CA1201122A - 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines, their preparation and their use - Google Patents
3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines, their preparation and their useInfo
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- CA1201122A CA1201122A CA000427630A CA427630A CA1201122A CA 1201122 A CA1201122 A CA 1201122A CA 000427630 A CA000427630 A CA 000427630A CA 427630 A CA427630 A CA 427630A CA 1201122 A CA1201122 A CA 1201122A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Abstract of the disclosure New 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyrida-zines of the general formula I
Description
~q~
The ;nvent;on relates to new 3-am;no-6-aryl-1,2,4-triazolo~4,3-b~pyridazines of the general formula I
Ej2 >==S
~r ~\ ,~=N
N ~ ¦
~N
N~
and their salts with a physiologically tolerated acid, wherein Ri and R2 are identical or different and re-present hydro~en, alkyl groups having 1-6 carbon atoms, phenyl or chlor;ne and Ar represents aromat;c rad;cals such as phenyl, biphenylyl, phenoxyphenyl, phenylth;o-phenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or
The ;nvent;on relates to new 3-am;no-6-aryl-1,2,4-triazolo~4,3-b~pyridazines of the general formula I
Ej2 >==S
~r ~\ ,~=N
N ~ ¦
~N
N~
and their salts with a physiologically tolerated acid, wherein Ri and R2 are identical or different and re-present hydro~en, alkyl groups having 1-6 carbon atoms, phenyl or chlor;ne and Ar represents aromat;c rad;cals such as phenyl, biphenylyl, phenoxyphenyl, phenylth;o-phenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or
2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methy(-2-pyrrolyl, 2-~ 3- or 4-pyridyl, ~h;ch can opt;onally be substituted by one, two, three, four or five radicals such as fluor;ne, chlorine, bromine, ;od;ne, alkyl groups having 1-6 carbon atoms~ cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1~4 alkyl carbon atoms, alkoxy or alkylth;o groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl groups, the;r esters w;th C1-C6-alcohols, aminocarbonyl, am;no, acetam;do or alkoxycarbonylam;no hav;ng 1-6 carbon 0 atoms ;n the alkyl radical~ ~
hmong the compounds of the general formula I, those are preferred ;n which R1 and R2 are ;dent;cal or different and denote hydrogel1, methyl, ethyl, phenyL or chlor;ne and in which Ar denotes phenyl, biphenylyl, 2-or 3-thienyl, 2-furyl, 2-~ 3- or 4-pyridyl ~hich can op-tionally be substituted by one, two or three fluorine, chlor;ne, bromine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups havin~ 3-6 carbon atoms or trifluoro-methyl~
Those compounds of the formula I in which R1 and R2 are identical or different and denote hydrogen, methyl or ethyl and Ar deriotes phenyl, 2- or 3-~hienyl, 2-, 3- or 4-pyr;dyl, opt;onally subst;tuted by one or two fluor;ne, chlorine, methyl, ethyl or tr;fluorome~hyl are particularly preferred.
The invention also relates to processes for the preparation of these compounds and pharmaceut;cal formu-lations of these compounds and their use as medicaments.
The process for the preparat;on of the compounds of the formula I comprises reac~ing an arylhydraz;nopyri-dazine of the -formula II
R1 R~
~ II
~r ~ ~ NHN~I2 wherein R1, R2 and Ar have the meanings ind;cated for formula I, a) with a cyclization reagent such as cyano~en chlo-ride, cyanogen brom;de~ 0-methyl;sourea or S-methyl;so-~5 thiourea, guan;d;ne or the;r sal~s, chloroformamidinehydrochLoride or cyanamide, or ~L2~
6, b) with a N-(R3~oxy)carbonyl-0-me~hylisourea, to give a cornpound of the formula III
~ r~
~1 3 NHCOO~
wherein Ar, R1 and R~ have the meanings indicated for formula I and R3 denotes alkyl having 1-10 carbon a~oms, benzyl or phenyl, and ~hen hydrolyzing the compound thus obtained, or c) comprises reacting a compound of the formula IV
l~r - ~ . IV
. ~
where;n R4 denotes chlor;ne, brom;ne or methylthio, and Ar, R1 and R2 have the meanin~s indicated for formula I, with ammonia, or d) comprises cyclizing a compound of the formula V
~ ~ ' V
Ar--6~ k NH Nl~ C N1l2 .
wherein Ar, R1 and R2 have the meanings indica~ed for formula I and ~ represents 0, S or NH, by heating~
opt;onally w;th the add;t;on of a condens1ng agent, to g;ve a compound of ~he formula I.
Compounds of the formula II are known, for example, from J. Heretocyclic Chem. 15, 881 (1978) and can be pre-pared from chlor;ne compounds of the formula VI
. ~
. Ar --~1 . VI
~;th hydrazine hydrate by processes known from the l;te-rature tThe Chem;stry of Heterocycl;c Compounds, Vol. 28, Pyr;daz;nes, Ed;tors A. Weissberger and E~C. Taylor, John ~;ley, New York 1973~. Both literature c;tat;ons also 1Q descr;be the synthes;s of the chlor;ne compounds VI and the;r precursors.
The process a) ;s cacr;ed out ;n a suitable sol-vent in a temperature range from 0C to the bo;l;ng po;nt of the solvent used, preferably at 50 to 100C.
Examples of su;table solvents for the process a) are water~ acet;c ac;d, al;phat;c alcohols, such as meth-anol, ethanol and ;sopropanol, dioxane, DMF~ toluene and chlorinated hydrocarbons, such as methyLene chlor;de, chloroform, d;chloroethane and carbon tetrachloride.
The process b) ;s carr;ed out in a su;table sol-vent in the presence of an ac;d. For example, ;t ;s carr;ed ou~ in a m;xture of methanol and glac;al acet;c ac;d in a volume ratio of, for example, 10 1 at the reflux temperature. The hydrolys;s of the carbam;nate III takes place under alkaline conditions by heating with an alkali retal or alkaline earth metal hydrox;de such as~ for . ~
example, NaOI~, K~H, CatOH)2 or Ba(OH)2 in a solvent or m;xture of solvents at 60-1~0C, preferably at 100-140C. Part;cularly su;table solvents are water and aliphatic aLcohols and diols such as ethanol~ propanol, isopropanol, butanol, 2-methoxyethanol and glycol.
For process c), the starting materials of the for-mula IV are converted, by heating arylhydrazinopyridazines II w;th form;c ac;d or i~s esters (when R4 = H), chloro-form;c esters or a dial~yl carbonate ~when R4 = ~H) or 1D with carbon disulfide and alkali ~when R~ ~ SH), op-tionally with the addition of a solvent or diluent, such as chloroform, toluene, dioxane~ water or ethanol, to give a compound of the formula IV' in which R~ denotes H, OH or SH. From this the corresponding compounds IV w;th R4 = Br, Cl or SCH3 are obtalned by heating ~ith bro-mine in glacial acetic acid/sodium acetate ~Ihen R4 = H), phosphorus oxychloride (when R~ = OH) or ~ethyl iodide or dimethyl sulfate (when R4 = SH).
