NO851035L - PROCEDURE FOR THE PREPARATION OF NEW 1,2,4-TRIAZACYCYCLOALCADER DIVERSES - Google Patents

Description

The invention relates to a process for the production of new 1,2,4rtriazacycloalkadiene derivatives with the formula

where the residues R1 and R2 mean independently of each other unsubsti-

tuated or with aliphatic hydrocarbon residues, free, etherified or esterified hydroxy, optionally S-oxidized etherified mercapto, free or aliphatic substituted amino, nitro and/

or trifluoromethyl substituted aryl- or optionally N-

oxidized heteroaryl groups and means an unsubstituted, containing at least 2 C atoms or with a cyano group, an optionally esterified or amidated carboxy group, one or two optionally esterified (e), or etherified (e). hydroxy group (r), one or two etherified mercapto group(s), an oxidized etherified mercapto group or an oxo group substituted, optionally by thia or oxo interrupted aliphatic or an unsubstituted cycloali-

phatic hydrocarbon residue, and their salts.

Heteroaryl residues are, for example, monocyclic, one oxygen atom

or sulfur atom and optionally also a nitrogen atom containing 5-membered or one or two nitrogen atoms containing 6-membered heteroaryl residues, such as furyl, e.g. 2-furyl, thienyl, e.g. 2-thienyl, thiazolyl, e.g. 2-thiazolyl, optionally N-oxidized pyridyl, e.g. 2-, 4- or especially 3-pyridyl or 3-(1-oxidopyridyl), or pyrimidyl, e.g. 2-pyrimidyl or 2-(1-Oxidopyrimidyl).

Aryl residues are aryl residues with up to 10 carbon atoms (C atoms), for example monocyclic aryl residues, such as phenyl.

Aryl or heteroaryl radicals may contain one or more than

one, e.g. one, two or three, the same or different of the said substituents.

Etherated hydroxy is thereby, for example, aliphatic, etherified hydroxy, as lower alkoxy or vicinally bound lower alkylenedioxy or lower alkylidenedioxy.

Esterified hydroxy as substituents of R, resp. R2 is e.g. with a mineral acid or an organic carboxylic acid esterified hydroxy, such as halogen or lower alkanoyloxy, further optionally as indicated for aryl, e.g. with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, substituted benzyloxy.

Optionally oxidized etherified mercapto as a substituent of R-^

respectively R2 is e.g. lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl.

Aliphatic substituted amino substituents are e.g. with

lower alkyl N-mono- or N,N-disubstituted amino, such as mono- or dilower alkylamino, or in the second row 4- to 7-membered alkylene- or 3-aza-, 3-oxa- or 3-thia-alkyleneamino.

Aliphatic hydrocarbon residues are, for example, lower alkyl residues or, in other words, lower alkenyl or lower alkynyl residues.

As substituents, especially of lower alkyl, for example hydroxy, with an organic carboxylic acid esterified hydroxy, e.g. lower alkanoyloxy, or aliphatic etherified hydroxy, e.g. lower alkoxy, lower alkylenedioxy or lower alkylidenedioxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, lower alkylenedithio, carboxy, lower alkoxycarbonyl or free or N-mono-, N,N-dilower alkylated or with 4- to 7-membered alkylene or 3-aza-, 3-oxa- or 3-thia-alkylene disubstituted carbamoyl, cyano and oxo.

Residues R^ are therefore, for example: lower alkyl, further lower alkenyl and lower alkynyl, likewise mono- or dihydroxy lower alkyl, mono- or dilower alkanoyloxy lower alkyl, mono- or dilower alkoxy lower alkyl, hydroxy lower alkoxy lower alkyl, lower alkoxy lower alkoxy lower alkyl, hydroxy lower alkylthio lower alkyl, lower alkoxy lower alkylthio lower alkyl, lower alkylenedioxy lower alkyl, lower alkylidenedioxy lower alkyl, mono- or dilower alkylthio-, lower alkanesulfinyl-, respectively. lower alkanesulfonyl lower alkyl, lower alkylenedithio lower alkyl, oxo lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, cyano lower alkyl, carbamoyl lower alkyl or Ki-mono- or N,N-dilower alkylcarbamoyl lower alkyl, further 4- to 7 -membered N,N-lower alkylene- or N,N-(3-aza-, 3-oxa-or 3-thia)-lower alkylenecarbamoyl lower alkyl.

Cycloaliphatic hydrocarbon residues are, for example, mono-cycloaliphatic hydrocarbon residues with 3 to 8, especially with 5 to 7 ring members, as corresponding cycloalkyl residues.

Above and following are to be understood as "lower" organic residues and compounds, preferably those containing up to and including 7, above all up to and including 4, carbon atoms (C atoms).

Lower alkyl R^ is, for example, attached via a secondary or tertiary C atom lower alkyl with 3 to 7 C atoms, such as 2-propyl (isopropyl), 2-butyl (secondary butyl), 2-(2-methyl)- propyl (tertiary butyl), 2-pentyl, 3-pentyl, 2-(3-methyl)-butyl, 2-(2-methyl)-butyl, 2-hexyl, 3-hexyl, 2-(2,3-dimethyl) -butyl, 3-heptyl or 3-(2,3-dimethylpentyl or, secondly, primarily lower alkyl with 2 to 7 carbon atoms, such as ethyl, 1-propyl, 1-butyl, 1-pentyl, 1- hexyl or 1-heptyl.

Other lower alkyl as R 1 is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, further pentyl, hexyl or heptyl.

Lower alkenyl is, for example, vinyl, preferably above

a saturated C atom bound lower alkenyl, such as allyl, methallyl or but-2-enyl..

Lower alkynyl is, for example, ethynyl, preferably above

a saturated C atom bound lower alkynyl, such as propargyl or but-2-inyl.

Lower alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, further pentyloxy, hexyloxy or heptyloxy.

Lower alkylenedioxy is, for example, methylenedioxy, ethylenedioxy, 1,3-propylenedioxy, 2,3-butylenedioxy or 1,3-(2,2-dimethyl)propylenedioxy; lower alkylidenedioxy e.g. ethylenedioxy or isopropylidenedioxy.

Lower alkanoyloxy is, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, further formyloxy or pivalyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio or tertiary butylthio, further pentylthio, hexylthio or heptylthio.

Lower alkylenedithio are, for example, ethylenedithio, 1,3-propylenedithio or 1,3-(2,2-dimethyl)propylenedithio.

Lower alkanesulfinyl is, for example, methane, ethane, 1- or 2-propane, butane or isobutanesulfinyl.

Lower alkanesulfonyl is, for example, methane, ethane, 1- or 2-propane, butane or isobutanesulfonyl.

Mono- or dilower alkylamino is, for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino or butylamino.

4- to 7-membered alkyleneamino or 3-aza-, 3-oxa- or 3-thia-alkyleneamino is, for example, pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino respectively. 4-methyl- or 4-ethylpiperazino.

4- to 7-membered N,N-alkylene or N,N-(3-aza-, 3-oxa- or 3-thia)-alkylenecarbamoyl lower alkyl is, for example, pyrrolidino-, piperidino-, morpholino-, thiomorpholino- or piperazino- or 4-methyl- or 4-ethylpiperazinocarbonylmethyl.

Carboxy lower alkyl is, for example, carboxymethyl, 1- or 2-carboxyethyl, 1-, 2- or 3-carboxypropyl, 2-(2-carboxy)-propyl or 4-carboxybutyl, further 2-(2-carboxy)-butyl.

Lower alkoxycarbonyl lower alkyl is, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, 1- or 2-methoxycarbonylethyl, 1- or 2-ethoxycarbonylethyl, 1-, 2- or 3-methoxycarbonylpropyl, 1-, 2- or 3-ethoxycarbonylpropyl , 2-(2-methoxycarbonyl)- or 2-(2-ethoxycarbonyl)-propyl or 4-ethoxycarbonyl- or 4-methoxycarbnyl, further 2-(2-methoxy- -; carbonyl)-respectively 2-(2-ethoxycarbonyl)-butyl.

Carbamoyl lower alkyl or N-mono- or N,N-lower alkylcarbamoyl lower alkyl is, for example, carbamoylmethyl, 1- or 2-carbamoylethyl or 2-(2-carbamoyl)-propyl, N-methyl-,

N-ethyl- or N,N-dimethylcarbamoylmethyl, 1- or 2-(N-methyl-, N-ethyl- or N,N-dimethylcarbamoyl)-ethyl or 2-[2-(N-methyl-, N-ethyl) - or N,N-dimethylcarbamoyl)]-propyl.

Cyano lower alkyl is, for example, cyanomethyl, 1-cyanoethyl or 2-(2-cyano)-propyl.

Mono- or dilower alkoxy lower alkyl is, for example, 2-methoxy-, 2-ethoxy-, 2-propyloxy- or 2-isopropyloxy-, 2,2-dimethoxy- or 2,2-diethoxyethyl, 3-methoxy- or 3-ethoxypropyl or 3,3-dimethoxy-, 3,3-diethoxy-, 2,3-dimethoxy- or 2,3-diethoxypropyl or 4,4-dimethoxybutyl, likewise methoxy-, ethoxy-, dimethoxy-, propyloxy- or isopropyloxymethyl.

Lower alkylenedioxy lower alkyl is, for example, 2,2-ethylenedioxy- or 2,2-propylenedioxyethyl or 3,3- or 2,3-ethylenedioxypropyl, likewise ethylenedioxy- or propylenedioxymethyl.

Lower alkylidenedioxy lower alkyl is, for example, 2,3-ethylidenedioxy or 2,3-isopropylidenedioxypropyl.

Mono- or dilower alkanoyloxy lower alkyl is an example

1- or 2-acetoxyethyl, 1- or 2-pivaloyloxyethyl, 1-acetoxy-propyl-(2), 1-pivaloyloxypropyl-(2), l-acetoxy-2-methyl-propyl-(2) or l-pivaloyloxy- 2-methyl-propyl-(2) or 3-acetoxy- or 2,3-diacetoxypropyl, but may also be pivaloyloxymethyl or acetoxymethyl.

Mono- or dilower alkylthio lower alkyl means, for example, 2-methylthio-, 2-ethylthio-, 2-propylthio or 2-isopropylthio-, 2.2-dimethylthio- or 2,2-diethylthioethyl, 3-methylthio- or 3-ethylthiopropyl or 3, 3-bis(methylthio)-, 3,3-bis(ethylthio)-, 2.3-bis(methylthio)- or 2,3-bis(ethylthio)-propyl or 4,4-bis(methylthio)-butyl, likewise methylthio -, ethylthio-, bis(methylthio)-, propylthio- or isopropylthiomethyl.

Lower alkanesulfinyl lower alkyl is, for example, 2-methanesulfinyl-, 3-ethanesulfinyl-, 2-propanesulfinyl- or 2-(2-propanesulfinyl)-ethyl, 3-methanesulfinyl- or 2-ethanesulfinylpropyl, likewise methanesulfinyl-, ethanesulfinyl- or 1- or 2-propanesulfinylmethyl.

Lower alkanesulfonyl lower alkyl is, for example, 2-methanesulfonyl-, 3-ethanesulfonyl-, 2-propanesulfonyl- or 2-(2-propanesulfonyl)-ethyl, 3-methanesulfonyl- or 3-ethanesulfonylpropyl, likewise methanesulfonyl-, ethanesulfonyl- or 1- or 2-propanesulfonylmethyl.

Lower alkylenedithio lower alkyl is, for example, 2,2-ethylenedithio- or 2,2-propylenedithioethyl or 3,3- or 2,3-ethylenedithiopropyl, likewise ethylenedithio- or propylenedithiomethyl.

Mono- or dihydroxy lower alkyl is, for example, hydroxymethyl, 1- or 2-hydroxyethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 2-hydroxypropyl-(2), 1-hydroxy-2-methyl-propyl-(2 ), 4-hydroxy- or 2,4-dihydroxybutyl, 5-hydroxy-, 2,5-dihydroxy- or 3,5-dihydroxypentyl.

