NZ207691A

NZ207691A - 1,2,4-triazolo(4,3-b)pyridazine derivatives and pharmaceutical compositions

Info

Publication number: NZ207691A
Application number: NZ207691A
Authority: NZ
Inventors: M Rosner; F Hock
Original assignee: Hoechst Ag
Priority date: 1983-03-31
Filing date: 1984-03-29
Publication date: 1986-07-11
Also published as: HU189076B; AU2634684A; GR81812B; FI841238A; MA20080A1; IL71412A; JPS59184179A; CA1246568A; ES531084A0; IL71412A0; ATE32723T1; EP0121490B1; DK144884A; PT78343B; EP0121490A1; NO841270L; AU563556B2; HUT34193A; PT78343A; ZA842389B

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £07691 20769 f Priority Date(s): vO,; ^ . Complete Specification Filed: Class: ZQ7&&1:,.. A6IJS3J,/^Q .... Publication Date: P.O. Journal, No: ... Nfi fi.Z.; ; 2 9 MAR 1984 RECEIVED NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION N.Z. No. "SUBSTITUTED 6-ARYL-1, ? , 4-TRIAZOLO /4,3-b/ PYRIDAZINES THEIR PREPARATION AND THEIR USE." We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of D-62 30 Frankfurt/Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the ;method by which it is to be performed, to be particularly described in and by the following statement -1- - 2 - The invention relates to new substituted 6-aryl-1,2,4-triazo loC4,3-bDpyridazines of the general formula I (I) and salts thereof with a physiologically acceptable acid, 1 *5 5 in which formula R' and R4- are identical or different and represent hydrogen,, alkyl groups having 1-6 carbon atoms, phenyl or chlorine, represents hydrogen, linear or branched alkyl having 1-6 carbon atoms or phenyl which is optionally monosubstituted, disubstituted 10 or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, and R ^ 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 '15 monosubstituted, disubstituted or trisubstituted in the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, alkyl-carbonyl having 1-6 carbon atoms in the alkyl part, cycloalkylcarbonyl having 5-7 carbon atoms in the cyclo-20 alkyl part or benzoyl which is optionally monosubstituted, 207693 - 3 - disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyI or alkyl having 1-4 cai— bon atoms, or denotes Ar, and in which Ar represents an aromatic radical, such as phenyl, biphenyl, phenoxy-5 phenyl, phenyIthiopheny I, pheny I suIfinyIphenyI, phenyl-suIfonyIphenyI, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methy l1-2-py r ro ly I or 2-, 3- or 4-pyridyl, each of which can optionally be substituted by one, two, three, four or five radicals such as 10 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 having in each case 1-6 carbon atoms, hydroxyl, nitro, cyano, trif luoromethyI or car-15 boxyl groups, esters of the latter with C-j-C^-a Icoho Is, aminocarbonyI, amino, acetamino or a Ikoxycarbonylamino having 1-6 carbon atoms in the alkyl radical, and in /*■ which can also represent a radical of the \R" general formula II zo _N y (ID VcH,)„ J 2 n. in which X denotes CHg/ CHR^, C = 0, 0, S or NR-* in which r5 denotes hydrogen, alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, a Iky Icarbony I h E 1-6 carbon atoms in the alkyl radical, a Ikoxycarbon; 2 076 9 1 - 4 - having 1-4 carbon atoms in the alkoxy radical, optionally substituted phenylalkyl having 1-4 carbon atoms in the alkyl radical, optionally substituted phenyl or optionally substituted benzoyl, it being possible for each of 5 the phenyl rings to be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-6 carbon atoms, and m and n denote 1, 2 or 3. Amongst the compounds of the general formula I, 10 preference attaches to those in which R ^ and R ^ are identical or different and denote hydrogen,methyl, ethyl, phenyl or chlorine, R ^ denotes hydrogen or alkyl having 1-6 carbon atoms, R^ denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 15 carbon atoms, or phenylalkyl which has 1-4 carbon atoms in the alkyl part and is optionally monosubstituted or disubstituted in the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, or denotes Ar, and Ar denotes phenyl, bi-20 phenyl, phenoxypheny I, pheny IthiophenyI, 2-thienyl, 3-thienyl, 2-furyl or 2-, 3- or 4-pyridyl, each of which can optionally be monosubstituted, disubstituted or tri-substituted by fluorine, chlorine, bromine, trifluoromethyl, alkyl groups having 1-6 carbon atoms or cyclo-. 