the generic name "1, 2,4-triazolo/~4,3-b7pyridazine" is used

i det følgende forkortelsen "TP"). hereinafter the abbreviation "TP").

6-(3-fluor fenyl)-3-fenylamino-TP6-(3-fluorophenyl)-3-phenylamino-TP

6-(4-fluorfenyl)-3-fenylamino-TP 6-(4-fluorophenyl)-3-phenylamino-TP

6-(3-trifluormetylfenyl)-3-fenylamino-TP 6-(3-trifluoromethylphenyl)-3-phenylamino-TP

6-(3,4-difluorfenyl)-3-fenylamino-TP 6-(3,4-difluorophenyl)-3-phenylamino-TP

6-(4-fenoksyfenyl)-3-fenylamino-TP 6-(4-phenoxyphenyl)-3-phenylamino-TP

6-(4-fenyltiofenyl)-3-fenylamino-TP 6-(4-phenylthiophenyl)-3-phenylamino-TP

6-(4-(4-fluorfenoksy)fenyl)-3-fenylamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-phenylamino-TP

6-(3-klorfenyl)-3-fenylamino-TP6-(3-chlorophenyl)-3-phenylamino-TP

6-(3-bromfenyl)-3-fenylamino-TP 6-(3-bromophenyl)-3-phenylamino-TP

6-(5-klor-2-tienyl)-3-fenylamino-TP6-(5-chloro-2-thienyl)-3-phenylamino-TP

6-(3-fluorfenyl)-3(subst. fenylamino)-TP 6-(3-fluorophenyl)-3(subst. phenylamino)-TP

6-(4-fluorfenyl)-3-(subst, fenylamino)-TP 6-(4-fluorophenyl)-3-(subst, phenylamino)-TP

6-(3-trifluormetylfenyl)-3-(subst. fenylamino)-TP 6-(3,4-difluorfenyl)-3-(subst. fenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(subst. phenylamino)-TP 6-(3,4-difluorophenyl)-3-(subst. phenylamino)-TP

6-(4-fenoksyfenyl)-3-(subst, fenylamino)-TP 6-(4-phenoxyphenyl)-3-(subst, phenylamino)-TP

6-(4-fenyltiofenyl)-3-(subst. fenylamino)-TP 6-(4-phenylthiophenyl)-3-(subst. phenylamino)-TP

6-(4-(4-fluorfenoksy)fenyl)-3-(subst. fenylamino)-TP 6-(3-klorfenyl)-3-(subst. fenylamino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(subst. phenylamino)-TP 6-(3-chlorophenyl)-3-(subst. phenylamino)-TP

6-(3-bromfenyl)-3-(subst. fenylamino)7TP 6-(3-bromophenyl)-3-(subst. phenylamino)7TP

6-(5-klor-2-tienyl)-3-(subst, fenylamino)-TP.6-(5-chloro-2-thienyl)-3-(subst, phenylamino)-TP.

hvori "subst, fenyl" spesielt betyr 2,3- eller 4-fluorfenyl, 2-, 3- eller 4-klorfenyl, 2-, 3- eller 4-bromfenyl, 2-, 3-eller 4-trifluormetylfenyl, 3,4-diklor- eller 3,4-difluorfenyl, 2,4-diklor-,eller 2,4-difluorfenyl, 2,5-diklor- eller 2,5-difluorfenyl, 3,5-diklor- eller 3,5-difluorfenyl, 2,6-diklor- eller 2,6-difluorfenyl. wherein "subst, phenyl" specifically means 2,3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4 -dichloro- or 3,4-difluorophenyl, 2,4-dichloro- or 2,4-difluorophenyl, 2,5-dichloro- or 2,5-difluorophenyl, 3,5-dichloro- or 3,5-difluorophenyl, 2,6-dichloro- or 2,6-difluorophenyl.

6-(3-fluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-fluorophenyl)-3-(N-methyl-N-phenylamino)-TP

6-(4-fluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fluorophenyl)-3-(N-methyl-N-phenylamino)-TP

6-(3-trifluormetylfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3,4-difluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fenoksyfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fenyltiofenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fluorfenoksyfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-klorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(N-methyl-N-phenylamino)-TP 6-(3,4-difluorophenyl)-3-(N-methyl-N-phenylamino)-TP 6-(4-phenoxyphenyl) )-3-(N-methyl-N-phenylamino)-TP 6-(4-phenylthiophenyl)-3-(N-methyl-N-phenylamino)-TP 6-(4-fluorophenoxyphenyl)-3-(N-methyl -N-phenylamino)-TP 6-(3-chlorophenyl)-3-(N-methyl-N-phenylamino)-TP

6-(3- bromfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-bromophenyl)-3-(N-methyl-N-phenylamino)-TP

6-(5-klor-2-tienyl)-3-(N-metyl-N-metyl-N-fenylamino)-TP 6-(3-fluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3-trifluormetylfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3,4-difluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fenoksyfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fenyltiofenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-(4-fluorfenoksy)fenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3-klorfenyl)-3-(N-metyl-N-subst. fenylamino) 6-(3-bromfenyl)-3-(N-metyl-N- subst, fenylamino)-TP 6-(5-klor-2-tienyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(5-chloro-2-thienyl)-3-(N-methyl-N-methyl-N-phenylamino)-TP 6-(3-fluorophenyl)-3-(N-methyl-N-subst. phenylamino) -TP 6-(4-fluorophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6- (3,4-difluorophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4-phenoxyphenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4 -phenylthiophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-( 3-chlorophenyl)-3-(N-methyl-N-subst. phenylamino) 6-(3-bromophenyl)-3-(N-methyl-N- subst. phenylamino)-TP 6-(5-chloro-2- thienyl)-3-(N-methyl-N-subst. phenylamino)-TP

hvori "subst.fenyl" spesielt betyr 2-, 3- eller 4-fluorfenyl, wherein "subst.phenyl" specifically means 2-, 3- or 4-fluorophenyl,

2-, 3- eller 4-klorfenyl, 2-, 3- eller 4-bromfenyl, 2-, 3- eller 4-trifluormetylfenyl, 3,4-diklor- eller 3,4-difluorfenyl, 2,4-diklor- eller 2,4-difluorfenyl, 2,5-diklor- eller 2,5-difluorfenyl, 3,5-diklor- eller 3,5-difluorfenyl, 2,6-diklor eller 2,6-difluorfenyl. 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichloro- or 3,4-difluorophenyl, 2,4-dichloro- or 2,4-difluorophenyl, 2,5-dichloro- or 2,5-difluorophenyl, 3,5-dichloro- or 3,5-difluorophenyl, 2,6-dichloro or 2,6-difluorophenyl.