Hydroxy lower alkoxy lower alkyl means, for example, 2-(2-hydroxyethoxy)-, 2-(3-hydroxypropyloxy)- or 2-(2,3-dihydroxyethoxy)-ethyl or 3-(2-hydroxyethoxy)- or 3-(3 -hydroxypropyloxy)-propyl, likewise 2-hydroxyethoxy-or 3-hydroxypropyloxymethyl.

Lower alkoxy lower alkoxy lower alkyl means, for example, 2-(methoxyethoxy)-, 2-(ethoxymethoxy)-, 2-(2-methoxypropyloxy)-or 2-(2-ethoxyethoxy)-ethyl or 3-(3-methoxyethoxy)-propyl , likewise methoxyethoxy-, ethoxymethoxy- or ethoxyethoxy-methyl.

Hydroxy lower alkylthio lower alkyl means, for example, 2-(2-hydroxyethylthio)-, 2-(3-hydroxypropylthio)- or 2-(2,3-dihydroxypropylthio)-ethyl or 3-(2-hydroxyethylthio)- or 3-(3 -hydroxypropylthio)-propyl, likewise 2-hydroxyethylthio-or 3-hydroxypropylthiomethyl.

Oxo lower alkyl means, for example, 2-oxoethyl, 2- or 3-oxopropyl or 2-, 3- or 4-oxobutyl, further corresponding to oxopentyl, oxohexyl or oxoheptyl or formyl.

Cycloalkyl with 3 to 8 ring members is, for example, cyclopentyl, cyclohexyl or cycloheptyl, further cyclopropyl or cyclooctyl.

Halogen is, for example, halogen with an atomic number up to and including 35, such as fluorine, chlorine or bromine.

Salts of compounds of formula I are above all pharmaceutically usable salts, on the one hand pharmaceutically usable acid addition salts of strong acids, such as mineral acids, e.g. salts of hydrohalic acids, above all hydrochloric acid or hydrobromic acid, i.e. hydrohalides,

above all hydrochlorides and hydrobromides, or sulfuric acid salts, i.e. hydrogen sulphates and sulphates, as well as salts of suitable organic acids, such as dicarboxylic acids or organic sulphonic acids, e.g. maleates, fumarates, maleates, tartrates

or methane sulfonates, and N-cyclohexyl sulfaminates, on the other hand inner salts of compounds of formula I, where R, contains carboxy, or their pharmaceutically usable metal salts, such as alkali or alkaline earth metal salts or ammonium salts of ammonia or suitable organic amines,

as mono-, di- or tri-lower alkylamines, e.g. diethylamine, mono-, di- or tri-hydroxy lower alkylamines, e.g. triethanolamine or 2-dimethylaminoethanol, or heteroaliphatic amines, e.g. morpholine.

Compounds of formula I exhibit valuable pharmacological properties. In particular, they exhibit a pronounced antinociceptive effect as well as an inhibitory effect on prostaglandin synthesis, as well as a clear anti-inflammatory effect. Thus, they show in mice Writhing syndrome triggered by phenyl-p-benzoquinine according to J. Pharmacol. exp. Therapy. 125, 237 (1959) in the dose range of approx. 4-40 mg/kg p.o. as excellently effective.

Likewise, they show at doses from approx. 10 to 100 mg/kg p.o. a clear inhibitory effect on the experimental Carrageenan paw edema in rats, Di Pasquale et al. Agents and Actions 5, 256, 1975.

Furthermore, they exhibit in vitro in the concentration range from approx.

0.1 to 1.5 uM/L a clear inhibitory effect on prostaglandin synthesis of arachidonic acid, demonstrated in the experimental device according to Prostaglandins 7, 123 (1974).

The compounds of formula I are therefore excellently suitable as active substances for pharmaceutical preparations for the treatment of painful inflammatory diseases, above all chronic pain conditions of a rheumatic nature, such as chronic arthritis.

The invention primarily relates to compounds of formula I, where the radicals R 1 and R 2 independently of each other mean unsubstituted or with lower alkyl, lower alkoxy or to vicinal C atoms lower alkyl (id)endioxy, hydroxy, halogen,

lower alkanoyloxy, but also unsubstituted or with lower alkyl, lower alkoxy and/or halogen substituted benzyloxy,

lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, mono- or dilower alkylamino, further 4- to 7-membered-alkylene- or 3-aza-, 3-oxo- or 3-thia-alkyleneamino, nitro and/or trifluoromethyl substituted 6 up to and including 10 C atoms containing an aryl residue or an oxygen atom or sulfur atom and optionally a further nitrogen atom containing the 5-membered or optionally N-oxidized one or two nitrogen atom(s) containing a 6-membered heteroaryl residue and R^means lower alkyl with at least 2 C atoms, 3- to 8-membered cycloalkyl, mono- or dihydroxy lower alkyl, mono- or dilower alkanoyloxy lower alkyl, hydroxy lower alkoxy lower alkyl, lower alkoxy lower alkoxy lower alkyl, hydroxy lower alkylthio lower alkyl, lower alkoxy lower alkylthio lower alkyl, mono- or dilower alkoxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylenedithio lower alkyl, mono- or dilower alkylthio lower alkyl, lower alkanesulfinyl lower alkyl, lower alkanesulfonyl lower alkyl, oxo lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, cyano lower alkyl, carbamoyl lower alkyl, N-mono- or N,N-dilower alkylcarbamoyl lower alkyl, further 4- to 7-membered N,N-lower alkylene, respectively N,N-(3-aza-, 3-oxa- or 3-thia)-lower alkylenecarbamoyl lower alkyl, and their salts.

The invention relates in particular to compounds of formula I,

where the radicals R^ and R2 independently of each other mean unsubstituted or with lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulfonyl, dilower alkylamino and/or trifluoromethyl substituted phenyl or unsubstituted or with lower alkyl, lower alkoxy, halogen or hydroxy substituted furyl, such as 2-furyl, thienyl, such. 2-thienyl, pyridyl, as 2-, . 3- or 4-pyridyl- or 1-oxidopyridyl, such as 2-, 3- or 4-(1-oxido)-pyridyl, and R₂ means lower alkyl with at least 2-C atoms, mono- or dihydroxy lower alkyl, mono- or dilower alkoxy lower alkyl , lower alkylenedioxy lower alkyl, oxo lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, cyan lower alkyl, carbamoyl lower alkyl, N-mono- or N,N-dilower alkylcarbamoyl lower alkyl,

and their salts, especially their pharmaceutically acceptable salts.

The invention relates above all to compounds of formula I, where the radicals R1 and R2 independently of each other mean unsubstituted or with lower alkoxy with up to 4 C atoms, such as methoxy, lower alkylthio with up to 4 C atoms, such as methylthio, or halogen with atomic numbers up to and including 35, as fluorine or chlorine, substituted phenyl, optionally N-oxidized pyridyl, as 3-pyridyl or unsubstituted thienyl, as 2-thienyl, and R^means over a secondary or tertiary C atom bonded lower alkyl with 3

empty. 7 C atoms, such as isopropyl or tertiary butyl, the cyan or lower alkylthio group in the a-position carries cyan lower alkyl with up to 4 C atoms in the lower alkyl part, such as cyano-

methyl or 2-cyanopropyl-(2), or lower alkylthio lower alkyl with each t.o.m. 4 C atoms, such as alkylthiomethyl, or means hydroxy lower alkyl with up to 4 C atoms such as hydroxyethyl, hydroxymethyl, 2-hydroxypropyl-(2) or 1-hydroxy-2-methyl-propyl-(2), lower alkanoyloxy lower alkyl with up to 7 C atoms in the lower alkanoyloxy part and up to 4 C atoms in the lower alkyl part, such as 1-pivaloyloxy-2-methyl-propyl-(2), oxo lower alkyl with up to 4 C-atoms, such as acetyl or 3-oxoethyl, or dilower alkoxy lower alkyl or lower alkylenedioxy lower alkyl with each t.o.m. 4 C atoms in each alkyl(ene) moiety, such as 2,2-dimethoxyethyl, 3,3-dimethoxypropyl, dimethoxymethyl or 2,2-ethylenedioxyethyl, and their, especially pharmaceutically usable, salts.

The invention relates entirely specifically to compounds of formula I, where R 1 and R 2 are lower alkoxy with up to 4 C atoms,

as methoxy, substituted phenyl or R^ means pyridyl and R2 means phenyl and R^ means over a tertiary C atom attached

lower alkyl with up to 7 C atoms, such as tertiary butyl,

carboxy-, cyano-, lower alkoxycarbonyl-, lower alkylthio-, hydroxy lower alkylthio-, oxo lower alkylthio-, dilower alkoxy lower alkylthio respectively. lower alkylenedioxy lower alkylthio group in a-position bearing carboxy lower alkyl, such as carboxymethyl or 1-carboxyethyl, cyan lower alkyl, such as cyanomethyl or 2-cyanopropyl-(2), lower alkoxycarbonyl lower

alkyl, such as 2-ethoxycarbonylpropyl-(2), lower alkylthio lower alkyl, such as ethylthiomethyl, u-hydroxy lower alkylthio lower alkyl, u-oxo lower alkylthio lower alkyl, dilower alkoxy lower alkylthio lower alkyl or lower alkylenedioxy lower alkylthio lower alkyl with together empty. 7 C atoms, such as 2-hydroxyethylthio-, 2-oxoethylthio-, 2,2-dimethoxyethylthio-

or 2,2-ethylenedioxyethylthiomethyl, hydroxy lower alkyl with up to 7 C atoms, such as 2-hydroxypropyl-(2) or 1-hydroxy-2-methyl-propyl-(2), and their, especially pharmaceutically usable, salts.

The invention primarily relates to compounds of formula I, where and R2 means lower alkoxy with up to 4 C-atoms substituted phenyl and R^ means over a tertiary C-atom bonded lower alkyl with up to 7 C atoms, such as tertiary butyl, cyano-, lower alkylthio- or dilower alkoxy lower alkylthio group in a-position bearing cyan lower alkyl with a total of up to 7 C atoms, such as cyanomethyl or 2-cyanopropyl-(2), lower alkylthio lower alkyl with a total of up to 7 C atoms, such as ethylthiomethyl, dilave alkoxy lower alkylthio lower alkyl with a total of up to 7 C atoms or hydroxy-lower alkyl with up to 7 C atoms such as 2-hydroxypropyl-(2) or 1-hydroxy-2-methyl-propyl-(2), and their especially pharmaceutically usable salts.

Namely, the invention relates to the new compounds of formula I mentioned in the examples and their pharmaceutically usable salts, methods for their preparation, pharmaceutical preparations containing these and their use.

The compounds of formula I can be prepared according to methods known per se, for example in the case of a compound of the formula where one of the residues Y-^ and Y2 means a cleavable residue Y and the other a hydrogen atom and Y^ and Y4 together mean an additional bond . isolates the isomer of formula I and, if desired, converts a compound obtained by the method into another compound of formula I and/or transfers a free compound obtained by the method in a salt or a salt obtained by the method in the free compound or in another salt .

Cleavable residues Y are, for example, optionally esterified or esterified "hydroxy or mercapto groups, further amino, ammonium and sulfonium groups. Esterified hydroxy comes into consideration, for example, with an inorganic acid or with an organic carboxylic acid esterified hydroxy, such as halogen, e.g. chlorine or bromine, or lower alkanoyloxy, e.g. acetoxy. Etherated hydroxy groups are, for example, lower alkoxy groups, e.g. methoxy or ethoxy. Esterified mercapto groups are, for example, esterified mercapto groups with a lower alkanecarboxylic acid, such as acetylthio. Etherated mercapto groups or sulfonium groups are, for example lower alkylthio or dilower alkylsulfonium groups, such as methylthio, ethylthio or dimethylsulfonium Amino groups are, in addition to groups R^-NH-for example dilower alkyl or alkylene or aza-, oxa- or thia-lower alkylene amino groups, e.g. dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or thiomorpholino, further anilino. Ammonium groups are e.g. for example the above-mentioned amino groups corresponding to tertiary amino groups or quaternary amino groups, such as lower alkylamino or pyridino.