25 alkyl groups having 3-6 carbon atoms, or those in which /*3 -N has the meanings indicated for formula II. "V1 Compounds of the formula I which are particularly preferred are those in which R'^ and R2 are identical or - 5 - different and denote hydrogen, methyl or ethyl, R ^ denotes hydrogen or alkyl having 1-6 carbon atoms, denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, benzyl or phenylethyl 5 which is optionally monosubstituted or disubstituted in the phenyl ring by fluorine, chlorine, trifluoromethyl, methyl or ethyl, or denotes Ar, and Ar denotes phenyl, phenoxyphenyl, phenylthiophenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-pyridyl, each of which is optionally mono-10 substituted or disubstituted by fluorine, chlorine, trir fluoromethy I, methyl or ethyl. Compounds of the formula I in which R^, and denote hydrogen, R^" denotes phenyl and Ar denotes phenyl, 4-methy IphenyI or 4-bromophenyI are, however, not 15 claimed. These compounds have been described in Rev. Roum. Chim. 1_0/ ^41 (1965) and Rev. Med. Chir. 81_, 469 (1977), and are stated to have an antihypertensive action in some cases. As opposed to this, the compounds, according to the invention, of the formula I have an anxiolytic 20 and anticonvulsive action. The invention also relates to a process for the preparation of these compounds and pharmaceutical formulations of these compounds and to their use as drugs. The process for the preparation of the compounds of the 25 formula I comprises a) cyclizing a compound of the formula III - 6 - z r3 II / (III) NH-NH-C-Nv h >R in which Ar, R^, R^, and R^ have the meanings \ indicated for formula I and Z represents 0 or S, by heating, if appropriate with the addition of a condensa-5 tion agent, to give a compound of the formula I or b) reacting a compound of the formula IV V R? Ar_CH Vj r6 in which R ^ denotes chlorine, bromine or methylthio and Ar, R^ and R^ have the meanings indicated for formula 10 I, with an amine of the formula V X h-n (v) \ 4 R in uhich R^ and R ^ - if appropriate together with the nitrogen atom - have the meanings indicated for formula I, or 15 c) reacting, if appropriate with the addition of a condensation agent or catalyst, a compound of the formula VI - 7 - 207691 R1 R2. Ar> «l» Vl XI ' n-n V=N. nh2 \ or one of its salts in which Ar, R^ and R^ have the meanings indicated for formula I, with a compound of the formula VII R4-Y (VII) in which R4 has the meaning indicated for formula I and Y represents a leaving group, such as, for example, 0 11 ^5 fluorine, chlorine, bromine, iodine, -0-C-RJ or the 3 tosylate radical^ in which R has the meaning given for Formula I above In process a), the starting materials of the formula III are obtained, for example, by reacting aryl-hydrazinopyridazines of the formula VIII nhnh2 (viii> in which R , R and Ar have the meanings indicated for formula I, with isocyanates or isothiocyanates of the formula IX R'*-N=C=Z (IX) in which R4 and Z have the meanings indicated for formula I and III, respectively, by heating at A0-150°C, adyfarr- o) 'v tageously in a solvent, such as, for example, methariol^ . 20769J - 8 - ethanol, isopropanol, diisopropyl ether, dioxane, tetra-hydrofuran, toluene, methylene chloride, chloroform or di chloroethane. 5 into compounds of the formula I by heating at 40-150°C, for example in one of the solvents mentioned and, if appropriate, with the addition of a condensation agent, such as, for example, glacial acetic acid, cyclohexyl-carbodiimide, 1-hydroxybenztriazo le, phosphorus oxy-10 chloride, phosphorus oxych loride/N,N-dimethylaniIine, phosphorus oxybromide, phosphorus pentachloride, thionyl chloride, mercury oxide or lead oxide. The compounds of the general formula III can also be obtained by reacting chloropyridazines of the formula X formula I, with substituted semicarbazides or thiosemi-carbazides of the formula XI The compounds of the formula III are converted 15 (X) n-n in which Ar, and have the meanings indicated for z r 3 ll / (XI) h^n-NII-C-N^ 20 in which R^, R4 and Z have the meanings indicated for formula iii,by heating at 40-150°C, for example in one of the solvents mentioned or in DMF, DMSO or acetonitrile. For process b), the starting materials of the formu areobtained by heating a r y Ih ydr a z i nopy r i daz i nes VI - 9 - with formic acid or esters thereof' (for R ^ = H), phosgene, ch loroformic acid esters, a dialkyL pyrocarbonate or a dialkyL carbonate (for R ^ = OH) or carbon disulfide and an alkali (for R^ = SH), if appropriate with the addi- 5 tion of a solvent or diluent, such as