6-(3-flurofenyl)-3-acetamino-TP 6-(3-Fluorophenyl)-3-acetamino-TP

6-(4-fluorfenyl)-3-acétamino-TP 6-(4-fluorophenyl)-3-acetamino-TP

6-(3-trifluormetylfenyl)-3-acetamino-TP 6-(3-trifluoromethylphenyl)-3-acetamino-TP

6-(3,4-difluorfenyl)-3-acetamino-TP 6-(3,4-difluorophenyl)-3-acetamino-TP

6-(4-fenoksyfenyl)-3-acetamino-TP 6-(4-phenoxyphenyl)-3-acetamino-TP

6-(4-fenyltiofenyl)3-acetamino-TP 6-(4-phenylthiophenyl)3-acetamino-TP

6-(4-(4-fluorfenoksy)fenyl)-3-acetamino-TP 6-(3-klorfenyl)-3-acetamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-acetamino-TP 6-(3-chlorophenyl)-3-acetamino-TP

6-(3-bromfenyl)-3-acetamino-TP 6-(3-Bromophenyl)-3-acetamino-TP

6-(5-klor-2-tienyl)-3-acetamino-TP 6-(5-Chloro-2-thienyl)-3-acetamino-TP

6-(3-fluorfenyl)-3-benzoylamino-TP 6-(3-fluorophenyl)-3-benzoylamino-TP

6-(4-fluorfenyl)-3-benzoylamino-TP 6-(4-fluorophenyl)-3-benzoylamino-TP

6-(3-trifluormetylfenyl)-3-benzoylamino-TP 6-(3,4-difluorfenyl)-3-benzoylamino-TP 6-(3-trifluoromethylphenyl)-3-benzoylamino-TP 6-(3,4-difluorophenyl)-3-benzoylamino-TP

6-(4-fenoksyfenyl)-3-benzoylamino-TP 6-(4-phenoxyphenyl)-3-benzoylamino-TP

6-(4-fenyltiofenyl)-3-benzoylamino-TP 6-(4-phenylthiophenyl)-3-benzoylamino-TP

6-(4-(4-fluorfenoksy)fenyl)-3-benzoylamino-TP 6-(3-klorfenyl)-3-benzoylamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-benzoylamino-TP 6-(3-chlorophenyl)-3-benzoylamino-TP

6-(3-bromfenyl)-3-benzoylamino-TP 6-(3-Bromophenyl)-3-benzoylamino-TP

6-(5-klor-2-tienyl)-3-benzoylamino-TP 6-(5-Chloro-2-thienyl)-3-benzoylamino-TP

6-(3-fluorfenyl)-3-subst. benzoylamino)-TP 6-(4-fluorfenyl)-3-(subst. benzoylamino)-TP 6- (3-trif luormetylf enyl )-3-( subst. benzoylamino) -TP 6-(3,4-difluorfenyl)-3-(subst. benzoylamino)-TP 6-(4-fenoksyfenyl)-3-(subst, benzoylamino)-TP 6-(4-fenyltiofenyl)-3-(subst, benzoylamino)-TP 6-(4-(4-fluorfenoksy)fenyl)-3-(subst. benzoylamino)-TP 6-(3-klorfenyl)-3-(subst. benzoylamino)-TP 6-(3-bromfenyl)-3-(subst, benzoylamino)-TP 6-(5-klor-2-tienyl)-3-(subst, benzoylamino)-TP 6-(3-fluorophenyl)-3-subst. benzoylamino)-TP 6-(4-fluorophenyl)-3-(subst. benzoylamino)-TP 6-(3-trifluoromethylphenyl)-3-(subst. benzoylamino)-TP 6-(3,4-difluorophenyl)- 3-(subst. benzoylamino)-TP 6-(4-phenoxyphenyl)-3-(subst, benzoylamino)-TP 6-(4-phenylthiophenyl)-3-(subst, benzoylamino)-TP 6-(4-(4 -fluorophenoxy)phenyl)-3-(subst. benzoylamino)-TP 6-(3-chlorophenyl)-3-(subst. benzoylamino)-TP 6-(3-bromophenyl)-3-(subst, benzoylamino)-TP 6 -(5-chloro-2-thienyl)-3-(subst, benzoylamino)-TP

hvori "subst, benzoyl" spesielt betyr 2-, 3- eller 4-fluorbenzoyl, wherein "subst, benzoyl" specifically means 2-, 3- or 4-fluorobenzoyl,

2- , 3- eller 4-klorbenzoyl, 2-, 3- eller 4-brombenzoyl, 2-,2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-bromobenzoyl, 2-,

3- eller 4-trifluormetylbenzoyl, 3,4-diklor- eller 3,4-difluorbenzoyl, 2,5-diklor- eller 2,5-difluorbenzoyl, 3,5-diklor- eller 3,5-difluorbenzoyl, 3,5-diklor- eller 3,5-difluorbenzoyl, 2,6-diklor- eller 2,6-difluorbenzoyl. 3- or 4-trifluoromethylbenzoyl, 3,4-dichloro- or 3,4-difluorobenzoyl, 2,5-dichloro- or 2,5-difluorobenzoyl, 3,5-dichloro- or 3,5-difluorobenzoyl, 3,5- dichloro- or 3,5-difluorobenzoyl, 2,6-dichloro- or 2,6-difluorobenzoyl.

