NZ206696A - 1,2,3-triazole derivatives and pharmaceutical compositions - Google Patents

1,2,3-triazole derivatives and pharmaceutical compositions

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Publication number
NZ206696A
NZ206696A NZ206696A NZ20669683A NZ206696A NZ 206696 A NZ206696 A NZ 206696A NZ 206696 A NZ206696 A NZ 206696A NZ 20669683 A NZ20669683 A NZ 20669683A NZ 206696 A NZ206696 A NZ 206696A
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New Zealand
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lower alkyl
triazole
amino
formula
carboxamide
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NZ206696A
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R Meier
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Ciba Geigy Ag
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Publication of NZ206696A publication Critical patent/NZ206696A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

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  • General Chemical & Material Sciences (AREA)
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  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £06696 2 066 96 Priority Date(s): Complete Specification Filed: Class: . .ft £jj£3t/4h)....
Publication Date: .... .2-1-F6B-1986— P.O. Journal, No: Patents Form Nd. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "ARALKYLTRIAZOLE COMPOUNDS" f A?$ - Krto WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us,.and the method by which it is to be performed, to be particularly described in and by the following statement (follcwed ty IA> - 1A - 206696 Case 4-14247/+ Neuseeland Aralkyltriazole compounds The invention relates to novel aralkyltriazole compounds, especially 1-phenyl-lower alkyl-1H-1,2,3 triazole compounds of the formula / N=N Ph-alk-N \ id.
R1R2 in which Ph represents phenyl substituted by lower alkyl, halogen and/or trifluoromethyl, alk represents lower alkylidene, Rj represents hydrogen, lower alkyl, lower alkoxy, or an amino group or carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, " oxa- or thia-lower alkylene, and fhs 2 066 9 R2 represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene or, if represents an amino group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents cyano or, if R1 represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen or lower alkyl, and to salts of salt-forming compounds of the formula I and to processes for the manufacture of the novel compounds, to pharmaceutical preparations containing these compounds and to the use thereof.
The phenyl radical Ph contains, for example, up to and including three, especially one or two, of the mentioned substituents.
The invention relates, for example, to those compounds of the formula I in which Ph represents phenyl substituted in the 2-position by lower alkyl, halogen or trifluoromethyl and optionally substituted, in addition, by lower alkyl or halogen, which is located, for example, in the 3-, 4- or 6-position, preferably in the 3- or 6-position, alk represents lower alkylidene, R^ represents hydrogen, lower alkyl, lower alkoxy, or an amino group or carbamoyl group that is unsubstituted or substituted by lower alkyl and R2 represents carbamoyl that is unsubstituted or substituted by lower alkyl or, if R^ represents amino that is unsubstituted or substituted by lower alkyl, represents cyano, to processes for their manufacture, to pharmaceutical preparations containing these compounds and to the use thereof. 206696 Amino optionally substituted by acyl, lower alkyl, lower alkylene or by aza-, oxa- or thia-lower alkylene is, for example, amino, acylamino, wherein acyl is easily removable under physiologic conditions, lower alkylamino, di-lower alkylamino, 5- or 7-membered lower alkyleneamino or aza-, oxa- or thia-lower alkyleneamino. Likewise, carbamoyl optionally substituted by lower alkyl is, for example, carbamoyl, N-acylcarbamoyl, wherein acyl is easily removable under physiologic conditions, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-lower alkylene- or N,N-(aza-, oxa-or thia)-lower alkylene-carbamoyl having from 4 to 6 ring members in the lower alkylene or aza-, oxa- or thia-lower alkylene moiety, respectively.
The acyl group in acylamino or N-acylcarbamoyl, resp. which is easily removable under physiologic conditions, is especially the acyl group of a lower alkanecarboxylic acid which may be substituted by lower alkoxy or lower-alkylated amino, of a lower alkanesulphonic acid or of an aliphatic semi-ester or semi-amide of carbonic acid. It denotes, inter alia, lower alkanoyl, for example formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl, lower alkoxy-lower alkanoyl, such as methoxy- or ethoxyacetyl, di-lower alkylamino-lower alkanoyl, for example N,N-dimethylglycyl, lower alkanesul-phonyl, such as methane- or ethanesulphonyl, lower alkoxy-carbonyl, such as methoxy-, ethoxy-, isopropyloxy- or tertiary butyloxycarbony1, ureido, 3-lower alkylureido, 3,3-di-iower alkylureido or 3,3-lower alkyleneureido or 3,3-(aza-, oxa- or thia)-lower alkyleneureido.
By "lower" organic groups and compounds there is to be understood hereinbefore and hereinafter those organic groups and compounds that have up to and including 7, especially up to and including 4, J I £ carbon atoms. ;< ' ~ 2 066 Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, and also one of the isomeric pentyl, hexyl or heptyl groups.
Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.
Lower alkylidene is, for example, 1,1-lower alkylidene having up to and including 4 carbon atoms, such as methylene, ethylidene, 1,1-propylidene, 1,1-butylidene, but may also be isopropylidene, 1,1-isobutylidene or a 1,1-pentylidene, 1, 1-hexylidene or 1,1-heptylidene group.
Lower alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy or tertiary butoxy, or also one of the isomeric pentyloxy, hexyloxy or heptyloxy groups.
Lower alkylamino and lower alkylamino in 3-lower alkylureido is, for example, straight-chain lower alkylamino having up to and including 4 carbon atoms, such as methyl-, ethyl-, propyl- or butyl-amino, but may be branched lower alkylamino having up to and including 4 carbon atoms, such as isopropyl-, isobutyl- or tertiary butyl-amino, or a pentylamino, hexylamino or heptylamino group. Di-lower alkylamino and di-lcwer alkylamino in 3,3-di-lower alkylureido is, for example, straight-chain di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety, such as dimethylamino, diethylamino, methyl-ethylamino, dipropylamino or dibutylamino, but may also be singly branched di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety, such as methylisopropylamino. 5- to 7-membered lower alkylene- '2 066 94? amino or aza-, oxa- or thia-lower alkyleneamino, also as constituent of ureido groups, is, for example, pyrrolidino, piperidino, piperazino, or N'-lower alkylpiperazino, such as N'-methylpiperazino, morpholino or thiomorpholino.
N-lower alkylcarbamoyl is, for example, straight-chain N-lower alkylcarbamoyl having up to an including 4 carbon atoms in the lower alkyl moiety, such as N-methyl-, N-ethyl, N-propyl- or N-butyl-carbamoyl, but may also be branched N-lower alkylcarbamoyl having up to and including 4 lower alkyl carbon atoms, such as N-isopropyl-, N-isobutyl, N-secondary butyl- or N-tertiary butyl-carbamoyl, or a pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoyl group.
N,N-di-lower alkylcarbamoyl is, for example, straight-chain N,N-di-lower alkylcarbamoyl having up to and including 4 carbon atoms in each of the lower alkyl moieties, such as N,N-dimethyl-, N,N-diethyl-, N-ethyl-N-methyl-, N,N-di-propyl- or N,N-dibutyl-carbamoyl, but may also be singly branched N,N-di-lower alkylcarbamoyl having up to an including 4 carbon atoms in each of the lower alkyl moieties, such as N-isopropyl-N-methyl or N-isobuty1-N-methy1-carbamoyl, or an N,N-dipentyl-, N,N-dihexyl- or N,N-diheptyl-carbamoyl group. N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl is, for example, pyrrolidino-carbonyl, piperidinocarbonyl, piperazino- or N'-lower alkylpiperazino, such as N'-methylpiperazinocarbonyl, morpholino-carbonyl or thiomorpholinocarbonyl.
Salt-forming compounds of the formula I are, for example, those in which R1 represents an amino group substituted by aza-lower alkylene, and/or in which carbamoyl R^ and/or R2 contain(s) such an amino group. There come into consideration as salts of such compounds especially the pharmaceutically acceptable % 2 066 9 6 acid addition salts thereof with strong acids, such as mineral acids, for example salts with hydrohalic acids, especially hydrochloric acid or hydrobromic acid, that is to say hydrohalides, especially hydrochlorides and hydrobromides, or sulphuric acid salts, that is to say hydrogen sulphates and sulphates, also salts with suitable organic acids, such as dicarboxylic acids or organic sulphonic acids, for example maleates, fumarates, malates, tartrates or methanesulphonates, also N-cyclohexyl sulphamates.
The novel compounds have valuable pharmacological properties, especially a marked anti-convulsive activity, which may be demonstrated, for example, in mice in the form of a clear metrazole antagonism in a dosage range of approximately from 30 to 300 mg/kg p.o., and in mice and rats in the form of a marked protective action against convulsions induced by electric shock in a dosage range of approximately from 10-100 mg/kg p.o. (mice) and approximately from 5-50 mg/kg p.o. (rats). The compounds of the formula I are therefore outstandingly suitable for the treatment of convulsions of various origins, for example for the treatment of epilepsy. They can therefore be used as active ingredients in anti-convulsive, for example anti-epileptic, medicaments. 206696 The invention relates especially to compounds of the formula I in which Ph represents phenyl substituted by lower alkyl, halogen and/or trifluoromethyl, alk represents lower alkylidene, represents hydrogen, lower alkyl, lower alkoxy, amino, acylamino, N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkyleneamino, carbamoyl, N-acylcarbamoyl or N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl and R2 represents carbamoyl, N-acylcarbamoyl, N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl or, if R^ represents amino, acylamino, N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-amino, represents cyano or, if R^ represents carbamoyl, N-acylcarbamoyl, N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl, represents hydrogen or lower alkyl, in which acyl denotes lower alkanoyl, lower alkoxy-lower alkanoyl, di-lower alkylamino-lower alkanoyl, lower alkanesulphonyl, lower alkoxycarbonyl, ureido, 3-lower alkyl- or 3,3-di-lower alkylureido, 3,3-lower alkyleneureido or 3,3-(aza-, oxa- or thia)-lower alkylureido of up to and including 7 carbon atoms, lower alkyl, lower alkyl in N-lower alkyl-amino or -carbamoyl and N,N-di-lower alkylamino or -carbamoyl# Lower alkoxy and lower alkylidene have up to and including 7 carbon atoms, and lower alkylene or aza-, oxa-or thia-lower alkylene have from 4 up to and including 6, ring members.