chloroform, toluene, \ dioxane, ethyl acetate, water or ethanol, to give a compound of the formula IV' in which R^ denotes H, OH or SH. The corresponding compounds IV in which R^ = Br, Cl or SCH3 are obtained therefrom by heating with brom-10 ine in glacial acetic acid/sodium acetate (in the case of = H), phosphorus oxychloride (in the case of R^ = OH) or methyl iodide or dimethyl sulfate (in the case of R = SH). The reaction of the compounds of the formula IV 15 with amines of the formula V is effected in accordance with process b) without a solvent or in an inert solvent, such as methanol, isopropanol, 2-methoxyethano I, tetra-hydrofuran, dioxane, toluene, chloroform, DMF, DMSO, acetonitriIe, acetone or ethyl acetate, at temperatures 20 of 20-200°C, preferably 50-150°C, under normal pressure or under pressure in an autoclave. The reaction with gaseous amines can be carried out under normal pressure by passing the latter into the mixture or can likewise be carried out under pressure. If appropriate, a cata-25 lyst, such as copper(I) chloride or other copper(I) salts, can be added in order to accelerate the reaction. In process c), the reaction of the compounds of the formula VI, which are obtained, for example, by cyclizing arylhydrazinopyridazines of the formula VIII 2 07 69 1 - 10 - by means of cyanogen chloride or cyanogen bromide, with compounds of the formula VII is effected in the absence or presence of a solvent or diluent, such as, for example, acetone, methyl ethyl ketone, ethyl acetate, 5 toluene, xylene, dioxane, tetrahydrofuran, DMF, DMSO, acetonitri le, methylene chloride, chloroform or dichloro-ethane. If appropriate, it is possible.to add inorganic or organic bases, such as, for example, sodium hydroxide, 10 triethylamine or pyridine, in order to bind any acids formed in the reaction, or, especially in the case of the reaction with acid anhydrides, to add catalytic amounts of a strong acid, such as, for example, hydrochloric acid, sulfuric acid or trifluoroacetic acid. 15 Arylhydrazinopyridazines of the formula VIII are known, for example from J. Heterocyclic Chem. 1_5, 881 (1978), or can be prepared from chlorine compounds of the formula X using hydrazine hydrate in accordance with processes known from the literature (The Chemistry of 20 Heterocyclic Compounds, Volume 28 Pyridazines, Editors A. Weissbergerand E.C. Taylor, John Wiley, New York 1973). The two literature references also describe the synthesis of the chlorine compounds X and their precursors. 25 If the compounds of the formula I are obtained in accordance with the processes described in the form of salts, the appropriate base can'be set free from the latter by means of ammonia, amines or hydroxides. The free" bases of the formula I can be converted into the corresponding salts by means of physiologically acceptable acids. Suitable acids are inorganic or organic acids, such as hydrochloric or hydrobromic acid, phosphoric acid, acetic acid, benzoic acid, citric acid, 5 maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid or acetyIg lycine. The compounds, according to the invention, of the formula I are suitable for the preparation of drugs. The drugs can contain one or more of the compounds 10 according to the invention or mixtures thereof with other pharmaceutica I ly active substances. The customary pharmaceutical excipients and auxiliaries and known pharmaceutical processes can be used to prepare the drugs. The drugs can be administered enterally, paren-15 terally, orally or perlingually. For example, administration can be effected in the form of tablets, capsules, pills, coated tablets, suppositories, jellies, creams, p'owders, liquids, dusting powders or aerosols. The following are examples of suitable liquids: oily or 20 aqueous solutions or suspensions, emulsions and injectable solutions or suspensions. The compounds according to the invention can also be used as intermediates for the preparation of other drugs. 25 The following compounds according to the inven tion may be mentioned: (the abbreviation "TP" is used in the following text for the root name "1,2,4-triazolo-C4 ,3-bUpy r i daz i ri e ".) 