The cleavage of HY shears usually occurs spontaneously or upon light heating, e.g. to approx. 40 to 100°C, if necessary in the presence of an aid and/or an inert solvent. Acidic agents, such as mineral acids or their anhydrides or acid salts, e.g. hydrohalic acid, above all hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, alkali metal hydrogen sulphate, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride, phosphorus oxychloride or phosphorus tribromide, organic sulphonic acids, such as p-toluenesulphonic acid, or carboxylic acids or their anhydrides, such as lower alkanoic acids and their anhydrides or halides, e.g. acetic acid, acetic anhydride or acetyl chloride, further buffered acid solutions, e.g. phosphate or acetate buffers, hydrohalides of nitrogen base, e.g. ammonium or pyridinium chloride.

Often, however, one can also use basic condensation agents, such as hydroxides, carbonates or lower alkanolates of alkali or alkaline earth metals, e.g. sodium,

potassium or calcium hydroxide, sodium or potassium carbonate or sodium methanolate, further organic nitrogen bases,

as lower alkylamines, e.g. triethylamine, or aromatic tertiary bases, such as pyridine.

The starting substances with formula II are preferably prepared in situ, for example by cyclizing a compound with the formula

where either R means a group of the formula R^-NH-N=C()-

and Rg means a group R2 or R^ means a group with the formula R2~C(=NH)-N(R1)- and Rg means a group R3 and Y5 and Yg independently means residues Y, which optionally esterified or, etherified hydroxy, etherified mercapto or optionally substituted amino or together means oxo, thiooxo or optionally substituted imino, such as lower alkylimino, optionally substituted anilo or groups with the formula =N-R^, or a salt thereof.

The cyclization of compounds of formula III takes place in the usual way under neutral, acidic or basic conditions, if necessary, in the presence of one of the aforementioned acidic or basic agents, in the presence or absence of an inert solvent or diluent, under heating, e.g. e.g. in the temperature range from approx. 40-200°C, preferably from approx. 60-140°C, and/or inert gas, such as nitrogen.

For the preparation of compounds of formula III, several formation methods are available. Thus compounds of formula III are obtained, where R is a group with the formula R^-NH-N=C(R^)-

and Rfi is a group R2 and Y1- and Yg together mean oxo, for example when a compound with the formula R^-NH-N=C(R^)-NH2(IV) is brought into reaction, which is easily available, for example

by reacting an imino compound with the formula Y-C(=NH)-R3(V), where Y has the stated meaning and means in particular lower alkoxy, halogen or amino, or an acid addition salt, e.g. hydrohalide, hence, e.g. in ethanol, respectively by reacting a triazine derivative with the formula

with a substituted hydrazine of the formula R-^-NH-NH,, (VII) or by cleavage of a 5-R^-tetrazole in the presence of an amine of the formula R-^-NH2 (VIII) or a salt thereof with a connection with the formula Y<1->C(Y5)(Yg)-R2(IX), where Y5 and Yg have the indicated meanings and Y' means a group Y respectively, if Y1- and Yg together stand for oxo, means a lower alkoxycarbonylmethyl, lower alkanoyloxy, 1-imidazolyl or a phthaliminoxy group or a group of the formula R2~C(=O)-O-, in the usual way, e.g. in the presence of a basic condensing agent.

But one can also react an amide with the formula R2-C(=0)-NH2(X) with an orthocarboxylic acid derivative with the formula R-^-C (Y^.) (Yg )-Y (XI,,. Y5= Yg= etherified hydroxy or mercapto or halogen,

Y = disubstituted amino, especially dilower alkylamino) to a compound of the formula R2~C(Y^)(Yg)-N=C(Y)-R3(XII, Y^ +

Yg = oxo, Y = substituted amino, e.g. dilute alkylamino) e.g. in dimethylformamide at approx. 80-160°C, and then condense this under acidic conditions, e.g. in acetic acid at approx. 50-100°C, with a hydrazine of the formula F^-NH-Nf^ (VII).

Compounds of formula III, where Ra is a group of the formula R2-C(=NH)-N(R1)-, Y5+ Yg = oxo and Rfi is an R3~ group,

one obtains, for example, by reacting a compound with the formula R2-C(=NH)-Y (XIII) or a hydrohalide thereof with a compound of the formula R^NH-NH-C (Y5 ) (Yg ) -R3 (XIV), where Y means esterified or etherified hydroxy, e.g. halogen or lower alkoxy, and Y^ + Yg stands for oxo in particular, e.g. in a lower alkanol, such as ethanol.

In general, however, the intermediate product with formula III is also not isolated, as the synthesis of final products with formula I can be carried out over intermediate products with formulas III and II in accordance with some important process variants without isolation of intermediates. According to an important variant of the method, one can transact with each other, e.g. compounds with the formulas R1-NH-NH2(VII) and R2~C(Y^)(Yg)-NH-C(=0)-R3(XV), where Y£ +

Yg denotes oxo or optionally substituted imino with the formula R^-N=. The reaction takes place in the usual way, for example in the presence of one of the aforementioned acidic or basic condensation agents, if necessary in the presence of an inert solvent or diluent, underheating, e.g. in the temperature range approx. 40-200°C, preferably approx. 60-140°C, and/or under inert gas, such as nitrogen.

Preferred embodiments of this intermediate formed intermediates of the formulas III or II during direct syntheses of compounds of the formula I are the reaction of compounds of the formula VII with compounds of the formula XV

(Y[L and Yg = oxo) under weakly acidic conditions, e.g. in the presence of an organic carboxylic acid, such as acetic acid, an ammonium mineral acid salt, e.g. of pyridinium chloride in acetic acid, or an acidic buffer system, such as an acetate or phosphate buffer, the condensation of compounds of formulas XIII and XIV,

e.g. in ethanol at approx. 10-50°C, and subsequent cyclization at approx. 80-160°C, e.g. in boiling xylene, likewise reaction of an amidrazine of the formula IV with an acid anhydride of the formula IX (Y' is e.g. halogen, lower alkanoyloxy or R 2 COO-;

Y^+ Yg = oxo or thio) and subsequent base treatment, e.g. with sodium or potassium hydroxide.

Similarly, the reaction of compounds of the formula R^-NH-NH2(VII) with a compound of the formula Y-C(Y5)(Yg)-R^(XI) and subsequently with a nitrile of the formula R2" proceeds over intermediate products of the formulas II and III. CN (XVI)-According to another variant, an amidrazone with the formula R-^-N (NH2 )-C(R2) =NH (XVII) can be condensed at elevated temperatures, e.g. in a melt at about 100-230 °C, for example at about 190-210°C, or in a high-boiling organic solvent, for example in boiling xylene or dimethylformamide, with a compound of formula XV. Also

here, an intermediate product with formula II is formed, which then, according to the invention, further reacts during HY cleavage.

The new compounds of formula I can further be prepared in a compound of the formula

where R^' means a residue transferable in a group R^, transfers R^<*>in the desired group R^and if necessary, respectively if desired, carry out one or more of the mentioned secondary reactions.

In residues R^transferable residues R^<1> are, for example, residues R^ substituted with an additional carboxy group, especially 1,1-dicarboxy lower alkyl or 1-carboxy-2-oxo-lower alkyl residues or residues with the formula -C (=0)-0-R3. The transfer of these residues into residues R occurs by splitting off carbon dioxide.

The separation of carbon dioxide can take place in the usual way, for example by acid action, such as treatment with a protonic acid, such as a mineral acid, e.g. with hydrochloric or sulfuric acid, advantageously in a solvent or diluent, if necessary under heating, e.g. to approx. 50 to approx. 250°C. Thus, one can transfer compounds of the formula XVIII, where ' means a 1-carboxy-2-oxo-lower alkyl residue, by heating with aqueous acid solutions,

e.g. with the same parts of approx. 15% hydrochloric acid and acetic acid

at approx. 60-100°C, in compounds of formula I, where R 1 means

a 2-oxo lower alkyl residue.

Furthermore, one can transfer compounds with the formula XVIII, where R^<1>means a residue with the formula -C(=0)-0-R3, by heating with a mineral acid, e.g. with hydrogen chlorine in tetrahydrofuran,

during carbon dioxide decomposition in the corresponding compounds of formula I.

Furthermore, in group R^transferable residues R^' are, for example, residues R^reducible to residues, such as a carboxy group possibly present in an ester, anhydride or salt form as well as 1 or 2 with an a-phenyl lower alkanol etherified hydroxy group(s) ) or 1 or 2 with a halogenated lower alkanoic acid or the carboxylic acid or with a half-ester or half-amide of this esterified hydroxy group(s) containing residues R^<1>.

Carboxy groups present in an ester form are, for example

carboxy groups esterified with an aliphatic, cycloaliphatic, araliphatic or aromatic alcohol, such as lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl, optionally substituted benzoyloxymethoxycarbonyl in the phenyl part, 2-halo lower alkoxycarbonyl, e.g. 2,2,2-trichloro- or 2-iodoethoxycarbonyl, 3- to 8-, especially 5- to 7-membered cycloalkoxycarbonyl, e.g. ;cyclopentyloxycarbonyl or cyclohexyloxycarbonyl, optionally substituted phenyl lower alkoxycarbonyl-, especially a-phenyl lower alkoxycarbonyl-, e.g. benzyloxycarbonyl residues or optionally substituted phenyloxycarbonyl.

In an anhydride form, the carboxy present is, in particular, carboxyl groups, especially chlorocarbonyl, anhydritized with a hydrohalic acid.

Carboxy present in a salt form exists in particular in an alkali metal or alkaline earth metal or ammonium salt form, e.g. as sodium, potassium or ammonium salt.

Hydrocarbon residues with 1 or 2 hydroxy group(s) which are etherified with an a-phenyl lower alkanol or esterified with a halogenated lower alkanoic acid or with carboxylic acid or

with a half ester or a half amide thereof, has as substituents especially halogen lower alkanoyloxy, lower alkoxycarbonyloxy, optionally substituted benzylcarbonyloxy, dilower alkylcarbamoyloxy or carbonyldioxy and means, for example, optionally substituted mono- or dibenzyloxy lower alkyl, mono- or di(halogen lower alkanoyloxy) lower alkyl, carbonyldioxy lower alkyl, mono- or di(lower alkoxycarbonyloxy) lower alkyl or optionally substituted benzyloxycarbonyloxy lower alkyl.

As phenyl substituents of optionally substituted phenyl containing residues of the aforementioned kind come into consideration e.g. lower alkyl, lower alkoxy, halogen and/or nitro.

For the reduction of carboxy present in an anhydride form

(to hydroxymethyl) as well as to reductive cleavage of a-phenyl-lower alkoxy or a-phenyl lower alkoxycarbonyl groups come into consideration, for example, hydrogen in the presence of a hydrogenation catalyst, such as palladium charcoal.

Carboxy groups possibly present in an ester, anhydride or salt form can be further reduced by reaction with a hydride transfer agent to hydroxymethyl or is reduced by reaction with an alkyd converter to α-oxo lower alkyl residues or α-branched α-hydroxy lower alkyl residues.

Light metal or dilite metal hydrides, such as aluminum hydride, lithium aluminum hydride, lithium borohydride, lithium (triethyl) borohydride, are considered for example as hydride transfer agents, and sodium borohydride is further considered for the reduction of chlorocarbonyl. Suitable alkyd transfer agents are, for example, metal derivatives, especially alkali or alkaline earth derivatives of lower alkanes, such as lower alkyl, especially methyl lithium, or lower alkyl magnesium halide. For the reduction of chlorocarbonyl to a-oxo lower alkyl, lower alkyl zinc- is particularly suitable. as well as lower alkylcadmium halides, which are advantageously produced in situ from the corresponding lower alkylmagnesium halide and zinc, respectively. cadmium halide. The turnover with the aforementioned hydrides or alkyd transfer agents can take place in the usual way, for example in an aliphatic or cycloaliphatic ether, such as diethyl ether, tertiary butyloxymethane, tetrahydrofuran or dioxane, if necessary under cooling or heating, advantageously under inert gas.