According to process c), the reac~ion of the com-2n pounds of the formula IV takes place with liquid, aqueous or alcoholic ammonia, or with gaseous ammonia by passing in, or under pressure, in an inert solvent such as metha-nol~ dioxane or toluene. The temperature range extends from the temperature of liquid ammonia up to 200C.
According to process d), the compounds V obtained, for example, by reaction of chlorine compounds VI with semicarbazide, thiosemicarhazide or aminoguanidine in a solvent such as, for example, methanol~ ethanol~ lsopro-panol, D~F, tetrahydrofuran, toluene, chloroform or di-~ ~ ~2 chloroethane, are conver~ed into compounds of the formula I by heatin~, for example in one of the soLvents men--tioned, to ~0~150C, optionally with the addition of a condensing agent such as glacial acetic acid, cyclohexyl-carbod;imide or 1-hydroxybenzotriazole.
When the compounds of ~he formula I are obtained as salts by the processes described, then the correspond-;ng base can be liberated from these using ammonia, amines or hydrox;des.
The free bases of ~he formula I are converted into the corresponding salts with physiolog;cally tolerated acids. Suitable acids are inorganic or organic acids such as hydrochloric or hydrobromic acid, phosphoric acid, acetic acid, benzo;c acid~ citr;c acidO male;c acid, ~S fumar;c ac;d, lactic acid, tartaric acid, succinic acid, or acetylglyc;ne~ The hydrochlorides of the formula I
are preferred.
The compounds of the formula I according to the ;nvention are suitable for the preparation of medicaments.
~Q The medicaments can contain one or more of the compounds according to the invention or mixtures of them with other pharmaceutically active substances. In order to prepare the medicaments~ the customary pharmaceutica( vehicles and auxiliaries and known formulatin~ processes can be used. The medicamen~s can be used enterally, parenterally, orally or perlingually. For example, administration can take place in the form of tablets~ capsules, pills, coated tablets, suppositories~ gels, crearnsr powders, liquids~
dusting powders or aerosols. ~xamples of suitable liqu;ds are: oily or aqueous solutions or suspensions, emulsions, injectible aqueous solutions or suspensions.
Moreover, the compounds according to the inven-tion can be used as intermediate products for the prepara-t;on of other medicaments.
The following may be mentioned as compounds ac-cordin~ ~o the invention: 3-amino-6-t2-bromophenyl)-1,2,4-triazolo~4,3-bJpyridaz;ne, 3 amino-6-t2-trifluoromethyl-phenyl)-1~2,4-~riazolo~4,3-b~pyr;daz;ne, 3-amino-6-~4-chloro-3-tr;fluorome~hylphenyl)-1,2,4-triazoloC4,3-b~-pyridazine, 3-amino-6-t3-ethylphenyl)-1,2,4-triazoloC4~3-b~
pyridazine, 3-amino-6-(2-methylphenyl)-1,2,4-triazolo-C4,3-bJpyridazine, 3-amino-6-t2-ethylphenyl)-1f2,4-tri-azolor4,3-b]pyridazinef 3~am;no-6-(3-methoxyphenyl)-1,2r4-tr;azolo~',3-b]pyridazine, 3-amino-6-t4-propylthiophenyl)-1,2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-(4-acetamido-phenyl)-1,2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-t4-aminophenyl)-1,2,4-triazolo~4,3-bJpyridazine, 3-amino-6-t4-methoxycarbonylam;nophenyl)-1,2,4-~riazolo-C4,3~b~pyri-dazine, 3-am;no-6-(4-n;trophenyl)~1,2,4-triazolo~,3-b~-pyr;dazine, 3-amino-6-(3-nitrophenyl)-1,2,4-tr;azoLo-~4,3-b~pyr;dazine, 3-amino-6-(2-nitrophenyl~-1,2,4-tri-azolo~4,3-b]pyr;dazine, 3-amino-6-(4-cyanophenyl)-1,2,4-triazolo~4,3-bJpyridazine, 3-amino-6-(3-cyanophenyl)-1,2,4-~riazolo[4,3-b~pyridaz;ne, 3-am;no-6-(2-cyanophenyl)-1,2~4 tr;azolo~4,3-b]pyridazine, 3-amino-6-(4-phenylsulfinyl-phenyl)-1,2,4-triazolo/4,3-b7pyridazine~ 3-amino-6-(4-phenylsulfonylphenyl)-1,2~4 tr;azoloC4,3-b]pyridazine,
hmong the compounds of the general formula I, those are preferred ;n which R1 and R2 are ;dent;cal or different and denote hydrogel1, methyl, ethyl, phenyL or chlor;ne and in which Ar denotes phenyl, biphenylyl, 2-or 3-thienyl, 2-furyl, 2-~ 3- or 4-pyridyl ~hich can op-tionally be substituted by one, two or three fluorine, chlor;ne, bromine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups havin~ 3-6 carbon atoms or trifluoro-methyl~
Those compounds of the formula I in which R1 and R2 are identical or different and denote hydrogen, methyl or ethyl and Ar deriotes phenyl, 2- or 3-~hienyl, 2-, 3- or 4-pyr;dyl, opt;onally subst;tuted by one or two fluor;ne, chlorine, methyl, ethyl or tr;fluorome~hyl are particularly preferred.
The invention also relates to processes for the preparation of these compounds and pharmaceut;cal formu-lations of these compounds and their use as medicaments.
The process for the preparat;on of the compounds of the formula I comprises reac~ing an arylhydraz;nopyri-dazine of the -formula II
R1 R~
~ II
~r ~ ~ NHN~I2 wherein R1, R2 and Ar have the meanings ind;cated for formula I, a) with a cyclization reagent such as cyano~en chlo-ride, cyanogen brom;de~ 0-methyl;sourea or S-methyl;so-~5 thiourea, guan;d;ne or the;r sal~s, chloroformamidinehydrochLoride or cyanamide, or ~L2~
6, b) with a N-(R3~oxy)carbonyl-0-me~hylisourea, to give a cornpound of the formula III
~ r~
~1 3 NHCOO~
wherein Ar, R1 and R~ have the meanings indicated for formula I and R3 denotes alkyl having 1-10 carbon a~oms, benzyl or phenyl, and ~hen hydrolyzing the compound thus obtained, or c) comprises reacting a compound of the formula IV
l~r - ~ . IV
. ~
where;n R4 denotes chlor;ne, brom;ne or methylthio, and Ar, R1 and R2 have the meanin~s indicated for formula I, with ammonia, or d) comprises cyclizing a compound of the formula V
~ ~ ' V
Ar--6~ k NH Nl~ C N1l2 .
wherein Ar, R1 and R2 have the meanings indica~ed for formula I and ~ represents 0, S or NH, by heating~
opt;onally w;th the add;t;on of a condens1ng agent, to g;ve a compound of ~he formula I.