6-(3-Fluorophenyl)-3-phenylamino-TP, 6-(4-Fluoro~ phenyl)-3-phenylami no-TP, 6-(3-trifluoromethylphenyl)-3-phenylamino-TP, 6-(3,4-difluorophenyl)-3-phenylamino-TP, 6-(4-phenoxyphenyl)-3-phenylamino-TP, 6-(4-phenylthio-phenyD-3-phenylamino-TP, 6-(4-(4-fluorophenoxy)phenyl)-5 3-phenyI ami no-TP, 6-(3-ch toropheny I)-3-ph eny I ami no-TP, 6-(3-bromophenyl)-3-phenylamino-TP, 6-(5-chLoro~27thienyl)-3-phenylamino-TP, 6-(3-fluorophenyl)-3-(substituted-phenyI ami no)-TP, 6-<4 — fLuorophenyL)-3-(substituted-phenylamino)-TP, 6-(3-trifLuoromethylphenyl)-3-(substi-10 tuted-phenyLamino)-TP, 6-(3,4-dif luorophenyL)-3-(sub-stituted-phenyLami no)-TP, 6-(4-phenoxyphenyL)-3-(substituted -phenyLamino)-TP, 6- (4-phenylthiophenyl)-3-(subst i tuted-pheny Lam ino)-TP, 6-(4-(4-fluorophenoxy)phenyl)-3-(substituted-phenylami no)-TP, 6-(3-chlorophenyl)"3~ 15 (substituted-phenylamino)-TP, 6-(3-bromophenyl)-3-(sub-stituted-phenyLamino)-TP and 6-(5-chloro-2-thienyl)-3-(substituted-phenyLarnino)-TP, in which "substituted-phenyI" represents, in particular, 2-, 3- or 4-fLuorophenyI, 2-, 3- or 4-chLorophenyL, 2-, 20 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluoropheriyl, 2,4-dichloro-phenyL, 2,4-di f Luoropheny I, 2,5-dichlorophenyI, 2,5-di-fLuorophenyL, 3,5-dichlorophenyL, 3,5-difluorophenyl, 2,6-dichLorophenyL or 2,6-difLuorophenyL. 25 6-(3-F Luoropheny L)-3-(N-methyL-N-phenylainino)-TP, 6-(4-fluorophenyl)-3-(M-methyl-N-phenylamino)-TP, 6- (3 -trifluoromethylphenyl)-3-(N-methy'l"N-phenylamino)-TP, 6-(3,4-difLuorophenyl)~3-(N-methyL-N-phenylamino)-"TP, 6- (4-phenoxyphenyl)-3-(N-methyl-N-phenylamino)-TP, 6-(4- 2 0769 t phenylthiophenyL)-3-(N-methyl-N-phenylamino)-TP, 6-C4-C4-fluorophenoxy)phenyl)-3~(N~methyl-N-phenylamino)-TP, 6-(3-chlorophenyl)-3-(N-methyl-N-phenylamino)-TP, 6- CS-bromophenyD-S-CN-methyl-N-phenylamino^TP, 6-(5-chloro-5 2-thienyL)-3-(N-methyl-N-phenyLami no)-TP, 6-(3-fluoro-phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6- (4~ fluorophenyl)-3-(N-methyl-N-substitute'd-phenylamino)-TP, 6-(3-trifluoromethylphenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(3,4-dif Luoropheny L) -3 -(N-methyl-N-10 substituted-phenyLamino)-TP, 6-(4-phenoxyphenyI)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(4~phenylthio-phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6 - (4-(4-fluorophenoxy)-phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(3-ch LorophenyL)-3-(N-methyl-N-sub-15 stituteo'-phenylamino)-TP, 6-(3-bromophenyl)-3-(N-methyl-N-substituted-phenylamino)-TP and 6-(5-chloro-2-thienyl)-3-(N-methyL-N-substituted-phenyLanuno)-TP, in which "substituted-phenyL" represents, in particular, 2-, 3- or 4-fLuorophenyL, 2-, 3- or 4-chlorophenyI, 2-, 20 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2,4-dichtoro-phenyl, 2,4-difLuorophenyI, 2,5-dichLoropheny 1, 2,5-di-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyL, 2,6-dichIorophenyI or 2,6-difluorophenyI. 25 6-C3-Fluorophenyl)-3-acetamino-TP, 6-(4-fluoro- phenyD-3-acetamino-TP, 6-(3-trifluoromethylphenyl)-3-acetamino-TP, 6-(3,4-difluoropheny I)-3-acetami no-TP, 6-(4-phenoxyphenyl)-3-acetamino-TP, 6-(4-phenylthiophenyU- 3-acetamino-TP, 6-(4-(4~fluorophenoxy)phenyl)-3-acet- - 14 - amino-TP, 6-(3-chLorophenyl)-3-acetami no-TP, 6-(3~bromo-phenyl)-3-acetamino-TP, 6-(5-chloro-2-thienyl)-3-acet-ami no-TP, 6-(3-fluorophenyl)-3-benzoylamino-TP, 6-C4-■fluorophenyl)-3-benzoylamino-TP, 6-(3-trifluoromethyl-5 phenyl)-3-benzoylamino-TP, 6-(3,4-difluorophenyl)-3-benzoylami no-TP, 6-(4-phenoxyphenyl)-3-benzoylamino-TP, 6-(4-phenylthiophenyl)-3-benzoylami no-TP, 6-(4-(4-fluoro-phenoxy)phenyl)-3-benzoylamino-TP, 6-(3-chlorophenyl)-3-benzoyI ami no-TP, 6-(3-bromophenyL)-3-benzoy I a mi no-TP, 6-10 <5--c h lo ro-2-t h i eny I )-3-benzoy lami no-TP, 6-(3-fluoro-phenyl)-3-(substituted-benzoylamino)-TP, 6-(4-fluoro-phenyl)-3-(substituted-benzoylamino)-TP, 6-(3-trifluoro-methylphenyl)-3-(substituted-benzoylamino)-TP, 6 - (3 , 4-difluorophenyl)-3-(substituted-benzoylamino)-TP, 6 - (4-15 phenoxyphenyl)-3-(substituted-benzoylamino)-TP, 6-(4- phenylthiophenyl)-3-(substituted-benzoylamino)-TP, 6- (4-(4-fluorophenoxy)phenyl)-3-(substituted-benzoylamino)-TP, 6-(3-chlorophenyl)-3-(substituted-benzoylamino)-TP, 6- (3-bromophenyI)-3-(substituted-benzoyI ami no)-TP and 6-(5-20 chLoro-2-thienyl)-3-(substituted-benzoylamino)-TP, in which "substituted-benzoyL" represents, in particular, 2-, 3- or 4-fluorobenzoyl, 2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-bromobenzoyI, 2-, 3- or 4-trif luoromethyLbenzoyI, 3,4-dichlorobenzoy I, 3,4-difluorobenzoy I, 2,5-dichloro- 25 benzoyl, 2,5-difluorobenzoyl, 3,5-dichlorobenzoyl, 3,5-difLuorobenzoy I, 2,6-dichlorobenzoy I or 2,6-difLuorobenzoy I. 6"(3-Fluorophenyl)~3-(substituted-arnino)"TP, 