The invention relates especially to, for example, compounds of the formula I in which Ph represents 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, 2,3- or 2,6-dihalophenyl, 2-halo-3-lower alkylphenyl or 3 halo-2-lower alkylphenyl, 2-halo-6-lower alkylphenyl, 2,3- or 2,6-di-lower alkylphenyl, j] ^ 3-halo-2-trifluoromethylphenyl or 2-halo-3-trifluoro- 1 , 2 066 methylphenyl or 2-halo-6-trifluoromethylphenyl, alk represents 1,1-lower alkylidene, R^ represents hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, and R2 represents carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, lower alkyl and lower alkyl in N-lower alkyl-amino or -carbamoyl and N,N-di-lower alkylamino or -carbamoyl, lower alkoxy and lower alkylidene having, for example, up to and including 7 carbon atoms.
The invention relates especially to compounds of the formula I in which Ph represents phenyl substituted by up to and including 3 lower alkyl groups or halogen atoms, and/or by trifluoromethyl, lower alkyl having up to and including 4 carbon atoms and, for example, being methyl, and halogen having an atomic number of up to and including 35, that is to say fluorine, chlorine or bromine, for example: 2-lower alkylphenyl, 2- or 3-halophenyl, 2-trifluoromethylphenyl, 2,3- or 2,6-di-lower alkylphenyl or 2,3-, 2,4- or 2,6-dihalophenyl, alk represents 1,1-lower alkylidene having up to an including 4 carbon atoms, for example methylene, ethylidene or 1,1-propylidene, R^ represents amino, lower alkanoylamino of up to and including 7 carbon atoms, lower alkylamino or di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety, for example acetylamino, methyl-, ethyl- or propyl-amino, dimethyl- or diethyl-amino, and R2 represents carbamoyl, N-lower alkanoylcarbamoyl of up to and including 7 carbon atoms, N-lower alkyl-, N,N-di-lower alkyl- or N,N-lower alkylene-carbamoyl having up to and including 4 carbon atoms in each lower alkyl moiety and from 4 up to and including 6 ring members in the lower alkylene moiety, such as carbamoyl, N-acetyl-carbamoyl, N-methylcarbamoy1, N,N-dimethylcarbamoyl or piperidinocarbonyl, or cyano. 2 OS 6 9 5 The invention relates especially to compounds of the formula I in which a lower alkyl substituent in Ph is lower alkyl having up to and including 4 carbon atoms, for example methyl or ethyl, and a halogen substituent in Ph is halogen having an atomic number of up to and including 35, for example chlorine, and Ph represents 2-halophenyl, such as 2-fluoro-, 2-chloro-or 2-bromo-phenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, such as 2-methyl- or 2-ethylphenyl, 2,3-or 2,6-dihalophenyl, for example 2,6-dichlorophenyl, or 2,3- or 2,6-di-lower alkylphenyl, such as 2,3-dimethyl-phenyl, alk represents 1,1-lower alkylidene having up to and including 4 carbon atoms, for example methylene, ethylidene or 1,1-propylidene, Rj represents amino, lower alkylamino or di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety, for example methyl-, ethyl- or propyl-amino, dimethyl- or diethyl-amino, and R2 represents carbamoyl or cyano.
The invention relates especially to the compounds of the formula I specifically mentioned in the Examples.
The compounds of the formula I can be manufactured by methods known per se, for example as follows: an azide of the formula Ph - alk - N3 (II) is reacted with a compound of the formula in which R^ represents cyano or a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, 206696 Y1 represents an amino group disubstituted as indicated or, if represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen, lower alkyl, lower alkoxy or carbamoyl that is unsubstituted or substituted as indicated, and Y2 and Y^ together represent an additional bond, or in which represents cyano or a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, Y^ and Y2 together represent imino and Y^ is hydrogen, or with a tautomer and/or salt thereof, if necessary a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I.
Tautomers of compounds of the formula III are, for example, cyanoacetyl tautomers of the formula N=C-CH2-R2' (Ilia) of ketimine compounds of the formula III in which Yj and Y2 represent imino and Y-j represents hydrogen.
Salts of compounds of the formula III are, for example, metal salts, such as alkali metal salts, of compounds of the formula III in which Yj and Y2 together represent imino and Y^ represents hydrogen, or the tautomers thereof of the formula Ilia.
The reaction is carried out in customary manner, advantageously in an inert solvent, if necessary in the presence of a condensation agent and/or at elevated temperature. Inert solvents are, for example, aromatic or araliphatic hydrocarbons, such as benzene or toluene, or ethers, such as tertiary butoxymethane, tetrahydrofuran or dioxane, and, for the reaction with 2 066 96 - 11 " compounds of the formula Ilia, also alcohols, such as lower alkanols, for example methanol, ethanol or butanol. Condensation agents are, for example for the reaction with compounds of the formula III in which Yj and together represent imino and Y^ represents hydrogen, or the tautomers thereof of the formula Ilia, salt-forming condensation agents, such as metal alcoholates, for example sodium methoxide, sodium ethoxide, or other alkali metal lower alkoxides, metal amides, such as sodium amide, lithium diisopropyl amide and the like, or organometal compounds, such as lower alkylmagnesium halides or lower alkyllithium compounds, for example methyl- or butyl-magnesium bromide or butyllithium. Instead of carrying out the process in the presence of one of the mentioned condensation agents, the component of the formula III or Ilia may alternatively be.used in the form of a salt.
Preferred embodiments of this process are, for example, the reaction of an azide of the formula II with a compound of the formula III in which Yj represents hydrogen or lower alkyl, and Y2 and Y-j represent an additional bond, in benzene or dioxan at approximately from 60-120°C, preferably at boiling temperature, and the reaction with compounds of the formula Ilia in the presence of sodium methoxide or sodium ethoxide and methanol or ethanol, respectively, as the solvent, at approximately from 40 to 100°C, preferably at the boiling temperature.
The starting materials of the formula III and some of those of the formula II are known. Novel starting materials of the formula II can be obtained analogously to the method of formation of the known starting materials, for example by reacting a compound of the formula Ph-alk-X (IV), in which X represents reactive esterified hydroxy, such as halogen, for example 206696 chlorine, bromine or iodine, or sulphonyloxy, such as lower alkanesulphonyloxy, optionally substituted benzenesulphonyloxy, such as methane-, ethane-, benzene-, ja-toluene- or £-bromobenzene-sulphonyloxy, or fluorosulphonyloxy, with an alkali metal azide, for example with sodium azide, for example in dimethylsulphoxide or dimethylformamide, or by reacting an alcohol of the formula Ph-alk-X (IV? X = hydroxy) in the presence of triphenylphosphine and an azodicarboxylic acid ester, for example azodicarboxylic acid diethyl ester, with hydrazoic acid, for example in toluene.
The novel compounds may also be manufactured as follows: a compound of the formula Ph - alk - Z (IV) in which Z represents reactive esterified hydroxy is reacted with a 1H-1,2,3-triazole derivative of the formula ,N=N H-N (V) R. or a salt thereof, if necessary a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I.
Reactive esterified hydroxy Z is, for example, halogen, for example chlorine, bromine or iodine, or -V.
■L 2 066 sulphonyloxy, such as lower alkanesulphonyloxy, optionally substituted benzenesulphonyloxy, such as methane-, ethane-, benzene-, ^-toluene- or £-bromobenzene-sulphonyloxy, or fluorosulphonyloxy.
Salts of compounds of the formula V are, for example, alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts.
The reaction is carried out in customary manner, for example in the presence of a basic condensation agent or, advantageously, using the component of the formula V in the form of a salt, if necessary while heating, preferably in a solvent or diluent. Basic condensation agents are, for example, basic condensation agents that form salts with the component of the formula V, such as alkali metal alcoholates, for example sodium methoxide or sodium ethoxide, alkali metal or alkaline earth metal amides, for example sodium amide or lithium diisopropyl amide. As mentioned, the conversion of the component of the formula V into one of its salts is preferably carried out in advance, for example by reaction with one of the above-mentioned bases. Solvents for carrying out the reaction in the presence of an alcoholate are preferably the corresponding alcohols and, for carrying out the reaction in the presence of amides, are, for. example, aprotic organic solvents, such as phosphoric acid lower alkylamides or di-lower alkylsulphoxides, for example hexamethylphosphoric acid triamide or dimethylsulphoxide respectively.
The process is suitable especially for the manufacture of compounds in which an amino group R^ or the amino group as a constituent of a carbamoyl group R2 is at least N-mono-substituted, and 2 066 preferably N,N-di-substituted, that is to say represents acylamino, lower alkylamino or preferably di-lower alkylamino, lower alkyleneamino or (N'-lower alkyl) aza-, oxa- or thia-lower alkyleneamino.
