CA1246568A - Substituted 6-aryl-1,2,4-triazolo[4,3- b]pyridazines - their preparation and their use - Google Patents
Substituted 6-aryl-1,2,4-triazolo[4,3- b]pyridazines - their preparation and their useInfo
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- CA1246568A CA1246568A CA000451005A CA451005A CA1246568A CA 1246568 A CA1246568 A CA 1246568A CA 000451005 A CA000451005 A CA 000451005A CA 451005 A CA451005 A CA 451005A CA 1246568 A CA1246568 A CA 1246568A
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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
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- 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
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- 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
Abstract of the disclosure New compounds of the general formula I
(I) and salts thereof with a physiologically acceptable acid and a process for their preparation are described.
The new compounds have an anxiolytic and anti-convulsive action.
(I) and salts thereof with a physiologically acceptable acid and a process for their preparation are described.
The new compounds have an anxiolytic and anti-convulsive action.
Description
- 2 ~ 656~
The ;nvent;on relates to new substituted 6-aryl-1~2,4-triazoloC4,3-b3pyridazines of the general formula I
~,~ R2 Ar ~- N `
N _ N
N
:R4 R3 ..
and salts thereof w;th a phys;olog;cally acceptable acid~
in which formula R1 and R2 are ;dent;cal or different and represent hydrogen, alkyl ~roups hav;ng 1~6 carbon atoms, phenyl or chlorine, R3 represents hydroyen, linear or branched alkyl hav;ng 1-6 carbon atoms or phenyl wh;ch is opt;onally monosubst;tuted, disubst;tuted 10 o.r trisubstituted.by fluor;ne, chlor;ne, brom;ne,- ;od;ne, q : trifluoromethy! or alkyl having 1 4 carbon atoms, and R4 denotes l;near or branched alkyl having 1-6 carbon atoms, cycloalkyl hav;ng 3-8 carbon atorns, phenylalkyl which has 1-4 carbon atoms in the alkyl part and is optionally onosubstituted, disubstituted or trisubst;tuted ;n the phenyl part by fluor;ne, chlorine, brom;ne, 10dine, tri-fluoromethyl or alkyl having 1-4 carbon atoms, alkyl-carbonyl hav;ng 1-6 carbon atoms in the alkyl part, cycloalkyLcarbonyl havin~ 5~7 carbon atoms ;n the cyclo-- 20 alkyl par~ or ben7.0yl wh;ch is opt;onally monosubst;tuted, ~ 3 disubst;tu~ed or ~risubst;tuted by-fluor;ne, chlor;ne~
brom;ne, ;od;ne, tr;fluoromethyl or alkyl having 1~4 car-bon atoms, or denotes ~r, and in wh;ch Ar represents aromatic radicals, such as phenyl, biphenyl, phenoxy-phenyl, phenylth;ophenyl, phenylsulfinylphenyl~ phenyl-sulfonylphenyl, 1-naphthyl, 2-naphthyl, 2 thienyl, 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl or 2-,
The ;nvent;on relates to new substituted 6-aryl-1~2,4-triazoloC4,3-b3pyridazines of the general formula I
~,~ R2 Ar ~- N `
N _ N
N
:R4 R3 ..
and salts thereof w;th a phys;olog;cally acceptable acid~
in which formula R1 and R2 are ;dent;cal or different and represent hydrogen, alkyl ~roups hav;ng 1~6 carbon atoms, phenyl or chlorine, R3 represents hydroyen, linear or branched alkyl hav;ng 1-6 carbon atoms or phenyl wh;ch is opt;onally monosubst;tuted, disubst;tuted 10 o.r trisubstituted.by fluor;ne, chlor;ne, brom;ne,- ;od;ne, q : trifluoromethy! or alkyl having 1 4 carbon atoms, and R4 denotes l;near or branched alkyl having 1-6 carbon atoms, cycloalkyl hav;ng 3-8 carbon atorns, phenylalkyl which has 1-4 carbon atoms in the alkyl part and is optionally onosubstituted, disubstituted or trisubst;tuted ;n the phenyl part by fluor;ne, chlorine, brom;ne, 10dine, tri-fluoromethyl or alkyl having 1-4 carbon atoms, alkyl-carbonyl hav;ng 1-6 carbon atoms in the alkyl part, cycloalkyLcarbonyl havin~ 5~7 carbon atoms ;n the cyclo-- 20 alkyl par~ or ben7.0yl wh;ch is opt;onally monosubst;tuted, ~ 3 disubst;tu~ed or ~risubst;tuted by-fluor;ne, chlor;ne~
brom;ne, ;od;ne, tr;fluoromethyl or alkyl having 1~4 car-bon atoms, or denotes ~r, and in wh;ch Ar represents aromatic radicals, such as phenyl, biphenyl, phenoxy-phenyl, phenylth;ophenyl, phenylsulfinylphenyl~ phenyl-sulfonylphenyl, 1-naphthyl, 2-naphthyl, 2 thienyl, 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl or 2-,
3- or 4Npyr;dyl, each of which can optiona;ly be substi-tuted by one, two, three, four or five radicals such as fluor;ne, chlorine, bromine, iodine, alkyl groups having ~-6 carbon ato~s, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having ~-4 alkyl carbon atoms, alkoxy or alkylthio groups having ;n each case 1-6 carbon atoms, hydroxyl, nitro, cyano~ trifluoromethyl or car-boxyl groups, esters of the la~ter with C1-C6-alcohols, aminocarbonyl, amino, acetamino or alkoxycarbonylam;no hav;ng 1-6 carbon atoms ;n the alkyl radical, and in ~h;ch ~ N / can also represent a radical of the ~eneral formula II
~( C~12 )hi~
--N X tII) ~c~2~n J
in wh;ch X denctes CH2, CHR5, C=O, O, S or NR5 in ~h;ch R5 denotes hydrogen~ alkyl hav ng 1 6 carbon atoms, cycloalkyl having 3-8 carbon atoms, alkylcarbonyl hav;ng 1-6 carbon atoms in the alkyl radical, alkoxyc3rbonyl 2~68
~( C~12 )hi~
--N X tII) ~c~2~n J
in wh;ch X denctes CH2, CHR5, C=O, O, S or NR5 in ~h;ch R5 denotes hydrogen~ alkyl hav ng 1 6 carbon atoms, cycloalkyl having 3-8 carbon atoms, alkylcarbonyl hav;ng 1-6 carbon atoms in the alkyl radical, alkoxyc3rbonyl 2~68
- 4 -hav;ng 1-4 carbon atoms in the aLko~y radical, op~ionally subst;tuted phenylalkyl having 1-4 carbon atoms ;n the alkyl radical, opt;onally subst;tuted phenyl or option~
aLly substituted benzoyl, it being possible for each of the phenyl rings to be monosubstituted, disubstituted or trisubst;tuted by fluorine, chlorine, brom;ne, iod;ne, tr;fluoromethyl or alkyl having 1-6 carbon atoms, and m and n denote 1, 2 or 3.
Amongst the compounds o-f the general formula I, preference attaches to those in which R1 and R2 are identical or different and denote hydrogen, methyl, ethyl, phenyl or chlorine, R3 denotes hydrogen or alkyl hav;ng 1-6 carbon atoms, R4 denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, or phenylalkyl which has 1-4 carbon atoms ;n the alkyl part and ;s opt;onally monosubst;tuted or d;subst;tuted ;n the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, or denotes Ar, and Ar denotes phenyl~ b;-phenyl, phenoxyphenyl, phenylthiophenylr 2-thienyl, 3-th;enyl~ 2-furyl or 2~, 3- or 4-pyridyl, each o-f which can optionally be monosubstituted, d;subst;tuted or tri-substituted by fluor;ne, chlorine, brom;ne, trifluoro-methyl, alkyl groups having 1-6 carbon atoms or cyclo-alkyl groups hav;ng 3~6 carbon atoms, or those in which -N/ has the meanings ;ndicated for formula II.
R Compounds of the formula I wh;ch are particularly preferred are those ;n which R1 and ~2 are idemtical or , i8 different ano denote hydrogen, methyl or ethyl, R3 denotes hydrogen or alkyl having 1-o carbon atoms, R4 denotes linear or branched alkyl having 1-~ carbon atoms, cyclo-alkyl having 5 or 6 carbon atoms, oenzyl or phenylethyl which is optionally monosubstitut~ed or disubstituted in the phenyl ring by fluorine, chlorine, trifluoromethyl, methyl or ethyl~ or denotes Ar, and Ar denotes phenyl~
phenoxyphenyl, phenylth;ophenyl, 2 thienyl, 3-thienyl, 2-furyl or 3-pyridyl~ each of wh;ch ;s optionally mono~
subst;tuted or disubst;tuted by fluorine, chlor;ne~ tr;-- fluoromethyl, methyl or ethyl.
Compounds of the formula I ;n which R1, R2 and R3 denote hydrogen, R4 denotes phenyl and Ar denotes phenyl, 4-methylphenyl or 4-bromophenyl are, however, not 1S cla;med. These compounds have been descr;bed ;n Rev~
Roum. Ch;m. 10, 641 (1965) and Rev. Med. Ch;r. 81, 469 ~1977), and are stated to have an antihypertensive act;on ;n some cases~ As opposed to this, the compounds, accord-ing to the invention, of the formula I have an anxiolytic and ant;convulsive action.
The invent;on also relates to a process for the preparat;on of these compounds and pharmaceutical formu-lations of these compounds and to their use as drugs.
The process for the preparation of the compounds of the formula I compr;ses a) cycl;z;ng a compound of the formula III
,5~3 ~,1 R2 \ ~ Z R
i~==C 11 / ~III) Ar ~ ~ NH-N~I-c_N\ 4 N-N
;n ~h;ch Ar, R1, R2, R3 and R~ have the meanings indicated for formula I and Z represents 0 or S, by heat;ng, ;f appropriate with the addition of a condensa-
aLly substituted benzoyl, it being possible for each of the phenyl rings to be monosubstituted, disubstituted or trisubst;tuted by fluorine, chlorine, brom;ne, iod;ne, tr;fluoromethyl or alkyl having 1-6 carbon atoms, and m and n denote 1, 2 or 3.
Amongst the compounds o-f the general formula I, preference attaches to those in which R1 and R2 are identical or different and denote hydrogen, methyl, ethyl, phenyl or chlorine, R3 denotes hydrogen or alkyl hav;ng 1-6 carbon atoms, R4 denotes linear or branched alkyl having 1-6 carbon atoms, cycloalkyl having 3-8 carbon atoms, or phenylalkyl which has 1-4 carbon atoms ;n the alkyl part and ;s opt;onally monosubst;tuted or d;subst;tuted ;n the phenyl part by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1-4 carbon atoms, or denotes Ar, and Ar denotes phenyl~ b;-phenyl, phenoxyphenyl, phenylthiophenylr 2-thienyl, 3-th;enyl~ 2-furyl or 2~, 3- or 4-pyridyl, each o-f which can optionally be monosubstituted, d;subst;tuted or tri-substituted by fluor;ne, chlorine, brom;ne, trifluoro-methyl, alkyl groups having 1-6 carbon atoms or cyclo-alkyl groups hav;ng 3~6 carbon atoms, or those in which -N/ has the meanings ;ndicated for formula II.