Compounds of the formula II are known, for example, from J. Heretocyclic Chem. 15, 881 (1978) and can be pre-pared from chlor;ne compounds of the formula VI
. ~
. Ar --~1 . VI
~;th hydrazine hydrate by processes known from the l;te-rature tThe Chem;stry of Heterocycl;c Compounds, Vol. 28, Pyr;daz;nes, Ed;tors A. Weissberger and E~C. Taylor, John ~;ley, New York 1973~. Both literature c;tat;ons also 1Q descr;be the synthes;s of the chlor;ne compounds VI and the;r precursors.
The process a) ;s cacr;ed out ;n a suitable sol-vent in a temperature range from 0C to the bo;l;ng po;nt of the solvent used, preferably at 50 to 100C.
Examples of su;table solvents for the process a) are water~ acet;c ac;d, al;phat;c alcohols, such as meth-anol, ethanol and ;sopropanol, dioxane, DMF~ toluene and chlorinated hydrocarbons, such as methyLene chlor;de, chloroform, d;chloroethane and carbon tetrachloride.
The process b) ;s carr;ed out in a su;table sol-vent in the presence of an ac;d. For example, ;t ;s carr;ed ou~ in a m;xture of methanol and glac;al acet;c ac;d in a volume ratio of, for example, 10 1 at the reflux temperature. The hydrolys;s of the carbam;nate III takes place under alkaline conditions by heating with an alkali retal or alkaline earth metal hydrox;de such as~ for . ~
example, NaOI~, K~H, CatOH)2 or Ba(OH)2 in a solvent or m;xture of solvents at 60-1~0C, preferably at 100-140C. Part;cularly su;table solvents are water and aliphatic aLcohols and diols such as ethanol~ propanol, isopropanol, butanol, 2-methoxyethanol and glycol.
For process c), the starting materials of the for-mula IV are converted, by heating arylhydrazinopyridazines II w;th form;c ac;d or i~s esters (when R4 = H), chloro-form;c esters or a dial~yl carbonate ~when R4 = ~H) or 1D with carbon disulfide and alkali ~when R~ ~ SH), op-tionally with the addition of a solvent or diluent, such as chloroform, toluene, dioxane~ water or ethanol, to give a compound of the formula IV' in which R~ denotes H, OH or SH. From this the corresponding compounds IV w;th R4 = Br, Cl or SCH3 are obtalned by heating ~ith bro-mine in glacial acetic acid/sodium acetate ~Ihen R4 = H), phosphorus oxychloride (when R~ = OH) or ~ethyl iodide or dimethyl sulfate (when R4 = SH).
According to process c), the reac~ion of the com-2n pounds of the formula IV takes place with liquid, aqueous or alcoholic ammonia, or with gaseous ammonia by passing in, or under pressure, in an inert solvent such as metha-nol~ dioxane or toluene. The temperature range extends from the temperature of liquid ammonia up to 200C.
According to process d), the compounds V obtained, for example, by reaction of chlorine compounds VI with semicarbazide, thiosemicarhazide or aminoguanidine in a solvent such as, for example, methanol~ ethanol~ lsopro-panol, D~F, tetrahydrofuran, toluene, chloroform or di-~ ~ ~2 chloroethane, are conver~ed into compounds of the formula I by heatin~, for example in one of the soLvents men--tioned, to ~0~150C, optionally with the addition of a condensing agent such as glacial acetic acid, cyclohexyl-carbod;imide or 1-hydroxybenzotriazole.
When the compounds of ~he formula I are obtained as salts by the processes described, then the correspond-;ng base can be liberated from these using ammonia, amines or hydrox;des.
The free bases of ~he formula I are converted into the corresponding salts with physiolog;cally tolerated acids. Suitable acids are inorganic or organic acids such as hydrochloric or hydrobromic acid, phosphoric acid, acetic acid, benzo;c acid~ citr;c acidO male;c acid, ~S fumar;c ac;d, lactic acid, tartaric acid, succinic acid, or acetylglyc;ne~ The hydrochlorides of the formula I
are preferred.
The compounds of the formula I according to the ;nvention are suitable for the preparation of medicaments.
~Q The medicaments can contain one or more of the compounds according to the invention or mixtures of them with other pharmaceutically active substances. In order to prepare the medicaments~ the customary pharmaceutica( vehicles and auxiliaries and known formulatin~ processes can be used. The medicamen~s can be used enterally, parenterally, orally or perlingually. For example, administration can take place in the form of tablets~ capsules, pills, coated tablets, suppositories~ gels, crearnsr powders, liquids~
dusting powders or aerosols. ~xamples of suitable liqu;ds are: oily or aqueous solutions or suspensions, emulsions, injectible aqueous solutions or suspensions.
Moreover, the compounds according to the inven-tion can be used as intermediate products for the prepara-t;on of other medicaments.