2-halo-lower alkoxycarbonyloxy, e.g. 2, 2,2-trichloro-or 2-iodoethoxycarbonyloxy, benzyloxymethoxycarbonyloxy or 4-nitrobenzyloxycarbonyloxy can be split off, e.g. by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonyloxy can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonyloxy also

by treatment with an alkali metal, e.g. sodium dithionite.

Further residues ' are to a group of R^solvolizable residues which contain, for example, 1 or 2 halogen atom(s), a bivalent functional converted oxo group, e.g. imino,

one of an esterified and amidated carboxy group according to the definition given above and of a cyano functionally converted carboxy group, such as an iminoether grouping, an optionally substituted amidino grouping indicated for amidated carboxyl, halocarbonyl or optionally substituted phenoxycarbonyl, e.g. phenoxy-, p-nitrophenoxy- or 2,4-dinitrophenoxy-carbonyl, or at least one of a halogen or optionally substituted phenyl substituted alkanecarboxylic acid or with a

carboxylic acid half-ester derived acyloxy group, at least one silyloxy group or a 1,2-phenylenedioxy group, two geminally bonded phenyloxy groups or a vicinally bonded mono- or diphenyl lower alkylidenedioxy, respectively. mono- or diphenyl lower alkylidenedithio group.

Cleavable acyloxy groups are, for example, halogen lower alkanoyloxy, such as 2-halogenacetoxy, in the 1-position to the lower alkyl residue branched or in the 1- or 2-position suitable substituted lower alkyloxycarbonyloxy, especially tert.-lower alkoxycarbonyloxy, arylmethoxycarbonyloxy with one or two phenyl residues, which preferably optionally with lower alkyl, especially tert.-lower alkyl, such as tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyloxy or substituted diphenylmethoxycarbonyloxy, benzoylmethoxycarbonyloxy, in which the benzoyloxy group is preferably substituted with a halogen, such as bromine. Such residues are e.g. 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetoxy, tert-butyloxy-carbonyloxy, 4-nitrobenzyloxycarbonyloxy, phenacyloxy-carbonyloxy, 2-halo lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or 2-trilower alkylsilylethoxycarbonyloxy, such as 2-trimethylsilylethoxycarbonyloxy or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyloxy,

further 2-triphenylsilylethoxycarbonyloxy.

A silyloxy group is primarily an organic silyloxy group, where the silicon preferably contains as substituents lower alkyl, especially methyl, further lower alkoxy, e.g. methoxy, and/or halogen, e.g. chlorine. Corresponding silyloxy groups are primarily lower alkylsilyloxy, especially trimethylsilyloxy, further dimethyl-tert-butyl-silyloxy,

lower alkoxy lower alkylhalo-silyloxy, e.g. methoxy-methyl-chloro-silyloxy, or lower alkyl-halogensilyloxy, e.g. dimethyl-chloro-silyloxy.

At least one of the aforementioned acyloxy groups, at least one silyloxy group, a 1,2-phenylenedioxy group, two geminally bonded phenyloxy groups or a vicinally bonded mono- or diphenyl-lower alkylidenedioxy, respectively. mono- or diphenyl lower alkylidenedithio group containing residues 1 can be transferred solvolytically in hydroxy containing aliphatic residues R^, as mono- or dihydroxy lower alkyl, a halogen containing residues R^<1> can be further transferred in with etherified or organically esterified hydroxy or etherified mercapto substituted aliphatic residues R^, such as lower alkoxy lower alkyl,

lower alkanoyloxy lower alkyl or lower alkylthio lower alkyl, two halogen atoms or a functionally converted oxo group containing residues R^' can be transferred solvolytically in oxo containing or with etherified or organically esterified hydroxy substituted residues R^, such as oxo lower alkyl, dilower alkoxy lower alkyl or lower alkylenedioxy lower alkyl, and a functionally converted carboxy group containing residues R^ can be transferred solvolytically in optionally esterified or amidated carboxy R^, as carboxy lower alkyl, lower alkoxycarbonyl lower alkyl or optionally aliphatic N-substituted carbamoyl lower alkyl.

The solvolysis of R^solvolyzable groups R^' into residues occurs, for example, by hydrolysis (treatment with water), alcoholysis (treatment with an alcohol), mercaptolysis (reaction with a mercaptan), reaction with an organic carboxylic acid or

a salt thereof or ammono- or aminolysis (treatment with ammonia or an organic amine).

By hydrolysis, one can for example transfer at least one of the aforementioned acyloxy groups, at least one silyloxy group, a 1,2r phenylenedioxy group, two geminally bonded phenyloxy groups or a visinally bonded mono- or diphenyl lower alkylidenedioxy, respectively. mono- or diphenyl lower alkylidenedithio group containing residues R^' i with hydroxy substituted aliphatic R^, as mono- or dihydroxy lower alkyl, two halogen atoms or a bivalent functional converted oxo group containing residues R^" can be transferred in oxo containing aliphatic residues / as oxo lower alkyl, functionally converted carboxy lower alkyl R^' can be transferred into carboxy lower alkyl as well as an iminoether group or an optionally aliphatic N-substituted amidine group containing functionally converted carboxy lower alkyl residues R^' can be transferred into esterified or amidated carboxy lower alkyl R^ .

The hydrolysis is carried out in the usual way, if necessary, in the presence of a hydrolysis agent and/or an inert solvent, under cooling or heating and/or under inert-. gas. Hydrolyzing agents are, for example, acidic or alkaline agents. Acidic agents are, for example, mineral acids, hydrohalic acids, e.g. hydrochloric, hydrobromic or hydroiodic acid, or oxygen acids to sulfur or phosphorus respectively. their acid salts, such as sulfuric acid, potassium hydrogen sulphate or phosphoric acids, or organic carboxylic or sulphonic acids, e.g. lower alkanoic acids, such as acetic acid, trifluoroacetic acid or fluoroacetic acid, or p-toluenesulfonic acid. Basic agents are, for example, hydroxides or carbonates of alkali or alkaline earth metals, such as potassium, sodium or calcium hydroxide, or potassium or sodium carbonate. Inert solvents are, for example, polar, water-miscible solvents, such as alcohols, e.g. methanol or ethanol, lower alkylene ethers, such as dioxane, dilower alkyl ketones, such as acetone, tertiary amides, e.g. dimethylformamide, N-methylpyrrolidone, or hexamethylphosphoric acid triamide, or dilute alkylsulfonic acid, e.g. dimethyl sulfoxide.

In alcoholysis, for example, one or two halogen atoms or bivalent functionally converted oxo containing aliphatic residues R^' can be transferred into etherified hydroxy substituted aliphatic hydrocarbon residues R^, such as mono- or di-lower alkoxy lower alkyl, lower alkylenedioxy lower alkyl,

or halocarbonyl containing aliphatic residues R^<1> is transferred into esterified carboxy, as lower alkoxycarbonyl, containing residues R^ and in residues R^1 with organic carboxylic acid esterified hydroxy group is released by transesterification. Alcohololysis occurs in the usual way, for example in the presence of a

basic, by transesterification also in the presence of an acidic agent, if necessary, under cooling or heating and/or under an inert gas, such as nitrogen. SonT sure respectively. basic agents come into consideration the aforementioned agents, as basic agents come into consideration metal alcoholates, such as alkali metal or alkaline earth metal lower alkanolates, e.g. sodium methanolate.

In mercaptolysis one can for example transfer aliphatic residues 1 containing one or two halogen atoms or bivalent functionally converted oxo, i-aliphatic hydrocarbon residues R^ which are substituted with etherified mercapto, such as lower alktio lower alkyl, or hydroxy lower alkyltio lower alkyl. The mercaptolysis takes place in the usual way, e.g. in the presence of a basic condensing agent or in which the mercapto component is used in salt form, e.g. as an alkali metal salt.

Aliphatic residues R^' containing one or two halogen atoms can also be converted by reaction with a salt of a carboxylic acid, such as a lower alkanoic acid alkali metal salt, into residues R^

containing organically esterified hydroxy, as mono- or dilower alkanoyloxy lower alkyl...

In the case of amino or aminolysis, one can for example transfer aliphatic residues R^<1> containing halocarbonyl, i with amidated carboxy substituted aliphatic hydrocarbon residues R^, as possibly aliphatic N-substituted carbamoyl lower alkyl residues, advantageously in the presence of a basic condensing agent. But the hydroxy group of the aforementioned acyloxy groups can also be released by aminolysis.

But halogen lower alkyl can. also transferred by reaction with hydrocyanic acid or an alkali metal cyanide in cyano lower alkyl. 2-substituted silyl ethoxycarbonyl can advantageously be cleaved by treatment with an alkali metal fluoride, e.g. with potassium fluoride.

Furthermore, R^<1> can also mean optionally in salt form, e.g. as an alkali metal salt form, present mercapto, that by reaction with a reactive ester, for example a hydrohalic acid ester, such as hydrogen chloride, hydrogen bromide or hydroiodic acid ester, or a sulfonic acid ester, such as p-toluenesulfonic acid ester, optionally with 1 or 2 free, esterified or etherified hydroxy groups, 1 or 2 etherified mercapto groups or oxidized etherified mercapto substituted aliphatic alcohol can be transferred in an optionally correspondingly substituted, of tia interrupted aliphatic residue R^ .

The starting materials can be prepared according to methods known per se, for example by splitting off HY from compounds

with the formula

where Y-^, Y2, Y^ and Y^ have the meanings indicated under formula II.

Compounds of formula XVIII, where R^' means carboxy optionally present in an ester, anhydride or salt form, can further be prepared by N-acylating an aminomalonic acid diester in the usual way using a compound of the formula R2_C(=0 )-C1 (XX), -couples the reaction product with a diazotized amine of the formula R^-NH2(VIII) and cyclizes the obtained azo compound by base treatment, e.g. by the action of sodium methanolate, during cleavage of an esterified carboxy group. From the ester obtained, the free acid or a salt thereof can then be hydrolytically produced and the acid chloride produced from this/this with the aid of thionyl chloride.

The compounds of formula I can further be prepared by dehydrating a compound of the formula where and Y2 means hydrogen and Y^ and Y^ an additional bond or hydrogen or Y^ and Y2 mean an additional bond and Y^ and Y^ mean hydrogen.

Dehydration takes place in the usual way by treatment with a dehydrating, oxidizing agent, advantageously in a solvent or diluent, if necessary,

during cooling or heating, e.g. at approx. 0 to 200°C. Suitable oxidizing agents are, for example, oxygen, such as air-oxygen, if necessary, in the presence of a silver, manganese,

iron or cobalt catalyst, per compounds, such as hydrogen peroxide, metal peroxides, e.g. nickel peroxide, percarbonic acid and their salts or organic peracids, e.g. m-chloroperbenzoic acid, phthalmonoperic acid or peracetic acid, or their salts, oxidizing oxygen acids and their salts or anhydrides, such as hypohalic acids and their salts, e.g. sodium hypochloride, halogen acids and their salts, e.g. iodic acids, periodic acids, potassium iodate, sodium periodate or potassium chlorate, saltpeteric acid or nitric acid and their salts and anhydrides, e.g. potassium nitrate, sodium nitrite, nitrogen oxide, dinitrogen trioxide or nitrogen dioxide, or oxidizing heavy metal compounds, such as chromium-VI-, chromium-IV-, manganese-IV-, manganese-VII-, silver-II-, copper-II-, mercury-II -, vanadium-V or bismuth-II compounds, e.g. sodium dichromate, potassium dichromate, chromium trioxide, manganese dioxide, potassium permanganate, silver II oxide, copper II oxide, mercury oxide or bismuth oxide. Inert solvents are, for example, inert solvents such as water, ketones, e.g. acetone, carboxylic acids, e.g. acetic acid, halogenated hydrocarbons, aromatic, araliphatic or heteroaliphatic hydrocarbons, e.g. tetrachloromethane, or aromatics or heteroaromatics, e.g. benzene, toluene, xylene or pyridine, or their mixtures.