6-(3-fluorfenyl)-3-(subst. amino)-TP6-(3-fluorophenyl)-3-(subst. amino)-TP

6-(4-fluorfenyl)-3-(subst, amino)-TP 6-(4-Fluorophenyl)-3-(subst,amino)-TP

6-(3-trifluormetylfenyl)-3-(subst, amino)-TP 6-(3-trifluoromethylphenyl)-3-(subst,amino)-TP

6-(3,4-difluorfenyl)-3-(subst. amino)-TP 6-(3,4-difluorophenyl)-3-(subst. amino)-TP

6-(4-fenoksyfenyl)-3-(subst. amino)-TP6-(4-phenoxyphenyl)-3-(subst. amino)-TP

6 -(4-fenyltiofenyl)-3-subst. amino)-TP 6 -(4-phenylthiophenyl)-3-subst. amino)-TP

6-(4-(4-fluorfenoksy)fenyl)-3-(subst, amino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(subst,amino)-TP

6-(3-klorfenyl)-3-(subst, amino)-TP6-(3-chlorophenyl)-3-(subst,amino)-TP

6-(3-bromfenyl)-3-(subst, amino)-TP6-(3-bromophenyl)-3-(subst,amino)-TP

6-(5-klor-2-tienyl)-3-(subst, amino)-TP6-(5-chloro-2-thienyl)-3-(subst,amino)-TP

hvori "subst, amino" spesielt betyr dimetylamino, dietylamino, 1-pyrrolidinyl, piperidino, morfolino, tiomorfolino, 1-piperazinyl, 4-metyl-l-piperazinyl, 4-fenylpiperidino, 4-fenyl-l-piperazinyl, 4-piperidon-l-yl, 4-etoksykarbonyl-l-piperazinyl. wherein "subst, amino" specifically means dimethylamino, diethylamino, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 4-methyl-l-piperazinyl, 4-phenylpiperidino, 4-phenyl-l-piperazinyl, 4-piperidone- 1-yl, 4-ethoxycarbonyl-1-piperazinyl.

Forbindelsene med formel I ifølge oppfinnelsen virker på sentral-nervesystemet, spesielt virker de anxiolytisk og antikonvulsiv. Som indikasjoner kommer det derfor i betraktning søvnløshet, opphisselse og vegetativ depresjon. The compounds of formula I according to the invention act on the central nervous system, in particular they act anxiolytic and anticonvulsant. Insomnia, agitation and vegetative depression are therefore taken into consideration as indications.

De farmasøytiske tilberedninger inneholder vanligvis mellomThe pharmaceutical preparations usually contain between

1 til 10 % den eller de ifølge oppfinnelsen aktive komponenter. 1 to 10% of the active component(s) according to the invention.

Den anxiolytiske virkning av forbindelsene med formel V erThe anxiolytic effect of the compounds of formula V is

fulgt av en meget liten sedering og tålbarhet (LD_r> un i.a. >300 mg/ kg i.p. på mus). Dette fremgår av undersøkelser, hvor det ble målt innvirkningen av forbindelsen ifølge oppfinnelsen på followed by very little sedation and tolerability (LD_r> un i.a. >300 mg/ kg i.p. in mice). This is evident from investigations, where the impact of the compound according to the invention was measured on

den motoriske aktivitet, heksobarbital-narkose og cardiazol-krampe hos mus. Dessuten ble det anvendt Celler-anxiolyse- the motor activity, hexobarbital anesthesia and cardiazole convulsion in mice. In addition, Celler anxiolysis was used

prøve samt Lick-Shock-prøve på rotter.test as well as the Lick-Shock test on rats.

Den laveste allerede virksomme dosis i de overnevnte forsøkThe lowest already effective dose in the above trials

j; j;

er eksempelvis 5 mg/kg oral, 2,5 mg/kg sublingual, 1 mg/kg intravenøs. Som generelt dosisområde for virkning (dyre-forsøk som måleform) kommer det eksempelvis på tale: 5 til 50 mg/kg oralt, 2,5 til 25 mg/kg sublingualt, 1 til 10 mg/kg intravenøs. is, for example, 5 mg/kg oral, 2.5 mg/kg sublingual, 1 mg/kg intravenous. As a general dose range for effect (animal experiments as a form of measurement), the following are for example: 5 to 50 mg/kg orally, 2.5 to 25 mg/kg sublingually, 1 to 10 mg/kg intravenously.

Eksempelvis kan det appliseres tre ganger daglig 1 til 3 For example, it can be applied three times a day 1 to 3

tabletter med et innhold fra 10 til 100 mg virksomt stoff, eller eksempelvis ved intravenøs injeksjon 1 til 3 ganger daglig en ampulle fra 2 til 4 ml innhold med 0,5 til 5 mg stoff. tablets with a content of 10 to 100 mg of active substance, or for example by intravenous injection 1 to 3 times a day an ampoule of 2 to 4 ml content with 0.5 to 5 mg of substance.

Eksempel 1 Example 1

3-cykloheksylamino-6-fenyl-1,2,4-triazolo^ 4,3-b7pyradizin-hydroklorid 5 g 3-hydrazino-6-fenylpyridazin (formel VIII, sm.p. 146°C) oppløses varmt i 50 ml etanol og blandes med 3,8 g cykloheksyl-isotiocyanat. Man omrører 2 timer under tilbakeløp og avkjøler til 0°C, frasuger, vasker med etanol og tørker. Det dannede mellomprodukt (formel III Z = S) oppvarmes med 6,1 g dicykloheksylkarbodiimid i 50 ml 2-metoksyetanol i 5 timer under til-bakeløp. Reaksjonsoppløsningen inndampes under nedsatt trykk til tørrhet, og krystalliseres to ganger fra isopropanol. Ved blanding med etanolisk saltsyre får man hydrokloridet som frasuges, vaskes med vann og tørkes. Sm.p. 268°C. 3-cyclohexylamino-6-phenyl-1,2,4-triazolo^4,3-b7pyridazine hydrochloride 5 g of 3-hydrazino-6-phenylpyridazine (formula VIII, m.p. 146°C) are dissolved hot in 50 ml of ethanol and mixed with 3.8 g of cyclohexyl isothiocyanate. The mixture is stirred for 2 hours under reflux and cooled to 0°C, filtered off with suction, washed with ethanol and dried. The intermediate product formed (formula III Z = S) is heated with 6.1 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 5 hours under reflux. The reaction solution is evaporated under reduced pressure to dryness, and crystallized twice from isopropanol. By mixing with ethanolic hydrochloric acid, the hydrochloride is obtained which is sucked off, washed with water and dried. Sm.p. 268°C.