The following may be mentioned as compounds ac-cordin~ ~o the invention: 3-amino-6-t2-bromophenyl)-1,2,4-triazolo~4,3-bJpyridaz;ne, 3 amino-6-t2-trifluoromethyl-phenyl)-1~2,4-~riazolo~4,3-b~pyr;daz;ne, 3-amino-6-~4-chloro-3-tr;fluorome~hylphenyl)-1,2,4-triazoloC4,3-b~-pyridazine, 3-amino-6-t3-ethylphenyl)-1,2,4-triazoloC4~3-b~
pyridazine, 3-amino-6-(2-methylphenyl)-1,2,4-triazolo-C4,3-bJpyridazine, 3-amino-6-t2-ethylphenyl)-1f2,4-tri-azolor4,3-b]pyridazinef 3~am;no-6-(3-methoxyphenyl)-1,2r4-tr;azolo~',3-b]pyridazine, 3-amino-6-t4-propylthiophenyl)-1,2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-(4-acetamido-phenyl)-1,2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-t4-aminophenyl)-1,2,4-triazolo~4,3-bJpyridazine, 3-amino-6-t4-methoxycarbonylam;nophenyl)-1,2,4-~riazolo-C4,3~b~pyri-dazine, 3-am;no-6-(4-n;trophenyl)~1,2,4-triazolo~,3-b~-pyr;dazine, 3-amino-6-(3-nitrophenyl)-1,2,4-tr;azoLo-~4,3-b~pyr;dazine, 3-amino-6-(2-nitrophenyl~-1,2,4-tri-azolo~4,3-b]pyr;dazine, 3-amino-6-(4-cyanophenyl)-1,2,4-triazolo~4,3-bJpyridazine, 3-amino-6-(3-cyanophenyl)-1,2,4-~riazolo[4,3-b~pyridaz;ne, 3-am;no-6-(2-cyanophenyl)-1,2~4 tr;azolo~4,3-b]pyridazine, 3-amino-6-(4-phenylsulfinyl-phenyl)-1,2,4-triazolo/4,3-b7pyridazine~ 3-amino-6-(4-phenylsulfonylphenyl)-1,2~4 tr;azoloC4,3-b]pyridazine,
3-amino 6-(~-hydroxyphenyl)-1,2~4-triazolo~4,3-b~pyrida~
i z;ne, 3-amino-6~(3-hydroxyphPnyl)-1~2,~ triazoloC4,3-b]-pyridazine, 3-amino-6-~3,4-d;hydroxyphenyl)-1,2,4 triazolo-C4,3-b]pyridazine, 3-amino-6-(1-naphthyl)-1,2,4-triazolo-~4,3-b~pyr;daz;ne, 3-amino-6-(2-naphthyL)-1,2,4-tr;azolo-5 C4,3-b~pyr;daz;ne, 3-amino-6-(3-thienyl)-1,2,4-triazolo-C4~3-b~pyridazine, 3-am;no-6-t4-chloro-2-thienyl)-1,2,4-triazoloC4,3-b~pyridazine, 3-amino-6-(3-methyl-2-~hienyl)-1,2,4-triazoloC4,3-b~pyr;dazine~ 3-am;no-o-~4-methyl-2-th;enyl)-1,2,4-tr;azoloC4,3 b~pyridazine~ 3-amino-6-(2-furyl)-1,2,4-triazoloC4,3-b~pyr;daz;ne, 3-am;no-6-(5-methyl-2-furyl)-1,2,4-triazoloC4,3-b]pyr;dazine, 3-am;no-6-~4-pyridyl)-1f2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-~3~pyridyl)-1,2,4-tr;azoloC4~3-b]pyridazine, 3-amino~
6~2-pyr;dyl)-1,2,4-triazoloC4,3-b~pyr;dazine, 3-am;no-6-(2-pyrrolyl)-1,2,4-~riazolo~4,3-b]pyridazine and 3-amino-6-~1-methyl-2-pyrrolyl)-1,2,4-triazoloC4,3-b~pyri daz;ne.
The compounds of the formula I according to the ;nvention have pharmacological properties; in particular, ~0 they have anx;olyt;c and ant;convuls;ve effects. Thus, suitable indications are insomn;a, agitation and autonomic depression.
In general, the pharmaceutical formulations con-tain between 1 and 10% of the act;ve component(s) accor-d;ng to the ;nvent;on~
The anxiolytic effect of the compounds of theformula I is accompanied by a very slight sedation and good tolerance (LDso inter alia ~ 30n mg/kg i~pO in the mouse)D Th;s ;s clear from ;nvestigat;ons in which the ~JW~J ~ l~t effect of the compounds according to the invention on motor act;vity, hexobarbital-induced narcosis and cardia-zole-induced spasms in mice was measured~ In addition, the Geller anxiolysis test and the lick shock test were employed on rats.
In the tests ind;ca~ed above, examples of the lowest dose which still has activity are 5 mg/kg oral, 2~5 mg/kg sublingual and 1 mg/kg intravenous. Examples of generaLly suitable dose ranges for an effect (tests on an;mals as above) are: 5 to S0 mgtkg oral, 2.5 to 25 mg/
kg sublin~ual and 1 to 10 mg~kg intravenous.
For example, 1 to 3 tablets containing 10 to 100mg of act;ve substance can be adminîstered thr;ce daily or, for example for intravenous inject;on, a vial containing t5 2 to 4 ml w;th 0.5 to 5 mg of substance can be admin;s-tered once to thrice daily~
Example 1: Process a) 3-Amino~6-phenyl~1,2,4-triazolo~4,3-b~pyridazine hydro-chloride zn 25 g of 3-hydraYino-6-phenylpyridaz;ne and 17.1 g of cyanogen bromide in 150 ml of ethanol are stirred under reflux for 3 hours and then evaporated in a vacuum rotary evaporator. The residue is dissolved in hot water, fil tered and made alkaline w;th excess ammonia. The free base is filtered off w;th suct;on, washed to neutral;ty and dried, ~hen suspended ;n ethanol~ ethanolic hydro-chloric acid is added, and evaporated in vacuo~
The precipitated hydrochloride is filtered off wi~h suction, washed with ethanol and dr;ed, melting ,:
point 28CC (decomposition).
Example 2: Process a) 3-Amino~6-(4-fluorophenyl~-1,2,4-~riazoloC4,3~b~pyrida-z;ne hydrochloride A slight excess of cyanogen chloride is passed ;nto a solution of 5 9 of 3-(4-fluorophenyl)-6-hydrazino-pyr;daz;ne ;n 50 ml of ethanol at 0 - 10C and st;rring ;s continued at room temperature unt;l react;on is com-plete (checked by TLC).
The prec;pitated hydrochlor;de is filtered off w;th suct;on, washed w;th isopropanol and dried, melting po;nt 284C (decompos;t;on).
Example 3: Process b) 3-Amino-6-(3,4-dichlorophenyl)-102,4-~riazolor4,3-b]pyr;-daz;ne.
3 9 of 6~3,~i,-d;chlorophenyl~-3-methoxycarbonyl-amjno-1,2,4-tr;azolo~4,3-b~pyr;dazine and 3 g of potas-s;um hydroxide ;n 10 ml of water and 20 ml of 2-methoxy-ethanol are heated to reflux for 16 hours.
The prec;p;tated product is f;ltered off w;~h suction, washed to neutrality and recrystallized from iso-propar;ol, melting point 281C~
Example 4: Process c) ~ -Methylphenyl)~1,2,4-tr;azolo~4~3-b~pyr;daz;ne 5 g of ~-hydrazino-6-(4-methylphenyl)pyridazine ;n 1n ml of formic acid are stirred under reflux for 2 hours. After cooling down, the mixture ;s ~;luted with water and the prec;p;~ated product is filtered off w;th suction, washed to neutrali.y and dried, melting point ~2~2~
186C.
Example 5: Process c~
3-~romo-6-~4~methylphenyL)-1,2,4-tr;azolo~4,3-b~pyrida-z;ne ~ g of 6-(4-methylphenyl)-1,2,4-triazoloC4,3-b~-pyr;dazine and 3 g of sod;um acetate are suspended in 20 ml of glacial ace~ic acid. 1 ml of bromine in 5 ml of glacial acetic ac;d are added dropw;se and the solution is heated to reflux for S hours. It is then evaporated to dryness, water ;s added a~d the product ;s filtered off ~ith suction. After recrys~allizat;on from ;sopropanol and drying, the melting point is 211C.