The above-mentioned starting materials with formula II are preferably prepared in situ by condensing under oxidizing conditions such as under air access or in the presence of iron III chloride, preferably in xylene at approx. 100°C to the boiling temperature a compound with the formula R1-NH-N=C(R^)-NH2(IV), available for example by cleavage of a 5-R^-tetrazole in the presence of an amine with the formula R1~NH2 (VIII) respectively condensation of compounds with the formulas R-^-NH-NH2(VII) and Y-C(=NH)-R3(V,Y = etherified hydroxy), with a compound of the formula R2CH=0 (XXI).

Compounds of formula I obtainable by the method according to the invention or according to other methods not mentioned above can, if desired, be converted in a manner known per se into other compounds of formula I. If necessary,

an isomer mixture obtainable by the method according to the invention can be split into the pure isomers and, if desired, a compound obtainable by the method according to the invention can be transferred into another compound with formula I and/or a free compound obtainable by the method according to the invention can be transferred into a salt or a obtainable salt in the free compound.

In this way, one can, for example, possibly transfer etherified or esterified hydroxy groups into each other.

Contains, for example, at least one of the residues R, , R and R-, an o 2 J hydroxy group, then this can be etherified in the usual way. Thus, one can transfer hydroxy as a component of R^ with a lower alkylating agent, such as a lower alkanol, e.g. methanol, in the presence of an acid, such as a mineral acid, e.g. sulfuric acid, or in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide, and transfer hydroxy to a residue R^ resp. R2 for example in the presence of bases, such as alkali metal hydroxides or

-carbonates, e.g. sodium hydroxide or potassium carbonate,

with the help of dilower alkyl sulfates or diazole lower alkanes in correspondingly lower alkoxy groups. Conversely, ethers can be cleaved off, such as lower alkoxy groups, as substituents of R^ or R2, for example when treated with acids, such as with Lewis acids, e.g. boron tribromide or mineral acids, e.g. of hydrogen iodide.

Furthermore, hydroxy can be esterified, e.g. convert into lower alkanoyloxy, for example by reaction with a corresponding lower alkanecarboxylic acid, such as acetic acid, or a reactive derivative thereof, such as a symmetrical anhydride, or an anhydride with a hydrohalic acid, if necessary in the presence of a condensing agent, starting from anhydrides, e.g. . a basic condensing agent, such as an alkali metal hydroxide or carbonate or a tertiary nitrogen base, e.g. a lower alkylamine or of pyridine, and starting from an acid, e.g.

in the presence of an acid, such as a protonic acid, e.g. hydrochloric, sulphurous, phosphoric or a sulphonic acid, or a Lewis acid, e.g. boron trifluoride etherate.

Furthermore, free carboxyl can be esterified as a component of

In the usual way, e.g. by treatment with a diazole lower alkane, trilower alkyloxonium, trilower alkylcarboxonium or dilower alkylcarbonium salt, such as hexachloroantimonate or hexafluorophosphate, or above all by reaction with the corresponding alcohol or a reactive derivative, such as a carboxyl, phosphoric acid, sulfuric acid or carboxylic acid ester, e.g. a lower alkane carboxylic acid ester, tri-lower alkyl phosphite, di-lower alkyl sulphite or pyrocarbonate, or a mineral acid or sulphonic acid ester, e.g. hydrogen chloride

or hydrobromic acid or sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid ester, to the corresponding alcohol or an olefin derived therefrom, to an esterified carboxyl group.

The reaction with the corresponding alcohol itself can advantageously take place in the presence of an acidic catalyst, such as a protonic acid, e.g. of chloro or hydrobromic, sulphurous, phosphoric, boronic, benzene sulphonic and/or toluene sulphonic acid, or a Lewis acid, e.g. of boron trifluoride etherate, in an inert solvent, especially in an excess of the alcohol used and, if necessary, in the presence of a water-binding agent and/or under distillation, e.g. azeotrope, removal of the water of reaction and/or at elevated temperature.

The reaction with a reaction product derivative to the corresponding alcohol can be carried out in the usual way, starting from a carboxyl, phosphoric acid, sulfuric acid or carbonic acid ester, for example in the presence of an acidic catalyst, such as one of those mentioned above, in an inert solvent, as an aromatic hydrocarbon, e.g. in benzene or toluene, or in an excess of the alcohol derivative used or the corresponding alcohol. Starting from a mineral acid or sulphonic acid ester, the acid to be esterified is added, advantageously in the form of a salt, e.g. in the form of the sodium or potassium salt, and works if necessary in the presence of a basic condensing agent, such as an inorganic base, e.g. sodium or potassium or calcium hydroxide or carbonate, or in the presence of a tertiary organic nitrogen base, e.g. triethylamine or pyridine, and/or in an inert solvent, such as one of the above-mentioned tertiary nitrogen bases or a polar solvent, e.g. in dimethylformamide and/or at elevated temperature.

Cyan can be hydrolysed in the usual way to carbamoyl or carboxy or can be hydrolysed with intermediate formation of an iminoether or amidine grouping, as follows, also

without isolation, to an esterified or amidated carboxy group, reacted with an alcohol or ammonia or a primary or secondary amine.

A free carboxyl group can further be transferred by reaction with ammonia or an amine containing at least one hydrogen atom, in the usual way, during dehydration of the intermediately formed ammonium salt, e.g. by azeotropic distillation with benzene or toluene or dry heating, in an amidated carboxyl group.

However, the above-described conversions of free carboxyl groups into esterified or amidated carboxyl groups can also be carried out so that a compound of formula I, where R contains carboxy, is first transferred in the usual way into a reactive derivative, for example by means of a halide to phosphorus or sulphur, e.g. by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, in an acid halide or by reaction with a corresponding alcohol or amine transfers in a reactive ester, i.e. ester with electron-withdrawing structures, such as the ester of phenol,

thiophenyl, p-nitrophenol or cyanomethyl alcohol, or a reactive amide, e.g. the amide derived from imidazole or 3,5-dimethylpyrazole, and then reacts the formed reactive derivative in the usual way, e.g. which is subsequently described for the remastering or the mutual conversion of esterified and amidated carboxyl groups, with a corresponding alcohol, ammonia or the corresponding amine containing at least one hydrogen atom, to the desired group.

An esterified carboxyl group, likewise a trihalomethyl group, can be transferred in the usual way, e.g. by hydrolysis in the presence of a catalyst, for example in the presence of a basic or acidic agent, such as a strong base, e.g. sodium or potassium hydroxide, or a mineral acid, e.g. hydrochloric acid, sulfuric acid or phosphoric acid, in the free carboxyl group, esterified carboxy can further be transferred, e.g. by reaction with ammonia or a corresponding amine containing at least one hydrogen atom,

in an amidated carboxyl group.

An esterified carboxyl group can further be transesterified in the usual way, e.g. by reaction with a metal salt, such as a sodium or potassium salt, a corresponding alcohol or with this even in the presence of a catalyst, for example a strong base, e.g.

of sodium or potassium hydroxide, or a strong acid, such as a mineral acid, e.g. of hydrochloric, sulfuric or phosphoric acid, or an organic sulphonic acid, e.g. of p-toluenesulfonic acid, or a Lewis acid, e.g. of boron trifluoride etherate, to another esterified carboxyl group.

An amidated carboxyl group can be converted in the usual way, e.g. by hydrolysis in the presence of a catalyst, for example a strong base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. of sodium or potassium hydroxide

or -carbonate, or a strong acid, such as a mineral acid,

e.g. of hydrochloric acid, sulfuric acid or phosphoric acid in the free carboxyl group of unsubstituted carbamoyl, further converted by dehydration, e.g. by means of a carbodiimide or phosphorus pentoxide or polyphosphoric or sulfuric acid, in cyan.

Furthermore, one can optionally present in an ester, anhydride or salt form carboxy lower alkyl residues with the formula _CnH2n-C00H reduce in oxo or the hydroxy group in (i-position

bearing oxo lower alkyl residues with the formula -C ,nH_ ,,=0

Jn+1 2n+l

respectively hydroxy lower alkyl residues with the formula -C ,-,H„ ,_-0H.

-1 J J n+12n+Z

Reductions take place in the usual way, for example by reaction with a hydride transfer agent, which transfers hydrogen in anionic form to the C atom in the a-position, for example with a light metal or dilite metal hydride, e.g. with borohydride etherate or preferably lithium aluminum hydride, advantageously in an ether,

as a dilower alkyl or lower alkylene ether, e.g. in diethyl ether, tertiary butoxymethane or tetrahydrofuran, or by means of sodium borohydride or sodium cyanoborohydride, advantageously in alcoholic solution. Equally applicable are reducing agents that transfer the zero-valent metals or atomic hydrogen. These principles are used, for example, by a metallic reduction which can be obtained by the impact of finely divided metals, e.g. of zinc powder, in the same way by the reduction with nascent hydrogen, which can be prepared e.g. by the action of acid on base metals, such as the action of acetic acid on zinc, iron and hydrochloric acid or the action of water on sodium amalgam. With the aforementioned reducing agents, compounds of formula I are preferably obtained, where R 2 means a hydroxy lower alkyl residue. Salt forms of carboxy are, for example, base salt forms, such as alkali or alkaline earth metal salt forms, but can also be ammonium salt forms with ammonia or organic amines. Anhydride forms are, for example, mixed anhydride forms with hydrohalic acids, but can also be mixed anhydride forms with organic carboxylic acids, such as lower alkanoic acids. Ester forms are example-

show lower alkyl ester forms, but can also be other organic ester forms, such as optionally substituted phenyl ester forms.

As further ester forms, lactone forms, e.g., r-lactone forms, are contemplated. -When these are present in the u-position and in a lower than (u>-2) position, residues R^ are formed which contain two hydroxy groups. But the reduction can also be stopped at the oxo step, when selective reducing agents are used. Such are on the reduction of possibly present in salt form carboxy, for example mono- or dilower alkyl borohydrides, e.g. 2-(2,3-dimethyl-butyl)-borohydride, for the reduction of anhydride forms, for example hydrogen in the presence of palladium or hydrocyanic acid in the presence of tertiary aromatic nitrogen bases, such as quinoline, and for the reduction of ester forms, for example electro-negative substituted aluminium- or alkali metal aluminum hydrides, e.g. N-methylpiperazinoaluminum hydride or sodium bis-(2-methoxyethoxy)aluminum hydride, but also dibutylaluminum hydride.

As additional reducing agents for the reduction of any

in a salt, anhydride or ester form present carboxy groups to oxo or hydroxy groups are referred to as alkyd transferors, which transfer a lower alkyl residue in anionic form to the C atom in the a position, e.g. compounds of aliphatic hydrocarbons of the formula RQ"H (XXVI) with metals, e.g. compounds of the formula R -M<1>, R -M^-Hal or (R KM<*1>,

I o o o 2

where M means a metal atom from group IA and M means a metal atom from groups 2A and 2B in the periodic table of the elements and M<*>preferably stands for sodium or lithium and M"""1 preferably stands for magnesium or cadmium. The reduction with these reducing agents, by which carboxy groups present in a salt, anhydride or ester form are transferred into tertiary hydroxy groups, take place in the usual way, for example in an inert solvent, such as a dilower alkyl or lower alkylene ether, for example in diethyl ether or tetrahydrofuran, if necessary, during cooling or heating and/or under an inert gas such as nitrogen. Here too, the reduction of any carboxy compound present in a salt, anhydride or ester form can, if desired, be stopped at the oxo step, in which one uses: mild reducing agents, e.g. a cadmium or cadmium-halide compound or a magnesium halide compound in the presence of a cadmium halide, or working at low temperatures, e.g. under -25°C.