Eksempel 2 Example 2

3- benzylamino- 6- fenyl- 1, 2, 4- triazolo/~ 4, 3- b7pydidazin- hydroklorid 8 g 3-hydrazino-6-fenylpyridazin oppløses varmt i 70 ml etanol blandes med 7 g benzylisotiocyanat og omrøres i 1 time under tilbakeløp. Mellomtrinnet (formel III, Z = S) frasuges etter avkjøling, vaskes med etanol, tørkes og oppvarmes deretter med 8,9 g dicykloheksylkarbodiimid i 50 ml 2-metoksyetanol i 5 3- benzylamino- 6- phenyl- 1, 2, 4- triazolo/~ 4, 3- b7pydidazine hydrochloride 8 g of 3-hydrazino-6-phenylpyridazine are dissolved hot in 70 ml of ethanol, mixed with 7 g of benzyl isothiocyanate and stirred for 1 hour under backflow. The intermediate step (formula III, Z = S) is filtered off with suction after cooling, washed with ethanol, dried and then heated with 8.9 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 5

timer under tilbakeløp.hours during reflux.

Etter inndampning blånes med etanolisk saltsyre, inndampes og omkrystalliseres en gang fra iseddik og en gang fra toluen, og vaskes med diisopropyleter. Sm.p. 236°C under spaltning. After evaporation, blue with ethanolic hydrochloric acid, evaporate and recrystallize once from glacial acetic acid and once from toluene, and wash with diisopropyl ether. Sm.p. 236°C during decomposition.

Eksempel 3 Example 3

6-(4-fluorfenyl)-3-metylamino-l,2,4-triazolo/~4,3-b/pyridazin-hydroklorid 6-(4-Fluorophenyl)-3-methylamino-1,2,4-triazolo[4,3-b]pyridazine hydrochloride

Til 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin (formel VIII, sm.p. 1940C) i 40 ml kokende dioksan dryppes 1,65 ml metyliso-cyanat i 10 ml dioksan. Man oppvarmer ennå 2 timer til til-bakeløp, inndamper oppløsningen under nedsatt trykk, utrører med etanol, frasuger og tørker. Mellomproduktet (formel III, To 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine (formula VIII, m.p. 1940C) in 40 ml of boiling dioxane, 1.65 ml of methyl isocyanate in 10 ml of dioxane are added dropwise. It is heated for a further 2 hours to reflux, the solution is evaporated under reduced pressure, stirred with ethanol, filtered off with suction and dried. The intermediate (formula III,

Z = 0) oppvarmes med fosforoksyklorid 4 timer til tilbakeløp. Reaksjonsoppløsningen hydrolyseres forsiktig med is. Det ut-felte hydroklorid av produktet frasuges, vaskes med vann, utkokes med ispropanol, frasuges og tørkes. Sm.p. 2 97°C. Z = 0) is heated with phosphorus oxychloride for 4 hours to reflux. The reaction solution is carefully hydrolysed with ice. The precipitated hydrochloride of the product is suctioned off, washed with water, boiled off with isopropanol, suctioned off and dried. Sm.p. 2 97°C.

Eksempel 4 Example 4

6-( 4- fluorfenyl)- 4- fenylamino- 1, 2, 4- triazolo/~ 4, 3- b7pyridazin 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin og 3,7 g fenyliso-tiocyanat omrøre.s i 50 ml etanol i 3 timer .under tilbakeløp. Etter avkjøling frasuges mellomproduktet, (formel III, Z = S) vaskes med etanol, tørkes, smeltepunkt 223°C under sintring. 6-(4-Fluorophenyl)-4-phenylamino-1,2,4-triazolo/~4,3-b7pyridazine 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine and 3.7 g of phenylisothiocyanate stir.s 50 ml of ethanol for 3 hours under reflux. After cooling, the intermediate product is sucked off, (formula III, Z = S) washed with ethanol, dried, melting point 223°C during sintering.

7,5 g av dette mellomprodukt oppvarmes med 5 g dicykloheksylkarbodiimid i 5 0 ml 2-metoksyetanol i 2 timer under tilbakeløp. Den ved avkjøling dannede utfelling frasuges, vaskes med etanol og om krystalliseres fra isopropanol, sm.p. 265°C. 7.5 g of this intermediate product are heated with 5 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 2 hours under reflux. The precipitate formed by cooling is suctioned off, washed with ethanol and recrystallized from isopropanol, m.p. 265°C.

Eksempel 5 Example 5

3-(4-klorfenylamino)-6-(4-fluorfenyl)-1,2,4-triazolo^~4,3-b/ pyridazin 3-(4-chlorophenylamino)-6-(4-fluorophenyl)-1,2,4-triazolo^~4,3-b/ pyridazine

Til 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin i 40 ml dioksan drypper man 4,1 g 4-klorfenylisocyanat oppløst i 15 ml dioksan og oppvarmer 2,5 timer under tilbakeløp. Etter avkjøling frasuger man, vasker med isopropanol, tørker, sm.p. 223°C. To 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine in 40 ml of dioxane, 4.1 g of 4-chlorophenyl isocyanate dissolved in 15 ml of dioxane is added dropwise and heated under reflux for 2.5 hours. After cooling, vacuum off, wash with isopropanol, dry, m.p. 223°C.

5 g av dette mellomprodukt (formel III, Z = 0) oppvarmes 4 05 g of this intermediate product (formula III, Z = 0) is heated to 4 0

ml tørr toluen med 3,5 ml N,N-dimetylanilin og 1,4 ml fosforoksyklorid i 3 timer under tilbakeløp. Etter avkjøling avdekanteres toluenet og gjenblivende oljeaktig residu utrøresmed 2- n HCl. Man frasuger det faste stoff (hydroklorid, sm.p. ml of dry toluene with 3.5 ml of N,N-dimethylaniline and 1.4 ml of phosphorus oxychloride for 3 hours under reflux. After cooling, the toluene is decanted and the remaining oily residue is stirred with 2-n HCl. The solid substance (hydrochloride, m.p.