Example 6: Process c~
3 Amino-6-~4-me~hylphenyl)-1,2,4-triazolo~4,3-bJpyr;daz;ne 3 g of 3-bromo-6-(~-methylphenyl)-1,2,4-tr;azolo-~4,3-b3pyr;daz;ne are treated w;th 25 ml of methanol and 25 ml of concentrated ammon;a solut;on ;n an autoclave at 100C. After cool;ng down, the m;xture is d;luted ~;th ~ater, f;ltered off w;ch suct;on, washed to neutra-lity and dr;ed, melt;ng po;nt 261Co Example 7: Process d) 3-Phenyl-6-thiosem;carbazidopyridazine 6 g of 3 chloro-6-phenylpyr;daz;ne and 6 g of th;osem;carbazide in 60 ml of ethanol are heated to re-flux for 3 hours. The prec;pi~ate produced ;s fil~eredoff w;th suct;on, washed w;th ethanoL and water and dr;ed ;n vacuo, MeLt;n~ point 213C (decomposition~.
~xample 8: Process d~
3-Amino-6-phenyL-1,2,4-tr;azolo~4,3-b3pyr;dazine ~20~
2 ~ of 3-phenyl-6-thiosem;carbazidopyridazine in 20 rnl of glaciaL acetic acid are heated to reflux for 6 hours. After evaporation of the reaction solution, the residue is thoroughly stirred with aqueous ammonia, fil-S tered off with suction, washed with water to neutrality,dried and recrystalLized from isopropanoL, meLting point 21 2C .
The follo~,~ing compounds can be prepared in anaLogy to Examp Les 1 - 8:
ExampLe Compound Melting SaltProcess poi nt 9. 3-Amino-6-(4-bromophenyL)-1,2,4- 317C HBr b triazoloL4,3-b~pyridazine (decomp.) 10. 3-Amino-6-(4-chlorophenyl)- 264C - c 1,2,4-triazolo[4,3-b~pyridazine 11~ 3-Amino-6-(4-iodophenyl)-1,2,4- a triazolo~4,3 b3pyridazine 12. 3-Amino-6-(4-trif luoromethyl- 289C HCl a phenyl)-1,2,4-triazolo[4,3-b~-(de-comp.)`
pyridazine 13. 3-Amino-6-(3-bromophenyl)-1,2,4- 273C HCl d tr;azolor4,3-b~pyridazine (decomp`.) 14. 3-Amino-6-(3-chlorophenyl)- 288C HCl a 1,2,4-triazolo~4,3-b~pyr;daz;ne(decomp.) 15. 3-Amino-6-(3-f luorophenyl)- 266C HCl a 1,2,4-~riazolor4,3-b~pyridazine(decomp.) 16. 3-Amino-6-(3-trif LuoromethyL- 276C HCL a pheny l)-1,2,4-t ri azoLo r4,3-t~ - (decomp. ) pyridazi ne 17. 3-Amino-6-(2-chlorophenyl)- 258C HCl a 1,2,4-triazolo~4,3-bJpyridazine(decomp.) 18. 3-Amino-6-(2-fluorophenyl)- 234C HCL a 1,2,4-triazoLo~4,3-b~pyridazine(decomp.) - 14 ~
Example Compound Melting Salt Process point 19. 3-Amino-6-(4-ethylphenyl)- 263C HCl b 1,2,4-triazolor4,3-b~pyridazine (deccmp.) 20. 3-Amino-6~(4-isopropylphenyl)- 253C HCl d 1,2,4-triazolof4,3-b3pyridazine (decomp.) 21. 3-Amino-6-(4-tert.butylphenyl)- 272C HCl d 1,2,4-triazolo[4,3-b~pyridazine (decomp.) 22. 3-Amino-6-(4-cyclohexylphenyl)- 259C HCL a 1,2,4-triazolo[4,3-b~pyridazine (decomp.~
23. 3-Amino-6-(4-biphenylyl)-1,2,4- 274C HCl a triazolor4,3-b3pyridazine (decomp.) 24. 3-Amino-6-(4-benzylphenyl)- 297C HBr c 1,2,4-triazolor4,3-blpyridazine (decomp.) 25. 3-Amino-6-(3-methylphenyl)- 290C HCl c 1,2,4-tr;azolo~4,3-b~pyridazine (decomp.) 26. 3-Amino-6-(4-methoxyphenyl)- 275C HC l d 1,2,4~triazolor4,3-b~pyr;daz;ne ~decom~.) 27. 3-Am;no-6-(3,4-dimethoxyphenyl)- 259C HBr a 1~2,4-triazolo~4,3-b~pyridazine (decomp.) 28. 3 Amino-6 (4-methylthiophenyl)- 316C HCl a 1,2,4-tr;azolor4,3-b3pyridazine (decomp.) 29. 3-Amino-6-(4-phenoxyphenyl)- 236C H C l a 152,4-triazolo~4,3-b~pyridazine 30. 3-Am;no-6-(4-phenylthiophenyl)- 274C HCl a 1,2,4-triazolor4,3-b~pyridazine 31. 3-Amino-6-(2-thienyl)-1,2,4- 280C HCl a tr;azolo~4,3-b~pyridazine 32. 3-Amino-6-(5-methyl-2-thienyl)- 318C HCl a 1,2,4 triazolof4,3-blpyr;dazine (decomp.) 33. 3-Amino-6-(5-chloro-2-thienyl)- 306C HCl a 1,2,4-triazoLor4,3-b~pyridazine (decomp.) 34. 3-Amino-6-(5-bromo-2-thienyl)- 316C HCl b 1,2,4-triazolor4,3-b~pyridazine (decomp.)
i z;ne, 3-amino-6~(3-hydroxyphPnyl)-1~2,~ triazoloC4,3-b]-pyridazine, 3-amino-6-~3,4-d;hydroxyphenyl)-1,2,4 triazolo-C4,3-b]pyridazine, 3-amino-6-(1-naphthyl)-1,2,4-triazolo-~4,3-b~pyr;daz;ne, 3-amino-6-(2-naphthyL)-1,2,4-tr;azolo-5 C4,3-b~pyr;daz;ne, 3-amino-6-(3-thienyl)-1,2,4-triazolo-C4~3-b~pyridazine, 3-am;no-6-t4-chloro-2-thienyl)-1,2,4-triazoloC4,3-b~pyridazine, 3-amino-6-(3-methyl-2-~hienyl)-1,2,4-triazoloC4,3-b~pyr;dazine~ 3-am;no-o-~4-methyl-2-th;enyl)-1,2,4-tr;azoloC4,3 b~pyridazine~ 3-amino-6-(2-furyl)-1,2,4-triazoloC4,3-b~pyr;daz;ne, 3-am;no-6-(5-methyl-2-furyl)-1,2,4-triazoloC4,3-b]pyr;dazine, 3-am;no-6-~4-pyridyl)-1f2,4-tr;azoloC4,3-bJpyridazine, 3-amino-6-~3~pyridyl)-1,2,4-tr;azoloC4~3-b]pyridazine, 3-amino~
6~2-pyr;dyl)-1,2,4-triazoloC4,3-b~pyr;dazine, 3-am;no-6-(2-pyrrolyl)-1,2,4-~riazolo~4,3-b]pyridazine and 3-amino-6-~1-methyl-2-pyrrolyl)-1,2,4-triazoloC4,3-b~pyri daz;ne.