The starting materials of the formulae IV and V that are not already known can be manufactured in customary manner. Thus, compounds of the formula IV are obtained, for example, by reactively esterifying a corresponding alcohol of the formula IV (Z = hydroxy), for example by means of thionyl chloride, phosphorus tribromide or a sulphonyl chloride. Compounds of the formula V can be manufactured as follows: hydrazoic acid or trimethylsilylazide is reacted with a compound of the formula in which represents cyano or a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents an amino group disubstituted as indicated, or if R^ represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen, lower alkyl, lower alkoxy or carbamoyl that is unsubstituted or substituted as indicated, and Y2 and Y^ together represent an additional bond, or in which R^ represents cyano or a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa-or thia-lower alkylene, Y^ and together represent imino and Y^ represents hydrogen, or with a tautomer and/or salt thereof and, if desired, an amino group R^ and/or a carbamoyl group R2 is acylated, lower-alkylated or substituted by 2 066 9 6 lower alkylene or aza-, oxa- or thia-lower alkylene in a 1-trimethylsilyl triazole derivative so obtained and the trimethylsilyl group is subsequently removed by mild hydrolysis.
The novel compounds can also be manufactured as follows: in a compound of the formula N=N / Ph-alk-N (VI) *.=, Y.
Y5 in which represents a radical Y^ and Yj. represents an Rj group or a radical Yg, or Y^ represents an R2 group and Y5 represents a radical YQ, YA representing a radical that can be converted into carbamoyl that is unsubstituted or substituted as indicated or, if Y^ represents amino Rj optionally substituted as indicated, into cyano, and YB representing a radical that can be converted into carbamoyl optionally substituted as indicated, or in a salt thereof, YA is converted into cyano or into carbamoyl optionally substituted as indicated, and/or Yg is converted into carbamoyl optionally substituted as indicated, if necessary a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I.
Radicals YA and Yg according to the above definition are, for example, free carboxy groups or carboxy groups present in salt or anhydride form, 2 066 9 6 amidino groups that are optionally N-lower alkylated or N,N-disubstituted by lower alkylene or by aza-, oxa- or thia-lower alkylene, or esterified carboxy groups; radicals Y0 are also cyano groups.
Esterified carboxy groups are, for example, carboxy groups esterified by a lower alkanol or a lower alkylmercaptan, that is to say, lower alkoxy- or lower alkylthio-carbonyl groups, but may also be esterified by any other alcohol or mercaptan, for example by an optionally substituted phenol or thiophenol.
Carboxy groups present in salt form are, for example, carboxy groups present in an ammonium salt form derived from ammonia or a mono- or di-lower alkylamine, or also carboxy groups present in metal salt form, for example in alkali metal or alkaline earth metal salt form.
Carboxy groups present in anhydride form are, for example, carboxy groups present in the form of a halide, such as chlorocarbonyl, but may also be anhydridised by a reactive carboxylic acid, and represent for example, alkoxycarbonyloxycarbonyl or tr ifluoroacetoxycarbonyl.
Amidino groups optionally lower alkylated or N,N-di-substituted by lower alkylene or by aza-, oxa- or thia-lower alkylene are, for example, amidino groups that are unsubstituted or N-mono-, N,N-di- or N,N'-di-lower alkylated or N,N-disubstituted by lower alkylene or by aza-, oxa- or thia-lower alkylene.
The conversion of the above-mentioned groups Y^ into cyano or carbamoyl optionally substituted as indicated or of Y5 into carbamoyl optionally substituted as indicated is carried out in customary manner, using as the starting materials carboxy groups that are free, esterified or in anhydride form and amidino groups that are optionally N-lower alkylated or 2 066 9 6 N,N-disubstituted by lower alkylene or by aza-, oxa- or thia-lower alkylene, by means of solvolysis, that is to say hydrolysis, or ammonolysis or aminolysis (reaction with ammonia or with a mono- or di-lower alkylamine, lower alkyleneamine or aza-, oxa- or thia-lower alkyleneamine).
By means of hydrolysis, for example amidino groups Y4 and/or Y5 that are optionally lower alkylated or N,N-disubstituted by lower alkylene or by aza-, oxa- or thia-lower alkylene can be converted into optionally correspondingly substituted carbamoyl, and cyano Y^ can be converted into carbamoyl. The hydrolysis is carried out, for example, in the presence of an acidic hydrolysing agent, such as a mineral, sulphonic'or carboxylic acid, for example sulphuric acid, phosphoric acid, hydrochloric acid or a different hydrohalic acid, £-toluenesulphonic acid or a different organic sulphonic acid, or a lower alkanoic acid, such as acetic acid, preferably in catalytic amounts.
By means of ammonolysis or aminolysis, for example carboxy groups that are free, present in salt form or esterified can be converted into carbamoyl that is unsubstituted or substituted as indicated. The operation is carried out, if necessary, in the presence of a condensation agent, advantageously in an inert solvent. Using carboxy in anhydride form as the starting material, condensation agents are, for example, basic condensation agents, such as alkali metal hydroxides or carbonates, or organic nitrogen bases, such as amines, in excess, corresponding to the amino group to be introduced, or tertiary organic nitrogen bases, such as tri-lower alkylamines or tertiary heteroaromatic nitrogen bases, such as triethylamine or pyridine, and, using esterified carboxy as the starting material, acidic condensation 2©66 96 agents, such as mineral acids, such as hydrohalic acids and the like. Free carboxy groups can be converted into optionally lower alkylated carbamoyl by dehydrating the ammonium salts formed as intermediates, for example by heating or by the action of dehydrating agents, such as acid anhydrides, for example phosphorus pentoxide, acetyl chloride and the like, or carbodiimides, for example N,N1-dicyclohexyl carbod iimide.
The starting materials of the formula VI that are not already known can be manufactured in customary manner, for example as follows: an azide of the formula Ph - alk - N3 (II) is reacted with a compound of the formula Y, - C = C - Y„ (VII) 1 | , 4 Y Y 2 3 in which Y^ represents a group Y^ and Y2 and Y^ represent an additional bond, or Yi represents hydrogen or lower alkyl, Y2 represents hydroxy and Y^ represents hydrogen, or. Y^ and Y2 together represent imino and Y3 represents hydrogen, or with a tautomer and/or salt thereof, for example as described for the reaction with the corresponding compounds of the formula III.
Starting materials of the formula VI in which Y^ represents lower alkoxy and Y^ represents a YA group may also be manufactured as follows: an azide of the formula II is reacted with an acid of the formula H00C-CH2-Ya (XI), or an ester, such as a lower alkyl ester, thereof, for example a malonic acid di-lower alkyl ester, and/or a salt thereof, preferably in 2 06696 - 19 the presence of an alkali metal alkoxide and, in the 5-hydroxy-1-Ph-alk-4-YA~1H-1,2,3-triazole formed, the hydroxy group is lower alkylated, preferably by reaction with a reactive lower alkyl ester, such as dimethyl sulphate, in the presence of sodium hydroxide.
The novel compounds may also be manufactured by removing H-Yg from a compound of the formula N=N Ph-alk-N (IX) R1 —— I I Y6H in which Yg represents a removable radical, and, if necessary, separating a resulting isomeric mixture into its components and isolating the isomer of the formula I and, if desired, converting the compound obtainable according to the process into a different compound of the formula I.
Removable radicals Yg are, for example, hydroxy, lower alkoxy or optionally substituted amino groups, lower alkoxy preferably being identical to lower alkoxy Rj and optionally substituted amino preferably being identical to free or substituted amino R^.
The removal of H-Yg generally takes place spontaneously; in individual cases the supply of thermal energy or the presence of an acidic or basic agent, such as a mineral acid, for example sulphuric or hydrochloric acid, or a carboxylic or sulphonic acid, for example acetic or £-toluenesulphonic acid, or an alkali metal hydroxide or alcoholate, for example 20659 6 sodium methoxide, can be advantageous.
The starting materials of the formula IX are preferably manufactured _in_ situ and reacted further without being isolated, for example by reacting a compound of the formula Ph - alk - N3 (II) with a compound of the formula Y7 Y8 YI - C - C - R2' {x)f Y Y 2 3 in which R2' represents cyano or a carbamoyl group that is unsubstituted or substituted by lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, Yi and Y2 represent lower alkoxy or optionally substituted amino R^, Y3 represents hydrogen and Y-j and Yg represent an additional bond, or Y|, Y2 and Y-y represent lower alkoxy and Y-j and Yg represent hydrogen, or Y^ and Y2 together represent oxo, Y-j represents hydrogen or lower alkyl and Y^ and Yg represent hydrogen, or with a tautomer and/or salt thereof, for example with a compound of the formula Y^'-C(=0)-CH2-R21 (Xa; Y^' = hydrogen or lower alkyl), Y^-C(Y2)=CH-R2' (Xb; Y^ and - lower alkoxy or, independently of one another, amino that is unsubstituted or substituted as indicated for Rj), or Y1-C(Y2)(Y7)-CH2-R2' (Xc; Yj, Y2 and Y? = lower alkoxy). % 2 066 96 Compounds of the formula I in which Rj represents lower alkoxy may also be manufactured as follows: in a compound of the formula ^/N=N Ph-alk-N R (XII)' r2 HO the hydroxy group is converted into lower alkoxy and, if necessary, a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I.
The conversion of hydroxy into lower alkoxy is effected, for example, by reaction with a reactive lower alkyl ester, such as a hydrohalic, such as hydrochloric, hydrobromic or hydriodic, acid ester, a sulphuric acid ester, that is to say a di-lower alkyl sulphate, or a sulphonic acid ester, such as a lower alkane- or optionally substituted benzene-sulphonic acid ester, for example methane-, benzene-, o-toluene-or d-bromobenzene-sulphonic acid ester of a lower alkanol, advantageously in the presence of a basic agent, such as an alkali metal hydroxide, carbonate or alcoholate, for example sodium or potassium hydroxide, potassium carbonate or sodium methoxide, or a tertiary organic nitrogen base, such as a tri-lower alkylamine, for example triethylamine, or pyridine.
