NO851036L - PROCEDURE FOR THE PREPARATION OF NEW 3-MERCAPTO-1,2,4-TRIAZACYCLOALCADER DERIVATIVES - Google Patents

Description

The invention relates to a process for the production of new 3-mercapto-1,2,4-triazacycloalkadiene derivatives of formula I

in which the residues R, and R2 independently of each other 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 or optionally N-oxidized heteroaryl residues, n means 0, 1 or 2,

and R^means a at an optionally esterified or amidated carboxy group, cyano or in a position higher than α with one or two optionally esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidized mercapto group or an oxo group substituted aliphatic hydrocarbon residue as well as their salts.

Heteroaryl residues are, for example, monocyclic, an oxygen or sulfur atom and optionally in addition a nitrogen atom containing 5-membered or one or two nitrogen atom containing 6-membered heteroaryl residues, such as furyl, e.g. 2-furyl, thienyl, e.g. 2-thienyl, thiazolyl, e.g. 2-thiazolyl, pyridyl, e.g. 2-, 4- or especially 3-pyridyl resp. 3-(1-oxidopyridyl) or pyrimidyl, e.g. 2- or 4-pyrimidyl resp. 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 resp. heteroaryl residues can have 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, lower alkoxy or vicinally bound lower alkylenedioxy or lower alkylidenedioxy, however, can also be lower alkenyloxy or lower alkynyloxy.

Esterified hydroxy as a substituent of resp. R£ is example-, show with a mineral acid or an organic carboxylic acid esterified hydroxy, such as halogen, lower alkanoyloxy, further optionally as indicated, e.g. with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, substituted benzoyloxy.

Optionally oxidized etherified mercapto is, for example, lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl.

Aliphatic substituted amino substituents are, for example, with lower alkyl mono- or disubstituted amino, such as N-mono- or N,N-dilower alkylamino, however, can also be 4 to 4-membered alkylene- or 3-aza-, 3-oxa- or 3-thia-alkyleneamino.

Esterified carboxy means, for example, aliphatic esterified carboxy, such as lower alkoxycarbonyl.

Amidated carboxy is, for example, unsubstituted or aliphatically substituted carbamyl, such as carbamyl, N-mono- or N,N-dilower alkylcarbamyl, but can also be 4- to 7-membered N,N-lower alkylene or N,N-(3-aza-, 3-oxa- or 3-thialaverealkylenecarbamyl).

Aliphatic hydrocarbon residues are, for example, lower alkyl, further lower alkenyl or lower alkynyl residues. As substituents of R 1 , which in particular means substituted lower alkyl, an organic carboxylic acid esterified hydroxy, e.g. lower alkanoyloxy or aliphatic etherified hydroxy, e.g. lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally oxidized etherified mercapto, such as lower alkylthio, lower-alkanesulfinyl, lower alkanesulfonyl, lower alkylenedithio, optionally esterified or amidated carboxy, such as carboxy, lower alkylcarbonyl, carbamyl or N-mono- or N,N-di-lower alkylcarbamyl, cyano as well as oxo. Residues R^ are consequently, for example, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamyl lower alkyl, N-mono- and N,N-dilower alkyl carbamyl lower alkyl, cyanone lower alkyl or hydroxy-, lower alkanoyloxy- lower alkoxy-, lower alkylenedioxy-, lower alkylthio-, lower alkylenedithio-, lower alkanesulfinyl, lower sulfalkane onyl- or oxo group(s) higher than the α-position containing mono- or dihydroxy lower alkyl, lower alkanoyloxy lower alkyl, mono- or dilower alkyl lower alkyl, lower alkylenedioxy lower alkyl, mono- or dilower alkylthio-, lower alkanesulfinyl- or lower alkanesulfonyl lower alkyl, lower alkylene dithio lower alkyl or oxola lower alkyl.

Above and in the following, "lower" organic residues and compounds preferably mean those containing up to and including 7, above all up to and including 4, carbon atoms (C atoms).

Lower alkyl 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 lower alkenyl, such as allyl, metallyl or but-2-enyl, bound over a saturated C atom.

Lower alkynyl is, for example, ethynyl, but preferably lower alkynyl, such as propargyl or but-2-inyl, is bound over a saturated C atom.