The compounds of the formula I according to the ;nvention have pharmacological properties; in particular, ~0 they have anx;olyt;c and ant;convuls;ve effects. Thus, suitable indications are insomn;a, agitation and autonomic depression.
In general, the pharmaceutical formulations con-tain between 1 and 10% of the act;ve component(s) accor-d;ng to the ;nvent;on~
The anxiolytic effect of the compounds of theformula I is accompanied by a very slight sedation and good tolerance (LDso inter alia ~ 30n mg/kg i~pO in the mouse)D Th;s ;s clear from ;nvestigat;ons in which the ~JW~J ~ l~t effect of the compounds according to the invention on motor act;vity, hexobarbital-induced narcosis and cardia-zole-induced spasms in mice was measured~ In addition, the Geller anxiolysis test and the lick shock test were employed on rats.
In the tests ind;ca~ed above, examples of the lowest dose which still has activity are 5 mg/kg oral, 2~5 mg/kg sublingual and 1 mg/kg intravenous. Examples of generaLly suitable dose ranges for an effect (tests on an;mals as above) are: 5 to S0 mgtkg oral, 2.5 to 25 mg/
kg sublin~ual and 1 to 10 mg~kg intravenous.
For example, 1 to 3 tablets containing 10 to 100mg of act;ve substance can be adminîstered thr;ce daily or, for example for intravenous inject;on, a vial containing t5 2 to 4 ml w;th 0.5 to 5 mg of substance can be admin;s-tered once to thrice daily~
Example 1: Process a) 3-Amino~6-phenyl~1,2,4-triazolo~4,3-b~pyridazine hydro-chloride zn 25 g of 3-hydraYino-6-phenylpyridaz;ne and 17.1 g of cyanogen bromide in 150 ml of ethanol are stirred under reflux for 3 hours and then evaporated in a vacuum rotary evaporator. The residue is dissolved in hot water, fil tered and made alkaline w;th excess ammonia. The free base is filtered off w;th suct;on, washed to neutral;ty and dried, ~hen suspended ;n ethanol~ ethanolic hydro-chloric acid is added, and evaporated in vacuo~
The precipitated hydrochloride is filtered off wi~h suction, washed with ethanol and dr;ed, melting ,:
point 28CC (decomposition).
Example 2: Process a) 3-Amino~6-(4-fluorophenyl~-1,2,4-~riazoloC4,3~b~pyrida-z;ne hydrochloride A slight excess of cyanogen chloride is passed ;nto a solution of 5 9 of 3-(4-fluorophenyl)-6-hydrazino-pyr;daz;ne ;n 50 ml of ethanol at 0 - 10C and st;rring ;s continued at room temperature unt;l react;on is com-plete (checked by TLC).
The prec;pitated hydrochlor;de is filtered off w;th suct;on, washed w;th isopropanol and dried, melting po;nt 284C (decompos;t;on).
Example 3: Process b) 3-Amino-6-(3,4-dichlorophenyl)-102,4-~riazolor4,3-b]pyr;-daz;ne.
3 9 of 6~3,~i,-d;chlorophenyl~-3-methoxycarbonyl-amjno-1,2,4-tr;azolo~4,3-b~pyr;dazine and 3 g of potas-s;um hydroxide ;n 10 ml of water and 20 ml of 2-methoxy-ethanol are heated to reflux for 16 hours.
The prec;p;tated product is f;ltered off w;~h suction, washed to neutrality and recrystallized from iso-propar;ol, melting point 281C~
Example 4: Process c) ~ -Methylphenyl)~1,2,4-tr;azolo~4~3-b~pyr;daz;ne 5 g of ~-hydrazino-6-(4-methylphenyl)pyridazine ;n 1n ml of formic acid are stirred under reflux for 2 hours. After cooling down, the mixture ;s ~;luted with water and the prec;p;~ated product is filtered off w;th suction, washed to neutrali.y and dried, melting point ~2~2~
186C.
Example 5: Process c~
3-~romo-6-~4~methylphenyL)-1,2,4-tr;azolo~4,3-b~pyrida-z;ne ~ g of 6-(4-methylphenyl)-1,2,4-triazoloC4,3-b~-pyr;dazine and 3 g of sod;um acetate are suspended in 20 ml of glacial ace~ic acid. 1 ml of bromine in 5 ml of glacial acetic ac;d are added dropw;se and the solution is heated to reflux for S hours. It is then evaporated to dryness, water ;s added a~d the product ;s filtered off ~ith suction. After recrys~allizat;on from ;sopropanol and drying, the melting point is 211C.
Example 6: Process c~
3 Amino-6-~4-me~hylphenyl)-1,2,4-triazolo~4,3-bJpyr;daz;ne 3 g of 3-bromo-6-(~-methylphenyl)-1,2,4-tr;azolo-~4,3-b3pyr;daz;ne are treated w;th 25 ml of methanol and 25 ml of concentrated ammon;a solut;on ;n an autoclave at 100C. After cool;ng down, the m;xture is d;luted ~;th ~ater, f;ltered off w;ch suct;on, washed to neutra-lity and dr;ed, melt;ng po;nt 261Co Example 7: Process d) 3-Phenyl-6-thiosem;carbazidopyridazine 6 g of 3 chloro-6-phenylpyr;daz;ne and 6 g of th;osem;carbazide in 60 ml of ethanol are heated to re-flux for 3 hours. The prec;pi~ate produced ;s fil~eredoff w;th suct;on, washed w;th ethanoL and water and dr;ed ;n vacuo, MeLt;n~ point 213C (decomposition~.
~xample 8: Process d~
3-Amino-6-phenyL-1,2,4-tr;azolo~4,3-b3pyr;dazine ~20~
2 ~ of 3-phenyl-6-thiosem;carbazidopyridazine in 20 rnl of glaciaL acetic acid are heated to reflux for 6 hours. After evaporation of the reaction solution, the residue is thoroughly stirred with aqueous ammonia, fil-S tered off with suction, washed with water to neutrality,dried and recrystalLized from isopropanoL, meLting point 21 2C .