6-(4-fluorophenyl)-3-(substituted-amino)-TP, 6-(3-trifluoro- 20769J 15 methylphenyl)-3-(substituted-amino)-TP, 6-(3,4-difluoro-phenyl) -3 -(subst i tuted-ami no)-TP, 6-(4-phenoxyphenyl)-3-(substituted-amino)-TP, 6 - (4-pheny Lthiopheny I)-3- (substituted- amino)-TP, 6-(4-(4-fluorophenoxy)phenyl)-3-(sub stituted-amino)-TP, 6-(3-chlorophenyl)-3-(substituted-amino)-TP, 6-(3-bromophenyL)-3-(substituted-amino)-TP and 6-(5-chloro-2-thienyl)-3-(substituted-amino)-lP, in which "substituted-amino" represents, in particular, dimethylamino, diethylamino, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-phenyIpiperidino, 4-pheny 1-1-piperaziny I, 4-piperidon-1-yl and 4-ethoxycarbonyl-1-piperazinyl. formula I act on the central nervous system; in particular, they have an anxiolytic and anticonvulsive action. Possible indications are, therefore, sleeplessness, emotional tension and autonomic depression. The pharmaceutical formulations generally,contain by weight 1 to 10 % jo f the active component(s) according to the invention. The anxiolytic action of the compounds of the formula I is accompanied by a very.slight sedation and by good tolerance (LDgg ^ 300 mg/kg i.p. on mice). This is shown by investigations in which the effect of the compounds according to the invention on motor activity, hexobarbital-induced narcosis and cardi-azot spasms in mice was determined. In addition, the The compounds, according to the invention, of the were also used Geller anxiolytic test and the lick-shock test on r *' ' 2 076$ f The Lowest dose still effective in the tests indicated above is, for example, 5 mg/kg on oral administration, 2.5 mg/kg on sublingual administration and 1 mg kg on intravenous administration. Examples of suitable 5 general dose ranges for action (animal test as above) are: 5 to 50 mg/kg on oral administration, 2.5 to 25 mg kg on sublingual administration and 1 to 10 mg/kg on intravenous administration. For example, 1 to 3 tablets containing 10 to 100 10 mg of active substance can be administered 3 times a day or, in the case of intravenous injection, for example, an ampoule of 2 to ml capacity containing 0.5 to 5 mg of substance can be administered 1 to 3 times a day. Examp le 1 : 15 3-CycLohexylamino-6-phenyl-1,2,4~triazoLoC4/.3-b!]pyridaz-ine hydrochloride 5 g of 3-hydrazino-6-phenyIpyridazine (formula VIII, melting point 146°C) are dissolved in 50 ml of hot ethanol, and 3.8 g of cyclohexyl isothiocyanate are 20 added. The mixture is stirred for two hours under reflux and cooled to 0°C, and the product is filtered off with suction, washed with ethanol and dried. The resulting intermediate (formula III, Z=S) is heated with 6.1 g of dieyelohexyIcarbodiimide in 50 ml of 2-methoxyethanoI for 25 5 hours at reflux temperature. The reaction solution is evaporated to dryness under reduced pressure, and the residue is crystallized twice from isopropanol. Treatment with ethanolic hydrochloric acid gives the hydrochloride, which is filtered off with suction, washed with ethanol and dried, melting point 268°C. ExampIe 2: 3"BenzyLamino-6-phenyl-1,2,,4-triazoLoC4,3-bIlpyridazine hydroch Lori de 5 8 g of 3-hydrazino-6-pheriylpyridazine are dis solved in 70 ml of hot ethanol, 7 g of benzyl isothio-cyanate are added and the mixture is stirred under reflux for one hour. After cooling, the intermediate stage (formula III, Z=S) is filtered off with suction, washed 10 with ethanol, dried and then heated with 8.9 g of dicyclo-h e xy 1 c a rbodi i ini de in 50 ml of 2-methoxyethano I for 5 hours at reflux temperature. The mixture is concentrated and ethanolic hydrochloric acid is added, after which the mixture is evapo-15 rated to dryness and the residue is re crysta Ilized once from glacial acetic acid and once from toluene and washed with diisopropyl ether, melting point 236°C (decomposition). Example 3: 6-(4-Fluorophenyl)-3-methylamino-1,2,4-triazoloC4,3-b3-20 pyridazine hydrochloride 1.65 ml of methyl isocyanate in 10 ml of dioxane are added dropwise to 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine (formula VIII, melting point 194°C) in 40 ml of boiling dioxane. The solution is heated at 25 reflux temperature for a further two hours and concentrated under reduced pressure, the residue is stirred with ethanol, and the product is filtered off with suction and dried. The intermediate (formula III, Z=0) is heated with phosphorus oxychLoride for 4 hours at reflux - 18 - temperature. The reaction solution is hydrolyzed cautiously with ice. The precipitated hydrochloride of the product is filtered off with suction, washed with water, extracted by boiling with isopropanol, filtered off with 5 suction and dried, melting point 297°C. \ Example 4; 6-(4-Fluorophenyl)-3-phenyLamino-1 ,2,4-tri azoloC4,3-bI)-py ri dazi ne 5 g of 3-C4-f luoropheny I)-6-hydrazinopyridazine 10 and 3.7 g of phenyl isothiocyanate in 50 ml of ethanol are stirred under reflux for 3 hours. After cooling, the intermediate (formula III, Z=S) is filtered off with suction, washed with ethanol and dried, melting point 223°C(sintering). 