R Compounds of the formula I wh;ch are particularly preferred are those ;n which R1 and ~2 are idemtical or , i8 different ano denote hydrogen, methyl or ethyl, R3 denotes hydrogen or alkyl having 1-o carbon atoms, R4 denotes linear or branched alkyl having 1-~ carbon atoms, cyclo-alkyl having 5 or 6 carbon atoms, oenzyl or phenylethyl which is optionally monosubstitut~ed or disubstituted in the phenyl ring by fluorine, chlorine, trifluoromethyl, methyl or ethyl~ or denotes Ar, and Ar denotes phenyl~
phenoxyphenyl, phenylth;ophenyl, 2 thienyl, 3-thienyl, 2-furyl or 3-pyridyl~ each of wh;ch ;s optionally mono~
subst;tuted or disubst;tuted by fluorine, chlor;ne~ tr;-- fluoromethyl, methyl or ethyl.
Compounds of the formula I ;n which R1, R2 and R3 denote hydrogen, R4 denotes phenyl and Ar denotes phenyl, 4-methylphenyl or 4-bromophenyl are, however, not 1S cla;med. These compounds have been descr;bed ;n Rev~
Roum. Ch;m. 10, 641 (1965) and Rev. Med. Ch;r. 81, 469 ~1977), and are stated to have an antihypertensive act;on ;n some cases~ As opposed to this, the compounds, accord-ing to the invention, of the formula I have an anxiolytic and ant;convulsive action.
The invent;on also relates to a process for the preparat;on of these compounds and pharmaceutical formu-lations of these compounds and to their use as drugs.
The process for the preparation of the compounds of the formula I compr;ses a) cycl;z;ng a compound of the formula III
,5~3 ~,1 R2 \ ~ Z R
i~==C 11 / ~III) Ar ~ ~ NH-N~I-c_N\ 4 N-N
;n ~h;ch Ar, R1, R2, R3 and R~ have the meanings indicated for formula I and Z represents 0 or S, by heat;ng, ;f appropriate with the addition of a condensa-
5 tion agent, to g;ve a compound of the formula I orb) react;ng a compound of the formula IV
Ar~ ~=N
I V ) ~i R
in which R~ denotes chlor;ne, bromine or Methylthio and Ar, R1 and R2 have the mean;ngs indicated for form~lla ; 10 I, w;th an am;ne of the formula V
~R3 H-N 4 ~V3 R
in which R3 and R4 - if aporopriate together w;th the nitrogen atom - have the mean;ngs indicated for formula I, or c~ react;ng, if appropriate w;th the addition of a con-densation agent or catalyst, a compound of the formula VI
56~3 Rl R2 ~r \~1 r ( v I, --N
~T
~H2 - or one of ;ts saLts in which Ar, R1 and R2 have the mean;ngs indicated for formula I, with a com~ound of the formula VII
R4-Y (VII) in ~h;ch R4 has the meaning indicated for formula I and Y represents a leav;ng group, such as, for example, O
fluorine, chlorine, bromine, iodine, -û~C-R3 or the tosylate radical.
In process a), the starting materials of the formula III are obtained, for example, by reacting aryl-hydraz;nopyridaz;nes o~ the formula VIII
~1 ~2 VIII) Ar~ T~N~ 2 in wh;ch R1~ R2 and Ar have the meanings ind1cated for 15 formula I, w;th isocyanates or isothiocyanates of the formula IX
R4-N=C-Z (IX) ;n which R4 and Z have the mean;ngs ;ndicated for formula I and III, respectivelyr by heating at 40~15CC~ advan-ta~qeously in a solvent, such as, for exdmple~ methanol, ., .
ethanol, ;sopropanol, diisopropyl ether, dioxane, tetra-hydrofuran, toluene, methylene chloride, chloroform or dichloroethane.
The compounds of the formuLa III are converted ;nto compounds of the formula I by heating at 40-150C, for example in one of the solvents mentioned and, if appropriate~ with the add;tion of a c-ondensat;on a~ent, such as, for example, glacial acet;c acid, cyclohexyl-carbodi;mide, 1-hydroxybenztriazole, phosphorus oxy-chloride, phosphorus oxychLoride/N,N-dimethylaniline, phosphorus oxybrom;de, phosphorus pentachloride~ th;onyl chlor;de, mercury oxide or lead ox;de. The compounds of the general formula III can also be obtained by react;n~
chloropyridaz;nes of the formula X
Rl R2 Ar~l ~X) N--M
in wh;ch Ar, R1 and R2 have the meanings indicated ~or formula I, ~I;th substituted sem;carbaz;des or thiosemi~
carbaz;des of the formula XI
H2N-NH-c-N~ 4 (XI) 2n ;n wh;ch R3, R4 and Z have the meanings indicated for formula I, by heating at 4û 150~C, for example in one of the solvents ment;oned or ;n DMF, GMS0 or acetonitri-e.
For process b), the starting mater;als of the formula IV
are reacted" by heat;ng arylhydrazinopyridazines VIII
w;th for~;c acid or esters thereof tfor R6 = H)~ phosgene, chloroformic acld esters, a d;alkyl pyrocarbonate or a d;alkyl carbonate (for R6 = OH) or carbon disuLfide and an alkal; (for R6 - SH), ;f appropr;ate with the addi-t;on of a solvent or diluent~ such as chloroform, toluene~d;oxane, ethyl acetate, water or ethanol, to give a com-pound of the formula IV' in ~h;ch R6 denotes H, 0~ or SH~ The corresponding compounds IV ;n wh;ch R6 = Br, Gl or SCH3 are obtained there~rom by heatin~ w;th brom~
1D ;ne ;n glacial acetic acid/sodium acetate tin the case of R~ = H), phosphorus oxychloride t;n the case of Rb - OH) or methyl ;odide or dimethyl sulfate tin the case of R = SH).
The reaction of the compounds of the formula IV
w;th amines of the formula V is effected ;n accordance w;th process b) w;thout a solvent or in an inert solvent, such as methanol, isopropanol, 2-methoxyethanol, tetra h~drofuran~ dioxane, toluene, chloroform, DMF, DMSO, aceton;trile, acetone or ethyl acetate, at temperatures of 20-200C, preferably 50-150C~ under normal pressure or under pressure in an autoclave. The reaction wit gaseous am;nes can be carried out under normal pressure by p3s(sing the latter ;nto the mixture or can likewise be carr;ed out under pressure. If appropriate, a cata-lyst, such as copper(I) chloride or other coppertI) salts,can be added in order to accelerate the reaction~
In process c), the reaction of the compour)ds of the formula VI~ which are obtained, for exa~ple, by cyclizin~ arylhydrazinopyr;dazines of the formula V
.
.
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 d;luent, such as, for example, acetone, methyl ethyl ketone, ethyl acetate, toluene, xylene~ dioxane9 tetrahydrofuran, D~F, DMS0, aceton;trile, methylene chloride~ chloroforM or dichloro-ethane.
If appropr;ate, it ;s poss;ble to add ;nor~anic or organ;c bases, such as, for exaMple, sod;u~ hydroxide, tr;ethylam;ne or pyrid;ne, ;n order to b;nd any ac;ds formed ;n the react;on, or, espec;ally ;n the case of the reaction w;th acid anhydrides, to add catalytic alnounts of a strong acid, such as, for example, hydro-chloric ac;d, sulfur;c ac;d or tr;fluoroacet;c ac;d Arylhydraz;nopyr;daz;nes of the formula VIII are known, for example from J. Heterocycl;c Chem. 15, 881 (1978~, or can be prepared from chlorine compounds of the formula X us;ny hydraz;ne hydrate ;n accordance with pro-cesses known from the literature ~The Chem;stry of Heterocyclic Compounds, Volume 28 Pyr;daz;nes, Editors A. ~1e;ssberger and E.C. Taylor, John W;ley, New York 1973). The two literature references also describe the synthesis of the chlorine compounds X and their precur-sors.
If the compounds of the formula I are obtained in accordance ~;th the processes descr;bed in the form of salts, the appropriate base can be set free from the latter by means of ammon;a, amines or hydroxidej~ The free bases of the formula I can he converted ;nto the , ~2~i5~
correspond;ng sal1:s by means oF physiolog;caLly accep~
able acids. Suitable ac;ds are inorganic or orsanic acids, such as hydrochloric or hydrobromic acid, phos-phor;c ac;d, acet;c acid, benzoic ac;d, c;tr;c acid, male;c acid~ fumar;c acid, lact;c ac;d, tartaric acid, succin;c acid or acetylglycine.
The compounds, according to the ;nvention, of the formula I are su;table for the preparation of drugsn The drugs can conta;n one or more of the compounds according to the invention or mixtures thereof with o.her pharmaceutically active substances. The customary pharmaceutical excipients and auxiliaries and kno~n pharmaceutical processes can be used to prepal~ the drugs. The dru~s can be adm;nistered enterally, paren~
terally, orally or perl;ngually. For example, adnlirlis--tration can be ef~ected in the form of tablets, capsules, ; pills, coated tablets, suppos;tories, jellies, creams~
~wders, liquids, dustiny powders or aerosols. The followin~ are examples of suitable liquids: o;ly or aqueous solutions or suspens;ons~ emulsions and inject-able solutions or suspens;ons.
The compounds accord;ng to the ;nvention can also be used as intermediates for the preparation o~ other drugs.
The following compounds according to the ;nven-tion may be mentioned: (the abbreviation "TP" is used in the follo~ing text for the root name "102,4-triazolo-[4,3 b~pyr;dazine'~.) h~(3-Fluorophenyl)~3-phenylam;no-Tpr 6~t4 Fluoro phenyl)-3-ph~nyl~mino-TP, 6-~3-trifluoromethylphenyl~ 3 phenylaM;no-TP, ~-(3,4-difluorophenyl)-3 phenylamino~lP,
Ar~ ~=N
I V ) ~i R
in which R~ denotes chlor;ne, bromine or Methylthio and Ar, R1 and R2 have the mean;ngs indicated for form~lla ; 10 I, w;th an am;ne of the formula V
~R3 H-N 4 ~V3 R
in which R3 and R4 - if aporopriate together w;th the nitrogen atom - have the mean;ngs indicated for formula I, or c~ react;ng, if appropriate w;th the addition of a con-densation agent or catalyst, a compound of the formula VI
56~3 Rl R2 ~r \~1 r ( v I, --N
~T
~H2 - or one of ;ts saLts in which Ar, R1 and R2 have the mean;ngs indicated for formula I, with a com~ound of the formula VII
R4-Y (VII) in ~h;ch R4 has the meaning indicated for formula I and Y represents a leav;ng group, such as, for example, O
fluorine, chlorine, bromine, iodine, -û~C-R3 or the tosylate radical.
In process a), the starting materials of the formula III are obtained, for example, by reacting aryl-hydraz;nopyridaz;nes o~ the formula VIII
~1 ~2 VIII) Ar~ T~N~ 2 in wh;ch R1~ R2 and Ar have the meanings ind1cated for 15 formula I, w;th isocyanates or isothiocyanates of the formula IX
R4-N=C-Z (IX) ;n which R4 and Z have the mean;ngs ;ndicated for formula I and III, respectivelyr by heating at 40~15CC~ advan-ta~qeously in a solvent, such as, for exdmple~ methanol, ., .
ethanol, ;sopropanol, diisopropyl ether, dioxane, tetra-hydrofuran, toluene, methylene chloride, chloroform or dichloroethane.