Conversely, groups can be oxidized in compounds of the formula I

R-, with the formula -C,.H. ,.-0H to groups R-, with the formula

3 n+1 2n+2 ^ ■ ^ 3

-C ,nH„ ,=0 and groups R-, with the formulas -C H~ -CH-.OH respectively.

n+1 2n+l ~3 ? rr 2n 2n 2

-C H„ -CH=0 to those with the formula C n H~ -COOH.

n 2n n 2n

The oxidation of groups with the formula _<-:n+iH2n+2-<^H to s^-^ e with the formula -(-:n+]_H2n+l=<^ s^^is, for example, by treatment with a for the oxidation of primary and secondary alcohols to aldehydes or ketones usual oxidizing agents, such as non-oxidizing metal compounds, e.g. chromyl chloride in pyridine, chromium trioxide in 2,5-dimethylpyrazole, nitrosium tetrafluoroborate or the complexes of chlorine or methanesulfonic anhydride and dimethylsulfoxide, and others, but for all by treatment with an aliphatic or cycloaliphatic ketone, such as an oxo-

lower alkane, e.g. acetone, or a cycloalkanone, e.g. cyclohexanone, in the presence of an aluminum alcoholate, e.g. aluminum isopropanolate.

Oxidation of groups with the formulas -C H„ -CH-OH or -C H„ -

J J 3crnZn 2. n 2n

CH=0 to those with the formula -CnH2n-COOH occurs, for example, by treatment with an oxidizing agent common for the oxidation of alcohols and aldehydes, such as oxidizing heavy metal compounds, e.g. manganese IV and manganese VII, chromium VI, lead IV or bismuth III compounds, especially with potassium permanganate, chromium trioxide or chromic acid respectively. alkali metal chromates. Also suitable is peroxysulphuric acid, e.g. Caro's acid, whereby by carrying out the oxidation in an alcohol by esterification of the primarily formed acid, the corresponding ester is obtained.

Furthermore, compounds of formula I can be prepared, where R^ contains esterified hydroxy groups on vicinal C atoms,

as lower alkanoyloxy, by oxidative acyloxylation of the double bond in corresponding compounds of formula I as

contains non-aromatic double bond(s). The oxidative acyloxylation takes place, for example, by treatment with a heavy metal salt of an organic carboxylic acid, e.g. with lead tetraacetate, or with a silver salt of an organic carboxylic acid in the presence of halogen, e.g. with silver acetate in the presence of iodine or bromine.

Furthermore, one can a-deprotonate compounds of formula I, where R, contains an optionally esterified or amidated carboxy group or cyan and in the a-position to this at least one hydrogen atom, by reaction with a tertiary ammonium base, such as tetra-butylammonium hydroxide, or a metal base, as an alkali metal or alkaline earth metal hydride or amide, e.g. with sodium hydride or sodium amide, and then with a reactive ester of a lower alkanol, such as a lower alkyl halide, lower alkyl sulfonate, e.g. lower alkyl-p-toluenesulfonate, or dilower alkyl sulphate, α-mono- or, if desired, also α,α-dilower alkylates.

Furthermore, additional C-substituents can optionally be introduced into the residues R 1 and/or R 2 . Thus, you can halogenate in the usual way, e.g. by reaction with chlorine or bromine in the presence of iron or by means of N-chlorosuccinimide. You can also alkylate in the usual way, e.g. by reaction with an alkyl halide, alkanol or alkene in the presence of aluminum trichloride. You can also nitrite in the usual way, e.g. using nitric/sulfuric acid, reduce the nitro group, e.g. with stannous chloride. to amino and replace this using sodium nitrite and tetrafluoroboric acid with fluorine, using hydrochloric acid, sodium nitrite and copper-I chloride (-bromide) with chlorine (bromine), respectively. by means of sodium nitrite and potassium iodide with iodine or transfer by means of sodium nitrite and a lower alkyl mercaptan to lower alkylthio resp. using sodium nitrite to hydroxy.

Furthermore, in residues R^ which contain oxo, oxo can be reduced to hydroxy or replace reductively with hydrogen, for example by the influence of nascent hydrogen, for example produced

by. treatment of base metals with proton donors, e.g.

by treating zinc with hydrochloric or acetic acid, amalgamated aluminum or sodium amalgam with water or sodium with an alcohol, such as methanol. The reductive replacement of oxo with hydrogen can also take place by reaction with hydrazine in the presence of a metal base, e.g. with sodium or potassium hydroxide or an alkali metal alcoholate, as with sodium methanolate in a high-boiling alcohol, such as ethylene glycol, diethylene glycol or diethylene glycol monomethyl ether, preferably at elevated temperatures, e.g. at approx. 150 to 250°C. Oxo can further be reduced in the usual way to hydroxy, for example by reaction with a light metal hydride, such as borane-tetrahydrofuran or diborane, or with a dilate metal hydride, such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride or by reaction with a secondary alcohol, such as isopropanol or cyclohexanol,

in the presence of an aluminum alcoholate. But the reduction of oxo to hydroxy can also take place during the simultaneous introduction of a hydrocarbon residue to the carbonyl carbon atom, in which one reacts with a lower alkyl metal compound, e.g. with a lower alkyl lithium or lower alkyl magnesium halide. In an analogous way, by aldol addition of a ketone or aldehyde to an aldehydic oxo group during reduction of this, a residue containing oxo can be introduced to hydroxy in the g position. Oxo can further by treatment with an orthocarboxylic acid ester, e.g.

an orthoformic acid lower alkyl ester, or under water-splitting conditions and acid catalysis with a lower alkanol, lower alkane diol, lower alkyl mercaptan, resp. lower alkyl dimercaptan, transferred into dilower alkoxy, lower alkylenedioxy, dilower alkylthio resp. lower alkylenedithio.

Furthermore, in residues R^ containing hydroxy, the hydroxy group(s) can be reductively replaced with hydrogen, for example as indicated above for the reductive replacement of oxo by the action of hydrogen. Hydroxy can be further transferred by reaction with a halogenating agent, such as thionyl chloride or phosphorus tribromide, or a sulfonic acid chloride, as an alkane-

or optionally substituted benzene sulphochloride, e.g. with p-toluene sulphochloride,^in halogen or sulfonyloxy, as then

by reaction with a salt of hydrocyanic acid, such as ammonium or an alkali metal cyanide, can be replaced by cyan or by reaction with an unsubstituted or as substituents a cyano group, an optionally esterified or amidated carboxy group, a. or two optionally esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidized etherified mercapto group or an oxo group containing aliphatic alcohol or mercaptan or a metal salt thereof at the missing part of an optionally correspondingly substituted,

with oxo or thia interrupted aliphatic hydrocarbon residue. But the halogen atom can also be converted by treatment with an alkali or alkaline earth metal with a metallic residue, e.g. in lithium or a halomagnesium residue, which can then be replaced by reaction with a reactive carbonic acid derivative, such as carbon dioxide,

a haloformic acid residue, e.g. chloroformic acid residue or an optionally N-substituted carbamoyl chloride with optionally esterified or amidated carboxy. Furthermore, hydroxyalkyl R 2 can be transferred

by acid treatment during water splitting in alkenyl.

In the residues R^, geminally bonded dilower alkoxy, dilower alkylthio, lower alkylenedioxy and lower alkylenedithio can be hydrolysed to oxo, respectively. vicinally bonded lower alkylidenedioxy containing lower alkyl to dihydroxy lower alkyl, preferably acid-catalytic.

Furthermore, one hydrolyzes esterified hydroxy, such as lower alkanoyloxy or possibly residues R^ containing substituted benzoyloxy, to the corresponding residues containing hydroxy, e.g. as indicated above for the hydrolysis of compounds of formula XVIII.

If, by the method according to the invention, compounds of formula I are obtained which contain mixtures of isomers, these can, in the same way as obtainable stereoisomer mixtures according to the invention, be split into the components in the usual way.

Then such isomer mixtures, e.g. mixtures of stereoisomers or diastereomers are split into the components due to difference in physical properties of the components by common physical separation methods, such as crystallisation, chromatography, distillation or phase distribution methods.

Enantiomeric mixtures, such as racemates, can be resolved into the enantiomers by crystallization of optically active solvents, chromatography on optically active solids, action of microorganisms or reaction with an optically active auxiliary compound in diastereomer mixtures, e.g. with an optically active acid in mixtures of diastereomeric acid addition salts and separating these into the diastereomers from which the enantiomers can be liberated in the usual way. For this purpose, common optically active acids are suitable, e.g. D- or L-tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid.

Furthermore, free compounds formed can be transferred in a manner known per se into acid addition salts, e.g. by reacting a solution of 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.

Formed acid addition salts can be converted in a manner known per se into the free compounds, e.g. by treating a basic final substance with an acid or an acidic end product with a base,

such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia or with a suitable anion exchanger.

Formed salts can be transferred in a manner known per se into other salts, e.g. by treating a salt with a suitable metal salt, such as a sodium, barium or silver salt, in a suitable solvent, in which a formed inorganic salt is insoluble and thus separates from the reaction mixture.

The compounds, including their salts, can also be obtained in the form of the hydrates or include that used for the crystallization

solvents.

P.g.ia. of the close relationship between the new compounds in free form and in the form of their salts, in the above and below with the free compounds or their salts it is appropriate to understand possibly also the corresponding salts or free connections.

The invention also relates to such embodiments of the method in which one starts from any method step as intermediate obtainable compounds and performs the missing method steps or forms a starting material under the reaction conditions or in the form of a derivative thereof, possibly using a salt.

In the method according to the present invention, such starting materials are preferably used which lead to the compounds mentioned above as particularly valuable. Processes for the production of new starting materials also form an object of the present invention.

The pharmaceutical preparations containing compounds of formula I or pharmaceutically usable salts thereof are for enteral as well as oral or rectal and parenteral administration as well as for topical use on warm-blooded beings, which contain the pharmacological active ingredient alone or together with a pharmaceutical applicable carrier material. The dosage of the active substance depends on the nature of the warm-blooded creature, its age and individual condition as well as on the method of application.

In normal cases, it is to be used for an approx. 75 kg heavy warm-blooded being by oral application an approximate daily dose of approx. 50-500 mg, advantageously divided into more equal partial doses.

The new pharmaceutical preparations contain e.g. from approx. 10% to approx. 80%, preferably from approx. 20% to approx. 60% of the active substance. Pharmaceutical preparations according to the invention for enteral or parenteral administration is e.g. such in dosage unit forms such as dragees, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. using conventional mixing, granulation, dragee, dissolution or lyophilization methods. In this way, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture and processing the mixture or the granulate, if desired,

or necessary, after the addition of suitable excipients,

into tablets or dragee cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, explosives such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium -alginate. Auxiliaries are primarily viscosity-regulating agents and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are supplied with suitable, possibly gastric juice-resistant covers, whereby one uses e.g. concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures or,

for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate.

The tablets or dragee coatings may have added dyes or pigments, e.g. for identification or for the characterization of different active ingredient doses.

Further orally usable pharmaceutical preparations are suppositories of gelatins, as well as soft, closed capsules of gelatins and a plasticizer, such as glycerin or sorbitol. The capsules may contain the active substance in the form of a granule, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, which may optionally contain stabilizers.

As rectally applicable pharmaceutical preparations come into consideration e.g. suppositories, which consist of a combination of the active ingredient with a suppository base.

As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active substance with a base mass can also be used. As base material comes into question e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g.

a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lyophilic solvents or carriers, such as fatty oils, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or water-containing injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

As topically applicable pharmaceutical preparations come into question

primarily creams, ointments, pastes, foams, tinctures and solutions, which contain from approx. 0.5 to approx. 20% of the active substance.