Lower oxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy or tertiary butyloxy, further pentyloxy, hexyloxy or heptyloxy. Lower alkenyloxy is e.g. allyloxy, lower alkynyloxy, e.g. propargyloxy.

Lower alkylene dioxy is, for example, methylenedioxy, ethylenedioxy, 1,3-propylenedioxy, 2,3-butylenedioxy or 1,3-(2,2-dimethyl)propylenedioxy, loweralkylidenedioxy, e.g. ethylenedioxy or isopropylidenedioxy.

Lower alkanoyloxy is, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, further formyloxy or pivaloyy-oxy.

Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio or tertiarybutylthio, further pentylthio, hexylthio or heptylthio. Lower alkylenedithio is, 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 resp. 3-aza-, 3-oxa- or 3-thiaalkylenamino is, for example, pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, respectively. 4-methyl-

or 4-ethylpiperazino.

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

Carboxyl 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 oxycarbonyllower alkyl is, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, 1- or 2-methoxycarbonylethyl, 1- or 2-ethoxycarbonylethyl, 1-, 2- or 3-methoxycarbonyl, 1-, 2- or 3-ethoxycarbonylpropyl, 2-(2-methoxycarbonyl) - or 2-(2-ethoxycarbonyl)-propyl or 4-ethoxycarbonyl-resp. 4-methoxycarbonylbutyl, further 2-(2-methoxycarbonyl)-resp. 2-(2-ethoxycarbonyl)-butyl.

Carbamyl lower alkyl resp. N-mono- or N,N-dilower alkyl-carbamyl lower alkyl is, for example, carbamylmethyl, 1- or 2-carbamylethyl or 2-(2-carbamyl)-propyl or N-methyl-, N-ethyl- or N,N-dimethylcarbamylmethyl, 1- or 2-(N-methyl-, N-ethyl- or N,N-dimethylcarbamyl)-ethyl or 2-(2-(N-methyl -, N-ethyl- or N,N-dimethylcarbamyl)_7-propyl.

Cyanolower alkyl is, for example, cyanomethyl, 1-cyanoethyl

or 2-(2-cyano)-propyl.

Mono- or divareal oxylaverealkyl 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, 2-(1-dimethoxy-2-methyl)propyl or 4,4-dimethoxybutyl.

Lower alkylene dioxy lower alkyl is, for example, 2,2-ethylenedioxy- or 2,2-propylenedioxyethyl or 3,3- or 2,3-ethylenedioxypropyl, likewise 2-(1-ethylenedioxy-2-methyl)-propyl.

Lower alkanoyloxy lower alkyl is, for example, 1- or 2-acetoxyethyl, 1- or 2-pivaloyloxyethyl, 1-acetoxypropyl-(2), 1-pivaloyloxypropyl-(2), l-acetoxy-2-methylpropyl-(2) or l-pivaloyloxy-2 -methylpropyl-(2) or 3-acetoxy-propyl.

Mono- or dilaverealkylthiolaveraalkyl means, for example, 2-methylthio-, 2-ethylthio-, 2-propylthio-, 2-isopropylthio-, 2,2-dimethylthio or 2,2-diethylthioethyl, 3-methylthio- or 3-ethylthio-propyl 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.

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

Lower alkanesulfonyl lower alkyl is, for example, 2-methanesulfonyl-, 3-ethanesulfonyl-, 2-propanesulfonyl- or 2-(2-propanesulfonyl)-ethyl, 3-methanesulfonyl- or 3-ethanesulfonyl-propyl.

Lower alkylenedithiolower alkyl is, for example, 2,2-ethylenedithio- or 2,2-propylenedithioethyl or 3,3- or 2,3-ethylenedithiopropyl.

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

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

Halogen is, for example, halogen of even atomic number

25, 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 with strong acids, such as mineral acids, e.g. salts with hydrohalic acids, above all hydrochloric 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 with suitable organic acids, such as dicarboxylic acid or organic sulphonic acids, e.g. maleates, fumarates, maleates, tartrates or methanesulphonates and N-cyclohexyl sulphaminates, on the other hand inner salts of compounds of formula I in which R has carboxy or pharmaceutically usable metal, such as alkali or alkaline earth metal salts or ammonium salts with ammonia or suitable organic amines , such as mono-, di- or tri-lower alkylamines, e.g. diethylamine, mono-, di- or trihydroxy lower alkylamines, e.g. triethanolamine or 2-dimethylaminoethanol or heteroaliphatic amines, e.g. morpholine.