286°C) koker opp med halvkonsentrert ammoniakk og frasuger basen etter avkjøling og omkrystal liser er. fra isopropanol, sm.p. 257°C. 286°C) boils with semi-concentrated ammonia and sucks off the base after cooling and recrystallisation. from isopropanol, m.p. 257°C.

Eksempel 6 Example 6

3- (3-fluorfenylamino)-6-(3-trifluormetylfenyl)-1,2,4-triazolo / 4, 3- b7 pyridazin 5 g 3-hydrazino-6-(3-trifluormetylfenyl)-pyridazin (formel VIII, sm.p. 167°C) oppvarmes i 40 ml etanol til ca. 50°C. Man tildrypper 3,3 g 3-fluorfenylisotiocyanat oppløst i 10 ml etanol oppvarmer 3 timer til tilbakeløp, og frasuger etter avkjøling den dannede utfelling. Etter vasking med etanol og tørkning, oppvarmes 6 g av mellomproduktet (formel III, Z = S) sm.p. 3-(3-fluorophenylamino)-6-(3-trifluoromethylphenyl)-1,2,4-triazolo / 4,3- b7 pyridazine 5 g 3-hydrazino-6-(3-trifluoromethylphenyl)-pyridazine (formula VIII, sm .p. 167°C) is heated in 40 ml of ethanol to approx. 50°C. 3.3 g of 3-fluorophenyl isothiocyanate dissolved in 10 ml of ethanol is added dropwise, heated to reflux for 3 hours, and after cooling the formed precipitate is filtered off with suction. After washing with ethanol and drying, 6 g of the intermediate product (formula III, Z = S) is heated m.p.

164°C i 40 ml toluen med 3,8 ml N,N-dimetylanilin og 1,5 ml fosforoksyklorid i 3 timer under tilbakeløp. Etter avkjøling avdekanteres toluenfasen og det gjenblivende oljeaktige residu utrøres med 2-n HCl. Det derved dannede faste stoff (hydroklorid)'' suges fra, kokes opp med halvkonsentrert ammoniakk, frasuges koldt (base). Etter omkrystallisering fra iseddik/vann, sm.p. 209°C. 164°C in 40 ml of toluene with 3.8 ml of N,N-dimethylaniline and 1.5 ml of phosphorus oxychloride for 3 hours under reflux. After cooling, the toluene phase is decanted and the remaining oily residue is stirred with 2-n HCl. The resulting solid (hydrochloride)'' is sucked off, boiled with semi-concentrated ammonia, sucked off cold (base). After recrystallization from glacial acetic acid/water, m.p. 209°C.

Eksempel 7 Example 7

3- (4-fluorfenylamino)-6-(4-fenyltio-fenyl)-1,2,4-triazolo / 4, 3- b/ pyridazin- hydroklorid 3-(4-fluorophenylamino)-6-(4-phenylthio-phenyl)-1,2,4-triazolo / 4, 3-b/ pyridazine hydrochloride

5 g 3-hydrazino-6-(4-fenyltio-fenyl) pyridazin (formel VIII,5 g of 3-hydrazino-6-(4-phenylthio-phenyl)pyridazine (formula VIII,

sm.p. 142°C ) oppvarmes i 40 ml etanol til tilbakeløp. Man tildrypper 2,9 g 4-fluorfenylisotiocyanat i 10 ml etanol langsomt, og oppvarmer til sammen 3 timer under tilbakeløp. sm.p. 142°C ) is heated in 40 ml of ethanol to reflux. 2.9 g of 4-fluorophenyl isothiocyanate in 10 ml of ethanol are slowly added dropwise and heated under reflux for a total of 3 hours.

Etter avkjøling frasuges utfellingen, vaskes med etanol og tørk-es, sm.p. 188°C. 6 g av dette mellomprodukt (formel III, Z = After cooling, the precipitate is suctioned off, washed with ethanol and dried, m.p. 188°C. 6 g of this intermediate (formula III, Z =

S) omrøres med 3 g dicykloheksylkarbodiimid i 40 ml 2-metoksy- S) is stirred with 3 g of dicyclohexylcarbodiimide in 40 ml of 2-methoxy-

etanol i 5 timer under tilbakeløp. Etter avkjøling fra-ethanol for 5 hours under reflux. After cooling from

suger man og vasker med isopropanol. Utfellingen kokes opp med etanolisk saltsyre, inndampes, frasuges, vaskes med eta- vacuum and wash with isopropanol. The precipitate is boiled with ethanolic hydrochloric acid, evaporated, filtered off with suction, washed with ethanol

nol og tørkes, sm.p. 263°C.nol and dried, m.p. 263°C.

Analogt eksempel 1-7 kan det fremstilles følgende forbindelser Stamnavnet "1,2,4-triazolo/ 4,3-b7pyridazin" forkortes i det følgende som "TP". Analogous to examples 1-7, the following compounds can be prepared. The generic name "1,2,4-triazolo/4,3-b7pyridazine" is abbreviated in the following as "TP".

8. 3-metylamino-6-fenyl-TP-HCl, sm.p. 254°C.8. 3-methylamino-6-phenyl-TP-HCl, m.p. 254°C.

9. 3-propylamino-6-fenyl-TP-HCl, sm.p. 206°C9. 3-propylamino-6-phenyl-TP-HCl, m.p. 206°C

10. 3-heksylamino-6-fenyl-TP-HCl, sm.p. 164°C.10. 3-hexylamino-6-phenyl-TP-HCl, m.p. 164°C.

11. 3-(3-fluorfenylamino)-6-fenyl-TP-HCl, sm.p. 266°C under spaltning . 11. 3-(3-fluorophenylamino)-6-phenyl-TP-HCl, m.p. 266°C during decomposition.

12. 3-(4-fluorfenylamino)-6-fenyl-TP-HCl, sm.p. 265°C.12. 3-(4-fluorophenylamino)-6-phenyl-TP-HCl, m.p. 265°C.