15 7.5 g of this intermediate are heated with 5 g of dicycI ohexyIcarbodiimide in 50 ml of 2-methoxyethanol for 2 hours at reflux temperature. The precipitate which is formed on cooling is filtered off with suction, washed with ethanol and recrystallized from isopropanol, melting 20 poi nt 265°C. Example 5: 3-(4-Chlorophenylamino)-6-(4-fluorophenyl)-1,2,4~triazoL o-C4,3-b3pyridazine 4.1 g of 4-chlorophenyl isocyanate, dissolved in 25 15 ml of dioxane, are added dropwise to 5 g of 3-(4- \ fluorophenyl)-6-hydrazinopyridazine in 40 ml of dioxane, and the mixture is heated for 2.5 hours at reflux temperature. After cooling, the product is filtered off with suction, washed with isopropanol and dried, melting - 19 - point 223°C. 5 g of this intermediate (formula III, Z=0) are heated in 40 ml of dry toluene with 3.5 ml of N,N-dimethylaniline and 1.4 ml of phosphorus oxychLoride for 3 hours at reflux temperature. After cooling, the 5 toLuene is removed by decantation and the oily residue which remains is stirred with 2N HCl. The solid (hydrochloride, melting point 286°C) i's filtered off with suction and boiled up with semi-concent rated ammonia; after cooling, the base is filtered off with suction and 10 recrystallized from isopropanol, melting point 257°C. Example 6: 3-(3-FluorophenyLarnino)-6-(3-trifluoromethylphenyl)-1,2,4-triazoLoC4,3-bIlpyridazine 5 g of 3-hydrazino-6-(3-trif luoromethyLpheny I)-15 pyridazine (formula VIII, melting point 167°C) in 40 ml of ethanol are warmed to about 50°C. 3.3 g of 3-fluoro-phenyl isothiocyanate, dissolved in 10 ml of ethanol, are added dropwise, the mixture is heated for 3 hours at reflux temperature and, after cooling, the resulting pre-20 cipitate is filtered off with suction. After it has been washed with ethanol and dried, 6 g of the intermediate (formula III, Z = S), melting point 164°C, are heated in 40 ml of toluene with 3.8 ml of N,N-dimethylaniIine and 1.5 in L of phosphorus oxychLoride for 3 hours at refLux 25 temperature. After cooling, the toluene phase is removed by decantation and the oily residue which remains is stirred with 2N HCl. The solid (hydrochloride) thus formed is filtered off with suction and boiled up with semi"concentrated ammonia, and, when cold, the product - 20 - (base) is filtered off with suction. Melting point 209°C, after recrystallization from glacial acetic acid/water. Examp le 7: 5 3-(4-Fluorophenylamino)-6-(4-phenylthiophenyl)-1,2,4-triazoloC4/3-bjpyridazine hydrochloride 5 g of 3-hydrazino-6-(4-phenylthiophenyl)-pyridazine (formula VIII, melting point 142°C) in 40 ml of ethanol are heated to reflux temperature. 2.9 g of 10 4-fluorophenyl isothiocyanate in 10 ml of ethanol are added dropwise slowly, and the mixture is heated for a total of 3 hours at reflux temperature. After cooling, the precipitate is filtered off with suction, washed with ethanol and dried, melting point 188°C. 6 g of this 15 intermediate (formula III, Z=S) are stirred under reflux for 5 hours with 3 g of dicyclohexylcarbodiimide in 40 ml of 2-methoxyethano I. After cooling, the product is filtered off and washed with isopropanol. The precipitate is boiled up with ethanolic hydrochloric acid, the 20 mixture is concentrated, and the product is filtered off with suction, washed with ethanol and dried, melting point 2 6 3 0 C u The following compounds can be prepared analogously to Examples 1-7: the root name "1,2,4-triazolo-25 C4,3~bDpyridazine" is abbreviated to "TP" in the following text. 8. 3-Methy I amino-6-phenyl-TP HCl, melting point 254°C. 9. 3-Propy I amino-6-phenyl-TP HClr melting point 206°C. 10. 3-Hexy I amino-6-phenyl-TP HCl, melting point 164°C. -21- 2 07i 11. 3-(3-FLuorophenyLami no)-6-phenyL-TP HCL, melting point 266°C (decomposition). 12. 3-(4-Fluorophenylamino)-6-phenyl-TP HCL., melting point 264°C. 5 13. 