The compounds of formula I have valuable pharmacological properties. In particular, they show a pronounced antinociceptive effect as well as an inhibitory effect on prostaglandin synthesis, as well as a clear anti-inflammatory effect. Thus they prove to be excellently effective on mice in writhing syndrome induced by phenyl-p-benzoquinone according to J. Pharma-col. exp. Therapy. 125, 237 (1959) in the dose range of approx.

3-50 mg/kg p.o.

Likewise, they show at doses from approx. 25 mg/kg p.o. one

clear inhibitory effect on the experimental carrageenan paw edema of the rat (Di Pasquale et al: Agents and Actions 5, 256 /1975/) as well as in experimental coroton oil edema on the rat ear (Tonelli et al.: Endocrinology 77, 625 /I965/)

by topical application in a concentration from approx. 20 mg/ml a clear anti-inflammatory effect.

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

2-30 µm/L a clear inhibitory effect on the prostaglandin synthesis of arachidonic acid, demonstrated in the experimental device according to Prosta-glandins 7, 123 (1974).

The compounds of formula I are therefore preferably suitable

as active substances of pharmaceutical preparations for the treatment of painful-inflammatory diseases, above all chronic diseases of the rheumatic form, such as chronic arthritis.

The invention primarily relates to the preparation of compounds of formula I, in which the radicals R, and R2 independently of each other mean unsubstituted or with lower alkyl, lower alkoxy resp. to vicinal C atoms lower alkyl(id)endioxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, mono-

or difluoroalkylamino and/or trifluoromethyl substituted 6 to 10 C atom-containing aryl or monocyclic,

an oxygen or sulfur atom and possibly additionally a nitrogen-containing 5-membered or optionally N-oxidized one or two nitrogen atom-containing 6-membered heteroaryl residues, n means 0, 1 or 2 and R^ means carboxylower alkyl, lower alkoxycarbonyl lower alkyl, carbamyl lower alkyl, N-mono- and N,N-dilower alkyl carbamyl lower alkyl, cyanone lower alkyl or hydroxy-, lower alkanoyloxy-, lower alkoxy -, lower alkylenedioxy-, lower alkylthio-, lower alkylenedithio-;, lower alkanesulfinyl-, lower alkanesulfonyl- or oxy groups in higher than a<->positioned mono- or dihydroxy lower alkyl, lower alkanoyloxy lower alkyl, mono- or dilower oxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylene dithio lower alkyl, mono- or di lower alkyl thiola lower alkyl, lower alkanesulfinyl lower alkyl, lower alkanesulfonyl lower alkyl or oxola lower alkyl, as well as their salts.

The invention relates in particular to the preparation of compounds of formula I, in which the radicals R-^ and R£ 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 resp. unsubstituted or with lower alkyl, lower alkoxy, halogen or hydroxy substituted furyl, such as 2-furyl, thienyl, such as 2-thienyl, pyridy1, such as 2-, 3- or 4-pyridyl resp. 1-oxidopyridyl, such as 2-, 3- or 4-(1-oxido)-pyridyl, n means 0, 1 or 2 and R means carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamyl lower alkyl, N-mono- or N,N-di lower alkyl carbamyl lower alkyl or hydroxy-, lower alkoxy-, lower alkylenedioxy-, lower alkylidenedioxy- or oxo groups in higher than α-positioned hydroxyl lower alkyl, mono- or dilavereal oxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylidenedioxy lower alkyl or oxolave lower alkyl as well as their salts, especially their pharmaceutically usable salts.

The invention relates in particular to the preparation of compounds of formula I, in which the radicals R₁ and R₂ independently of each other mean unsubstituted or with lower alkoxy with up to and including 4 C atoms, such as methoxy, lower alkylthio with up to and including 4 C atoms, such as methylthio or halogen with atomic number up to and including 35, sem fluorine or chlorine, substituted phenyl, n means 0, and R^means the carboxy or lower alkoxycarbonyl group in α-positioned carboxy- or lower alkoxycarbonyl lower alkyl with up to 4 C atoms in the lower alkyl and possibly lower alkoxy part such as carboxymethyl, 1-carboxyethyl, methoxy or ethoxycarbonylmethyl or 2-(2-carboxy)-propyl, as well as their, particularly pharmaceutically usable, salts.