13. 3-(3-klor fenylamino)-6-fenyl-TP-HCl, sm.p. 260°C under spaltning. 14. 3-(4-klorfenylamino)-6-fenyl-TP-HCl sm.p. 258°C under spaltning . 13. 3-(3-Chlorophenylamino)-6-phenyl-TP-HCl, m.p. 260°C during decomposition. 14. 3-(4-chlorophenylamino)-6-phenyl-TP-HCl m.p. 258°C during decomposition.

15. 3-(3-trifluormetylfenylamino)-6-fenyl-TP-HCL, sm.p.245°C.15. 3-(3-trifluoromethylphenylamino)-6-phenyl-TP-HCL, mp 245°C.

16. 3-propylamino-6-(4-fluorfenyl)-TP-HC1, sm.p. 241°C.16. 3-propylamino-6-(4-fluorophenyl)-TP-HC1, m.p. 241°C.

17. 3-cykloheksylamino-6-(4-fluorfenyl)-TP-HCl, 262°C under spaltning . 17. 3-cyclohexylamino-6-(4-fluorophenyl)-TP-HCl, 262°C during decomposition.

18. 3-(3-klorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 250°C.18. 3-(3-chlorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 250°C.

19. 3-(3,4-diklorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 289-290°C. 19. 3-(3,4-dichlorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 289-290°C.

20. 3-(2-fluorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 242°C.20. 3-(2-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 242°C.

21. 3-(3-fl,uorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 260-262°C. 22. 3-(4-fluorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 282-284°C. 21. 3-(3-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 260-262°C. 22. 3-(4-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 282-284°C.

23. 3-(4-metylfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 312°C.23. 3-(4-methylphenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 312°C.

24. 3-(3-cyanofenylamino)-6-(4-fluorfenyl)-TP-HCl sm.p. 312°C.24. 3-(3-cyanophenylamino)-6-(4-fluorophenyl)-TP-HCl m.p. 312°C.

25. 3-(3-trifluormetylfenylamino)-6-(4-fluorfenyl)-TP-HCl,25. 3-(3-trifluoromethylphenylamino)-6-(4-fluorophenyl)-TP-HCl,

sm.p. 286°C.sm.p. 286°C.

26. 3-fenylamino-6-(3-fluorfenyl)-TP-HCl, sm.p. 266°C under spaltning. 26. 3-phenylamino-6-(3-fluorophenyl)-TP-HCl, m.p. 266°C during decomposition.

27. 3-(4-klorfenylamino)-6-(3-fluorfenyl)-TP, sm.p. 258°C.27. 3-(4-chlorophenylamino)-6-(3-fluorophenyl)-TP, m.p. 258°C.

28. 3-(3-fluorfenylamino)-6-(3-fluorfenyl)-TP sm.p. 236°C.28. 3-(3-fluorophenylamino)-6-(3-fluorophenyl)-TP m.p. 236°C.

29. 3-(4-fluorfenylamino)-6-(3-fluorfenyl)-TP, sm.p. 241°C.29. 3-(4-fluorophenylamino)-6-(3-fluorophenyl)-TP, m.p. 241°C.

30. 3-fenylamino-6-(3-trifluormetylfenyl)-TP, sm.p. 206°C.30. 3-phenylamino-6-(3-trifluoromethylphenyl)-TP, m.p. 206°C.

31. 3-(3-klorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 212°C. 32. 3-(4-klorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 208°C. 33. 3-(3,4-diklorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 198°C. 34. 3-82-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 198°C. 35. 3-(3-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 209°C. 36. 3-(4-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 234°C. 31. 3-(3-chlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 212°C. 32. 3-(4-chlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 208°C. 33. 3-(3,4-dichlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 198°C. 34. 3-82-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 198°C. 35. 3-(3-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 209°C. 36. 3-(4-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 234°C.

37. 3-fenylamino-6-(4-trifluormetylfenyl)-TP-HCl, sm.p. 271°C.37. 3-phenylamino-6-(4-trifluoromethylphenyl)-TP-HCl, m.p. 271°C.

38. 3-(3-fluorfenylamino)-6-(4-fenoksyfenyl)-TP, sm.p. 211°C.38. 3-(3-fluorophenylamino)-6-(4-phenoxyphenyl)-TP, m.p. 211°C.

39. 3-fenylamino-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 247°C.39. 3-phenylamino-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 247°C.

40. 3-(4-klorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 274°C. 41. 3-(3-fluorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 253°C. 42. 3-(4-fluorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 263°C, 40. 3-(4-chlorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 274°C. 41. 3-(3-fluorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 253°C. 42. 3-(4-fluorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 263°C,

43. 3-fenylamino-6-(5-klor-2-tienyl)-TP-HCl, sm.p. 271°C.43. 3-phenylamino-6-(5-chloro-2-thienyl)-TP-HCl, m.p. 271°C.

44. 3-(4-klorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p. 246°C.44. 3-(4-chlorophenylamino)-6-(5-chloro-2-thienyl)-TP, m.p. 246°C.

45. 3-(3-fluorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p. 287°C.45. 3-(3-fluorophenylamino)-6-(5-chloro-2-thienyl)-TP, m.p. 287°C.

46. 3-(2-fluorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p.232°C.46. 3-(2-fluorophenylamino)-6-(5-chloro-2-thienyl)-TP, mp 232°C.

47. 6-/~4-(4-fluorfenoksy)fenyl/-3-fenylamino-TP, sm.p. 235°C. 47. 6-/~4-(4-fluorophenoxy)phenyl/-3-phenylamino-TP, m.p. 235°C.

48. 6-/~4-(4-fluorfenoksy)fenyl7~3-(3-fluorfenylamino)-TP,48. 6-/~4-(4-fluorophenoxy)phenyl7~3-(3-fluorophenylamino)-TP,

sm.p. 233°C.sm.p. 233°C.

49. 3-(4-klorfenylamino)-6-/~4-(4-fluorfenoksy)fenyl7~TP,49. 3-(4-chlorophenylamino)-6-/~4-(4-fluorophenoxy)phenyl7~TP,

sm.p. 267°C.sm.p. 267°C.

50. 3-(3-fluorfenylamino)-6-(2-furyl)-TP, sm.p. 217-218°C.50. 3-(3-fluorophenylamino)-6-(2-furyl)-TP, m.p. 217-218°C.