The starting materials of the formula XII can be obtained, for example, by reacting an azide of the formula 2 06696 Ph - alk - N3 (II) with an acid of the formula HOOC-CH2~R2 (XI) or an ester, for example a lower alkyl ester, thereof, for example as indicated for the reaction with compounds of the formula Ilia. .
Compounds obtainable according to the process can be converted into different compounds of the formula I by converting one or more variables of the general formula I into different variables.
Thus cyano R2 can be hydrolysed to form carbamoyl, for example under basic conditions, such as in the presence of an alkali metal hydroxide, but cyano can also be converted into N-lower alkyl- or N,N-di-lower alkyl-carbamoyl, for example by first converting the nitrile of the formula I, for example by treatment with a lower alkanol, phenol or any other alcohol, into an imino ether, reacting the latter with a mono- or di-lower alkylamine, and hydrolysing the amidine formed, preferably under mildly acidic conditions.
Conversely, carbamoyl R2 can be dehydrated to form cyano, for example by treatment with a dehydrating agent, for example an acid anhydride, such as phosphorus pentoxide or phosphorus oxychloride, a cyclic silazane, or dichloro-carbene or trichloromethane in the presence of an approximately 40% sodium hydroxide solution and a phase transfer catalyst, for example benzyltrimethylammonium chloride.
In addition, a primary amino R^ can be converted into acylamino, mono- or di-lower alkylamino or lower alkyleneamino, aza-, oxa- or thia-lower alkyleneamino. Also mono-lower alkylamino R^ can be converted into di- 2 066 lower alkylamino. The acylation is effected, for example, by means of a corresponding acid anhydride or chloride, such as acetanhydride, the mixed anhydride of formic and acetic acid, a chloro- or bromoformic acid lower alkylester, methanesulphonylchloride or dimethyl-carbamoylchloride, if necessary, in the presence of a base, such as triethylamine or pyridine, or with an inorganic acid, e.g. sulphuric acid. Alkyl(en)ating agents are, for example, reactive esters of a lower alkanol, lower alkanediol or aza-, oxa- or thia-lower alkanediol, such as a lower alkyl(enedi)halide, for example, bromide or iodide, lower alkyl(ene di)-sulphonate, for example methanesulphonate or £-toluenesulphonate, or a di-lower alkyl sulphate, for example dimethyl sulphate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution and advantageously a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride. In an entirely analogous manner, also carbamoyl 1*2 and/or can be converted into N-acylcarbamoyl, N-mono-or N,N-di-lower alkylcarbamoyl or N,N-lower alkylenecarbamoyl or N,N-(aza-, oxa- or thia)-lower alkylenecarbamoyl and N-mono-lower alkylcarbamoyl can be converted into N,N-di-lower alkylcarbamoyl, but stronger basic condensation agents, such as alkali metal amides or alcoholates, for example sodium amide or sodium methoxide, may be necessary.
Depending on the choice of starting materials and procedures, the novel compound can be in the form of one of the possible isomers, for example with respect to the position of and R2r or in the form of mixtures thereof, and, depending on the number of asymmetrical carbon atoms, also in the form of optical isomers, such as antipodes, or mixtures thereof, such 2 066 96 as racemates, diastereoisomeric mixtures or racemic mix tures.
Resulting mixtures of position isomers as well as diastereoisomeric mixtures and racemic mixtures can be separated on the basis of the physical and chemical differences between their constituents in known manner into the pure position isomers, diastereoisomers and racemates, respectively, for example by chromatography and/or fractional crystallisation. Resulting racemates can also be separated by known methods into the optical antipodes, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or by reaction of an acidic precursor, for example of the formula VI (Y^ and/or = carboxy), with an optically active alcohol that forms esters with the racemic acid and separation of the esters obtained in this manner, for example on the basis of their different solubilities, into the diastereoisomers from which the antipodes can be freed by the action of suitable agents. Advantageously, the more active of the two antipodes is isolated.
Racemates of salt-forming compounds of the formula I can also be split by reaction with an optically active auxiliary compound into diastereoisomeric mixtures, for example with an optically active acid into mixtures of diastereoisomeric acid addition salts, and separation of the latter into the diastereoisomers from which the enantiomers can be freed in the customary manner in each case. Optically active acids customary for this purpose are, for example, D- or L-tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acids or quinic acid.
In addition, resulting free salt-forming compounds can be converted in a manner known per se into acid addition salts, for example by reacting a solution of 2 066 the free compound in a suitable solvent or solvent mixture with one of the above-mentioned acids or with a solution thereof, or with a suitable anion exchanger.
Resulting acid addition salts can be converted in a manner known per se into the free compounds, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or bicarbonate, or ammonia, or with a suitable anion exchanger.
Resulting acid addition salts can be converted in a manner known per se into different acid addition salts, for example by treating a salt of an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, of an acid in a suitable solvent in which the resulting organic salt is insoluble and thus separates out from the reaction mixture.
The compounds, including their salts, can also be obtained in the form of the hydrates or include the solvent used for crystallisation.
As a result of the close relationship between the novel compounds in the free form and in the form of their salts, hereinbefore and hereinafter the free compounds or their salts are to be understood, where appropriate and expedient, to include optionally also the corresponding salts or free compounds.
The invention also relates to those embodiments of the process according to which a compound obtainable as an intermediate at any stage of the process is used as the starting material and the remaining steps are carried out, or a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
Thus all intermediates of the formula IX can be formed in situ in accordance with the process variant of the reaction of compounds of the formulae II and X, 2 066 96 and reacted further without being isolated.
The invention also relates to novel starting materials of the formulae II, V, VI, IX and XII which have been developed especially for the- manufacture of the compounds according to the invention, especially the range of starting materials leading to the compounds of the formula I that are characterised as being preferred at the beginning, to the processes for their manufacture and to their use as intermediates.
The novel compounds of the formula I can be used, for example, in the form of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, and are suitable for enteral, for example oral, or parenteral administration. Thus tablets or gelatine capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or glycine, and/or glidants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorption agents, dyes, flavourings and sweeteners. In addition, the novel compounds of the formula I can be used in the form of preparations that can be administered parenterally, or in the form of infusion solutions.
Such solutions are preferably isotonic aqueous 206696 solutions or suspensions, it being possible for these to be manufactured before use, for example in the case of lyophilised preparations which contain the active ingredient alone or together with a carrier, for example mannitol. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, may contain further pharmacologically active substances, are manufactured in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and contain, from 0.1 % to 100 %, especially from 1 % to 50 %, and in the case of lyophilisates up to 100 %, of the active ingredient.
The invention also relates to the use of the compounds of the formula I, preferably in the form of pharmaceutical preparations. The dosage can depend on various factors, such as the method of administration, and the species, age and/or condition of the individual. The doses to be administered daily in the case of oral administration are between 5 and 50 mg/kg and for warm blooded animals weighing approximately 70 kg preferably between 0.5 g and approximately 5.0 g.
The following Examples serve to illustrate the invention; temperatures are given in degrees Centigrade. \ g *:,, 2 0 Example 1 23 g (1 mol) of sodium are dissolved in 1 litre of ethyl alcohol and 101 g (1.2 mol) of cyanoacetamide are added thereto. 167.5 g (1 mol) of o^-chlorobenzyl azide are added to this suspension at 40-45° and the whole is heated for 2 hours under reflux. After cooling to 30°, 1000 ml of water are added, the precipitated product is filtered off with suction and then washed several times with warm water. After recrystallisation from dioxan and toluene, 5-amino-l- (c>-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide is obtained in the form of colourless crystals having a melting point of 206-207°.
Example 2 In analogous manner, starting from 2,6-dichloro-benzyl azide, there is obtained 5-amino-l-(2,6-dichloro-benzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 243-245° (after crystallisation from methanol).
The starting material can be prepared, for example, as follows: 24 g (0.1 mol) of 2,6-dichlorobenzyl bromide in 50 of dimethyl sulphoxide are added at room temperature to a suspension of 7.2 g (0.11 mol) of sodium azide in 50 ml of dimethyl sulphoxide and the whole is stirred for 2 hours at room temperature. The mixture is then diluted with 250 ml of water and extracted with cyclo-hexane and the organic phase is washed several times with water. After drying over sodium sulphate, the cyclohexane is distilled off in vacuo at 50°. 2,6-dichlorobenzyl azide is obtained in the form of a 20669 6 colourless liquid. It is used without further purification .
Example 3 In a manner analogous to that described in Example 2, starting from o_-methy lbenzyl chloride, there is obtained via °C-azido-o-xylene, 5-amino-l-(^methyl-benzyl) -1H-1,2,3-triazole-4-carboxamide having a melting point of 227-228° (after crystallisation from di-oxan/ethanol) .
Example 4 In a manner analogous to that described in Example 1, starting from o-fluorobenzyl azide, there is obtained 5-amino-l - (_o-f luorobenzyl) -1H-1, 2, 3-triazole- 4-carboxamide having a melting point of 198-190° (from methanol).
Example 5 In a manner analogous to that described in Example 1, starting from o_-bromobenzyl azide, there is obtained -amino-l-(£-bromobenzyl)-1H-1,2,3-triazole-4-carbox-amide having a melting point of 211-213° (from ethanol).