3-(3-ChlorophenyLami no)-6-phenyL-TP HCL, melting point 260°C (decomposition). 14. 3-(4-Chlorophenylamino)-6-phenyl-TP HCL, melting point 258°C (decomposition). 15. 3-(3-Tri f Luoromet hy Lpheny Larni no)-6-'pheny L-TP HCL, 10 melting point 245°C. 16. 3-Propylamino-6-(4-fluorophenyl)-TP HCL, melting point 241°C. 17. 3-CycLohexyLa mino-6-(4-fLuorophenyL)-TP HCl, melting % point 262°C (decomposition). 15 18. 3-(3-Chloropheny I ami no)-6-(4-fluoropheny I)-TP HCI, meltingpoint250°C. 19. 3-(3,4-Dichloropheny I ami no)-6-(4-fLuorophenyL)-TP HCl melting point 289-290°C. 20. 3-(2-FIuorophenyLa mi no)-6-(4-fluorophenyI)-TP HCl, 20 melting point 242°C. 21. 3-(3-FLuoropheny I ami no)-6-(4-fLuoropheny I)-TP HCL, melting point 260-262°C. 22. 3-(4-FIuoropheny I ami no)-6-(4-fluorophenyL)-TP HCl, melting point 282-284°C. 25 23. 3-(4-Methylphenylamino)-6-(4-fluorophenyl)-TP HCl, melting point 263°C. 24. 3-(3-CyanophenyLami no)-6-(4-fLuorophenyL)-TP HCl, melting point 321°C. 25. 3-(3-Trifluoromethylphenylamino)-6-(4-fluorophenyl)- TP HCl, melting point 2 8 6 0 C . 22 26. 3-Phenylamino-6-(3-fluorophenyl)~TP HCl, melting point 266°C (decomposition). 5 27. 3-(4-Chlorophenylamino)-6-(3-fluorophenyl)-TP, melting point 258°C. 28. 3-(3-Fluorophenylamino)-6-(3-\fluorophenyl)-TP, melting point 236°C. 29. 3-(4-Fluorophenylamino)-6-(3-fluorophenyl)-TP, meltingpoint241°C. 10 30. 3-Phenylamino-6-(3-trifluoromethylphenyl)-TP, meltingpoint206°C. 31. 3-(3-Chlorophenylamino)-6-(3-trifluoromethylphenyl)-TP melting point 212°C. 32. 3-(4-Chlorophenylamino)-6-(3-trifluoromethylphenyl)-15 TP, melting point 208°C. 33. 3-(3,4-Dichlorophenylamino)-6-(3-trifluoromethyl-phenyl)-TP, melting point 198°C. 34. 3-(2-Fluorophenylamino)-6-(3-trifluoromethylphenyl)~ TP, melting point 198°C. 20 35. 3-(3-FluorophenyI ami no)-6-(3-trif luoromethyIphenyI)-TP, melting point 209°C. 36. 3-(4-Fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, melting point 234°C. 37. 3-Phenylamino-6-(4-trifluoromethylphenyl)-TP HCl, 25 melting point 271°C . 38. 3-(3-Fluorophenylamino)-6-(4-phenoxyphenyl)-TP, meltingpoint211°C. 39. 3-PhenyI a mino-6-(4-pheny 11hiopheny I)-TP HCl, melting point 247°C. 40. 3-(4-Chlorophenylamino)-6-(4-phenylthiophenyl)-TP HCl, melting point 274°C. 41. 3-(3-FIuorophenyI ami no)-6-(4-pheny IthiophenyI)-TP HCl, melting point 253°C. 5 42. 3-(4-FtuorophenyI amino)-6-(4-pheny IthiophenyI)-TP HCl, melting point 263°C. 43. 3-PhenyI amino-6-(5-chloro-2-thienyI)-TP HCl, melting point 271°C. 44. 3-(4-Ch lorophenylami no)-6-(5-ch loro-2-thienyl)-TP, 10 melting point 246°C. 45. 3-(3-Fluorophenylamino)-6-(5-chloro-2-thienyl)-TP, melting point 287°C. 46. 3-(2-FLuorophenylamino)-6-(5-chloro-2-thienyl)-TP, melting point 232°C. 15 47. 6-C4-(4-F I uorophenoxy)phenylD-3-phenyI ami no-TP, melting point 235°C. 48. 6-C4-(4-Fluorophenoxy)phenyl3-3-(3-fluorophenylamino)-TP, melting point 233°C. 49. 3-(4-Chlorophenylamino)-6-[I4-(4-fLuorophenoxy)phenylIl-20 TP, melting point 267°C. 50. 3-(3-Fluorophenylamino)-6-(2-furyl)-TP, melting point 217 - 218°C. 51. 3-(4-ChI or ophenyI ami no)-6-(2-fury I)-TP, melting point 201 - 202°C. 25 52. 3-Phenylamino-6-(2-thienyl)-TP, melting point 204°C. 53. 3-(3-Fluorophenylamino)-6-(2-thienyl)-TP, melting point 212°C. o/ - 24 - Example 54, process b) 3-Cy c lohexylamino-6-phenyl-l ,2,4-triazoLoC4,3-b3pyrida-zine hydrochloride 3 g of 3-bromo-6-phenyl-1,2,4-triazoloC4/3-b3-5 pyridazine in 10 ml of cyclohexylamine are heated at ref lu x. t empe ratu re for five hourss. After cooling, the product is stirred with diisopropyl ether, and the solid is filtered off with suction and recrystallized from isopropanol. Ethanolic hydrogen chloride gives the 10 hydrochloride, melting point 258°C. The compounds, according to the invention, of Examples 2 to 53 are obtained by an analogous procedure. In this procedure, a 6-ary l-3-bromo-1,2,4-tri-azo loC4,3-b3pyridazine (general formula IV) which has 15 been prepared in analogy with the literature process and which carries the same 6-substituent as the compound of the corresponding example is reacted with the amine (general formula V) which forms the basis of the 3-sub-stituent of the example. 20 Example 55, process c) 3-Benzylamino-6-phenyL-1,2/.4-triazoloC4,3-b!)pyri dazine hydrochloride 5 g of 3-amino-6-pheny 1-1/2,4-triazoLoC4,3-bU-pyridazine and 3 g of benzyl chloride in 25 ml of 25 dimethyLfor ma mide are heated under reflux with 5 g of potassium carbonate for 10 hours. After cooling, water is added, and the product is filtered off with suction, treated with ethanoLic hydrogen chloride and evaporated. The residue is recrystallized from glacial acetic acid, </div>