The compounds of the formuLa III are converted ;nto compounds of the formula I by heating at 40-150C, for example in one of the solvents mentioned and, if appropriate~ with the add;tion of a c-ondensat;on a~ent, such as, for example, glacial acet;c acid, cyclohexyl-carbodi;mide, 1-hydroxybenztriazole, phosphorus oxy-chloride, phosphorus oxychLoride/N,N-dimethylaniline, phosphorus oxybrom;de, phosphorus pentachloride~ th;onyl chlor;de, mercury oxide or lead ox;de. The compounds of the general formula III can also be obtained by react;n~
chloropyridaz;nes of the formula X
Rl R2 Ar~l ~X) N--M
in wh;ch Ar, R1 and R2 have the meanings indicated ~or formula I, ~I;th substituted sem;carbaz;des or thiosemi~
carbaz;des of the formula XI
H2N-NH-c-N~ 4 (XI) 2n ;n wh;ch R3, R4 and Z have the meanings indicated for formula I, by heating at 4û 150~C, for example in one of the solvents ment;oned or ;n DMF, GMS0 or acetonitri-e.
For process b), the starting mater;als of the formula IV
are reacted" by heat;ng arylhydrazinopyridazines VIII
w;th for~;c acid or esters thereof tfor R6 = H)~ phosgene, chloroformic acld esters, a d;alkyl pyrocarbonate or a d;alkyl carbonate (for R6 = OH) or carbon disuLfide and an alkal; (for R6 - SH), ;f appropr;ate with the addi-t;on of a solvent or diluent~ such as chloroform, toluene~d;oxane, ethyl acetate, water or ethanol, to give a com-pound of the formula IV' in ~h;ch R6 denotes H, 0~ or SH~ The corresponding compounds IV ;n wh;ch R6 = Br, Gl or SCH3 are obtained there~rom by heatin~ w;th brom~
1D ;ne ;n glacial acetic acid/sodium acetate tin the case of R~ = H), phosphorus oxychloride t;n the case of Rb - OH) or methyl ;odide or dimethyl sulfate tin the case of R = SH).
The reaction of the compounds of the formula IV
w;th amines of the formula V is effected ;n accordance w;th process b) w;thout a solvent or in an inert solvent, such as methanol, isopropanol, 2-methoxyethanol, tetra h~drofuran~ dioxane, toluene, chloroform, DMF, DMSO, aceton;trile, acetone or ethyl acetate, at temperatures of 20-200C, preferably 50-150C~ under normal pressure or under pressure in an autoclave. The reaction wit gaseous am;nes can be carried out under normal pressure by p3s(sing the latter ;nto the mixture or can likewise be carr;ed out under pressure. If appropriate, a cata-lyst, such as copper(I) chloride or other coppertI) salts,can be added in order to accelerate the reaction~
In process c), the reaction of the compour)ds of the formula VI~ which are obtained, for exa~ple, by cyclizin~ arylhydrazinopyr;dazines of the formula V
.
.
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 d;luent, such as, for example, acetone, methyl ethyl ketone, ethyl acetate, toluene, xylene~ dioxane9 tetrahydrofuran, D~F, DMS0, aceton;trile, methylene chloride~ chloroforM or dichloro-ethane.
If appropr;ate, it ;s poss;ble to add ;nor~anic or organ;c bases, such as, for exaMple, sod;u~ hydroxide, tr;ethylam;ne or pyrid;ne, ;n order to b;nd any ac;ds formed ;n the react;on, or, espec;ally ;n the case of the reaction w;th acid anhydrides, to add catalytic alnounts of a strong acid, such as, for example, hydro-chloric ac;d, sulfur;c ac;d or tr;fluoroacet;c ac;d Arylhydraz;nopyr;daz;nes of the formula VIII are known, for example from J. Heterocycl;c Chem. 15, 881 (1978~, or can be prepared from chlorine compounds of the formula X us;ny hydraz;ne hydrate ;n accordance with pro-cesses known from the literature ~The Chem;stry of Heterocyclic Compounds, Volume 28 Pyr;daz;nes, Editors A. ~1e;ssberger and E.C. Taylor, John W;ley, New York 1973). The two literature references also describe the synthesis of the chlorine compounds X and their precur-sors.
If the compounds of the formula I are obtained in accordance ~;th the processes descr;bed in the form of salts, the appropriate base can be set free from the latter by means of ammon;a, amines or hydroxidej~ The free bases of the formula I can he converted ;nto the , ~2~i5~
correspond;ng sal1:s by means oF physiolog;caLly accep~
able acids. Suitable ac;ds are inorganic or orsanic acids, such as hydrochloric or hydrobromic acid, phos-phor;c ac;d, acet;c acid, benzoic ac;d, c;tr;c acid, male;c acid~ fumar;c acid, lact;c ac;d, tartaric acid, succin;c acid or acetylglycine.
The compounds, according to the ;nvention, of the formula I are su;table for the preparation of drugsn The drugs can conta;n one or more of the compounds according to the invention or mixtures thereof with o.her pharmaceutically active substances. The customary pharmaceutical excipients and auxiliaries and kno~n pharmaceutical processes can be used to prepal~ the drugs. The dru~s can be adm;nistered enterally, paren~
terally, orally or perl;ngually. For example, adnlirlis--tration can be ef~ected in the form of tablets, capsules, ; pills, coated tablets, suppos;tories, jellies, creams~
~wders, liquids, dustiny powders or aerosols. The followin~ are examples of suitable liquids: o;ly or aqueous solutions or suspens;ons~ emulsions and inject-able solutions or suspens;ons.
The compounds accord;ng to the ;nvention can also be used as intermediates for the preparation o~ other drugs.
The following compounds according to the ;nven-tion may be mentioned: (the abbreviation "TP" is used in the follo~ing text for the root name "102,4-triazolo-[4,3 b~pyr;dazine'~.) h~(3-Fluorophenyl)~3-phenylam;no-Tpr 6~t4 Fluoro phenyl)-3-ph~nyl~mino-TP, 6-~3-trifluoromethylphenyl~ 3 phenylaM;no-TP, ~-(3,4-difluorophenyl)-3 phenylamino~lP,
6-(4~phenoxyphenyl)~3-phenylam;no-TP, 6-(4 phenylth;o-phenyl~-3-phenylamino-TP, 6-t4-(4-fluorophenoxy)phenyl)-3-phenylamino-TP, 6-t3-chlorophenyl)-3-phenylamino-TP, 6 (3-bromophenyl)-3-phenylamino-TP, 6-(5-chloro-2-thienyl)-3-phenylamino-TP, 6-~3-fluorophenyl)-3-(substituted-phenylamino)-TP, 6-(4-fluorophenyl)-3-(substituted-phenylamino) TP, 6-(3-trifluoromethylphenyl)-3-(subs~i-1~ tuted-phenylamino)-TP, 6-(3,4-d;fluorophenyl~-3~(sub-stituted-phenylamino)-TP, 6-t4-phenoxyphenyl)~3-(sub-stituted-phenylamino)~TP, 6-tlt-phenylthiophenyl)-3-~sub-stituted-phenylamino)-TP, 6-(L-(4-fluorophenoxy~phenyl~-3-~subslitut~d-phenylamino)-TP,. 6-(3-chlorophenyl)-3-~S (subst;tuted-phenylam;no) TP, 6-(3-~romophenyl)-3-(sub~
stituted-phenylamino)-TP and 6-(S-chloro-2-th;enyl~-3-(subst,tuted-phenylamino)-TP, ;n ~Ihich "substituted-phenyl" represents, in particular, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, ; 20 3- or 4-bromophenyl~ 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenylr 2r4-dichloro phenyl, 2,4-difluorophenyl~ 2,5-diclllorophenyl, 2,5-di-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 2,6~dichlorophenyl or 2,6-difluorophenyl.
6-(3-Fluorophenyl)-3-~N~methyl-N-phenylam;r,o)-TP, 6-t4-fluorophenyl)-3-(~-methyl~N-phenylamino)~TP, 6 (3-trifluoromethylphenyl)-3-(N-methyl~N~phenylamino)-TP, 6-.
~3,4~dlfluorophenyl~-3-(N-me';hyl-N phenylamino)~TP, 6~(4-phenoxyphenyl)-3-(N-methyl-N-phenylan1;no)-TP, 6~4-.. . .
5~
~ S3 -phenyLthiophenyl)-3-(r~-methyl-N~phenylamino) TP, 6-~4-(4-fluorophenoxy)phenyl~-3~(N-methyl-N-phenylarDino~TP, 6 t3-clllorophenyl)-3-(N-methyl-N-phenylam;no)-TP, o-(3~
bromophenyl)~3-(N-methyl-N-?henylamino)-TP, 6-~5-chloro-2-th;enyl) 3-(N-methyl-N-phenylarnino)-TP~ 6-~3-fluoro-- phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(4-fluorophenyl)-3-(N-methyl-N-substituted-phenylamino~TPf 6-(3-tr;f(uoromethylphenyl)-3-tN-methyl-N-substituted-phenylamino)-TP~ 6-(3,4 difluorophenyl)~3-(N ~ethyl-N-subs.;tuted-phenylamino)-TP~ 6-(4-phenoxyphenyl)-3-(N-methyl-N-subs~;tuted phenylam;no)-TP, 6-(4-phenylthio-phenyl)-3-(PJ-methyl N-substituted-pllenylamino)-TP, 6-~~4-fluorophenoxy)-phenyl)~3 tN-methyl-N-substituted-phenylam;no)-1P, 6-t3~chlorophenyl)-3-(N-methyl-N-sub~
stituted~phenylamino)-TP, 6-(3-bronlophenyl)-3 (N methyl-N-substituted-phenylam;no)-TP and 6 (5-chloro 2~thienyl)-3-(N-me~hyl-N subst;tuted-phenylam;no)-TP, ;n which "subst;tuted-phenyl" represents, in particular, 2-, 3 or 4-fluorophenyl, 2~, 3~ or ~ chloropheryl, 2-, 3- or 4-brornophenyl, 2-, 3- or 4-tr;fluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyL, 2~4-dichloro-phenyl, 2,4~difluorophenyl, 2,5 dichlorophenyl~ ~,5-di-fluorophenyl, 3,5-dichlorophenyl, 305-difluorophenyl, ~,6-dichloropllenyl or 2r6 d;fluorophenyl.
6-(3-Fluoropheny!~-3 acetamino-TP, o-~4 fluoro-phenyl)-3-acetamino-TP, 6-(3-tr;fluoromethylphenyl)-3-acetam;no~TPf 6-(3,4~d;fluorophenyL)-3-acetam;no TP, 6-~4~phenoYypheny'~-3~acetamino TP, 6-(4-phenylthiophenyl)-3-acetam;no-TP, 6-(4-(4-fluoropherloYm~pherlyl)-3-acet-5~3 - 14 ~
am;no-TP, 6~3 chloropherlyl)~3-acetamiro-TP, 6-(3-bromo-phenyl)-3-acetam;no-TP, 6 (S-chloro-2 thienyl)-3-acet-amino-TP, 6-(3-fluorophenyl)-3 benzoylamino-TP~ 6-(4-fluorophenyl)-3-benzoyiamino-TP, 6-(3-trifluoromethyl-phPnyl)-3 benzoylarnino-TP, 6-53,4-d;fluorophenyl)-3~
benzoylamino-TP, 6 (4-phenoxyphenyl) 3-benzoylamino-TP, 6-(4-phenylthiopnenyl)-3-benzoylarnino-TP~ 6-(4-(4-fluoro-phenoxy)phenyl)-3-benzoylamino-TP, 6-(3-chlorophenyl~-3 benzoylamino-TP, 6-(3-bromophenyl)-3-benzoylamino-TP~ 6 (5~chloro~2-thienyl)-3-benzoylamino-TP, 6-(3-fluoro-phenyl)~3~(substituted-benzoylamino)-TP, ~-~4-fluoro-phenyl)~3-(substitu~ed-benzoylamino)-TP, 6-(3-trifluoro-methylphenyl)-3-(substituted-benzoylamino)-TP, 6-~3,4-d;fluorophenyl)-3~(substituted-benzoylamino)-TP, 6-(4-phenoxyphenyl)-3-~substituted-benzoylamino~-TP, 6-(4-phenylthiophenyl)-3-(substituted-benzoylamino)-TP, ~-t4-(4-fluorophenoxy)phenyl~-3-~subs.ituted-ben20ylamino)-TP, ~-(3~chlorophenyl)-3-(substituted-bonzoylamino)-TP, 6-(3-brornophenyl)-3-(substituted~benzoylamino~-TP and 6-(5 chloro-2 thienyl)-3-(substituted-benzoylamino) TP, in which fsubst;tuted benzoyl represents, in particular, 2-, 3- or 4-fluorobenzoyl, 2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-bromobenzoyl, 2-, 3- or 4-tr;fluoromethylbenzoyl~
3,4-dichlorobenzoyl, 3~4-difluorobenzoyl, 2,5 dichloro-benzoyl, 2,5-difluorobenzoyl, 3,5-dichlorobenzoyl, 3,5-difluorobenzoyl, 2,6-dichlorobenzoyl or 2~6-d;fluoro-benzoyl.