The invention primarily relates to the preparation of compounds of formula I, in which R₂ and R₂ mean with lower alkoxy with up to and including 4 C atoms such as methoxy, which are especially bound in p-position substituted phenyl residues, n means 0, 1 or 2, and R^ means carboxy or lower alkoxycarbonyl group in α-positioned carboxy- or lower alkoxycarbonyl lower alkyl with up to and including 4 C atoms in the lower alkyl and possibly lower alkoxy part, such as carboxymethyl, 1-carboxyethyl, methoxy- or ethoxycarbonylmethyl or 2-(2-carbo-oxy)-propyl or hydroxy-, oxo-, lower alkoxy- or the lower alkylenedioxy group in higher than α-position hydroxy lower alkyl with 2 to 4 carbon atoms, such as 2-hydroxyethyl or 3-hydroxypropyl, oxola lower alkyl with

pp

IN

2 up to and including 4 C atoms, such as 2-oxoethyl or 3-oxopropyl or mono- or dilavereal oxylaverealkyl resp. lower alkylenedioxylaverealkyl with respectively up to and including 4 C atoms 1 each alkyl(en) part, such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2,2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-ethylenedioxyethyl as well as their, in particular pharmaceutically acceptable salts.

The invention relates above all to the preparation of new compounds of formula I, in which the radicals R, and R2 independently of each other mean unsubstituted or with lower alkoxy with up to and including 4 C atoms, such as methoxy, lower alkylthio with up to and including 4 C atoms, such as methylthio or halogen of atomic number up to and including 35, such as fluorine or chlorine, substituted phenyl, n means 0, and R^means hydroxy-, oxo-, lower alkoxy- or the lower alkylenedioxy group in higher than α-position hydroxy lower alkyl with 2 to 4 carbon atoms, such as hydroxyethyl or 3-hydroxypropyl, oxolave alkyl with 2 to 4 carbon atoms, such as 2-oxoethyl or 3-oxopropyl or mono- or dilavereal oxyla alkyl resp. . lower alkylenedioxylaverealkyl with respectively up to 4 C atoms in each alkyl(en) part, such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2,2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-ethylenedioxyethyl as well as their, in particular pharmaceutically acceptable salts.

The invention relates in particular to the preparation of compounds of formula I, in which R₂ and R₂ are lower alkoxy with up to 4 C atoms such as methoxy, which is especially bound in the p-position, substituted phenyl radicals, n means 0, 1 or 2 and R ^means the carboxy or lower alkoxycarbonyl group in the c.-position' containing carboxy- or lower alkoxycarbonyl lower alkyl with up to 4 C atoms in the lower alkyl and optionally lower alkoxy part, such as carboxymethyl, 1-carboxyethyl, methoxy- or ethoxycarbonylmethyl or 2-(2-carboxy)-propyl, and their, especially pharmaceutically usable, salts.

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

The process for the production of new compounds of formula I uses methods known per se and is characterized in that from a compound of formula

in which one of the residues Y^ and means a leaving residue residue Y and the other means a hydrogen atom, and Y^ and Y^ together means an extra bond, or in which Y^ means a leaving residue Y^, and Y^ means hydrogen, and and Y2 represents an additional bond, or from a salt thereof during the introduction of an additional bond, HY splits off, if necessary, an isomer mixture obtainable according to the method is divided into its components and the isomer of formula I is isolated, and if desired, a compound obtained according to the method is converted into a another compound of formula I and/or a free compound obtained according to the method is transferred in a salt or a salt obtained according to the method is transferred in the free compound or in another salt.

Cleavable residues Y are, for example, possibly esterified or etherified hydroxy or mercapto groups, further amino, ammonium and sulfonium groups. As 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. Preferred hydroxy groups are, for example, lower alkoxy groups, e.g. methoxy or ethoxy. Esterified mercapto groups are, for example, mercapto groups esterified with a lower alkane carboxylic acid, such as acetyl-thio. Preferred mercapto groups resp. sulfonium groups are, for example, lower alkylthio- or diloverealkylsulfonium groups, such as methylthio, ethylthio or dimethylsulfonium. Amino groups are next to groups R^-NH-, for example dilaverealkyl- 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, for example, those corresponding to the above-mentioned amino groups, tertiary ammonium groups or quaternary ammonium groups such as trilower alkylammonio or pyridinium.