The follo~,~ing compounds can be prepared in anaLogy to Examp Les 1 - 8:
ExampLe Compound Melting SaltProcess poi nt 9. 3-Amino-6-(4-bromophenyL)-1,2,4- 317C HBr b triazoloL4,3-b~pyridazine (decomp.) 10. 3-Amino-6-(4-chlorophenyl)- 264C - c 1,2,4-triazolo[4,3-b~pyridazine 11~ 3-Amino-6-(4-iodophenyl)-1,2,4- a triazolo~4,3 b3pyridazine 12. 3-Amino-6-(4-trif luoromethyl- 289C HCl a phenyl)-1,2,4-triazolo[4,3-b~-(de-comp.)`
pyridazine 13. 3-Amino-6-(3-bromophenyl)-1,2,4- 273C HCl d tr;azolor4,3-b~pyridazine (decomp`.) 14. 3-Amino-6-(3-chlorophenyl)- 288C HCl a 1,2,4-triazolo~4,3-b~pyr;daz;ne(decomp.) 15. 3-Amino-6-(3-f luorophenyl)- 266C HCl a 1,2,4-~riazolor4,3-b~pyridazine(decomp.) 16. 3-Amino-6-(3-trif LuoromethyL- 276C HCL a pheny l)-1,2,4-t ri azoLo r4,3-t~ - (decomp. ) pyridazi ne 17. 3-Amino-6-(2-chlorophenyl)- 258C HCl a 1,2,4-triazolo~4,3-bJpyridazine(decomp.) 18. 3-Amino-6-(2-fluorophenyl)- 234C HCL a 1,2,4-triazoLo~4,3-b~pyridazine(decomp.) - 14 ~
Example Compound Melting Salt Process point 19. 3-Amino-6-(4-ethylphenyl)- 263C HCl b 1,2,4-triazolor4,3-b~pyridazine (deccmp.) 20. 3-Amino-6~(4-isopropylphenyl)- 253C HCl d 1,2,4-triazolof4,3-b3pyridazine (decomp.) 21. 3-Amino-6-(4-tert.butylphenyl)- 272C HCl d 1,2,4-triazolo[4,3-b~pyridazine (decomp.) 22. 3-Amino-6-(4-cyclohexylphenyl)- 259C HCL a 1,2,4-triazolo[4,3-b~pyridazine (decomp.~
23. 3-Amino-6-(4-biphenylyl)-1,2,4- 274C HCl a triazolor4,3-b3pyridazine (decomp.) 24. 3-Amino-6-(4-benzylphenyl)- 297C HBr c 1,2,4-triazolor4,3-blpyridazine (decomp.) 25. 3-Amino-6-(3-methylphenyl)- 290C HCl c 1,2,4-tr;azolo~4,3-b~pyridazine (decomp.) 26. 3-Amino-6-(4-methoxyphenyl)- 275C HC l d 1,2,4~triazolor4,3-b~pyr;daz;ne ~decom~.) 27. 3-Am;no-6-(3,4-dimethoxyphenyl)- 259C HBr a 1~2,4-triazolo~4,3-b~pyridazine (decomp.) 28. 3 Amino-6 (4-methylthiophenyl)- 316C HCl a 1,2,4-tr;azolor4,3-b3pyridazine (decomp.) 29. 3-Amino-6-(4-phenoxyphenyl)- 236C H C l a 152,4-triazolo~4,3-b~pyridazine 30. 3-Am;no-6-(4-phenylthiophenyl)- 274C HCl a 1,2,4-triazolor4,3-b~pyridazine 31. 3-Amino-6-(2-thienyl)-1,2,4- 280C HCl a tr;azolo~4,3-b~pyridazine 32. 3-Amino-6-(5-methyl-2-thienyl)- 318C HCl a 1,2,4 triazolof4,3-blpyr;dazine (decomp.) 33. 3-Amino-6-(5-chloro-2-thienyl)- 306C HCl a 1,2,4-triazoLor4,3-b~pyridazine (decomp.) 34. 3-Amino-6-(5-bromo-2-thienyl)- 316C HCl b 1,2,4-triazolor4,3-b~pyridazine (decomp.)
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazine of the formula I
I
and their salts with a physiologically tolerated acid, wherein R1 and R2 are identical or different and represent hydrogen, alkyl groups having 1 - 6 carbon atoms, phenyl or chlorine and Ar represents aromatic radicals selected from the group of phenyl, biphenylyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphthyl, 2 or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which may be substituted by one, two, three, four or five radicals selected from the group fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl groups, their esters with C1-C6-alcohols, aminocarbonyl, amino, acetamido or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical, in which an arylhydrazinopyridazine of the formula II
II
wherein R1, R2 and Ar are as defined for the formula I, (a) is reacted with a cyclization reagent, or (b) is reacted with a N-(R3-oxy)carbonyl-0-methylisourea, to give a compound of the formula III
III
wherein Ar, R1 and R2 are as defined for the formula I
and R3 denotes alkyl having 1-10 carbon atoms, benzyl or phenyl and the compound thus obtained is hydrolyzed, or (c) a compound of the formula IV
IV
wherein R4 denotes chlorine, bromine or methylthio, and Ar, R1, and R2 are as defined for the formula I is reacted with ammonia, or (d) a compound of the formula V
V
wherein Ar, R1 and R2 are as defined for the formula I and Z represents 0, S or NH, is cyclized by heating to give a compound of the formula I, and the resultant compounds may be converted into a salt with a physiologically tolerated acid.
I
and their salts with a physiologically tolerated acid, wherein R1 and R2 are identical or different and represent hydrogen, alkyl groups having 1 - 6 carbon atoms, phenyl or chlorine and Ar represents aromatic radicals selected from the group of phenyl, biphenylyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphthyl, 2 or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which may be substituted by one, two, three, four or five radicals selected from the group fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl groups, their esters with C1-C6-alcohols, aminocarbonyl, amino, acetamido or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical, in which an arylhydrazinopyridazine of the formula II
II
wherein R1, R2 and Ar are as defined for the formula I, (a) is reacted with a cyclization reagent, or (b) is reacted with a N-(R3-oxy)carbonyl-0-methylisourea, to give a compound of the formula III
III
wherein Ar, R1 and R2 are as defined for the formula I
and R3 denotes alkyl having 1-10 carbon atoms, benzyl or phenyl and the compound thus obtained is hydrolyzed, or (c) a compound of the formula IV
IV
wherein R4 denotes chlorine, bromine or methylthio, and Ar, R1, and R2 are as defined for the formula I is reacted with ammonia, or (d) a compound of the formula V
V
wherein Ar, R1 and R2 are as defined for the formula I and Z represents 0, S or NH, is cyclized by heating to give a compound of the formula I, and the resultant compounds may be converted into a salt with a physiologically tolerated acid.
2. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a).
3. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b).
4. A 3-amino-6-ary-1,2,4-triazolo[4,3-b]pyrida-zine of the formula I as defined in claim 1, and the salts thereof with physiologically tolerated acids, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which the preparation is carried out according to reaction (c).