6-~3 F'uorophenyl~3-~substituted~amino)-TP, 6-(4-fluorophenyl)-3-(substituted-amino) TP~ 6 ~3-tr;fluoro-~&~
~ethylphenyl) 3-(substituted-alTIino)-~TP, 6-~3,4 difluoro-phenyl)-3-(substituted amino~ TP, ~-~4-phenoxyphenyl)-~-(substituted-amino)-TP, 6-t4-phenylthiophenyl) 3-(sub-st;tuted-amino)-TP~ 6 (4-(4-fluorophenoxy)phenyl)-3-~sub-st;tuted-amino)-TP, 6 ~3~chlorophenyl)-3 (substituted-amino)-TP~ 6-(3-broMophenyl)-3-tsubstituted-amino~-TP
and 6-~5-chloro-2-thienyl)-3-(subs~ituted-amino)-TP, ;n which "substituted-ar,l;no" represents; ;n particular, d;methylam;no, d;ethylam;no, 1-pyrrol;d-inyl, piperidino~
morpholino~ ti1iomorphol;no, 1-piperazinyL~ 4-me~hyl-1-p;peraz;nyl, 4~phenylpiper;d;no~ 4-phenyl-1-p;perazinyl, ~t-p;per;don~1 yl and 4-ethoxycarbonyl-1-piperaz;nyl.
The corr~pounds~ according to the ;nvention, of the formula I act on the central nervous system; in par~;cu-lar, they have an anx;olytic and ant;convulsive action.Poss;ble ;ndicat;ons are, therefore, sleeplessness, ernot;onal tens;on and autonom;c depress;on.
The pharmaceut;cal formulations generally contain 1 to 10,~ of the act;ve component(s) accordirlg to the inv~ntlon.
The anxiolytic action of the compounds of the formula I ;s accompan;ed by a ver~ sli~ht sedation and by good tolerance (LD5~ ~ 300 mg/kg i.p. on mice). ~his ;s shown by ;nvestig3t;0ns ;n which the effect of the compounds according to the invent;on on motor activityr hexobarbit3l-;nduced narcosis and card;-azol spasms ;n ~;ce was determ;ned. In addit;on~ the Geller anx;olytic test and the L;c~-shoc~ test on rats were also used~
~,Z4~
The lo~est dose still effective in the tests ;nd;cated above is, for e~ample, 5 mg/kg on oral adm;n;s-trat;on, 2.5 mglkg on sublingual adm;nistration and 1 mg kg on intravenous adm;n;stration. Examples of suitable general dose ranges for act;on ~an;mal test as above) are: 5 to 50 mg/kg on oral adm;n;strat;on, 2.5 ~o 25 Mg kg on subl;ngual administrat;on and 1 to 10 mg~kg on intravenous administrat;on.
For example, 1 to 3 tablets conta;n;ng 10 to 100 mg of act;ve substance can be adm;nistered 3 t;mes a day or~ in the case of intravenous injection, for example, an ampoule of 2 to ml capac;ty conta;n;ng 0.5 to 5 mg of substance can be adm;n;stered 1 to 3 times a clay.
Example 1 3~ ohexylamino-6~ yl~1L2~tr;azoloC4L~-b]~y---d ine hydrochlor;de 5 ~ of 3-hydrazino-6-phenylpyridaz;ne (formula ~III, melting point 146C) are d;ssolved in 50 ml of hot ethanol~ and 3~8 9 of cyclohexyl ;sothiocyanate are added. The mixture is st;rred for two hours under reflux and cooled to 0C, and the product ;s filtered off with suction, washed w;th ethanol and dried~ The result;ng ;ntermed;ate (formula Ill, Z-S~ ;s heated w;th 6.1 g of d;cyclohexylcarbod;im;de in 50 ml of 2-methoxyethanol for S hours at reflux temperature. The react;on solution ;s evaporated to dryness under reduced pressure, and the res;due ;s crystallized twice from isopropanol. Treat-mcnt with ethanol;c hydrochloric acid gives the hydro-chior;de, wh;ch is filtered off w;th suctionr washed with . .
~41~6~3 - ~7 ethanol and dr;ed, melting point 2~8~C.
Example 2-3-Benzylamino~-Dhen~ ,2 4-triazolo[4~b]~y~
h~drochlor;de 8 g of 3-hydrazino-6-pherlylpyridazine are d;s-solved in 7U ml of hot ethanolr 7 g of benzyl isothio-cyanate are added and the m;xture ;s stirred under reflux : for one hour. After cooling~ the inter~ediate stage (formula III, Z~S~ is filtered off with suction, washed with ethanol, dr;ed ar,d then heated with 8.9 g of d;cyclo-hexylcarbod;imide in 50 Ml of 2 me~hoxyethanol for S
hours at reflux temperature~
The mixture is concentrated and ethanol;c hydro chlor;c acid is added, after ~hich the mixture ;s e~apo-rated to dryness and the residue is recrystalli~ed oncefrom glacial acetic acid and once from toluene and washed w;th d; sopropyl ether, meltincJ point 236C (decomposit;or Ex~
6-(4-Fluorophenyl)-3-m hylamino 1L~ triazolo[4~-b~-~ daz;ne ~drochloride 1.65 inl of methyl ;socyanate in 10 ml of dioxaneare added dropwise to S g of 3 t4-fluorophenyl)-6-hydraz;nopyridazine (formula VIII, meltin~ point 194C) in 40 ~l of bo;ling dioxane. The solution ;s heaced at reflux temperature for A further two hours and concentra-ted under reduced pressure, the res;due is stirred with ethanol~ and the product ;s filtered off u;th suc-tion and dr;ed. rhe interMediate ~formula III, 7~0~ is heated with phosphorus oxychloride for 4 hours at reflux 5~i~
- 1E3 ~
temperature~ The reaction solution ;5 hydrolyzed caut ;ously w;th ;ce. The prec;pitated hydrochlor;de of the product is filtered off with suction, washed with water, extracted by boiling w;th isopropanol, f;ltered off w;th suct;on and dr;ed, melt;ng po;nt 297C~
Example 4:
~-(4~ Lg~ y~ phenylamino~ triazoloc4~3 b~
zine ~
5 g of 3-t4-fluorophenyl)-6-hydrazinopyridazine and 3.7 g of phenyl isothiocyanate ;n S0 ml of ethanol are sti red under reflux for 3 hours. After cool;ng, the intermed;ate tformula III, Z=S) ;s f;ltered off with suction, washed with ethanol and dried, melt;ng po;nt 223C ts i nter;nc~
stituted-phenylamino)-TP and 6-(S-chloro-2-th;enyl~-3-(subst,tuted-phenylamino)-TP, ;n ~Ihich "substituted-phenyl" represents, in particular, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, ; 20 3- or 4-bromophenyl~ 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenylr 2r4-dichloro phenyl, 2,4-difluorophenyl~ 2,5-diclllorophenyl, 2,5-di-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 2,6~dichlorophenyl or 2,6-difluorophenyl.
6-(3-Fluorophenyl)-3-~N~methyl-N-phenylam;r,o)-TP, 6-t4-fluorophenyl)-3-(~-methyl~N-phenylamino)~TP, 6 (3-trifluoromethylphenyl)-3-(N-methyl~N~phenylamino)-TP, 6-.
~3,4~dlfluorophenyl~-3-(N-me';hyl-N phenylamino)~TP, 6~(4-phenoxyphenyl)-3-(N-methyl-N-phenylan1;no)-TP, 6~4-.. . .
5~
~ S3 -phenyLthiophenyl)-3-(r~-methyl-N~phenylamino) TP, 6-~4-(4-fluorophenoxy)phenyl~-3~(N-methyl-N-phenylarDino~TP, 6 t3-clllorophenyl)-3-(N-methyl-N-phenylam;no)-TP, o-(3~
bromophenyl)~3-(N-methyl-N-?henylamino)-TP, 6-~5-chloro-2-th;enyl) 3-(N-methyl-N-phenylarnino)-TP~ 6-~3-fluoro-- phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(4-fluorophenyl)-3-(N-methyl-N-substituted-phenylamino~TPf 6-(3-tr;f(uoromethylphenyl)-3-tN-methyl-N-substituted-phenylamino)-TP~ 6-(3,4 difluorophenyl)~3-(N ~ethyl-N-subs.;tuted-phenylamino)-TP~ 6-(4-phenoxyphenyl)-3-(N-methyl-N-subs~;tuted phenylam;no)-TP, 6-(4-phenylthio-phenyl)-3-(PJ-methyl N-substituted-pllenylamino)-TP, 6-~~4-fluorophenoxy)-phenyl)~3 tN-methyl-N-substituted-phenylam;no)-1P, 6-t3~chlorophenyl)-3-(N-methyl-N-sub~
stituted~phenylamino)-TP, 6-(3-bronlophenyl)-3 (N methyl-N-substituted-phenylam;no)-TP and 6 (5-chloro 2~thienyl)-3-(N-me~hyl-N subst;tuted-phenylam;no)-TP, ;n which "subst;tuted-phenyl" represents, in particular, 2-, 3 or 4-fluorophenyl, 2~, 3~ or ~ chloropheryl, 2-, 3- or 4-brornophenyl, 2-, 3- or 4-tr;fluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyL, 2~4-dichloro-phenyl, 2,4~difluorophenyl, 2,5 dichlorophenyl~ ~,5-di-fluorophenyl, 3,5-dichlorophenyl, 305-difluorophenyl, ~,6-dichloropllenyl or 2r6 d;fluorophenyl.