Example 6 In a manner analogous to that described in Example 1, starting from o-trifluoromethylbenzyl azide, there is obtained 5-amino-l-(o^-trif luoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 197-198° (from methanol). 2 066 9 6 The starting material can be prepared, for example, as follows: First a solution of 17.4 g (0.1 mol) of azodicarboxylic acid diethyl ester in 50 ml of toluene is added dropwise at 10-20° to a solution of 26.2 g (0.1 mol) of triphenylphosphine in 260 ml of toluene and then, at 5-10°, a solution of 17.6 g (0.1 mol) of o^-trifluoromethylbenzyl alcohol in 120 ml of a IN solution of hydrazoic acid in toluene is added dropwise thereto and the whole is stirred at room temperature for 2 hours. The precipitated hydrazinodicarboxylic acid ester is filtered off with suction, the toluene solution is concentrated by evaporation and the residue is treated with cyclohexane. The cyclohexane solution is decanted off from the insoluble portions, filtered through a small amount of silica gel and concentrated by evaporation at 50° iri vacuo. In this manner o_-trifluoromethylbenzyl azide is obtained in the form of a colourless liquid.
Example 7 In a manner analogous to that described in Example 6, starting from 2,3-dimethylbenzyl alcohol, there is obtained via 2,3-dimethylbenzyl azide 5-amino-l-(2,3-dimethylbenzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 217-219° (from ethyl acetate).
Example 8 In a manner analogous to that described in Example 2, starting from 1-(o^chlorophenyl)-phenethyl chloride, there is obtained via 1- (c>-chlorophenyl) -ethyl azide 5-amino-l-[1-(o-chlorophenyl)-ethyl]-1H- 2 066 96 1,2,3-triazole-4-carboxamide having a melting point of 202-204° (from ethanol).
Example 9 In a manner analogous to that described in Example 2, starting from 1- (jD-chlorophenyl) -propyl chloride, there is obtained via 1-(£-chlorophenyl)-propyl azide 5-amino-l-[1-(o-chlorophenyl)-propyl]-1H-1,2,3-triazole-4-carboxamide having a melting point of 152-153° (from ethanol).
Example 10 In a manner analogous to that described in Example 6, starting from 1-(o-chlorophenyl)-butanol, there is obtained via 1-(£-chlorophenyl)-butyl azide 5-arnino-1-[1-(o-chlorophenyl)-butyl]-lH-l,2,3-triazole-4-carboxamide having a melting point of 150-152° (from methanol).
Example 11 .2 g (0.1 mol) of 5-amino-l-(<3-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide are dissolved in 100 ml of dimethylformamide and, while stirring at 0°, 30.6 g (0.2 mol) of phosphorus oxychloride are added dropwise. The whole is then heated rapidly until the reaction mixture has reached 80° and then cooled again immediately to 20°. At this temperature, 100 ml of IN hydrochloric acid are added dropwise and then the whole is heated rapidly and maintained for 5 minutes under reflux. The hot reaction solution is diluted with 400 ml of water and the precipitated product is filtered off with suction. After washing 2 066 several times with water and subsequent crystallisation from ethyl alcohol, there is obtained 5-amino-l-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylie acid nitrile having a melting point of 174-176°.
Example 12 A solution of 11.7 g (0.05 mol) of 5-amino-l-(<D-chlorobenzyl) -1H-1, 2, 3-tr iazole-4-carboxylic acid nitrile and 21.3 g (0.15 mol) of methyl iodide in 250 ml of acetonitrile is added dropwise at 20-25° to a stirred suspension of 11.2 g of pulverised potassium hydroxide and 1.6 g (0.005 mol) of tetrabutylammonium bromide in 100 ml of acetonitrile. After 1 hour, the inorganic material is decanted off and the acetonitrile is evaporated off i_n vacuo. The residue is dissolved in diethyl ether, undissolved material is filtered off and the ether solution is filtered through silica gel. After evaporation of the ether, there is obtained 1-(o^chlorobenzyl)-5-dimethylamino-lH-l,2,3-triazole-4-carboxylic acid nitrile having a melting point of 64-67°.
Example 13 ml of a 30 % strength hydrogen peroxide solution are added dropwise at 40-50° to a solution of 13.1 g (0.05 mol) of 1- (o^-chlorobenzyl) -5-dimethyl-amino-lH-1,2,3-triazole-4-carboxylic acid nitrile in 300 ml of ethanol and 25 ml of 5N sodium hydroxide solution. When the dropwise addition is complete, the whole is stirred for 2 hours at 40-50° and then diluted with 600 ml of water and the precipitated product is filtered off with suction. After washing with water and crystallisation from 70 % strength 2 066 9 6 ethanol, there is obtained 1- (o-chlorobenzyl)-5-dimethylamino-lH-1,2,3-triazole-4-carboxamide having a melting point of 164-166°.
Example 14 93 g (0.03 mol) of 1-(£-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 250 ml of methanol and saturated with ammonia at 50°. After being left to stand for 3 days at 60°, the reaction solution is cooled and the product that has crystallised out is filtered off with suction and washed with methanol. In this manner there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide having a melting point of 222-224°.
The starting material can be prepared, for example, as follows: A solution of 8 g (0.054 mol) of acetylene-dicarboxylic acid dimethyl ester in 25 ml of benzene is added dropwise to a solution of 8.4 g (0.05 mol) of o-chlorobenzyl azide in 50 ml of benzene that is boiling under reflux. After a further hour under reflux, the whole is diluted with 75 ml of cyclohexane and, after cooling, the substance that has crystallised out is filtered off with suction. After washing with a mixture of diethyl ether and 'nexane (1:1), there is obtained 1-(o-chlorobenzyl)-lH-l,2,3-triazole-4,5-dicarboxylic acid dimethyl ester having a melting point of 88-91°.
Example 15 2.7 g (10 mmol) of 1- (o~chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylie acid are heated under reflux for 30 minutes with 15 ml of thionyl chloride. 2.06 6 n ,j The excess thionyl chloride is distilled off _in vacuo at 60° and the remaining 1- (o^-chlorobenzyl)-5-methoxy-lH-1,2,3-triazole-4-carboxylic acid chloride is dissolved in 20 ml of toluene. This toluene solution is added dropwise at 0-5° to 20 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off with suction and washed several times with water. 1-(o-chlorobenzyl)-5-methoxy-lH-l,2,3-triazole-4-carboxamide having a melting point of 185-187° is obtained.
The starting material can be prepared, for example, as follows: A mixture of 8.4 g (50 mmol) of o_-chlorobenzyl azide and 8 g (50 mol) of malonic acid diethyl ester in 25 ml of ethanol is added to a solution of 1.15 g (50 mmol) of sodium in 50 ml of ethanol and the whole is left to stand for 20 hours at room temperature. 6.3 g (50 mmol) of dimethyl sulphate are then added dropwise at 10-20° and after one hour the whole is concentrated by evaporation rn vacuo at 25°. The residue is dissolved in ethyl acetate, washed with IN sodium hydroxide solution and then with water and the whole is again concentrated by evaporation. The remaining oil is crystallised with 50 ml of diethyl ether. In this manner there is obtained 1-(o-chloro-benzyl)-5-methoxy-lH-l,2,3-tr iazole-4-carboxylie acid ethyl ester having a melting point of 118-120°. 3.3 g (11.2 mmol) of 1-(o-chlorobenzyl)-5-methoxy-lH-1,2,3-triazole-4-carboxylic acid ethyl ester are dissolved in 50 ml of warm ethanol and, after the addition of 15 ml of IN sodium hydroxide solution, heated for 1 hour under reflux. The precipitated sodium salt is dissolved by the addition of 250 ml of water and then acidified with 15 ml of 2N hydrochloric acid. The precipitated product is filtered off with 2 066 suction and washed with water. In this manner there is obtained 1- (o^-chlorobenzyl) -5-methoxy-lH-l ,2,3-triazole-4-carboxy1ic acid having a melting point of 130-135° (with decarboxylation).
Example 16 6.4 g (27 mmol) of 1-(o^-chlorobenzyl)-1H-1, 2 , 3-triazole-4-carboxy1ic acid are heated under reflux for 1 hour with 50 ml of thionyl chloride. The excess thionyl chloride is then distilled jjl vacuo, the remaining 1- (jD-chl or obenzyl )-lH-1,2, 3-tr iazole-4-carboxylic acid chloride is dissolved in 50 ml of toluene and this solution is added dropwise at 5-10° to 50 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off with suction, washed with water, and recrystallised from dioxan/ethanol. In this manner there is obtained 1-(jO-ch lor obenzyl) -1H-1, 2, 3-tr iazole-4-car boxamide having a melting point of 237-239°.
In analogous manner, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-5-carboxamide having a melting point of 155-158° can also be prepared.
The starting materials can be prepared, for example, as follows: A solution of 16.75 g (100 mmol) of o^-chlorobenzyl azide, 7.35 g (100 mmol) of propynecarboxylic acid and 200 ml of toluene is stirred for 24 hours at 50°.
After being cooled to room temperature, the precipitated product is filtered off with suction and washed first with toluene and then with diethyl ether. In this manner there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxy1ic acid having a melting point of 175° (with decomposition). After concentration of the filtrates by evaporation and washing the residue with a little toluene, 1- (c^-chlorobenzyl) 1,2,3-triazole-5-carboxylic acid having a melting of 120° (with decomposition) remains. -1H-point Example 17 A mixture of 25.2 g (100 mmol) of 1-(o^-chloro-benzyl)-5-methyl-lH-l,2,3-triazole-4-carboxylie acid and 100 ml of thionyl chloride is heated under reflux for 30 minutes. The excess thionyl chloride is then removed vacuo and the remaining 1-(o-chlorobenzyl) -5-methyl-lH-l,2,3-tr iazole-4-carboxy1ic acid chloride is dissolved in 100 ml of toluene. This solution is added dropwise at 5-10° to 100 ml of a concentrated aqueous ammonia solution, the precipitated product is filtered off with suction and washed with water. After crystallisation from ethanol, 1-(_o-chlorobenzyl)-5-methyl-lH-l,2,3-tr iazole-4-carboxamide having a melting point of 181-183° is obtained.