Creams are oil-in-water emulsions containing more than 50%

water. Fatty alcohols are primarily used as an oily base, e.g. leuryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitic or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, roller wax or beeswax, and/or hydrocarbons, e.g. petroleum jelly (petrolatum) or paraffin oil. Emulsifiers include surface-active substances with predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, e.g. fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerin fatty acid esters or polyoxyethylene fatty alcohol ethers or fatty acid esters,

or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, e.g. sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. Additions to the water phase include agents that reduce the drying out of the cream, e.g. polyalcohols,

such as glycerin, sorbitol, propylene glycol and/or polyethylene glycols, further preservatives, fragrances, etc.

Ointments are water-in-oil emulsions that contain up to 70%, preferably from approx. 20% to approx. 50% water or aqueous phases. The fat phase is primarily hydrocarbons, e.g. petroleum jelly, paraffin oil and/or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, to improve the water-binding capacity, e.g. cetyl alcohol or wool wax alcohols, respectively wool-wax. Emulsifiers are corresponding lyophilic substances, such as sorbitan fatty acid esters (Spans), e.g. sorbitan oleate and/or sorbitan isostearate. Additions to the water phase include

agents that retain moisture, such as polyalcohols, e.g. glycerin, propylene glycol, sorbitol and/or polyethylene glycol, as well as preservatives, fragrances, etc.

Fat salves are anhydrous and contain hydrocarbons as a base, e.g. paraffins, vaselines and/or liquid paraffins, further natural or partially synthetic fats, e.g. coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, further fatty acid partial esters to glycerine, e.g. glycerin mono- and -distearate,

as well as e.g. the fatty alcohols mentioned in connection with the ointments which increase the water absorption capacity, emulsifiers and/or additives.

Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides, e.g. titanium oxide or zinc oxide, further talc and/or aluminum silicates which have the task of binding the moisture or secretions present.

Foams are administered by pressurized containers and are liquid oil-in-water emulsions available in aerosol form using halogenated hydrocarbons, such as chlorofluoro lower alkanes,

e.g. dichlorodifluoromethane and dichlorotetrafluoroethane, as propellants. As an oil phase, e.g. hydrocarbons, e.g. paraffin oil, fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myistate, and/or other waxes. As emulsifiers, e.g. mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lyophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are common additives, such as preservatives, etc.

Tinctures and solutions most often contain an aqueous-ethanolic base, which has been added i.a. polyalcohols, e.g. glycerin, glycols, and/or polyethylene glycol, as a humectant to reduce evaporation, and relubricating substances, such as fatty acid esters of lower polyethylene glycols, i.e. in aqueous mixture solutions, lyophilic substances to replace fatty substances, which are extracted with ethanol from the skin, and, if necessary, other aids and additives.

The preparation of the topically usable pharmaceutical preparations takes place in a manner known per se, e.g. when dissolving or suspending the active substance in the base or a part thereof, if necessary, when processing the active substance as a solution, this is usually dissolved in one of the two phases during the emulsification, when processing as a suspension it is mixed after the emulsification with a part of the base and then added the rest of the formulation.

The compounds of formula I and the salts of such compounds

with salt-forming properties is preferably used for the treatment of inflammation, primarily inflammatory, chronic diseases from the rheumatic form crisis, especially chronic arthritis.

The following examples illustrate the invention described above, but it should in no way limit this in its scope. Temperatures are indicated in degrees Celsius, pressure in mbar.

Example 1:

5.5 g (0.0214 Mol) N"'"-(p-methoxyphenyl)-tertiary butyramidrazone hydrochloride are dissolved in 20 ml of water and added with 12 ml of 2n-sodium hydroxide solution. The liberated base is extracted with ether. The extract is dried with sodium sulphate, filtered and evaporated. The oil obtained is refluxed for 20 hours with 20 ml of xylene (isomer mixture) and 2.75 g of 4-methoxybenzaldehyde. It is then evaporated under reduced pressure and the residue crystallized from petroleum ether. The 1,5-bis-(p-methoxyphenyl)-3-tertiarybutyl-1H-1,2,4-triazole is obtained in the form of colorless crystals with a melting point of 101-102°C.

The N<*->(p-methoxyphenyl)-tertiary-butyramidrazone hydrochloride used as starting material can be prepared in the following way: 7.6 g of pivaloimidic acid methyl ester hydrochloride is dissolved in 40 ml of methanol and added with a solution of 7.0 g of p-methoxyphenyl-hydrazine in 100 ml of methanol. After 24 hours at 20°C, it is evaporated under reduced pressure. The residue gives, on fine distribution with ether, N^-(p-methoxyphenyl)-tertiary butyramidrazone hydrochloride, which decomposes on heating above 170°C.

Example 2:

A solution of 8.2 g (36 mmol) of N<1->phenyl-tertiary-butyramidrazone hydrochloride in 50 ml of methanol is added with 6.66 ml of a 5.4-molar sodium methylate solution in methanol, the precipitated sodium chloride is filtered off and the filtrate is evaporated under reduced pressure. The residue is boiled for 20 hours under reflux with 100 ml of xylene and 3.4 ml of pyridine-3-aldehyde.

After distilling off the xylene, 1-phenyl-5-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole is obtained as colorless crystals with a melting point of 143-144°C (from petroleum ether).

The N^-phenyl-tertiary-butyramidra-zone hydrochloride used as starting material can be obtained in the following way:

A solution of 12.1 g of pivaloimidic acid methyl ester hydrochloride

in 100 ml of methanol was added with 8.6 g of phenylhydrazine and stored for 24 hours at 20°C. After evaporation under reduced pressure, the rest of the 2-propanol crystallizes. N<1->phenyl-tertiary-butyramidrazone hydrochloride is obtained as colorless crystals with a melting point of 237-239°C.

Example 3:

1.2 g (0.0052 mol) of N<*->(3-pyridyl)-tertiary butyramidrazone hydrochloride is dissolved in 3 ml of absolute methanol, added with 5.2 ml of 1-n. sodium methylate solution in methanol and filtered off from excreted sodium chloride. The filtrate is evaporated under reduced pressure, added with 20 ml of xylene (isomer mixture) and 0.6 benzaldehyde and then boiled for 20 hours at reflux. After distilling off the xylene, 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole is obtained as colorless crystals with a melting point of 146-147°C (from petroleum ether).

The N"*"-(3-pyridyl)-tertiary butyr-amidrazone hydrochloride used as starting material can be obtained in the following way:

A solution of 9.6 g of pivaloimidic acid methyl ester hydrochloride

1 40 ml of methanol was added with a solution of 6.9 g of 3-hydrazinepyridine in 50 ml of methanol and stored for 24 hours at 20°C. After evaporation under reduced pressure, the rest of the ether is crystallized. The N<*->(3-pyridyl)-tertiary butyramidrazone hydrochloride with a melting point of 221-222°C is obtained.

Example 4:

20.5 g (0.0897 Mol) N 2 -(3-pyridyl)-tertibutyramindrazone hydrochloride was dissolved in 150 ml of methanol, added with 16.6 ml of a 5.4 molar solution of sodium methylate in methanol and filtered from the separated sodium chloride. The filtrate is evaporated under reduced pressure, added with 200 ml of xylene (isomer mixture) and 12.2 g of p-methoxybenzaldehyde and then boiled for 20 hours at reflux. After distilling off the xylene, 5-(p-methoxyphenyl)- The 1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole as colorless crystals with melting point 115-116°C (of petroleum ether).

Example 5:

15.2 g of 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester are dissolved in a mixture of 450 ml of tetrahydrofuran and 450 ml of methanol. While stirring, 8.5 g of sodium borohydride are introduced in portions over 10 minutes. After 2 hours, the reaction mixture is added with 500 ml of water and freed from the organic solvent under reduced pressure. The remaining aqueous solution separates an oil which is absorbed in vinegar. The acetic ester solution is dried over sodium sulfate, filtered and evaporated. The residue gives from isopropanol 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3-methanol with a melting point of 108-109°C.

The starting material can be produced e.g. as the following:

70.3 g of aminomalonic acid dimethyl ester hydrochloride is heated for 48 hours with 65.4 g of 4-methoxybenzoyl chloride in 700 ml of methylene chloride with stirring and reflux. It is then cooled, filtered off from undissolved, and the filtrate washed with water and potassium bicarbonate solution. The organic phase is dried over sodium sulphate, filtered and evaporated. The residue gives p-methoxybenzoylaminomalonic acid dimethyl ester of isopropanol with a melting point of 114-115°C.

2.0 g of p-methoxyaniline is dissolved in a mixture of 16 ml of glacial acetic acid and 4 ml of concentrated hydrochloric acid, cooled to 0°C and added dropwise with an aqueous 5-molar solution of sodium nitrite. The reaction mixture is cooled to -10°C and added dropwise with a solution of 3.8 g of p-methoxybenzoylaminomalonic acid dimethyl ester in 40 ml of acetone. A solution of 22.8 g of potassium carbonate in 23 ml of water is then added dropwise and then stirred for another half hour at 0-5°C. Acetic acid is then added to the reaction mixture. The organic phase is separated, washed with water, dried over sodium sulfate, filtered and evaporated. The residue gives from isopropanol p-methoxy-benzoylamino-p-methoxyphenylazomalonic acid dimethyl ester with melting point 139°C (decomposition).

0.42 g of p-methoxybenzoylamino-p-methoxyphenylazomalonic acid dimethyl ester is suspended in 9 ml of methanol, added with 0.15 ml of a 1N-sodium methylate solution in methanol and stirred for 3 hours at 20°C. The resulting solution is then cooled to 0°C, after which crystallization takes place. The crystals are filtered off, washed with isopropanol and dried. The thus obtained 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester melts at 174-176°C.

Example 6:

7.1 g (0.0216 Mol) of 1,5-bis(p-methoxyphenyl)-3-chloromethyl-1H-1,2,4-triazole is heated for 20 hours at reflux with a solution of 4.6 g of ethyl mercaptan in 80 ml In sodium methylate solution. The reaction solution is evaporated under reduced pressure and the residue distributed between water and ether. Ether-

the phase is washed with saline, dried over sodium sulfate and evaporated. The residue gives petroleum ether 3-ethylthiomethyl-1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole with melting point 89-90°C.

The 1,5-bis(p-methoxyphenyl)-3-chloromethyl-1H-1,2,4-triazole used as starting material can be prepared as follows: 6.0 g 1,5-bis(p-methoxyphenyl)-1H- 1,2,4,-triazole-3-methanol is dissolved in 20 ml of chloroform and at 10-15°C added dropwise to a solution of 6.0 ml of thionyl chloride in 10 ml of chloroform. After 3 hours of storage at 20°C, the volatile components are distilled off under reduced pressure at 30-40°C bath temperature. The residue gives after crystallization of ether 1,5-bis(p-methoxyphenyl)-3-chloro-methyl-1H-1,2,4-triazole with melting point 90-91°C.

Example 7:

1.0 g of 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3-methyl-S-thiuronium chloride is refluxed in 10 ml of ethanol with 2.9 ml of 2-n caustic soda and 1.27 g of 1-bromo-2,2-dimethoxyethane. The ethanol is then allowed to distill off and the residue is divided between water and diethyl ether. The ether extract is washed with water, dried over sodium sulfate and evaporated. With the help of bubble tube distillation, 1-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3-ylmethyl-thio]-2,2-dimethoxy-ethane is obtained, boiling point = 170°C /2»10 mbar,

as colorless oil.

The starting material can be produced as follows:

3.3 g of 1,5-bis(p-methoxyphenyl)-3-chloromethyl-1H-1,2,4-triazole is boiled for 20 hours under reflux in 15 ml of ethanol with 0.84 g of thiourea. On cooling, 1,5-bis-(p-methoxyphenyl)-1H-1,2,4-triazole-3-methyl-S-thiuronium hydrochloride is obtained as colorless crystals, melting point 209-211°C. (3.8 g = 94% of theory).