6-(3-Fluoropheny!~-3 acetamino-TP, o-~4 fluoro-phenyl)-3-acetamino-TP, 6-(3-tr;fluoromethylphenyl)-3-acetam;no~TPf 6-(3,4~d;fluorophenyL)-3-acetam;no TP, 6-~4~phenoYypheny'~-3~acetamino TP, 6-(4-phenylthiophenyl)-3-acetam;no-TP, 6-(4-(4-fluoropherloYm~pherlyl)-3-acet-5~3 - 14 ~
am;no-TP, 6~3 chloropherlyl)~3-acetamiro-TP, 6-(3-bromo-phenyl)-3-acetam;no-TP, 6 (S-chloro-2 thienyl)-3-acet-amino-TP, 6-(3-fluorophenyl)-3 benzoylamino-TP~ 6-(4-fluorophenyl)-3-benzoyiamino-TP, 6-(3-trifluoromethyl-phPnyl)-3 benzoylarnino-TP, 6-53,4-d;fluorophenyl)-3~
benzoylamino-TP, 6 (4-phenoxyphenyl) 3-benzoylamino-TP, 6-(4-phenylthiopnenyl)-3-benzoylarnino-TP~ 6-(4-(4-fluoro-phenoxy)phenyl)-3-benzoylamino-TP, 6-(3-chlorophenyl~-3 benzoylamino-TP, 6-(3-bromophenyl)-3-benzoylamino-TP~ 6 (5~chloro~2-thienyl)-3-benzoylamino-TP, 6-(3-fluoro-phenyl)~3~(substituted-benzoylamino)-TP, ~-~4-fluoro-phenyl)~3-(substitu~ed-benzoylamino)-TP, 6-(3-trifluoro-methylphenyl)-3-(substituted-benzoylamino)-TP, 6-~3,4-d;fluorophenyl)-3~(substituted-benzoylamino)-TP, 6-(4-phenoxyphenyl)-3-~substituted-benzoylamino~-TP, 6-(4-phenylthiophenyl)-3-(substituted-benzoylamino)-TP, ~-t4-(4-fluorophenoxy)phenyl~-3-~subs.ituted-ben20ylamino)-TP, ~-(3~chlorophenyl)-3-(substituted-bonzoylamino)-TP, 6-(3-brornophenyl)-3-(substituted~benzoylamino~-TP and 6-(5 chloro-2 thienyl)-3-(substituted-benzoylamino) TP, in which fsubst;tuted benzoyl represents, in particular, 2-, 3- or 4-fluorobenzoyl, 2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-bromobenzoyl, 2-, 3- or 4-tr;fluoromethylbenzoyl~
3,4-dichlorobenzoyl, 3~4-difluorobenzoyl, 2,5 dichloro-benzoyl, 2,5-difluorobenzoyl, 3,5-dichlorobenzoyl, 3,5-difluorobenzoyl, 2,6-dichlorobenzoyl or 2~6-d;fluoro-benzoyl.
6-~3 F'uorophenyl~3-~substituted~amino)-TP, 6-(4-fluorophenyl)-3-(substituted-amino) TP~ 6 ~3-tr;fluoro-~&~
~ethylphenyl) 3-(substituted-alTIino)-~TP, 6-~3,4 difluoro-phenyl)-3-(substituted amino~ TP, ~-~4-phenoxyphenyl)-~-(substituted-amino)-TP, 6-t4-phenylthiophenyl) 3-(sub-st;tuted-amino)-TP~ 6 (4-(4-fluorophenoxy)phenyl)-3-~sub-st;tuted-amino)-TP, 6 ~3~chlorophenyl)-3 (substituted-amino)-TP~ 6-(3-broMophenyl)-3-tsubstituted-amino~-TP
and 6-~5-chloro-2-thienyl)-3-(subs~ituted-amino)-TP, ;n which "substituted-ar,l;no" represents; ;n particular, d;methylam;no, d;ethylam;no, 1-pyrrol;d-inyl, piperidino~
morpholino~ ti1iomorphol;no, 1-piperazinyL~ 4-me~hyl-1-p;peraz;nyl, 4~phenylpiper;d;no~ 4-phenyl-1-p;perazinyl, ~t-p;per;don~1 yl and 4-ethoxycarbonyl-1-piperaz;nyl.
The corr~pounds~ according to the ;nvention, of the formula I act on the central nervous system; in par~;cu-lar, they have an anx;olytic and ant;convulsive action.Poss;ble ;ndicat;ons are, therefore, sleeplessness, ernot;onal tens;on and autonom;c depress;on.
The pharmaceut;cal formulations generally contain 1 to 10,~ of the act;ve component(s) accordirlg to the inv~ntlon.
The anxiolytic action of the compounds of the formula I ;s accompan;ed by a ver~ sli~ht sedation and by good tolerance (LD5~ ~ 300 mg/kg i.p. on mice). ~his ;s shown by ;nvestig3t;0ns ;n which the effect of the compounds according to the invent;on on motor activityr hexobarbit3l-;nduced narcosis and card;-azol spasms ;n ~;ce was determ;ned. In addit;on~ the Geller anx;olytic test and the L;c~-shoc~ test on rats were also used~
~,Z4~
The lo~est dose still effective in the tests ;nd;cated above is, for e~ample, 5 mg/kg on oral adm;n;s-trat;on, 2.5 mglkg on sublingual adm;nistration and 1 mg kg on intravenous adm;n;stration. Examples of suitable general dose ranges for act;on ~an;mal test as above) are: 5 to 50 mg/kg on oral adm;n;strat;on, 2.5 ~o 25 Mg kg on subl;ngual administrat;on and 1 to 10 mg~kg on intravenous administrat;on.
For example, 1 to 3 tablets conta;n;ng 10 to 100 mg of act;ve substance can be adm;nistered 3 t;mes a day or~ in the case of intravenous injection, for example, an ampoule of 2 to ml capac;ty conta;n;ng 0.5 to 5 mg of substance can be adm;n;stered 1 to 3 times a clay.
Example 1 3~ ohexylamino-6~ yl~1L2~tr;azoloC4L~-b]~y---d ine hydrochlor;de 5 ~ of 3-hydrazino-6-phenylpyridaz;ne (formula ~III, melting point 146C) are d;ssolved in 50 ml of hot ethanol~ and 3~8 9 of cyclohexyl ;sothiocyanate are added. The mixture is st;rred for two hours under reflux and cooled to 0C, and the product ;s filtered off with suction, washed w;th ethanol and dried~ The result;ng ;ntermed;ate (formula Ill, Z-S~ ;s heated w;th 6.1 g of d;cyclohexylcarbod;im;de in 50 ml of 2-methoxyethanol for S hours at reflux temperature. The react;on solution ;s evaporated to dryness under reduced pressure, and the res;due ;s crystallized twice from isopropanol. Treat-mcnt with ethanol;c hydrochloric acid gives the hydro-chior;de, wh;ch is filtered off w;th suctionr washed with . .
~41~6~3 - ~7 ethanol and dr;ed, melting point 2~8~C.
Example 2-3-Benzylamino~-Dhen~ ,2 4-triazolo[4~b]~y~
h~drochlor;de 8 g of 3-hydrazino-6-pherlylpyridazine are d;s-solved in 7U ml of hot ethanolr 7 g of benzyl isothio-cyanate are added and the m;xture ;s stirred under reflux : for one hour. After cooling~ the inter~ediate stage (formula III, Z~S~ is filtered off with suction, washed with ethanol, dr;ed ar,d then heated with 8.9 g of d;cyclo-hexylcarbod;imide in 50 Ml of 2 me~hoxyethanol for S
hours at reflux temperature~
The mixture is concentrated and ethanol;c hydro chlor;c acid is added, after ~hich the mixture ;s e~apo-rated to dryness and the residue is recrystalli~ed oncefrom glacial acetic acid and once from toluene and washed w;th d; sopropyl ether, meltincJ point 236C (decomposit;or Ex~
6-(4-Fluorophenyl)-3-m hylamino 1L~ triazolo[4~-b~-~ daz;ne ~drochloride 1.65 inl of methyl ;socyanate in 10 ml of dioxaneare added dropwise to S g of 3 t4-fluorophenyl)-6-hydraz;nopyridazine (formula VIII, meltin~ point 194C) in 40 ~l of bo;ling dioxane. The solution ;s heaced at reflux temperature for A further two hours and concentra-ted under reduced pressure, the res;due is stirred with ethanol~ and the product ;s filtered off u;th suc-tion and dr;ed. rhe interMediate ~formula III, 7~0~ is heated with phosphorus oxychloride for 4 hours at reflux 5~i~
- 1E3 ~
temperature~ The reaction solution ;5 hydrolyzed caut ;ously w;th ;ce. The prec;pitated hydrochlor;de of the product is filtered off with suction, washed with water, extracted by boiling w;th isopropanol, f;ltered off w;th suct;on and dr;ed, melt;ng po;nt 297C~
Example 4:
~-(4~ Lg~ y~ phenylamino~ triazoloc4~3 b~
zine ~
5 g of 3-t4-fluorophenyl)-6-hydrazinopyridazine and 3.7 g of phenyl isothiocyanate ;n S0 ml of ethanol are sti red under reflux for 3 hours. After cool;ng, the intermed;ate tformula III, Z=S) ;s f;ltered off with suction, washed with ethanol and dried, melt;ng po;nt 223C ts i nter;nc~
7.S 0 of th;s ;ntermed;ate are heated w;th S g of d;cyclohexylcarbod;;mide ;n 50 ml of 2~methoxyethanol for 2 hours at reflux temperature. The prec;p;tate which is formed on cool;ng ;s filtered off w;~h suction, ~Jashed with ethanol and recrystall;zed from ;sopropanol, melt;ng 20 poin~ 265~.
Exam~le 5:
__ 3~4-~hl~ 'n) 6~t4-fluorop~ 2~triazol azin~
4.1 g of 4-chlorophenyl ;socyanate, d;ssolved in 1S ml of dioxane, are added dropwise to 5 g of 3~t4-fluorophenyl)-6 hydrazinopyridazine in 40 ml of dioxane, and the m;xture ;s heated for 2.5 hours at reflux tem perature. After coolingf the product ;s tiltered off witll suct;on~ washed with ;sopropanol and dried, melt;n~
~ 19 ~ 56 8 point 223C. 5 9 of this intermediate (Formùla III~
Z=0) are heated ;n 40 ml of dry toluene ~l;th 3.5 ml of N,N-d;methylan;l;ne and 1.~ ml of phosphorus oxychloride for 3 hours at reflux temperature. After cooling, the toluene ;s removed by decarltation and the o;ly res;due wh;ch remains ;s st;rred w;th 2N I~Cl~ The sol;d (hydrochloride, melt;ng point 286C) i5 f;ltered off with suction and boiled up with semi-concentrated ammon;a;
after cooling, the base ;s f;ltered off with suction and recrystall;zed from ;sopropanol, Meltin~ po;nt 257C~
Example 6:
3~3-FLuorpphenylam;no~-6-(3-tr;fluorometh~phe~
1 2 4~tr;azolo~4~3-b~p~daz;ne 5 g of ~-hydrazino-6-t3-trifluoromethylphenyl~-pyr;dazine (formula VIII, melting point 167C~ in 40 Ml ; of ethanol are ~armed to abou~ 50C. 3c3 9 of 3-fluoru-phenyl isothiocyanate, d;ssolved in 10 ml of ethanolr are added dropwise, the rnixture is heated for 3 hours at reflux temperature and, after cool;ng, the result;ng pre-c;p;~ate ;s f;ltered off w;th suction. P.-Fter ;t has been washed w;th ethanol and dr;ed~ 6 9 of the intermed;ate (forlnula III, Z=S), melt;ng po;nt 164C, are heated ;n 40 ml of toluene with 3.8 ml of NrN-d;methylanll;ne and 1.5 Inl of phosphorus oxychlor;de for 3 hours at ref;ux temperature. After cooling, the toluene phase ;s removed by decantat;on and the o;ly res;due which rema;ns ;s st;rred w;th 2N HCl~ The solld (hydrochlor;de) thus formed ;s f;ltered off with suction and bo;led up w;th senl,~concentrated ammonia~ alld~ wher~ cold, the product ~o - ~ :
(base) ;s filterecJ off ~;th suction. Melting point ~09C, af~er recrystall;zation from cJlac;al acetic acid/water.