51. 3-(4-klorfenylamino)-6-(2-furyl)-TP, sm.p. 201-202°C.51. 3-(4-chlorophenylamino)-6-(2-furyl)-TP, m.p. 201-202°C.

52. 3-fenylamino-6-(2-tienyl)-TP, sm.p. 204°C.52. 3-Phenylamino-6-(2-thienyl)-TP, m.p. 204°C.

53. 3-(3-fluorfenylamino)-6-(2-tienyl)-TP, sm.p. 212°C. 53. 3-(3-fluorophenylamino)-6-(2-thienyl)-TP, m.p. 212°C.

Eksempel 54 fremgangsmåte . b) Example 54 procedure. b)

3-cykloheksylamino-6-fenyl-1,2,4-triazolo/~4,3-b7pyridazin-hydroklorid 3-Cyclohexylamino-6-phenyl-1,2,4-triazolo/~4,3-b7pyridazine hydrochloride

3 g 3-brom-6-fenyl-1,2,4-triazolo/ 4,3-b7pyridazin oppvarmes3 g of 3-bromo-6-phenyl-1,2,4-triazolo/4,3-b7pyridazine is heated

1 10 ml cykloheksylamin 5 timer under tilbakeløp. Etter av-kjøling utrører man med diisopropyleter, frasuger og omkrystalliseres fra isopropanol. Med etanolisk saltsyre får man hydrokloridet, sm.p. 258°C. 1 10 ml cyclohexylamine 5 hours under reflux. After cooling, the mixture is stirred with diisopropyl ether, filtered off with suction and recrystallized from isopropanol. With ethanolic hydrochloric acid, the hydrochloride is obtained, m.p. 258°C.

Analogt får man forbindelsen ifølge oppfinnelsen med eksempelAnalogously, the compound according to the invention is obtained by example

2 til 53.2 to 53.

Derved omsetter en analogt til litteraturfremgangsmåten frem-stillet 6-aryl-3-brom-l,2,4-triazolo/ 4,3-b7pyridazin (generell formel IV), som har de samme 6-substituenter som forbindelsen angjeldende eksempel med diamin (generell formel V), som ligger til grunn for 3-substituenten av eksempelet. Thereby, one reacts analogously to the literature method prepared 6-aryl-3-bromo-1,2,4-triazolo/4,3-b7pyridazine (general formula IV), which has the same 6-substituents as the compound in question with diamine ( general formula V), which underlies the 3-substituent of the example.

Eksempel 55 fremgangsmåte c) Example 55 procedure c)

3-benzylamino-6-fenyl-1,2,4-triazolo/ 4,3-b7pyridazinhydro-klorid 3-benzylamino-6-phenyl-1,2,4-triazolo/4,3-b7pyridazine hydrochloride

5 g 3-amino-6-fenyl-1,2,4-triazolo/~4,3-b7pyridazin og 3 g benzyl-klorid oppvarmes i 25 ml dimetylformamid med 5 g kaliumkarbonat i 10 timer under tilbakeløp. Etter avkjøling blandes med vann, frasuges, og blandes med etanolisk saltsyre og inndampes. Etter omkrystallisering fra iseddik, vaskes med diisopropyleter og tørkes, sm.p. 236°C under spaltning. 5 g of 3-amino-6-phenyl-1,2,4-triazolo/~4,3-b7pyridazine and 3 g of benzyl chloride are heated in 25 ml of dimethylformamide with 5 g of potassium carbonate for 10 hours under reflux. After cooling, mix with water, suck off, and mix with ethanolic hydrochloric acid and evaporate. After recrystallization from glacial acetic acid, wash with diisopropyl ether and dry, m.p. 236°C during decomposition.

Analogt denne fremgangsmåte får man forbindelsene ifølge oppfinnelsen fra eksemplene 1 og 3 til.53. Analogous to this method, the compounds according to the invention are obtained from examples 1 and 3 to 53.

Derved omsettes den til de respektive eksempel tilgrunnliggende 3-amino-6-aryl-l,2,4-triazolo/~4,3-b/pyridazin (generell formel VI beskrevet i DE-OS 32 17 325) med R<4->Y (generell formel VII) hvis alkyl- eller arylrest ligger til grunn for 3-substituenten av det angjeldende eksempel. Thereby, it is converted to the respective example basic 3-amino-6-aryl-1,2,4-triazolo/~4,3-b/pyridazine (general formula VI described in DE-OS 32 17 325) with R<4- >Y (general formula VII) whose alkyl or aryl residue forms the basis of the 3-substituent of the relevant example.

Claims (4)