The splitting off of HY usually takes place spontaneously or by mild heating, e.g. to approx. 40-200°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 acids, above all chloric,

hydrobromic or iodic acid, sulfuric acid, alkali metal hydrogen sulphates, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride, phosphorus oxychloride or phosphorus tribromide, organic sulphonic acids, such as p-toluenesulphonic acid or carboxylic acids resp. 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 bases, 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, such as tri-lower alkylamines, e.g. triethylamine, or aromatic tertiary bases, such as pyridine.

The starting substances of formula II are preferably prepared in situ, a compound of formula

wherein either R^means a group of formula R^-NH-N=C(SR^)-and Rg a group R2or R^a group of formula R2-C(=NH)-N(R-^)- and Rg a group ~SR^ / and and Yg independently of each other means residues Y, which optionally esterified or etherified hydroxy, etherified mercapto or optionally substituted amino or together means oxo, thioxo or optionally substituted imino, such as lower alkylimino, optionally substituted anilo or the groups of formula =N-R^, or a salt thereof is cyclized.

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 of an inert solvent or diluent, under heating, 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 stands

there are several ways of formation available. Thus compounds of formula III are obtained, in which R^ means a group of formula R^-NH-N=C(ZR^)-, and Rg is a group R2, and Y,-

and Yg together mean oxo, for example a compound of formula R1-NH-N=C(SR^)-NH2(IV), which is, for example, easily accessible by reacting an imino compound of formula Y-C(=NH)-SR3 (V ), in which Y has the indicated meaning, and in particular means lower alkoxy, halogen or amino, resp. an isothiocyanate of the formula N=C-SR3(Va) or an acid addition salt, e.g. hydrohalide thereof, e.g.

in ethanol, is brought to reaction in the usual way, e.g.

in the presence of a basic condensing agent, with a substituted hydrazine of the formula R-^-NH-Nr^ (VII), or a salt thereof, is reacted in the usual way, e.g. in presence

of a basic condensing agent with a compound of formula Y1-C(Y5)(Yg)-R2 (IX), in which Y5 and Yg have the indicated meaning and Y<1>means a group Y respectively, if Y^ and Yg together mean oxo means a group of formula R2-C(=0)-0-. Compounds of formula III, in which R^ is a group of formula R2-C(=NH)-N(R-L)-, Y5+ Yg = oxo, and RQ is an R3S group,

one obtains, for example, a compound with the formula R2-C(=NH)-Y (XVI) resp. a hydrohalide thereof is reacted, e.g. a lower alkanol such as ethanol, with a compound of formula R^NH-NH-C(Y5)(Yg)-SR3 (XVII), where Y means esterified or etherified hydroxy, e.g. halogen or lower alkoxy, and Y,- + Yg means oxo in particular.

Usually, however, one does not also want to isolate the intermediate step of formula III, because the synthesis of the final substances of formula I via intermediate steps of formula III and II can be carried out according to some important process variants without isolation of intermediate products. As a result of an important method variant, e.g. compounds of formula R^-NH-NH2(VII)

and R2-C(Y^)(Yg)-NH-C(Y^)(Y^)-SR3 (XVIII), wherein Y£, Yg, Y£

and Yg independently of each other, trade with each other,

of one of the meanings mentioned for Y, or Y^ + Yg and/or Y^ + Yg means oxo, thioxo or optionally substituted imino, e.g. imino, lower alkylimino, anilo or such with formula R^-N=, as compounds of formula XVIII can also exist in tautomeric form, e.g. of formula R_-C(Y')(Y<*>)-N=C(Y)-SR_, (XVIIIa) or

R2-C(Y)=N-C(Y£) (Yg')-SR3 (XVIIIb). The reaction takes place in the usual way, for example in the presence of one of the aforementioned acidic or basic condensing agents, if necessary, in the presence of an inert dissolving or diluting agent during heating, . f. e.g. in the temperature range of approx. 40-200°C, preferably from approx. 60-140°C, and/or under inert gas, such as nitrogen.