Example 8:

18.4 g of tetrabutylammonium hydrogen sulfate are dissolved in 68 ml of 2-n. caustic soda and added at room temperature to a solution of 8.7 g of 1,5-bis(p-methoxyphenyl)-3-cyanomethyl-1H-1,2,4-triazole and 19.3 g of methyl iodide in 50 ml of dichloromethane. The mixture is stirred for 20 hours at room temperature. The dichloromethane phase is then separated, washed with water, dried over sodium sulfate, filtered and evaporated. Crystallization of the residue from ethanol gives 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-2-methyl-propionitrile with melting point 103-104°C.

Example 9:

To an ice-cooled suspension of 5.7 g of sodium cyanide i

50 ml of dimethyl sulfoxide are added portionwise while stirring to 12.7 g of 1,5-bis(p-methoxyphenyl)-3-chloromethyl-1H-1,2,4-triazole. The reaction mixture is then stirred for 2 hours at room temperature. After adding 350 ml of water, it is extracted with diethyl ether. The extracts are washed with water, dried over sodium sulphate, filtered and evaporated. The residue crystallizes from diethyl ether. The thus obtained 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3]-acetonitrile melts at 76-78°C.

Example 10:

1.85 g of magnesium shavings are treated with 10.6 g of methyl iodide and 20 ml of diethyl ether. After dissolving the metal, a solution of 10.2 g of 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester in 200 ml of tetrahydrofuran is slowly added dropwise with stirring and the reaction mixture becomes then heated for 2 hours at 50°C. The reaction mixture is then cooled to 0°C and added dropwise with 100 ml of saturated ammonium chloride solution. Two phases form, of which the upper one is separated and washed with saturated ammonium chloride solution. The tetrahydrofuran solution is then dried over sodium sulphate and evaporated under reduced pressure. Crystallization of the residue from ether-hexane gives 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-propan-2-ol with melting point 96-97°C.

Example 11:

2.75 g (0.0107 Mol) of N"*"-(p-methoxyphenyl)-tertiary butyramidrazone and 10 g of p-methoxybenzoyl chloride are heated for 12 hours at 120°C with stirring. The reaction mixture is then stirred with excess 10% sodium carbonate solution, until all excess acid chloride is decomposed. Extract several times with diethyl ether, dry the extracts over sodium sulphate, filter and evaporate the filtrate. 1,5-bis(p-methoxy-phenyl)-3-tertiarybutyl-1H-1,2,4-triazole with a melting point of 101-102°C is obtained.

Analogously, 1.2 g of N"<*>"-(3-pyridyl)-tertiarybutyramidrazone is obtained 5-(p-methoxyphenyl)-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4- triazole with melting point 115-116°C, and by reaction with the corresponding amount of benzoyl chloride, 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole with melting point 146-147°C .

Example 12:

In an analogous manner as described in examples 1 to 11, one can further prepare: 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-2-methyl-propionic acid ethyl ester, melting point 106-107°C;

2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-2-methyl-propan-1-ol, melting point 109-110°C, and

2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3-yl]-2-methyl-1-pivaloyloxy-propane, melting point 90-92°C.

Example 13:

Tablets, which contain 25 mg of active ingredient, e.g. 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole can be prepared in the following way:

Manufacturing

All solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. The active substance, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water

and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, driven through a sieve with a mesh size of 1.2 mm and pressed into concave tablets with approx. 6 mm diameter.

Tablets can also be prepared in an analogous manner, each containing 25 mg of one of the compounds of formula I mentioned in examples 1, 2 and 4 to 11, whereby these compounds also

can be present in the form of salt.

Example 14:

Chewable tablets, which contain 30 mg of active ingredient, e.g. 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole, can e.g. produced in the following way:

Manufacturing

All solid ingredients are first passed through a sieve with a mesh size of 0.25 mm. The mannitol and lactose are mixed, granulated with the addition of gelatin solution, passed through a sieve with a mesh size of 2 mm, dried at 50°C and again passed through a sieve with 1.7 mm mesh size. The active substance, glycine and saccharin are mixed thoroughly, the mannitol, lactose granules, stearic acid and talc are added, everything is thoroughly mixed and pressed into concave tablets with approx. 10 mm diamter with breaking drill on the upper side.

Tablets can also be prepared in an analogous manner, each containing 30 mg of a compound of formula I mentioned in examples 1, 2 and 4 to 11, whereby these compounds can also be present in the form of salts.

Example 15:

Tablets containing 100 mg of active ingredient, e.g. 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole, can e.g. produced as follows:

Manufacturing

The solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. The active substance, lactose, talc, magnesium stearate and half of the starch are then thoroughly mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water and the mixture granulated, if necessary, while adding water. The granulate is dried overnight at 35°C, driven through a sieve with a mesh size of 1.2 mm and pressed into concave tablets with approx. 6 mm diameter.

Tablets can also be prepared in an analogous manner, each containing 100 mg of one of the compounds of formula I mentioned in examples 1, 2 and 4 to 11, whereby these compounds can also be present in the form of salts.

Claims (10)

1. Process for the preparation of new 1,2,4-triazacycloalkadiene derivatives with the formula where the residues and R2 independently mean unsubstituted or with aliphatic hydrocarbon residues, free, etherified or esterified hydroxy, optionally S-oxidized etherified mercapto, free or aliphatically substituted amino, nitro and/or trifluoromethyl substituted aryl groups or optionally N-oxidized heteroaryl groups and R means an unsubstituted, at least 2 C atoms containing or with a cyano group, a possibly esterified or amidated carboxy group, one or two possibly esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidized etherified mercapto group or an oxo group substituted, possibly by thia or oxa interrupted aliphatic or an unsubstituted, cycloaliphatic hydrocarbon residue, and their salts, characterized in that one of a compound with the formula where one of the residues Y, and Y2 means a cleavable residue Y and the other a hydrogen atom and Y^ and Y4 together mean an additional bond, or where Y^ means a cleavable residue Y and Y^ means hydrogen and Y, and Y2 means a further bond, or of a salt thereof, during the introduction of a further bond cleaves HY, or in a compound of the formula where means a residue transferable in a group R^, transfers R-j in the desired group R^ or dehydrates a compound of the formula where and Y2 means hydrogen and Y^ and Y^ means an additional bond or hydrogen or Y-^ and Y2 means an additional bond and Y^ and Y^ means hydrogen, if necessary, split an isomer mixture formed by the process into its components and isolate the isomer with formula I and, if desired, converts a compound obtained by the process into another compound with formula I and/or transfers a free compound formed by the process into a salt or transfers a in the process formed salt in the free compound or in another salt. 2. Process according to claim 1, characterized in that compounds of formula I are prepared, where the residues R-1 and R2 independently of each other mean unsubstituted or with lower alkyl, lower alkoxy or to vicinal C atoms with lower alkyl(ide)endioxy, hydroxy, halogen, lower alkanoyloxy, but also unsubstituted or with lower alkyl, lower alkoxy and/or halogen substituted benzoyloxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, mono- or dilower alkylamino, further 4- to 7-membered alkylene- or 3-aza-, 3-oxa- or 3-thialolower alkyleneamino, nitro and/or trifluoromethyl substituted 6 to 10 C atoms containing an aryl residue or an oxygen or sulfur atom and optionally a further nitrogen atom containing the 5-membered or optionally N-oxidized one or two nitrogen atom(s) containing a 6-membered heteroaryl residue and means lower alkyl with at least 2 C atoms, mono- or dihydroxy lower alkyl, mono- or dilower alkanoyloxy lower alkyl, hydroxy lower alkoxy lower alkyl, lower alkoxy lower alkylthio lower alkyl, mono- or dilower alkoxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylenedithio lower alkyl, mono- or dilower alkylthio lower alkyl, lower alkanesulfinyl lower alkyl, lower alkanesulfonyl lower alkyl, oxo lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, cyan lower alkyl, carbamoyl lower alkyl, N -mono- or N,N-dilower alkylcarbamoyl lower alkyl, further 4- to 7-membered N,N-lower alkylene- or N,N-(3-aza-, 3-oxa- or 3-thia)-lower alkylenecarbamoyl lower alkyl, and their salts. 3. Process according to claim 1, characterized in that compounds of formula I are prepared, where the radicals R 1 and R 2 independently of each other mean unsubstituted or with lower alkoxy with up to 4 C atoms, lower alkylthio with up to 4 C atoms or halogen with atomic numbers up to and including 35 substituted phenyl, optionally N-oxidized pyridyl or unsubstituted thienyl and R^ means over a secondary or tertiary C atom bonded lower alkyl to 3 up to and including 7 C atoms, the cyano or lower alkylthio group carries in the a-position cyano lower alkyl with up to 4 C atoms in the lower alkyl part or means lower alkylthio lower alkyl with each up to 4 C atoms or means hydroxy lower alkyl with up to 4 C atoms, lower alkanoyloxy lower alkyl with up to 7 C atoms in the lower alkanoyl oxide part and up to 4 C atoms in the lower alkyl part, or lower alkyl with up to 4 C atoms or dilower alkoxy lower alkyl resp. lower alkylenedioxy lower alkyl with each t.o.m. 4 C atoms in each alkyl(en) moiety, or their salts. 4. Method according to claim 1, characterized in that compounds of formula I are prepared, where R-^ and R2 mean lower alkoxy with up to 4 C atoms substituted phenyl or R-, means pyridyl and R0 means phenyl and R, means above a tertiary C atom bonded lower alkyl with up to 7 C atoms, carboxy-, cyano-, lower alkoxycarbonyl-, lower alkylthio-, hydroxy lower alkylthio-, oxo lower alkylthio-, dilower alkoxy lower alkylthio respectively. lower alkylenedioxy lower alkylthio group bearing in a-position carboxy lower alkyl, cyano lower alkyl, lower alkoxycarbonyl lower alkyl, lower alkylthio lower alkyl, u-hydroxy lower alkylthio lower alkyl, 10-oxo lower alkylthio lower alkyl, dilower alkoxy lower alkylthio lower alkyl or lower alkylenedioxy lower alkylthio lower alkyl with a total of up to 7 C atoms or hydroxy lower alkyl with up to 7 C atoms, or their salts. 5. Process according to claim 1, characterized in that compounds of the formula I are prepared, where R-^ and R2 mean lower alkoxy with up to 4 C-atoms substituted phenyl and R^ means over a tertiary C-atom bonded lower alkyl with up to 7 C atoms, cyano, lower alkylthio or dilower alkoxy lower alkylthio group in the a-position carries cyan lower alkyl with a total of up to 7 C atoms, lower alkylthio lower alkyl with a total of up to 7 C atoms, dilower alkoxy lower alkylthio lower alkyl with a total of up to 7 C atoms or hydroxy lower alkyl with up to 7 C atoms or their salts. 6. Process according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-tertiarybutyl-1H-1,2,4-triazole or a salt thereof is produced. 7. Process according to claim 1, characterized in that 5-phenyl-1-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole or a salt thereof is produced. 8. Process according to claim 1, characterized in that 3-ethylthiomethyl-1,5-bis (p-methoxyphenyl)-1H-1,2,4-triazole or a salt thereof is prepared. 9. Method according to claim 1, characterized in that 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-propan-2-ol or a salt is prepared hence. 10. Method according to claim 1, characterized in that one produces 1- phenyl-5-(3-pyridyl)-3-tertiarybutyl-1H-1,2,4-triazole, 5-(p-methoxyphenyl)-1-(3-pyridyl)-3-tertiarybutyl-1H-1, 2,4-triazole, 1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3-methanol, 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole-3]-acetonitrile, 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4 -triazole-3]-2-methyl-propionitrile, 2-[1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazol-3]-2-methyl-propanol or lr[ 1,5 -bis(p-methoxyphenyl)-1H-1,2,4-triazol-3-ylmethylthio]-2,2-dimethoxyethane or a salt thereof.