1. Forbindelse,med den qenerelle formel I 1. Compound with the general formula I og deres salter med en fysiologisk tålbar syre, hvori R og R 2 er like eller forskjellige, og betyr hydrogen, alkylgruppe med 1-6 C-atomer, fenyl eller klor, R 2 betyr hydrogen, rettlinjet eller forgrenet alkyl med 1-6 C-atomer eller fenyl, som eventuelt er substituert med 1, 2 eller 3 fluro, klor, brom, jod, trifluormetyl, eller alkyl med 1-4 C-atomer, og R 4 betyr rettlinjet eller forgrenet alkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, fenylalkyl med 1-4 C-atomer, i alkyldelen og eventuelt i fenyldelen substituert med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, alkylkarbonyl med 1-6 C-atomer i alkyldelen, cykloalkylkarbonyl med 5-7 C-atomer, i cykloalkyldelen, eventuelt med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, substiutert benzoyl eller Ar, og hvori Ar betyr aromatiske rester som fenyl, bifenyl, fenoksyfenyl, fenyltiofenyl, fenylsulfinylfenyl, fenylsulfonylfenyl, 1-eller 2-naftyl, 2- eller 3-tienyl, 2-furyl, 2-pyrrolyl, 1-metyl-2-pyrrolyl, 2- eller 3- eller 4-pyridyl, som eventuelt kan være substiutert med 1, 2, 3, 4 eller 5 rester som fluor, klor, brom, jod, alkylgrupper med 1-6 C-atomer, cykloalkylgrupper med 3-8 C-atomer, fenylalkylgruppe med 1-4 alkyl-C-atomer, alkoksy, eller alkyltiogrupper med hver gang 1-6 C-atomer, hydroksy, nitro, cyano, trifluormetyl, karboksygrupper, deres estere med C1 ,-Cb,-alkoholer, aminokarbonyl, amino, acetamino, alkoksykarbonylamino med 1-6 C-atomer i alkylresten, hvori videre and their salts with a physiologically tolerable acid, wherein R and R 2 are the same or different, and means hydrogen, alkyl group of 1-6 C atoms, phenyl or chlorine, R 2 means hydrogen, straight or branched alkyl of 1-6 C -atoms or phenyl, which is optionally substituted with 1, 2 or 3 fluoro, chlorine, bromine, iodo, trifluoromethyl, or alkyl with 1-4 C atoms, and R 4 means straight or branched alkyl with 1-6 C atoms , cycloalkyl with 3-8 C atoms, phenylalkyl with 1-4 C atoms, in the alkyl part and optionally in the phenyl part substituted with 1, 2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms , alkylcarbonyl with 1-6 C atoms in the alkyl part, cycloalkylcarbonyl with 5-7 C atoms, in the cycloalkyl part, optionally with 1, 2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms, substituted benzoyl or Ar, and wherein Ar means aromatic residues such as phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1-or 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2 - or 3- or 4-pyridyl, which may optionally be substituted with 1, 2, 3, 4 or 5 residues such as fluorine, chlorine, bromine, iodine, alkyl groups with 1-6 C atoms, cycloalkyl groups with 3-8 C- atoms, phenylalkyl group with 1-4 alkyl C atoms, alkoxy, or alkylthio groups with each time 1-6 C atoms, hydroxy, nitro, cyano, trifluoromethyl, carboxy groups, their esters with C1,-Cb,-alcohols, aminocarbonyl, amino, acetamino, alkoxycarbonylamino with 1-6 C atoms in the alkyl residue, in which further kan danne en rest med den generelle formel II can form a residue of the general formula II hvori X betyr CH2 , CHR <5> , C=0, 0, S eller NR <5> , hvori R5 betyr hydrogen, alkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, alkylkarbonyl med 1-6 C-atomer i alkylresten, alkoksykarbonyl med 1-4 C-atomer i alkoksyresten, eventuelt substituert fenylalkyl, med 1-4 C-atomer i alkylresten, eventuelt substiutert fenyl eller eventuelt substituert benzoyl, hvori fenylringene hver gang kan være substituert med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-6 C-atomer, og m og n betyr 1,2 eller 3, med unntak av de forbindelser med formel I, hvori R 1 , R 0 ogR<3> betyr hydrogen, R 4betyr fenyl og Ar betyr fenyl, 4-metylfenyl eller 4-bromfenyl.in which X means CH2 , CHR <5> , C=0, 0, S or NR <5> , in which R5 means hydrogen, alkyl with 1-6 C atoms, cycloalkyl with 3-8 C atoms, alkylcarbonyl with 1- 6 C atoms in the alkyl residue, alkoxycarbonyl with 1-4 C atoms in the alkoxy residue, optionally substituted phenylalkyl, with 1-4 C atoms in the alkyl residue, optionally substituted phenyl or optionally substituted benzoyl, in which the phenyl rings can each be substituted with 1, 2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-6 C atoms, and m and n mean 1,2 or 3, with the exception of the compounds of formula I, in which R 1 , R 0 and R<3> means hydrogen, R 4 means phenyl and Ar means phenyl, 4-methylphenyl or 4-bromophenyl. 2. Fremgangsmåte til fremstilling av forbindelser med formel I ifølge krav 1, karakterisert ved ata) en forbindelse,med formel III 2. Process for the preparation of compounds of formula I according to claim 1, characterized by ata) a compound of formula III 12 3 4 hvori Ar, R , R , R og R har de under formel I angitte betydning, og Z betyr 0 eller S, cykliseres ved oppvarming, eventuelt under tilsetning av et kondensasjonsmiddel til en forbindelse med formel I eller b) en forbindelse med formel IV 12 3 4 in which Ar, R , R , R and R have the meaning given under formula I, and Z means 0 or S, is cyclized by heating, optionally with the addition of a condensing agent to a compound of formula I or b) a compound of formula IV 6 12 hvori R betyr klor, brom eller metyltio, og Ar, R og R har den under formel I angitte betydning, omsettes med aminer; med formel V 6 12 in which R means chlorine, bromine or methylthio, and Ar, R and R have the meaning given under formula I, are reacted with amines; with formula V hvori RJ o og R 4 eventuelt sammen med N-atomet har den under formel I angitte betydning, eller c) en forbindelse med formel VI eller en av dets salter in which RJ o and R 4 optionally together with the N atom have the meaning given under formula I, or c) a compound of formula VI or one of its salts hvori Ar, R 1 og R 2 ha—r den under formel I angitte betydning, omsettes med en forbindelse med formel VIII in which Ar, R 1 and R 2 have the meaning given under formula I, is reacted with a compound of formula VIII hvori R 4 har den under formel I angitte betydning, og Y betyr en avspaltbar gruppe, som f. eks. fluor, klor, brom, jod, 0 " 3 -O-C-R eller en tosylatrest, eventuelt under tilsetning av et kondensasjonsmiddel eller katalysator.in which R 4 has the meaning given under formula I, and Y means a leaving group, which e.g. fluorine, chlorine, bromine, iodine, 0 "3 -O-C-R or a tosylate residue, optionally with the addition of a condensing agent or catalyst. 3. Farmasøytiske preparater med anxiolytiske og antikonvulsiv virkning, karakterisert ved et innhold av en forbindelse med den generelle formel I i krav 1.3. Pharmaceutical preparations with anxiolytic and anticonvulsant effects, characterized by a content of a compound with the general formula I in claim 1. 4. Anvendelse av en forbindelse med den generelle formel I ifølge krav 1, til behandling av opphisselsestilstander, søvn-løshet, krampetilstander og vegetativ dystoni.4. Use of a compound with the general formula I according to claim 1, for the treatment of states of excitement, insomnia, convulsive states and vegetative dystonia.
NO841270A 1983-03-31 1984-03-30 SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, AND THEIR PREPARATION AND USE NO841270L (en)

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