Example 7:
-3-(4-FI )-6-~4-phenylthiop~y~)-1f~4 tr;azolo[4 3-b~pyridazine hydrochloride 5 g of 3~hydrazino-6-(4-phenyl~hiophenyl)-pyr;daz;ne (formula VIII, n~elting point 142C) in 40 ml of ethanol are heated to reflux ternperature. 2.9 g of 4-fluorophellyl isothiocyanate in 10 ml of ethanol are added dropw;se slowly, and the mixture is heated for a total of 3 hours at reflux temperature. After cool;ng, the precipitate is f;ltered off w;th suct;on, washed with ethanol and dried, melting point 188C. 6 g o~ th;s ;ntermediate (formula III, Z-S) are st;rred under reflux for S hours with 3 g of dicyclohexylcarbodiimide in 40 ml of 2-methoxyethanol. After cooling, the product is f;ltered off and washed with isopropanolv 1he precipi-tate is boiled up w;th ethanolic hydrochloric acid, the mixture ;s concentrated, and the product is f;ltered off w;th suct;onr washed with ethanol and dried, Meltina po;nt 263C.
The foLlowing compounds can be prepared analo-gously to Examples 1 - 7: the root name "1r2,4-triazolo-C4,3~b~pyr;dazine" is abbreviated to "TP" ;n the follow-;ng text.
3. 3-Methylamino~6-phenyl-rP HCl~ melting po;nt 254Co 9. 3-Propylanl;no-6-phenyl-TP HCl, melting point 206C.
10~ 3-Hexylamino~6-phenyl-TP HCl~ meltin0 point~ 164C.
~ 21 ~ 568 11. 3-(3-FLuorophenylamino) 6-phenyl-TP HCl ~elting point 266C tdecomposition).
12. 3-~4 Fluorophenyla~ino)-6-phenyl-TP HCl melt;ng point 264C.
13. 3~(3-Chlorophenylamino)-6-phenyl-TP HCl melting po;nt 260C (decompos;t;on)~
14. 3-(4-Chlorophenylamino)-6-phenyl-TP HCl meltin~
point 258C tdecompos;tion).
15. 3-(3-Trifluoromethylphenylamino~-6~phenyl-TP HCl~
melting point 245C.
16. 3-Propylamino-6-(4-fluorophenyl~-TP HCl melt;ng po;nt 241C.
170 3-Cyclohexylamino-6-t4-fluorophenyl)-TP HCl melt;ng po;nt 262C (decomposition).
15 18. 3-~3 Chlorophenylamino)-6-~4-fluorophenyl)-TP HCl melting point 250C.
19 3-(3 4-D;chlorophenylam;no)-6-(4-fluorophenyl)-TP HCl melt;ng point 289-290C.
20. 3-(2-Fluorophenylam;no)-6-(4-fluorophenyl)-TP HCl melt;ng point 242C.
21 3~(3-Fluor~ophenylamino)-6~(4-fluorophenyl)-TP HCl meltins po;nt 260-262C.
- 22. 3-(4-Fluorophenylam;no)-6-(4-fluorophenyl~ TP HCl~
melt;rlg pOt nt 282 284C.
25 23. 3 (4 Methylphenylamino)-6-(4-fluorophenyl~ TP HCl melt;ng point 263C.
24. 3-~3-Cyanophenylamirlo)-6-(4 fluorophenyl)-TP HCl melting point 321C.
2S. 3-(3-Trifluoromethylplenylam;no)-6-(4-fluorophenyl)-- 22 ~ 56~ `
TP HCl, melt;ng point 286C~
26r 3 PhenylaMino-6 (3-fluorophenyl)-TP HCl, melting point Z66C ~decomposition~.
27. 3-(4-Chlorophenylam;no)-6-(3-fluorophenyl)-TP, 5 melt;ng po;nt 258C.
28. 3-(3-Fluorophenylam;no)-6-~3-~fluorophenyl)-TP, melting po;nt 23 6C.
29. 3-(4~Fluorophenylamino)-o-(3-fluorophenyl)~TP, melt;ng point 241C.
10 30 3-Phenylamino-6-(3-tr;fluoromethylphenyl)-TP, melt;ng po;nt 206C.
31. 3-(3-Chlorophenylam;no)-6-~3-tr;fluoromethylphenyl)-TP melt;ng po;nt 212C.
32. 3-(4-Chlorophenylamino)-6-(3 trifluoromethylphenyl)-TP, melt;ng point 208C.
33O 3-(3,4 D;chlorophenylam;rIo)-6-(3-tr;fluoromethyl phenyl)-TP, melt;ng po;nt 198C.
34. 3-(2-Fluorophenylam;no)-6-(3-tr;fluorome~hylphenyl~-TP, melt;ng po;nt 198C.
20 35. 3-(3-Fluorophenylam;no)-6 (3-trifluoromethylphenyl)-TPr rnelt;ng point 209C
36 3 (4-Fluorophenylam;no~-6 t3-trifluoromethylphenyl)-TP, melting po;nt 234C.
37. 3-Phenylam;no-6-(4-tr;fluoromethylphenyl)-TP HCl, melt;ng po;n 271C.
38. 3-(3-Fluorophenylamino)-6-(4-phenoxyphenyl~-TP, melting point 211C.
- 39. 3-Phenylam;no~ 4-phenylthiophenyl~-rP HCl, mel ing point 247C.
, .
~41~`56~3 - 23 - .
40. 3-(4 Chlorophenylamino)-6-(4-phenylth;ophenyl)-TP HCl, melting Po;nt 274C.
41. 3-(3~Fluorophenylamino)-6-(4-phenylth;ophenyl~TP HCl, melt;ng point 253C.
42. 3~t4-Fluorophenylam;no)-6-(4-phenylthiophenyl)-TP HCl, melting point 263C.
43. 3-PhenyLamino-6-(5-chloro-2-thienyl)-TP HCl, meltin0 po;nt 271C.
44. 3-(4-Chlorophenylam;no)-6-(S-chloro~2~thienyl)-TPr melting point 246C
45. 3-(3-Fluorophenylamino)-6-(S-chloro-2-thienyl)-TPO
melting point 287C.
46. 3~(2-Fluorophenylamino)-6~(5-chloro 2-thienyl)-TP, melting point 232C.
47. 6-~4~(4~Fluorophenoxy)phenyl3-3-phenylamino-TPr melt;ng point 235C.
48. 6-c4-~4-Fluorophenoxy)phenyl]-3-(3-fluorophenylam;no?
TP, melt;ng po;nt 233C.
49. 3-(4~Chlorophenylam;no)-6~C4-(4-fluorophenoxy)phenyl~-TP, melting point 267C.
50. 3 t3-Fluorophenylamino)-6 (2-furyl)-TP, melting point 2'l7 - 218C.
51~ 3 (4-Chlorophenylamino)-6-52-furyl)-TP, melting po;nt 52O 3-Phenylamino-6-t2-th;enyl)~TP, melt;ng po;nt 204C.
53~ 3-(3-Fluorophenylamino)-6-t2-thienyl)-TP, melt;ng po;nt 212C~
- 24 - '~ 5~
Example 54, process b) 3-Cyclohexylamino 6-p_enyl~1,2 4-triazolo~4~3-b~pyrida-zine ~y~
_. , 3 g of 3-bromo-6-phenyl-1,2,4~triazoloL'4,3-b]-5 pyridaz;ne in 10 ml of cyclohexylamine are heated atreflux temperature for five hours`. After cooling, the product is stirred w;th diisopropyl ether, and the sol;d ;s f;ltered off w;th suct;on and recrystall;zed from isopropanol~ Ethanolic hydrogen chloride gives the hydrochloride~ melt;ng point 258C.
The compounds, according to the invention, of Examples 2 to 53 are obtained by an analogous procedure.
In th;s procedure, a 6 aryl-3-bromo-1~2,4-tri-azolo~4,3-b~pyridazine (general formula IV) wh;ch has been prepared ;n analo~y w;th the literature process and wh;ch carries the same 6-substituent as the compound of the corresponding example is reacted with the amine tgeneral formula V) which forms the basis of the 3-sub stituent of the example.
Example 55, process c) 3-Benzylamino-6-phe~y~ ~4-triazolo~ b]pyridaz;ne hydrochlor;de 5 9 of 3-am;no-6-phenyl-1,2,4-tr;azolo~4,3-b~
pyr;daz;ne and 3 g of benzyl chlor;de ;n 2S ml of d;methylformam;de are heated under reflux w;th 5 g of potassium carbonate for 10 hours. After cooling, ~Jater ;s addedr and the product is f;ltered off with suct;on, ' treated with ethanolic hydrogen chlor;de and evaporated~
The residue ;s recrystallized from giacial acetic acidr - 25 - ~2~56~
~ashed w;th diisopropyl ether and dr;ed, meLt;ng poinc 236C (decomposit;on~.
The compounds, accord;ng to the ;nvent;on~ of Examples 1 and 3 to 53 are obta;ned by an anaLogous pro--cedure In this procedure the 3-am;no-6-aryl-1,2,4-triazolo~4,3-b}pyr1ddzine ~general formula VI, described in German Offenlegungsschr;ft 3,217,325) on which the example concerned ;s based ;s reacted with the R4-Y
compound (general formula VII) the alkyl or aryl rad;cal of wh;ch forms the bas;s of the 3-substituent of the corresponding example~
Exam~le 5:
__ 3~4-~hl~ 'n) 6~t4-fluorop~ 2~triazol azin~
4.1 g of 4-chlorophenyl ;socyanate, d;ssolved in 1S ml of dioxane, are added dropwise to 5 g of 3~t4-fluorophenyl)-6 hydrazinopyridazine in 40 ml of dioxane, and the m;xture ;s heated for 2.5 hours at reflux tem perature. After coolingf the product ;s tiltered off witll suct;on~ washed with ;sopropanol and dried, melt;n~
~ 19 ~ 56 8 point 223C. 5 9 of this intermediate (Formùla III~
Z=0) are heated ;n 40 ml of dry toluene ~l;th 3.5 ml of N,N-d;methylan;l;ne and 1.~ ml of phosphorus oxychloride for 3 hours at reflux temperature. After cooling, the toluene ;s removed by decarltation and the o;ly res;due wh;ch remains ;s st;rred w;th 2N I~Cl~ The sol;d (hydrochloride, melt;ng point 286C) i5 f;ltered off with suction and boiled up with semi-concentrated ammon;a;
after cooling, the base ;s f;ltered off with suction and recrystall;zed from ;sopropanol, Meltin~ po;nt 257C~
Example 6:
3~3-FLuorpphenylam;no~-6-(3-tr;fluorometh~phe~
1 2 4~tr;azolo~4~3-b~p~daz;ne 5 g of ~-hydrazino-6-t3-trifluoromethylphenyl~-pyr;dazine (formula VIII, melting point 167C~ in 40 Ml ; of ethanol are ~armed to abou~ 50C. 3c3 9 of 3-fluoru-phenyl isothiocyanate, d;ssolved in 10 ml of ethanolr are added dropwise, the rnixture is heated for 3 hours at reflux temperature and, after cool;ng, the result;ng pre-c;p;~ate ;s f;ltered off w;th suction. P.-Fter ;t has been washed w;th ethanol and dr;ed~ 6 9 of the intermed;ate (forlnula III, Z=S), melt;ng po;nt 164C, are heated ;n 40 ml of toluene with 3.8 ml of NrN-d;methylanll;ne and 1.5 Inl of phosphorus oxychlor;de for 3 hours at ref;ux temperature. After cooling, the toluene phase ;s removed by decantat;on and the o;ly res;due which rema;ns ;s st;rred w;th 2N HCl~ The solld (hydrochlor;de) thus formed ;s f;ltered off with suction and bo;led up w;th senl,~concentrated ammonia~ alld~ wher~ cold, the product ~o - ~ :
(base) ;s filterecJ off ~;th suction. Melting point ~09C, af~er recrystall;zation from cJlac;al acetic acid/water.