Preferred embodiments of these over intermediately formed intermediate steps, with formulas III and II proceeding direct syntheses of compounds of formula I, are the reaction of compounds of formula VII with compounds of formula XVIII { Y5 ' and Y6 ' = oxo, and Y^ = thioxo) respectively XVIIIa (Y^ and Yg = oxo, Y reactive esterified hydroxy, e.g. halogen or etherified hydroxy, e.g. lower alcohol or dilower alkylamino) under slightly 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, condensation of compounds of formula XVI and XVII, e.g. in ethanol at approx. 10-50°C, and subsequent cyclization at approx. 80-160°C, e.g. in boiling xylene.

Similarly, over intermediate steps with formulas II and III, the formation mode of l-R-^-R^-S-R^lH-l, 2, 4-triazoles proceeds by reaction of acylated thiosemicarbazides of formula R2-C(=0)-NH-C(=S )-NH-NH-R1(XXIII) with compounds of formula R3-Y (XXIV), in which R^ has the indicated meaning and Y means reactive esterified hydroxy, or with aliphatic epoxides.

The compounds of formula I can further be prepared, as compounds, with the formulas

in which Y^^means a mercapto group optionally present in salt form and Y-^means reactive esterified hydroxy, or Y^ means sulfonyl and Y12a mercapto group optionally present in salt form, are condensed with each other to corresponding compounds of formula I, in which n means 0, and if necessary, resp. if desired, one or more of the aforementioned additional reactions are carried out.

Sulfonyl is, for example, lower alkanesulfonyl, e.g. methane or ethanesulfonyl or optionally substituted benzenesulfonyl, e.g. benzene-, p-toluene- or p-bromobenzenesulfonyl, further fluorosulfonyl.

As a salt form of the mercapto groups, their metal salt forms, such as alkali metal or alkaline earth metal salt forms, if n is 1 or 2, further their ammonium salt forms with ammonia or organic amines, such salts are preferably produced by the action of the equivalent amount of the relevant base on the free mercaptor reaction component in situ and used without isolation.

The condensation takes place in the usual way, preferably in an inert solvent, if necessary, during cooling or heating, e.g. in the temperature range of approx. 0-100°C,

in a closed vessel and/or under inert gas, such as nitrogen. As inert solvents, polar solvents, such as lower alkanols, dilower alkyl ketones, N,N-dilower alkylalkanecarboxylic acid amides or N-lower alkyl lactams or di-lower alkyl sulfoxides.

If necessary, one works with catalysts, if Y-^ means etherified hydroxy, e.g. in the presence of dilithium palladium tetrachloride.

The starting materials of formula XXXI can be prepared according to methods known per se.

Thus, e.g. compounds of formula XXXI, in which Y^ means mercapto, are obtained, a compound of formula R1-NH-NH-C(=S)-NH-C(=0)-R2(XXXIV) available, for example, by reacting a thiosemicarbazide with formula R1-NH-NH-C(=S)-NH2(XXXV) is cyclized with a compound of formula R2~C(=0)-Y (IXb, Y = halogen or R2~C(=0)-0-) , in a regular way. Compounds of formula XXXI, wherein Y-^

is mercapto, is obtained further, as a compound of formula R^-NH-NH2(VII) is reacted with thiophosgene or an alkali rhodanide and then with a compound of formula IXb.

Compounds of formula I can further be prepared, as compounds of the formulas

in which one of the residues Y, , and Y.^means a metallic residue and the other a group~S(0)n-Y.^, in which Y, -. means halogen, are condensed with each other and, if necessary or desirable, one or more of the aforementioned additional reactions are carried out.

R 3 thereby means an unsubstituted or substituted with etherified hydroxy and/or mercapto groups aliphatic hydrocarbon residue.

Metallic residues are, for example, groups with the formulas

-M*, -M^/2 or -MII-Hal, in which M1 means a metal atom from group IA of the periodic table, e.g. lithium or sodium, and M<11>means a metal atom from groups 2A and 2B of the periodic table, e.g. magnesium, cadmium or zinc, and Hal means halogen atom.

Halogen is, for example, chlorine, bromine or iodine.