The starting material can be prepared, for example, as follows: 14.3 g (110 mmol) of ethyl acetoacetate and 16.8 g (100 mmol) of o-chlorobenzyl azide are added to a solution of 2.53 g (110 mmol) of sodium in 100 ml of ethanol, and the whole is then heated under reflux for 20 hours.
After the addition of 100 ml of IN sodium hydroxide solution the whole is heated under reflux for a further 2 hours and then, while still warm, acidified with hydrochloric acid. The precipitated product is filtered off with suction and washed with water. After crystallisation from ethanol, there is obtained 1-(o-chlorobenzyl)-5-methyl-lH-l,2,3-tr iazole-4-carboxylie acid having a melting point of 186-187° (with decarboxylation). 2 066 Example 18 A solution of 14.7 g (100 mmol) of o-methylbenzyl azide and 8.3 g (100 mmol) of but-2-ynecarboxamide in 20 ml of dioxan is heated for 16 hours at 100°.
After evaporation of the dioxan, the isomers are separated by column chromatography.
In this manner there is obtained l-(£-methyl-benzyl)-5-methyl-lH-l,2,3-triazole-4-carboxamide having a melting point of 185-187° (from ethanol), as well as a by-product which is discarded.
Example 19 In a manner analogous to that described in Example 1, by reacting o-chlorobenzyl azide with 2-cyano-N-methylacetamide there is obtained 5-amino-l-(c^-chloro-benzyl) -1H-1,2,3-tr iazole-4-(N-methyl)-carboxamide having a melting point of 140-142° (from acetonitrile).
Example 20 In a manner analogous to that described in Example 1, by reacting o-chlorobenzyl azide with 2-cyano-N,N-dimethylacetamide there is obtained 5-amino-l-(o-chlorobenzyl)-1H-1,2,3-triazole-4-(N,N-dimethyl)-carboxamide having a melting point of 143-145° (from acetonitrile).
Example 21 In a manner analogous to that described in Example 2, by reacting 2,3-dichlorobenzyl azide with 2 066 96 cyanoacetamide there is obtained 5-amino-l-(2,3-dichlorobenzyl)-lH-1,2,3-tr iazole-4-carboxamide having a melting point of 224-226° (from ethanol). The starting material can be produced from 2,3-dichloro-benzyl alcohol as starting material by halogenation, for example with phosphorus tribromide, and reaction with sodium azide.
Example 22 .4 g of crude, approximately 65 % strength 1-(£-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylie acid dimethyl ester are suspended in 50 ml of a 4N solution of ammonia in methanol and the suspension is stirred for 1 hour at 50°. The whole is allowed to cool and filtered with suction and 1-(^-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, which is moderately soluble in dioxane,is dissolved out of the filter cake using dioxane. It precipitates in the form of crystals having a melting point of 222-224° when the dioxan solution is concentrated and cooled.
The starting material can be produced, for example, as follows: 1.15 g (50 mmol) of sodium are dissolved in 100 ml of methanol. 9.25 g (50 mmol) of 1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester and 8.05 g (50 mmol) of £-chlorobenzyl chloride are added thereto and the whole is boiled for 24 hours. The reaction mixture is then concentrated until crystallisation begins, allowed to cool and filtered with suction. The residue can then be used, after drying, without purification.
Example 23 In a manner analogous to that described in Example 2 066 6, starting from 2,4,6-trimethylbenzyl alcohol there is obtained via 2,4,6-trimethylbenzy1 azide 5-amino-l-(2,4,6-1rimethylbenzyl)-1H-1,2,3-tr iazole-4-carboxamide having a melting point of 195-196° (from ethyl acetate).
Example 24 In a manner analogous to that described in Example 6, starting from 5-chloro-2-methylbenzyl alcohol, there is obtained via 5-chloro-2-methylbenzyl azide 5-amino-1-(5-chloro-2-methylbenzyl)-lH-l,2,3-triazole-4-carboxamide having a melting point of 247-248° (from acetic acid).
Example 25 In a manner analogous to that described in Example 1, starting from o-chlorobenzyl azide and cyanoacetic acid piperidide, there, is obtained 5-amino-l-(o- chlorobenzyl)-1H-1,2,3-triazole-4-carboxy1ic acid piperidide having a melting point of 138-140° (from ethanol) .
Example 26 In a manner analogous to that described in Example 2, starting from m-chlorobenzyl chloride, there is obtained via m-chlorobenzyl azide 5-amino-l-(m-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 196-198° (from ethanol). 206696 Example 27 In a manner analogous to that described in Example 2, starting from in-tr if luoromethylbenzyl chloride, there is obtained via m-trifluoromethylbenzyl azide 5-amino-l- (in-tr if luoromethylbenzyl) -1H-1,2 ,3-triazole-4-carboxamide having a melting point of 206-207° (from ethanol).
Example 28 In a manner analogous to that described in Example 16, starting from 11.8 g (50 mmol) of 1-(£-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylie acid, converting this into the acid chloride and treating the latter with piperidine (50 mmol), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylie acid piperidide having a melting point of 141-142° (from ethanol) and, by treating the acid chloride with dimethylamine (50 mmol), there is obtained 1-(o_-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid N,N-dimethylamide having a melting point of 120-121° (from ethanol).
Example 29 In a manner analogous to that described in Example 1, starting from m-methylbenzyl azide, there is obtained 5-amino-l-(m-methylbenzyl)-lH-l,2,3-triazole-4-carboxamide having a melting point of 200-202° (from ethanol). 2 0S69 6 Example 30 In a manner analogous to that described in Example 16, starting from m-chlorobenzyl azide, there is obtained via 1- (in-chlorobenzyl)-1H-1, 2, 3-tr iazole-4-carboxylic acid having a melting point of 174-176° (with decomposition) 1-(m-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 223-224° (from ethanol).
Example 31 In a manner analogous to that described in Example 16, starting from m-trifluoromethylbenzyl azide, there is obtained via 1-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxylic acid having a melting point of 171° (with decomposition) 1-(m-trifluoromethylbenzyl) -1H-1,2,3-triazole-4-carboxy1ic acid amide having a melting point of 193-195° (from ethanol) .
Example 32 In a manner analogous to that described in Example 1, by reaction of o-chlorobenzyl azide and cyanoacetic acid (4-methyl)-piperazide, there is obtained 5-amino-l-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (4-methyl)-piperazide having a melting point of 114-116°. The methanesulphonate melts at 208-210° (from acetone).
Example 3 3 ,1 g of 5-amino-l-(o-chlorobenzyl)-lH-triazole-4-carboxamide are added, portionwise with stirring, to a mixture of 30,7 g of acetanhydride and 0,1 ml of sulphuric acid and heated to 60°. Stirring is continued for additional 30 minutes at 60 to 70°, the reaction mixture is poored into 250 ml of ethanol, heated to reflux for 30 minute's and evaporated in vacuo to dryness. The residue is triturated with 250 ml of ethyl acetate, the crystalline precipitate is collected and re-crystallised from ethyl acetate yielding 5-acetylamino-l-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 181-183°.
The ethylacetate mother liquors are combined and evaporated to dryness. The residue is purified chromatographically by means of silica gel and toluene/ethyl acetate. The eluate is evaporated to dryness and re-crystallised from toluene yielding 5-acetylamino-l-(o-chlorobenzyl)-1H-1,2,3-triazole -4-(N-acetyl)carboxamide of m.p. 140-142°.
Example 34: In an analogous manner as described in Examples 1 to 3 3 also the following compounds can be prepared: 1-(o-chlorobenzyl)-5-formylamino-lH-1,2,3-triazole-4-carbox-amide, 1-(o-chlorobenzyl)-5-formylamino-lH-l,2,3-triazole-4-(N-formyl)carboxamide, 1-(o-chlorobenzyl)-5-ethoxycarbonylamino-lH-l,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-(3,3-dimethylureido)-1H-1,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-(N1,N'-dimethylglycylamino)-1H-1,2,3-triazole-4-carboxamide, 1- (o-chlorobenzyl)-5-ethoxyacetylamino-lH-l,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-(4-methyIpiperazinocarbonylamino)-1H-1,2,3-triazole-4-carboxamide. 6696 Example 35: Tablets, each containing 50 mg of 5-amino-l- (o-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide, can be manufactured, for example, as follows: Composition (10000 tablets) active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatine 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly dispersed) 20.0 g ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an alcoholic solution of the gelatine and granulated through a sieve. After drying, the whole is mixed with the rest of the potato starch, the talc, the magnesium stearate and the highly dispersed silica, and the mixture is compressed to form tablets each weighing 145.0 mg and containing 50.0 mg of active ingredient; these tablets can, if desired, be provided with break notches for more accurate control of the dose.
Example 36 Lacquered tablets, each containing 100 mg of 5-amino-l- (£-methylbenzyl)-lH-l,2,3-triazole-4-carboxamide, can be manufactured as follows: Composition (for 1000 tablets) Active ingredient 100.00 g lactose 100.00 g corn starch 70.00 g talc 8.50 g calcium stearate 1.50 g hydroxypropyImethylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s.