Example 7:
-3-(4-FI )-6-~4-phenylthiop~y~)-1f~4 tr;azolo[4 3-b~pyridazine hydrochloride 5 g of 3~hydrazino-6-(4-phenyl~hiophenyl)-pyr;daz;ne (formula VIII, n~elting point 142C) in 40 ml of ethanol are heated to reflux ternperature. 2.9 g of 4-fluorophellyl isothiocyanate in 10 ml of ethanol are added dropw;se slowly, and the mixture is heated for a total of 3 hours at reflux temperature. After cool;ng, the precipitate is f;ltered off w;th suct;on, washed with ethanol and dried, melting point 188C. 6 g o~ th;s ;ntermediate (formula III, Z-S) are st;rred under reflux for S hours with 3 g of dicyclohexylcarbodiimide in 40 ml of 2-methoxyethanol. After cooling, the product is f;ltered off and washed with isopropanolv 1he precipi-tate is boiled up w;th ethanolic hydrochloric acid, the mixture ;s concentrated, and the product is f;ltered off w;th suct;onr washed with ethanol and dried, Meltina po;nt 263C.
The foLlowing compounds can be prepared analo-gously to Examples 1 - 7: the root name "1r2,4-triazolo-C4,3~b~pyr;dazine" is abbreviated to "TP" ;n the follow-;ng text.
3. 3-Methylamino~6-phenyl-rP HCl~ melting po;nt 254Co 9. 3-Propylanl;no-6-phenyl-TP HCl, melting point 206C.
10~ 3-Hexylamino~6-phenyl-TP HCl~ meltin0 point~ 164C.
~ 21 ~ 568 11. 3-(3-FLuorophenylamino) 6-phenyl-TP HCl ~elting point 266C tdecomposition).
12. 3-~4 Fluorophenyla~ino)-6-phenyl-TP HCl melt;ng point 264C.
13. 3~(3-Chlorophenylamino)-6-phenyl-TP HCl melting po;nt 260C (decompos;t;on)~
14. 3-(4-Chlorophenylamino)-6-phenyl-TP HCl meltin~
point 258C tdecompos;tion).
15. 3-(3-Trifluoromethylphenylamino~-6~phenyl-TP HCl~
melting point 245C.
16. 3-Propylamino-6-(4-fluorophenyl~-TP HCl melt;ng po;nt 241C.
170 3-Cyclohexylamino-6-t4-fluorophenyl)-TP HCl melt;ng po;nt 262C (decomposition).
15 18. 3-~3 Chlorophenylamino)-6-~4-fluorophenyl)-TP HCl melting point 250C.
19 3-(3 4-D;chlorophenylam;no)-6-(4-fluorophenyl)-TP HCl melt;ng point 289-290C.
20. 3-(2-Fluorophenylam;no)-6-(4-fluorophenyl)-TP HCl melt;ng point 242C.
21 3~(3-Fluor~ophenylamino)-6~(4-fluorophenyl)-TP HCl meltins po;nt 260-262C.
- 22. 3-(4-Fluorophenylam;no)-6-(4-fluorophenyl~ TP HCl~
melt;rlg pOt nt 282 284C.
25 23. 3 (4 Methylphenylamino)-6-(4-fluorophenyl~ TP HCl melt;ng point 263C.
24. 3-~3-Cyanophenylamirlo)-6-(4 fluorophenyl)-TP HCl melting point 321C.
2S. 3-(3-Trifluoromethylplenylam;no)-6-(4-fluorophenyl)-- 22 ~ 56~ `
TP HCl, melt;ng point 286C~
26r 3 PhenylaMino-6 (3-fluorophenyl)-TP HCl, melting point Z66C ~decomposition~.
27. 3-(4-Chlorophenylam;no)-6-(3-fluorophenyl)-TP, 5 melt;ng po;nt 258C.
28. 3-(3-Fluorophenylam;no)-6-~3-~fluorophenyl)-TP, melting po;nt 23 6C.
29. 3-(4~Fluorophenylamino)-o-(3-fluorophenyl)~TP, melt;ng point 241C.
10 30 3-Phenylamino-6-(3-tr;fluoromethylphenyl)-TP, melt;ng po;nt 206C.
31. 3-(3-Chlorophenylam;no)-6-~3-tr;fluoromethylphenyl)-TP melt;ng po;nt 212C.
32. 3-(4-Chlorophenylamino)-6-(3 trifluoromethylphenyl)-TP, melt;ng point 208C.
33O 3-(3,4 D;chlorophenylam;rIo)-6-(3-tr;fluoromethyl phenyl)-TP, melt;ng po;nt 198C.
34. 3-(2-Fluorophenylam;no)-6-(3-tr;fluorome~hylphenyl~-TP, melt;ng po;nt 198C.
20 35. 3-(3-Fluorophenylam;no)-6 (3-trifluoromethylphenyl)-TPr rnelt;ng point 209C
36 3 (4-Fluorophenylam;no~-6 t3-trifluoromethylphenyl)-TP, melting po;nt 234C.
37. 3-Phenylam;no-6-(4-tr;fluoromethylphenyl)-TP HCl, melt;ng po;n 271C.
38. 3-(3-Fluorophenylamino)-6-(4-phenoxyphenyl~-TP, melting point 211C.
- 39. 3-Phenylam;no~ 4-phenylthiophenyl~-rP HCl, mel ing point 247C.
, .
~41~`56~3 - 23 - .
40. 3-(4 Chlorophenylamino)-6-(4-phenylth;ophenyl)-TP HCl, melting Po;nt 274C.
41. 3-(3~Fluorophenylamino)-6-(4-phenylth;ophenyl~TP HCl, melt;ng point 253C.
42. 3~t4-Fluorophenylam;no)-6-(4-phenylthiophenyl)-TP HCl, melting point 263C.
43. 3-PhenyLamino-6-(5-chloro-2-thienyl)-TP HCl, meltin0 po;nt 271C.
44. 3-(4-Chlorophenylam;no)-6-(S-chloro~2~thienyl)-TPr melting point 246C
45. 3-(3-Fluorophenylamino)-6-(S-chloro-2-thienyl)-TPO
melting point 287C.
46. 3~(2-Fluorophenylamino)-6~(5-chloro 2-thienyl)-TP, melting point 232C.
47. 6-~4~(4~Fluorophenoxy)phenyl3-3-phenylamino-TPr melt;ng point 235C.
48. 6-c4-~4-Fluorophenoxy)phenyl]-3-(3-fluorophenylam;no?
TP, melt;ng po;nt 233C.
49. 3-(4~Chlorophenylam;no)-6~C4-(4-fluorophenoxy)phenyl~-TP, melting point 267C.
50. 3 t3-Fluorophenylamino)-6 (2-furyl)-TP, melting point 2'l7 - 218C.
51~ 3 (4-Chlorophenylamino)-6-52-furyl)-TP, melting po;nt 52O 3-Phenylamino-6-t2-th;enyl)~TP, melt;ng po;nt 204C.
53~ 3-(3-Fluorophenylamino)-6-t2-thienyl)-TP, melt;ng po;nt 212C~
- 24 - '~ 5~
Example 54, process b) 3-Cyclohexylamino 6-p_enyl~1,2 4-triazolo~4~3-b~pyrida-zine ~y~
_. , 3 g of 3-bromo-6-phenyl-1,2,4~triazoloL'4,3-b]-5 pyridaz;ne in 10 ml of cyclohexylamine are heated atreflux temperature for five hours`. After cooling, the product is stirred w;th diisopropyl ether, and the sol;d ;s f;ltered off w;th suct;on and recrystall;zed from isopropanol~ Ethanolic hydrogen chloride gives the hydrochloride~ melt;ng point 258C.
The compounds, according to the invention, of Examples 2 to 53 are obtained by an analogous procedure.
In th;s procedure, a 6 aryl-3-bromo-1~2,4-tri-azolo~4,3-b~pyridazine (general formula IV) wh;ch has been prepared ;n analo~y w;th the literature process and wh;ch carries the same 6-substituent as the compound of the corresponding example is reacted with the amine tgeneral formula V) which forms the basis of the 3-sub stituent of the example.
Example 55, process c) 3-Benzylamino-6-phe~y~ ~4-triazolo~ b]pyridaz;ne hydrochlor;de 5 9 of 3-am;no-6-phenyl-1,2,4-tr;azolo~4,3-b~
pyr;daz;ne and 3 g of benzyl chlor;de ;n 2S ml of d;methylformam;de are heated under reflux w;th 5 g of potassium carbonate for 10 hours. After cooling, ~Jater ;s addedr and the product is f;ltered off with suct;on, ' treated with ethanolic hydrogen chlor;de and evaporated~
The residue ;s recrystallized from giacial acetic acidr - 25 - ~2~56~
~ashed w;th diisopropyl ether and dr;ed, meLt;ng poinc 236C (decomposit;on~.
The compounds, accord;ng to the ;nvent;on~ of Examples 1 and 3 to 53 are obta;ned by an anaLogous pro--cedure In this procedure the 3-am;no-6-aryl-1,2,4-triazolo~4,3-b}pyr1ddzine ~general formula VI, described in German Offenlegungsschr;ft 3,217,325) on which the example concerned ;s based ;s reacted with the R4-Y
compound (general formula VII) the alkyl or aryl rad;cal of wh;ch forms the bas;s of the 3-substituent of the corresponding example~
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the Formula I
(I) and salts thereof with a physiologically acceptable acid, wherein Formula R1 and R2 are identical or different and represent hydrogen, alkyl groups having 1 - 6 carbon atoms phenyl or chlorine, R3 represents hydrogen, linear or branched alkyl having 1 - 6 carbon atoms or phenyl which may be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1 - 4 carbon atoms, and R4 represents 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 may be 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 may be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1 - 4 carbon atoms, or represents Ar, and wherein Ar represents aromatic radicals, selected from the group consisting of phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-furyl, 2 pyrrolyl, 1-methyl-2-pyrrolyl or 2-, 3- or 4-pyridyl, each of which may be substituted by one, two, three, four or five radicals 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 carboxyl groups, esters of the latter with C1-C6-alcohols, aminocarbonyl, amino acetamino or alkoxycarbonylamino having 1 - 6 carbon atoms in the alkyl radical, and wherein can also represent a radical of the general Formula II
(II) wherein X represents CH2, CHR5, C=O, O, S or NR5 wherein R5 represents 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, phenylalkyl which may be substituted having 1 - 4 carbon atoms in the alkyl radical, phenyl which may be substituted or benzoyl which may be substituted, 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 represent 1, 2 or 3, with the exception of the compounds of the Formula I in which R1, R2 and R3 represent hydrogen, R4 represents phenyl and Ar represents phenyl, 4-methylphenyl or 4-bromophenyl, which comprises:
a) cyclizing a compound of the Formula III
(III) wherein R1, R2, R3, R4, and Ar 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) reacting a compound of the Formula IV
(IV) wherein R6 represents chlorine, bromine or methylthio and Ar, R1 and R2 have the meanings indicated for Formula I, with an amine of the Formula V
(V) wherein R3 and R4 - if appropriate together with the nitrogen atom - have the meanings indicated for Formula I, or, c) reacting, if appropriate with the addition of a condensation agent or catalyst, a compound of the Formula VI
(VI) or one of its salts wherein Ar, R1 and R2 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, selected from the group consisting of fluorine, chlorine, bromine, iodine, or the tosylate radical.