The turnover takes place in the usual way, preferably in a

inert solvent, if necessary, during cooling or heating and/or inert gas, such as nitrogen, for example in the temperature range from -80 to approx. 60°C, preferably from approx. -25 to approx. 40°C. In a preferred embodiment of this method, one starts, for example, with a compound of formula XXXI, in which Y^ is a halosulfenyl group, and this is reacted at approx. -10 to 10°C in tetrahydrofuran or hexamethylphosphoric triamide with a compound

else of formula XXXII, in which Y12 is an alkali metal atom or a halogen-alkaline earth group. In another preferred embodiment, for example, a compound of formula XXXI is reacted, wherein an alkali metal atom means with a compound of formula R3-S-S-R3(XXXIIa).

Starting substances of formula XXXI, in which Y^ means a group of formula -S-Y^3 and Y^3 means halogen, are obtained, for example, as a compound of formula XXXI, in which Y^^ means mercapto, is halogenated in the usual way, for example by reaction with chlorine, e.g. in tetrachloromethane, optionally after previous treatment with iodine.

Compounds of formula XXXI, in which Y11 means a metallic residue, can for example be prepared, a compound of formula XXXI, in which Y^ means hydrogen, which is available, for example, by reacting compounds with the formulas R2-C(=0)-NH-CHO ( XXXVI) and R^-NH-NE^(VII), with a metal-organic compound, such as an alkali metal or alkaline earth metal hydrocarbon compound, e.g. with butyllithium, phenylsodium or butylmagnesium bromide. However, one can also start from a compound of formula XXXI, in which Y^

is halogen, reacting this with an alkaline earth metal,

e.g. magnesium.

A further method for preparing compounds of formula I is characterized by a compound of formula

in which Y^^ is mercapto or a salt thereof, reacted with a vicinal epoxy derivative derived from a compound of formula R3-H (XXXVII), reacted to a compound of formula I, in which R3.1 Order has a hydroxy group and n is 0, and

if necessary or desirable, one or more of the aforementioned additional reactions are carried out.

As salts of compounds of formula XXXi, for example, their metal salts, preferably alkali metal or alkaline earth metal salts, come into consideration.

Vicinal epoxides derived from compounds of formula XXXVII are, for example, vicinal aliphatic epoxides, such as a, 3-epoxy-lower alkanes.

The reaction takes place in the usual way, for example in an inert solvent, such as a lower alkanol or a tertiary amine, e.g. in hexamethylphosphoric acid triamide, if necessary,

in the presence of a condensation agent, for example starting from free mercaptans with formula XXXI of a base agent suitable for salt formation, such as an alkali metal alcoholate or hydroxide, e.g. sodium methanolate or sodium hydroxide under cooling or heating and/or under inert gas,

as nitrogen.

A further method for preparing compounds of formula I is characterized by a compound of formula

R, -N-N.

^s>~Yll(XXXI)

R 2 -=Y

in which Y-j^ means mercapto or a salt thereof, is reacted with a compound of formula R3-H (XXXVIII), in which R^ means one derived from R^, at least in the a, 3-position containing a C-C double or C-C triple bond aliphatic residue, to a compound of formula I, in which R^ is a, 3-saturated or a, 3-monounsaturated and n is 0, and if necessary, respectively desirable, one or more of the aforementioned additional reactions are carried out.

as salts of mercaptans of formula XXXI, especially their metal salts, preferably alkali metal or alkaline earth metal salts, come into consideration.

As compounds of formula XXXVIII, for example: carboxyl lower alkenes, lower alkoxycarbonyl lower alkenes, carbamyl or N-lower alkyl, N,N-dilower alkyl-, N,N-lower alkylene- or N,N-(3-aza-, 3-oxa- or 3-thia)-lower alkylenecarbamyl lower alkenes, such as lower alkoxy-, lower alkylenedioxy-, lower alkylthio-, lower alkanesulfinyl-, lower alkanesulfonyl-, hydroxy, lower alkanoyloxy-, lower alkylenedithio-, resp. oxo groups in higher than #-positioned mono- or di-lower alkyl lower alkenes, lower alkylenedioxy-lower alkenes, lower alkanoyloxy lower alkenes, mono- or di-lower alkylthio lower alkenes, lower alkanesulfinyl- resp. lower alkanesulfonyl lower alkenes, lower alkylenedithiolower alkenes, mono- or dihydroxy lower alkenes and oxolave lower alkenes.