The active ingredient, the lactose and 40 g of the corn starch are mixed, moistened with a paste manufactured from 15 g of corn starch and water (while heating), and granulated. The granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 280 mg) and the tablets are lacquered with a

Claims (55)

2 066 9 6 - 45 - solution of the hydroxypropylmethylcellulose and shellac in methylene chloride: final weight of the lacquered tablet: 283 mg. Example 37 In a manner analogous to that described in Examples 35 and 36 it is also possible to manufacture tablets or lacquered tablets containing a different compound according to any one of Examples 1-32. Example 38 The compound according to Example 11 can also be obtained in the following, different manner: 1.15 g of sodium are dissolved in 50 ml of ethanol. A mixture of 8.4 g of o_-chlorobenzyl azide, 3.3 g of malodinitrile and 50 ml of ethanol are then added, the whole is left to stand for 24 hours at room temperature and the solvent is distilled off under reduced pressure. The residue is shaken with 50 ml of 2N hydrochloric acid and 100 ml of ethyl acetate, the organic phase is separated off and concentrated by evaporation, and the residue is recrystallised twice from ethanol. Likewise obtained in this manner is 5-amino-l- (o-chlorobenzyl)-lH-1,2,3-triazole-4-carboxylic acid nitrile, having a melting point of 174-176°. 2 06696 - 46 - WHAT -WWE CLAIM ISt- Patant Claims
1. 1-phenyl-lower alkyl-lH-1,2,3-triazole compounds of the formula N=N X Ph-alk-N (x) R1R2 in which Ph represents phenyl substituted by lower alkyl, halogen and/or trifluoromethyl, alk represents lower alkylidene, represents hydrogen, lower alkyl, lower alkoxy, or an amino group or carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, and R2 represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene or, if R^ represents an amino group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents cyano or, if R^ represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen or lower alkyl, or a salt of a salt-forming compound of the formula I. 206696 - 47 -
2. Compounds according to claim 1 of the formula I in which Ph represents phenyl substituted in the 2-position by lower alkyl, halogen or trifluoromethyl and optionally substituted, in addition, by lower alkyl or halogen, which is located in the 3—, 4- or 6-position, alk represents lower alkylidene, represents hydrogen, lower alkyl, lower alkoxy, or an amino group or carbamoyl group that is unsubstituted or substituted by lower alkyl and R2 represents carbamoyl that is unsubstituted or substituted by lower alkyl or, if Rj^ represents amino that is unsubstituted or substituted by lower alkyl, represents cyano.
3. Compounds according to claim 1 of the formula I in which Ph represents phenyl substituted by lower alkyl, halogen and/ or trifluoromethyl, alk represents lower alkylidene, R^ represents hydrogen, lower alkyl, lower alkoxy, amino, acylamino, N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-amino, carbamoyl, N- acylcarbamoyl or N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl and R2 represents carbamoyl or N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl or, if R^ represents amino, acylamino or N-lower alkyl-, N,N- di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-amino, represents cyano or, if R^ represents carbamoyl, N-acylcarbamoyl or N-lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene- or N,N-(aza-, oxa- or thia)-lower alkylene-carbamoyl, represents'hydrogen or lower alkyl, wherein acyl denotes lower alkanoyl / lower alkoxy-lower alkanoyl, di-lower alkylamino-lower alkanoyl, lower alkanesulphonyl, lower alkoxycarbonyl, ureidO/ 3-lower alkyl- or 3,3-di-lower alkylureido, 3,3- lower alkyleneureido or 3,3-(aza-, oxa- or thia)-lower c \ O *■' - 48 - 206696 alkylureido of up to and including 7 carbon atoms or a salt of a salt-forming compound of the type defined above.
4. Compounds according to claim 2 of the formula I in which Ph represents 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, 2,3- or 2,6-dihalophenyl, 2-halo-3-lower alkylphenyl, 3-halo-2-lower alkylphenyl, 2-halo-6-lower alkylphenyl, 2,3- or 2,6-di-lower alkylphenyl, 3-halo-2-trifluoromethylphenyl , 2-halo-3-trifluoromethylphenyl, or 2-halo-6-trifluoromethylphenyl , alk represents 1,1-lower alkylidene, represents hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, and R2 represents carbamoyl, N-lower alkylcarbamoyl, N,N-di-lgwer alkylcarbamoyl or lower alkyl. ■
5. Compounds according to claim 1 of the formula I in which Ph represents phenyl substituted by up to and including 3 lower alkyl groups or halogen atoms, and/or by trifluoromethyl, lower alkyl having up to and including 4 carbon atoms or halogen having an atomic number of up to and including 35, alk represents 1,1-lower alkylidene having up to and including 4 carbon atoms, represents amino, lower alkanoylamino, lower alkylamino or di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety and 1*2 represents carbamoyl, N-lower alkanoylcarbamoyl, N-lower alkyl-, N,N-di-lower alkyl- or N,N-lower alkylenecarbamoyl having up to and including 4 carbon atoms in each lower alkyl moiety and from 4 up to and including 6 ring members in the lower alkylene moiety, or cyano. - 49 - 206896
6. Compounds according to claim 2 of the formula I in which Ph represents 2-halophenyl, 2-lower alkylphenyl, 2,3- or 2,6-dihalophenyl, or 2,3- or 2,6-di-lower alkylphenyl, a halogen substituent being halogen having an atomic number of up to and including 35 and a lower alkyl substituent having up to and including 4 carbon atoms, or represents 2-trifluoromethylphenyl, alk represents 1,1-lower alkylidene having up to and including 4 carbon atoms, represents amino, lower alkylamino or di-lower alkylamino having up to and including 4 carbon atoms in each lower alkyl moiety and r2 represents carbamoyl.
7. 5-amino-l-(o-chlorobenzyl)-lH-l,2,3-triazole-4-carboxamide.
8. 5-amino-l-(2,6-dichlorobenzyl)-lH-l,2,3-triazole-4-carboxamide.
9. 5-amino-l-(o-methylbenzyl)-lH-l,2,3-triazole-4-carboxamide.
10. 5-amino-l-(£-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.
11. 5-amino-l-(o-bromobenzyl)-1H-1,2,3-triazole-4-carboxamide.
12. 5-amino-l-(£-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide. o J - '3 2 - 50 -
13. 5-amino-l-(2,3-dimethylbenzyl)-lH-l,2,3-triazole-4-carboxamide.
14 . 5-amino-l - [ 1- (o^-chlor opheny 1) - ethyl ]-lH-l,2,3-tr iazole-4-carboxamide.
15 . 5-amino-l - [ 1- (_o-chlorophenyl) -propyl ] -1H-1, 2, 3-triazole-4-carboxamide.
16. 5-amino-l-[1-(o-chlorophenyl)-butyl]-1H-1,2,3-triazole-4-carboxamide.
17. 5-amino-l-(£-chlorophenyl)-lH-l,2,3-triazole-4-carboxylic acid nitrile.
18. 1- (o-chlorobenzyl)-5-dimethylamino-lH-l,2,3-triazole-4-carboxylic acid nitrile.
19. 1- (£-chlorobenzyl)-5-dimethylamino-lH-l,2,3-triazole-4-carboxamide.
20. 1- (o-chlorobenzyl)-lH-l,2,3-triazole-4,5-dicarboxamide.
21. 1-(£-chlorobenzyl)-5-methoxy-lH-l,2,3-triazole-4-carboxamide.
22. 1- (£-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide .
23. 1- (£-chlorobenzyl)-5-methyl-lH-1,2,3-triazole-4-carboxamide.
24. 1-(o-methylbenzyl)-5-methyl-lH-1,2,3-triazole-4-carboxamide. ) 2 066 96 - 51 -
25. 5-amino-l-(o-chlorobenzyl)-lH-l,2,3-triazole~4-(N-methyl}-carboxamide.
26. 5-amino-l-(£-chlorobenzyl)-1H-1,2,3-triazole-4-(N,N-dimethy1)-carboxamide.
27. 5-amino-l-(2,3-dichlorobenzyl)-lH-l,2,3-triazole-4-carboxamide.
28. 1-(o-chlorobenzyl)-lH-l,2,3-triazole-4,5-di-carboxamide.
29. 5-amino-l-(5-chloro-2-methylbenzyl)-1H-1,2,3-tr iazole-4-carboxamide.
30. 5-amino-l-(£-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid piperidide.
31. 5-amino-l-(m-chlorobenzyl)-lH-l,2,3-triazole-4-carboxamide.
32 . 5-amino-l-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide.
33 . i- (o-chlorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid piperidide.
34 . 1- (_o-chl or obenzyl )-lH-l,2,3-triazole-4-carboxylic acid N,N-dimethylamide.
35. 5-amino-l-(m-methylbenzyl)-1H-1,2,3-tr iazole-4-carboxamide. - 52 2 066 9 6
36. 1-(m-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide.
37 . 1-(m-tr ifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide.
38 . 5-amino-l-(o-chlorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid (4-methyl)-piperazide or an acid addition salt thereof.
39. 5-acetylamino-l-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide.
40. 5-acetylamino-l-(o-chlorobenzyl)-1H-1,2,3-triazole -4-(N-acetyl)carboxamide.
41. 1-(o-chlorobenzyl)-5-formylamiho-lH-l,2,3-triazole-4-carboxamide.
42 . 1-(o-chlorobenzyl)-5-formylamino-lH-l,2,3-triazole-4-(N-formyl)carboxamide.
43. 1-(o-chlorobenzyl)-5-ethoxycarbonylamino-lH-l,2,3-triazole-4-carboxamide.
44 . 1-(o-chlorobenzyl)-5-(3,3-dimethylureido)-1H-1,2 ,3-triazole-4-carboxamide.
45. 1-(o-chlorbenzyl)-5-(N1,N1-dimethylglycylamino)-1H-1,2,3-triazole-4-carboxamide.
46. 1-(o-chlorobenzyl)-5-ethoxyacetylamino-lH-l,2,3-triazole-4-carboxamide. - 53 - 206696
47. 1-(o-chlorobenzyl)-5-(4-methylpiperazinocarbonylamino)-1H-1,2,3-triazole-4-carboxamide.