6. A process as claimed in claim 1 in which the preparation is carried out according to reaction (d).
7. A 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyrida-zine of the formula I as defined in claim 1, and the salts thereof with physiologically tolerated acids, whenever obtained according to a process as claimed in claim 5 or claim 6 or by an obvious chemical equivalent thereof.
8. A process as claimed in claim 1 wherein R1 and R2 are identical or different and denote hydrogen, methyl, ethyl, phenyl or chlorine and in which Ar denotes phenyl, biphenylyl, 2- or 3-thienyl 7 2-furyl, 2-, 3- or 4-pyridyl which may be substituted by one, two or three fluorine, chlorine, bromine, alkyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms or trifluoromethyl.
9. A 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyrida-zine of the formula I as set forth in claim 1 wherein R1, R2 and Ar are as defined in claim 8, whenever obtained according to a process as claimed in claim 8 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3217325.3 | 1982-05-08 | ||
| DE19823217325 DE3217325A1 (en) | 1982-05-08 | 1982-05-08 | 3-AMINO-6-ARYL-1,2,4-TRIAZOLO (4,3-B) -PYRIDAZINE, THEIR PRODUCTION AND USE |
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|---|---|
| CA1201122A true CA1201122A (en) | 1986-02-25 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3311753A1 (en) * | 1983-03-31 | 1984-10-04 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINE - THEIR PRODUCTION AND USE - |
| FR2562071B1 (en) * | 1984-03-30 | 1986-12-19 | Sanofi Sa | TRIAZOLO (4,3-B) PYRIDAZINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4654343A (en) * | 1985-10-31 | 1987-03-31 | American Cyanamid Company | N-substituted-N[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas |
| CA2589102C (en) | 2004-11-02 | 2013-08-13 | Northwestern University | Pyridazine compounds and methods for using the compounds to treat inflammatory diseases |
| JP5337375B2 (en) | 2004-11-02 | 2013-11-06 | ノースウェスタン ユニバーシティ | Pyridazine compounds, compositions and methods |
| CN101754762A (en) | 2006-04-28 | 2010-06-23 | 西北大学 | Formulations comprising pyridazine compounds for the treatment of neuroinflammatory diseases |
| EP2015750A2 (en) | 2006-04-28 | 2009-01-21 | Northwestern University | Compositions and treatments using pyridazine compounds and cholinesterase inhibitors |
| EP2131839A2 (en) * | 2007-03-02 | 2009-12-16 | Northwestern University | Compositions comprising derivatives of 3-phenylpyridazine for treating seizure-related disorders |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL128809C (en) * | 1966-06-18 | |||
| US3708484A (en) * | 1970-10-16 | 1973-01-02 | Sandoz Ag | Amino and substituted amino-s-triazolo-(4,3-b)-pyridazines |
| DE2113438A1 (en) * | 1971-03-19 | 1972-09-21 | Boehringer Mannheim Gmbh | Anti-microbial nitrofuryl-triazolo -(4,3-b) - pyridazine derivs - used for treating urinary system infections |
| CA1080712A (en) * | 1976-09-22 | 1980-07-01 | Jay D. Albright | Hypotensive agents |
| US4260756A (en) * | 1979-11-15 | 1981-04-07 | American Cyanamid Company | 6- And 8-heteroaryl-1,2,4-triazolo[4,3-b]pyridazines |
-
1982
- 1982-05-08 DE DE19823217325 patent/DE3217325A1/en not_active Withdrawn
-
1983
- 1983-05-04 GR GR71294A patent/GR79281B/el unknown
- 1983-05-05 EP EP83104427A patent/EP0094038B1/en not_active Expired
- 1983-05-05 DE DE8383104427T patent/DE3368931D1/en not_active Expired
- 1983-05-05 AT AT83104427T patent/ATE24728T1/en not_active IP Right Cessation
- 1983-05-05 FI FI831548A patent/FI831548L/en not_active Application Discontinuation
- 1983-05-06 IL IL68611A patent/IL68611A0/en unknown
- 1983-05-06 CA CA000427630A patent/CA1201122A/en not_active Expired
- 1983-05-06 JP JP58078423A patent/JPS58203992A/en active Pending
- 1983-05-06 ZA ZA833239A patent/ZA833239B/en unknown
- 1983-05-06 NZ NZ204153A patent/NZ204153A/en unknown
- 1983-05-06 AU AU14343/83A patent/AU1434383A/en not_active Abandoned
- 1983-05-06 IE IE1043/83A patent/IE55096B1/en unknown
- 1983-05-06 ES ES522144A patent/ES8405800A1/en not_active Expired
- 1983-05-06 DK DK204783A patent/DK204783A/en not_active Application Discontinuation
- 1983-05-06 HU HU831579A patent/HU189277B/en unknown
- 1983-05-06 NO NO831614A patent/NO831614L/en unknown
- 1983-05-06 MA MA20012A patent/MA19791A1/en unknown
- 1983-05-06 KR KR1019830001924A patent/KR840004753A/en not_active Application Discontinuation
- 1983-05-06 PT PT76654A patent/PT76654B/en unknown
-
1984
- 1984-03-15 ES ES530639A patent/ES8501399A1/en not_active Expired
- 1984-03-15 ES ES530638A patent/ES8501398A1/en not_active Expired
- 1984-03-15 ES ES530640A patent/ES530640A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58203992A (en) | 1983-11-28 |
| NO831614L (en) | 1983-11-09 |
| PT76654A (en) | 1983-06-01 |
| ES522144A0 (en) | 1984-06-16 |
| EP0094038B1 (en) | 1987-01-07 |
| ES530638A0 (en) | 1984-11-16 |
| ATE24728T1 (en) | 1987-01-15 |
| ES8501400A1 (en) | 1984-11-16 |
| EP0094038A1 (en) | 1983-11-16 |
| ES530640A0 (en) | 1984-11-16 |
| DK204783A (en) | 1983-11-09 |
| ES530639A0 (en) | 1984-11-16 |
| IL68611A0 (en) | 1983-09-30 |
| GR79281B (en) | 1984-10-22 |
| HU189277B (en) | 1986-06-30 |
| AU1434383A (en) | 1983-11-10 |
| IE831043L (en) | 1983-11-08 |
| MA19791A1 (en) | 1983-12-31 |
| NZ204153A (en) | 1985-04-30 |
| FI831548L (en) | 1983-11-09 |
| ZA833239B (en) | 1984-01-25 |
| ES8501399A1 (en) | 1984-11-16 |
| DE3368931D1 (en) | 1987-02-12 |
| FI831548A0 (en) | 1983-05-05 |
| KR840004753A (en) | 1984-10-24 |
| DK204783D0 (en) | 1983-05-06 |
| IE55096B1 (en) | 1990-05-23 |
| DE3217325A1 (en) | 1983-11-10 |
| ES8501398A1 (en) | 1984-11-16 |
| PT76654B (en) | 1986-01-28 |
| ES8405800A1 (en) | 1984-06-16 |
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