Claims

<div class="application article clearfix printTableText" id="claims"> washed with diisopropyl ether and dried, melting point 236°C (decomposition). The compounds, according to the invention, of Examples 1 and 3 to 53 are obtained by an analogous pro-5 cedure. In this procedure the 3-amino-6-aryI-1,2,4-t ri azo LoC4,3-bI]pyr i daz ine (general formula VI, described in German OffenLegungsschrift 3,217,325) on which the exampLe concerned is based is reacted with the R^-Y 10 compound (general formula VII) the alkyl or aryl radical of which forms the basis of the 3-substituent of the corresponding example. WHATJlAVt CLAIM IS: - 26 -

1. A compound of the formula I ,1 t>2 (I) and salts thereof with a physiologically acceptable acid, in which formula R ^ and R ^ are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine, R^ represents hydrogen, linear or branched alkyl having 1-6 carbon atoms or phenyl which is optionally monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, and 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, alkyl-carbonyl 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 207691 an f"- - 27 - from r GUI .1 (aromatic radica 1/selected j pheny t, biphenyl, phenoxy-phenyl, phenyIthiophenyI, pheny I suIfinyIphenyI, phenyl-sulf ony Ipheny I, "1-napht hyl,' 2-napht hy I; 2-thienyl, 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyL or 2-, 3- or 4-pyridyl, each of which can optionally be substituted by one, two, three, four or five r a d i c a I s selected from 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 having in each case 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluoromethyl or car-boxy I groups, esters of the latter with -C^-a I coho Is, aminocarbony I, amino, acetamino or a Ikoxycarbony lamino having 1-6 carbon atoms in the alkyl radical, and in /r3 which -N can also represent a radical of the V genera I formu la II /CIV)mA —N X (II) 2 n. in which X denotes CH2, CHR^, C=0, 0, S or NR^ in which R*5 denotes hydrogen, alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, alkylcarbonyl having 1-6 carbon atoms in the alkyl radical, alkoxycarbonyl having 1-4 carbon atoms in the alkoxy radical, optionally substituted phenylalkyl having 1-4 carbon atoms in the 7 UN E N alkyl radical, optionally substituted phenyl or o/j^fon- o 2.07 6?/ - 28 - ally substituted benzoyl, it being possible for each of the phenyl rings to be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-6 carbon atoms, and m and n denote 1, 2 or 3 , with the exception of the compounds of the formula I in which R^, R^ and denote hydrogen, R4 denotes phenyl and Ar denotes phenyl,' 4-methylphenyl or 4-bromophenyl.

2. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises a) cyclizing a compound of the formula III K? *2 3 /V_ " /R ar—^ //—ww c . n-n r4 (III) in which Ar, R^, R^, R^.and R4 have the meanings • |~ in claim 1 indicated for formula I and Z represents 0 or S, by heating, if appropriate with the addition of a condensation agent, to give a compound of the formula I or b) reacting a compound of the formula IV (IV) in which R^ denotes chlorine, bromine or methylthioand Ar, R** and R^ have the meanings indicated for formula r in claim 1 r„ with an amine of the formula V r J/* o\ 7 A/ -t\\ (Z - 5 MAY 1986S \..C 20763* - 29 - / H-N <V) \ n R in which and R4 - if appropriate together with the nitrogen atom - have the meanings indicated for formula r- in claim 1 i or c) reacting, if appropriate with the addition of a condensation agent or catalyst, a compound of the formula VI R1 R2 / Ar—\ ' )=^N N_N I <VI> -N mz or one of its salts in which Ar, and R2 have the Pin claim 1 with a compound of the formula VII R^-Y (VII) in which R4 has the meaning indicated for formula I and Y represents a leaving group, selected from 0 11 3 fluorine, chlorine, bromine, iodine, -O-C-R or the 3 .... tosylate radical^ in which R has the meaning given in claim 1, 3* A pharmaceutical composition having an anxiolytic and anticonvulsive action, which contains as the active ingredient a compound of the formula I as claimed in claim 1. - 30 - 207651 4_. A compound according to claim I substantially as herein described or exemplified. A process according to claim 7 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED </div>