48. Pharmaceutical preparations containing a compound according to any one of claims 1, 3, 5 and 28 to 47 in addition to customary pharmaceutical adjuncts and/or carriers.
49. Pharmaceutical preparations containing a compound according to any one of claims 2, 4 and 6 to 27 in addition to pharmaceutical adjuncts and/or carriers.
50. Process for the manufacture of 1-phenyl- lower alkyl-lH-1,2,3-triazole compounds of the formula N=N / Ph-alk-N I i R1R2 (I) in which Ph represents phenyl substituted by lower alkyl, halogen, and/or trifluoromethyl, alk represents lower alkylidene, R^ represents hydrogen, lower alkyl, lower alkoxy or an amino group or carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkyleneand R2 represents a carbamoyl group that is unsubstituted or substituted by acyl, lower 206696 - 54 - alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene or, if represents an amino group that is unsubstituted or substituted by acyl/lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents cyano or, if represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen or lower alkyl, and the salts of salt-forming compounds of the formula I, characterised in that an azide-of the formula Ph - alk - N3 (II) is reacted with a compound of the formula Y- - C = C - R • 1 | | 2 Y-, Y, (III) in which R^ represents cyano or a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents an amino group disubstituted by lower alkyl or lower alkylene or by aza-, oxa- or thia - lower alkylene, or, if R2* represents a carbamoyl group that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, represents hydrogen, lower alkyl, lower alkoxy, or carbamoyl that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, and Y2 and Y^ together represent an additional bond, or in which R2* represents cyano or a carbamoyl group that is unsubstituted or substituted 206696 - 55 - by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, Y^ and Y2 together represent imino and represents hydrogen, or with a tautomer and/or salt thereof, or a compound of the formula Ph - alk - Z (IV) in which Z represents reactive esterified hydroxy is reacted with a 1H-1,2,3-triazole derivative of the formula H-N / N=N - (V) • = • -R, or a salt thereof or, in a compound of the formula N=N in which Y^ represents a radical YA and Y^ represents an R^ group or a radical YQ, or Y^ represents an r2 group and Y5 represents a radical Yfi, YA representing a radical that can be converted into carbamoyl that is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, or, if Yg represents amino R^ optionally substituted by lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, into cyano, and Yg representing a radical 206696 - 56 - that can be converted into carbamoyl optionally substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, or in a salt thereof, is converted into cyano or into carbamoyl optionally substituted by acyl, lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, and/or Y_ is converted into carbamoyl optionally substituted by acyl, lower alkyl or lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, or H-Y, is removed from a compound of the formula 6 N=N Ph-alk-N Rl~ R„ (IX) Y6H in which Yg represents a removable radical or, in a compound of the formula N=N / Ph-alk-N \ (XII), •=•-R- I 2 HO the hydroxy group is converted into lower alkoxy and, if necessary, a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I and/or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process is converted into the free compound. - 57 - 206696
51. Process according to claim 50 for the manufacture of 1-phenyl-lower alkyl-lH-1,2,3-triazole compounds of the formula I as defined in claim 1 in which Ph represents phenyl substituted in the 2-position by lower alkyl, halogen or trifluoromethyl and optionally substituted, in addition, by lower alkyl or halogen, which is located in the 3-, 4- or 6-position, alk represents lower alkylidene, Rj^ represents hydrogen, lower alkyl' lower alkoxy, or an amino group or carbamoyl group that is unsubstituted or substituted by lower alkyl and R2 represents carbamoyl that is unsubstituted or substituted by lower alkyl or, if R^ represents amino that is unsubstituted or substituted by lower alkyl, represents cyano, characterised in that an azide of the formula Ph - alk - N3 (II) is reacted with a compound of the formula in which R2' represents a carbamoyl group that is unsubstituted or substituted by lower alkyl, represents hydrogen, lower alkyl, or carbamoyl that is unsubstituted or substituted by lower alkyl, and Y2 and Y3 together represent an additional bond, or R2' represents a carbamoyl group that is unsubstituted or substituted by lower alkyl, or cyano, Y^ and Y2 together represent imino and Y3 is hydrogen, or with a tautomer and/or salt thereof, or a compound of the formula - 58 - 206696 Ph - alk - Z (IV) in which Z represents reactive esterified hydroxy is reacted with a 1H-1,2,3-triazole derivative of the formula or a salt thereof, or in a compound of the formula N=N Ph-alk-N Y, (VI) in which Y^ represents a radical YA and Y^ represents an R^ group or a radical Yg, or Y^ represents an R2 group and Y^ represents a radical Yg, Yft representing a radical that can be converted ipto carbamoyl that is unsubstituted or substituted by lower alkyl or, if Y^ represents amino optionally substi tuted by lower alkyl, into cyano, and Y_ representing a radical that can be converted into carbamoyl optionally - 59 - substituted by lower alkyl, or in a salt thereof, is converted into cyano or into carbamoyl optionally substituted by lower alkyl, and/or Yg is converted into carbamoyl optionally substituted by lower alkyl, or H-Y, is removed from a compound of the formula 6 T=N Ph-alk-N (IX) * R- Y6H in v/hich Yg represents a removable radical, or in a compound of the formula / N=N Ph-alk-N \ ■=.— R, HO (XII), the hydroxy group is converted into lower alkoxy and, if necessary, a resulting isomeric mixture is separated into its components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into a different compound of the formula I. - 60 - 206696
52. Process according to claim 50, characterised in that any starting material is formed under the reaction conditions by reacting a compound of the formula Ph - alk - N3 (II) with a compound of the formula Y_ Y r i8 - C - C - R ' Y Y 2 3 (X) in which R2' represents cyano or a carbamoyl group that is unsubstituted or substituted by .lower alkyl or lower alkylene or by aza-, oxa- or thia-lower alkylene, Y^ and Y2 represent lower alkoxy or optionally substituted amino R^, Y^ represents hydrogen and Y7 and Yg represent an additional bond, or Y^, Y2 an<3 Yy represent lower alkoxy and Y-j and Yg represent hydrogen, or Y^ and Y2 together represent oxo, Y-j represents hydrogen or lower alkyl and Y-j and Yg represent hydrogen, or with a tautomer and/or salt thereof, and the reaction product of the formula (IX) as defined in claim 50 is reacted further without being isolated.
53. Process according to claim 50, characterised in that a starting material is formed under the reaction conditions by reacting a compound of the formula o V w-.. . - - - 61 - 206696 Ph - alk - (II) with a compound of the formula in which R2' represents cyano or a carbamoyl group that is unsubstituted or substituted by lower alkyl, Y^ and Y2 represent lower alkoxy or optionally lower alkylated amino R^, Y-j represents hydrogen and Y7 and Yg represent an additional bond, or Y^, Y2 and Y7 represent lower alkoxy and Y3 and Yg represent hydrogen, or Y^ and Y2 together represent oxo, Y7 represents hydrogen or lower alkyl and Y3 and Yg represent hydrogen, or with a tautomer and/or salt thereof, and the reaction product of the formula (IX) as defined in claim 50 is reacted further without being isolated.
54. The process as claimed in any one of claims 50 to 53 and described in anyone of Examples 1 to 34 and 38.
55. The compounds claimed in anyone of claims 1 to 47 obtainable according to the process of anyone of claims 50 to 54 . ""attoeneys'fob the applicants
NZ206696A 1982-12-23 1983-12-22 1,2,3-triazole derivatives and pharmaceutical compositions NZ206696A (en)

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DE3578499D1 (en) * 1984-02-02 1990-08-09 Merck & Co Inc 5- (AMINO OR SUBSTITUTED AMINO) -1,2,3-TRIAZOLE.
FI93544C (en) * 1985-04-18 1995-04-25 Ciba Geigy Ag Process for the preparation of fluorinated 1-benzyl-1H-1,2,3-triazole compounds with anticonvulsant action
US5498620A (en) * 1989-05-19 1996-03-12 The United States Of America As Represented By The Department Of Health And Human Services Signal transduction inhibitor 1,2,3-triazolo compounds
US5880129A (en) * 1989-05-19 1999-03-09 The United States Of America As Represented By The Department Of Health And Human Services Methods of inhibiting invasion and metastasis of malignant solid tumors
US5359078A (en) * 1989-05-19 1994-10-25 The United States Of America As Represented By The Department Of Health And Human Services Signal transduction inhibitor compounds
WO1997040025A1 (en) * 1996-04-19 1997-10-30 Novo Nordisk A/S Solid phase and combinatorial synthesis of substituted 1,2,3-triazoles and of arrays of substituted 1,2,3-triazoles
TW526195B (en) 1997-06-10 2003-04-01 Novartis Ag Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and their use
GB0507298D0 (en) 2005-04-11 2005-05-18 Novartis Ag Organic compounds

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IL50699A0 (en) * 1975-10-28 1976-12-31 Ici America Inc Triazole derivatives
CH632291A5 (en) * 1978-01-10 1982-09-30 Sandoz Ag ORGANIC AZO COMPOUNDS.
CH639376A5 (en) * 1979-02-14 1983-11-15 Sandoz Ag Process for preparing disperse dyes of the triazolylazo class

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GR79452B (en) 1984-10-30
NO834770L (en) 1984-06-25
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ES528267A0 (en) 1985-11-16
DK591983A (en) 1984-06-24
ES543624A0 (en) 1986-06-16
ES8608495A1 (en) 1986-06-16
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PT77867B (en) 1986-05-08
JPS59118775A (en) 1984-07-09
ES8601930A1 (en) 1985-11-16
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FI834666A0 (en) 1983-12-19
IL70508A (en) 1988-03-31
AU566730B2 (en) 1987-10-29
EP0114347A2 (en) 1984-08-01

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