(I) and salts thereof with a physiologically acceptable acid, wherein Formula R1 and R2 are identical or different and represent hydrogen, alkyl groups having 1 - 6 carbon atoms phenyl or chlorine, R3 represents hydrogen, linear or branched alkyl having 1 - 6 carbon atoms or phenyl which may be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1 - 4 carbon atoms, and R4 represents 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 may be 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 may be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl having 1 - 4 carbon atoms, or represents Ar, and wherein Ar represents aromatic radicals, selected from the group consisting of phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-furyl, 2 pyrrolyl, 1-methyl-2-pyrrolyl or 2-, 3- or 4-pyridyl, each of which may be substituted by one, two, three, four or five radicals 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 carboxyl groups, esters of the latter with C1-C6-alcohols, aminocarbonyl, amino acetamino or alkoxycarbonylamino having 1 - 6 carbon atoms in the alkyl radical, and wherein can also represent a radical of the general Formula II
(II) wherein X represents CH2, CHR5, C=O, O, S or NR5 wherein R5 represents 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, phenylalkyl which may be substituted having 1 - 4 carbon atoms in the alkyl radical, phenyl which may be substituted or benzoyl which may be substituted, 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 represent 1, 2 or 3, with the exception of the compounds of the Formula I in which R1, R2 and R3 represent hydrogen, R4 represents phenyl and Ar represents phenyl, 4-methylphenyl or 4-bromophenyl, which comprises:
a) cyclizing a compound of the Formula III
(III) wherein R1, R2, R3, R4, and Ar 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) reacting a compound of the Formula IV
(IV) wherein R6 represents chlorine, bromine or methylthio and Ar, R1 and R2 have the meanings indicated for Formula I, with an amine of the Formula V
(V) wherein R3 and R4 - if appropriate together with the nitrogen atom - have the meanings indicated for Formula I, or, c) reacting, if appropriate with the addition of a condensation agent or catalyst, a compound of the Formula VI
(VI) or one of its salts wherein Ar, R1 and R2 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, selected from the group consisting of fluorine, chlorine, bromine, iodine, or the tosylate radical.
2. A compound of the Formula I, as defined in claim 1, or a physiologically acceptable acid addition salt thereof.
3. A pharmaceutical composition having an anxiolytic and anticonvulsive action, which comprises a pharmaceutically acceptable excipient or auxiliary and, as the active ingredient, a compound of the Formula I as claimed in Claim 1.
4. The process as claimed in claim 1(a).
5. The process as claimed in claim 4, wherein R1, R2 and R4 are hydrogen, R3 is phenyl or phenyl monosubstituted by fluorine or chlorine and Ar is 4-fluorophenyl.
6. A compound of the Formula I, as defined in claim 1, wherein R1, R2 and R4 are hydrogen, R3 is phenyl or phenyl monosubstituted by fluorine or chlorine and Ar is 4-fluorophenyl.
7. A process for the preparation of 6-(4-fluorophenyl)-3-phenylamino-1,2,4-triazolo[4,3-b]-pyridazine which comprises reacting 3-(4-fluorophenyl)-6-hydrazinopyridazine with phenyl isothiocyanate and heating with dicyclohexylcarb-odiimide.
8. 6-(4-Fluorophenyl)-3-phenylamino-1,2,4-triazolo[4,3-b]-pyridazine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3311753.5 | 1983-03-31 | ||
| DE19833311753 DE3311753A1 (en) | 1983-03-31 | 1983-03-31 | SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINE - THEIR PRODUCTION AND USE - |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1246568A true CA1246568A (en) | 1988-12-13 |
Family
ID=6195196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000451005A Expired CA1246568A (en) | 1983-03-31 | 1984-03-30 | Substituted 6-aryl-1,2,4-triazolo[4,3- b]pyridazines - their preparation and their use |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0121490B1 (en) |
| JP (1) | JPS59184179A (en) |
| KR (1) | KR840008361A (en) |
| AT (1) | ATE32723T1 (en) |
| AU (1) | AU563556B2 (en) |
| CA (1) | CA1246568A (en) |
| DE (2) | DE3311753A1 (en) |
| DK (1) | DK144884A (en) |
| ES (1) | ES8501765A1 (en) |
| FI (1) | FI841238A (en) |
| GR (1) | GR81812B (en) |
| HU (1) | HU189076B (en) |
| IL (1) | IL71412A (en) |
| MA (1) | MA20080A1 (en) |
| NO (1) | NO841270L (en) |
| NZ (1) | NZ207691A (en) |
| PH (1) | PH20465A (en) |
| PT (1) | PT78343B (en) |
| ZA (1) | ZA842389B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7683060B2 (en) | 2006-08-07 | 2010-03-23 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
| US7767675B2 (en) | 2006-11-22 | 2010-08-03 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| US8420645B2 (en) | 2008-05-21 | 2013-04-16 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US8487096B2 (en) | 2010-02-03 | 2013-07-16 | Incyte Corporation | Imidazo[1,2-B][1,2,4]triazines as C-MET inhibitors |
| US9187486B2 (en) | 2011-04-29 | 2015-11-17 | Amgen Inc. | Bicyclic pyridazine compounds as Pim inhibitors |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4654343A (en) * | 1985-10-31 | 1987-03-31 | American Cyanamid Company | N-substituted-N[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL128809C (en) * | 1966-06-18 | |||
| DE2113438A1 (en) * | 1971-03-19 | 1972-09-21 | Boehringer Mannheim Gmbh | Anti-microbial nitrofuryl-triazolo -(4,3-b) - pyridazine derivs - used for treating urinary system infections |
| US3915968A (en) * | 1973-09-21 | 1975-10-28 | Lepetit Spa | Triazolopyridazines |
| DE3217325A1 (en) * | 1982-05-08 | 1983-11-10 | Hoechst Ag, 6230 Frankfurt | 3-AMINO-6-ARYL-1,2,4-TRIAZOLO (4,3-B) -PYRIDAZINE, THEIR PRODUCTION AND USE |
| DE3222342A1 (en) * | 1982-06-14 | 1983-12-15 | Hoechst Ag, 6230 Frankfurt | 6-Aryl-1,2,4-triazolo[4,3-b]pyridazine-3-carbamates, their preparation and medicaments containing them |
-
1983
- 1983-03-31 DE DE19833311753 patent/DE3311753A1/en not_active Withdrawn
-
1984
- 1984-02-29 DK DK144884A patent/DK144884A/en not_active Application Discontinuation
- 1984-03-26 HU HU841204A patent/HU189076B/en unknown
- 1984-03-28 EP EP84710009A patent/EP0121490B1/en not_active Expired
- 1984-03-28 FI FI841238A patent/FI841238A/en not_active Application Discontinuation
- 1984-03-28 DE DE8484710009T patent/DE3469530D1/en not_active Expired
- 1984-03-28 AT AT84710009T patent/ATE32723T1/en not_active IP Right Cessation
- 1984-03-29 GR GR74257A patent/GR81812B/el unknown
- 1984-03-29 PH PH30469A patent/PH20465A/en unknown
- 1984-03-29 KR KR1019840001627A patent/KR840008361A/en not_active Application Discontinuation
- 1984-03-29 ES ES531084A patent/ES8501765A1/en not_active Expired
- 1984-03-29 NZ NZ207691A patent/NZ207691A/en unknown
- 1984-03-30 IL IL71412A patent/IL71412A/en unknown
- 1984-03-30 PT PT78343A patent/PT78343B/en not_active IP Right Cessation
- 1984-03-30 AU AU26346/84A patent/AU563556B2/en not_active Ceased
- 1984-03-30 ZA ZA842389A patent/ZA842389B/en unknown
- 1984-03-30 CA CA000451005A patent/CA1246568A/en not_active Expired
- 1984-03-30 NO NO841270A patent/NO841270L/en unknown
- 1984-03-30 JP JP59061286A patent/JPS59184179A/en active Pending
- 1984-03-31 MA MA20302A patent/MA20080A1/en unknown
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7915408B2 (en) | 2006-08-07 | 2011-03-29 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
| US8143251B2 (en) | 2006-08-07 | 2012-03-27 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
| US7683060B2 (en) | 2006-08-07 | 2010-03-23 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
| US9944645B2 (en) | 2006-11-22 | 2018-04-17 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| US7767675B2 (en) | 2006-11-22 | 2010-08-03 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| US11261191B2 (en) | 2006-11-22 | 2022-03-01 | Incyte Holdings Corporation | Imidazotriaines and imidazopyrimidines as kinase inhibitors |
| US8461330B2 (en) | 2006-11-22 | 2013-06-11 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| US10738052B2 (en) | 2006-11-22 | 2020-08-11 | Incyte Holdings Corporation | Imidazotriaines and imidazopyrimidines as kinase inhibitors |
| US10245265B2 (en) | 2008-05-21 | 2019-04-02 | Incyte Incorporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US8901123B2 (en) | 2008-05-21 | 2014-12-02 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US10799509B2 (en) | 2008-05-21 | 2020-10-13 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US8420645B2 (en) | 2008-05-21 | 2013-04-16 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US11452726B2 (en) | 2008-05-21 | 2022-09-27 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US9221824B2 (en) | 2010-02-03 | 2015-12-29 | Incyte Holdings Corporation | Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors |
| US9988387B2 (en) | 2010-02-03 | 2018-06-05 | Incyte Holdings Corporation | Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors |
| US10472367B2 (en) | 2010-02-03 | 2019-11-12 | Incyte Incorporation | Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors |
| US8487096B2 (en) | 2010-02-03 | 2013-07-16 | Incyte Corporation | Imidazo[1,2-B][1,2,4]triazines as C-MET inhibitors |
| US10919901B2 (en) | 2010-02-03 | 2021-02-16 | Incyte Holdings Corporation | Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors |
| US9187486B2 (en) | 2011-04-29 | 2015-11-17 | Amgen Inc. | Bicyclic pyridazine compounds as Pim inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA842389B (en) | 1984-11-28 |
| NZ207691A (en) | 1986-07-11 |
| EP0121490A1 (en) | 1984-10-10 |
| HU189076B (en) | 1986-06-30 |
| GR81812B (en) | 1984-12-12 |
| AU563556B2 (en) | 1987-07-16 |
| ES531084A0 (en) | 1984-12-01 |
| PT78343A (en) | 1984-04-01 |
| FI841238A (en) | 1984-10-01 |
| IL71412A (en) | 1988-05-31 |
| DK144884A (en) | 1984-10-01 |
| NO841270L (en) | 1984-10-01 |
| EP0121490B1 (en) | 1988-03-02 |
| HUT34193A (en) | 1985-02-28 |
| AU2634684A (en) | 1984-10-04 |
| MA20080A1 (en) | 1984-10-01 |
| KR840008361A (en) | 1984-12-14 |
| ATE32723T1 (en) | 1988-03-15 |
| DE3311753A1 (en) | 1984-10-04 |
| ES8501765A1 (en) | 1984-12-01 |
| DK144884D0 (en) | 1984-02-29 |
| FI841238A0 (en) | 1984-03-28 |
| IL71412A0 (en) | 1984-06-29 |
| PT78343B (en) | 1986-07-14 |
| PH20465A (en) | 1987-01-14 |
| DE3469530D1 (en) | 1988-04-07 |
| JPS59184179A (en) | 1984-10-19 |
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