The reaction takes place in the usual way, for example in an inert solvent, such as a tertiary amine, e.g. in dimethylformamide or N-methylpyrrolidone, if necessary, in the presence of a condensing agent, under cooling or heating and/or under an inert gas, such as nitrogen. As a condensation agent, it comes into consideration when starting from mercaptans with formula XVI, for example organic nitrogen bases,

as di- or tri-lower alkylamines, e.g. diisopropylamine or triethylamine, resp. alkylene resp. aza-, oxa- or thiaalkylene amines, e.g. pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine.

The new compounds of formula I can further be prepared,

since in a connection with formula

in which means a residue transferable to a group R^, R<3>' is transferred to the desired group R^, and if necessary, respectively desirable, one or more of the aforementioned additional reactions are carried out.

Residues transferable to residues R^ are, for example, residues R^ substituted with an optional additional carboxy group, especially 1,1-dicarboxyl lower alkyl or 1-carboxy-2-oxo-lower alkyl residues or residues of the formula -C(=0)-0- R3. The transfer of these residues to residues R^ takes place by splitting off carbon dioxide.

The splitting off 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. of hydrogen chloride

or sulfuric acid, advantageously in a solvent or diluent, if necessary, under heating, e.g.

to approx. 50 to approx. 250°C.

Thus, compounds of formula IXL, in which R^ means

a 1-carboxy-2-oxo- or 1,1-dicarboxylave alkyl radical,

by heating with aqueous acid solutions, e.g. with equal parts approx. 15% hydrochloric acid and acetic acid to approx. 60-

100°C, is transferred to compounds of formula I, in which R^

means a 1-carboxy or 2-oxolave lower alkyl radical.

Furthermore, compounds of formula IXL can be prepared,

in which R<3>' means a residue of formula -C(=O)-O-R3, e.g. by heating with a mineral acid, e.g. with hydrogen chloride in tetrahydrofuran, during the elimination of carbon dioxide is transferred in the corresponding compounds of formula I.

Further to the group R^transferable residues R^' are, for example, at least one hydroxy group etherified with an o-phenyl lower alkanol resp. esterified carboxy group or at least one with a carboxylic acid, such as a halogenated lower alkanoic acid or carboxylic acid resp. a half-ester or a half-amide thereof esterified hydroxy groups, such as substituted benzyloxy, optionally halogenated lower alkanoyloxy or lower alkoxycarbonyloxy, benzyloxycarbonyloxy, dilower-alkylcarbamyloxy or carbonyldioxy containing residues R^' .

As such, for example: benzyloxy, benzyloxycarbonyloxy, optionally halogenated lower alkanoyloxy or lower alkoxycarbonyloxy groups respectively the carbonyldioxy group in a higher than α-position, optionally substituted mono- or dibenzyloxylavealkyl optionally halogenated mono- or diloweralkanoyloxylavealkyl resp. mono- or dilavereal oxycarbonyloxy- or carbonyldioxylaveraalkyl and benzyloxycarbonylloweralkyl. The transfer of these to R^ takes place, for example, reductively by treatment with a suitable reducing agent.

As a reducing agent, the reduction of a-phenyl lower alkoxy and cx-f phenyl alkoxy groups, for example hydrogen in the presence of a hybrid, preferably working in an inert solvent, if necessary, at elevated pressure and/or during cooling or heating. Hydroxy groups esterified with carboxylic acids, also ot-f-phenylareal oxycarbonyl-oxy groups, can for example be reduced with the help of dilett metal hydrides, e.g. with lithium aluminum hydride.

2-halo-lower oxycarbonyloxy, e.g. 2,2,2-trichloro or 2-iodoethoxycarbonyloxy, aroylmethoxycarbonyloxy or 4-nitrobenzyloxycarbonyloxy can e.g. is cleaved 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-nitro-benzyloxycarbonyloxy also

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

Further residues R^' are to a group R^solvolysable residues, for example residues R^', which have one or two halogen atoms, a bivalent functional modified oxo group,

e.g. imino, a functionally different from esterified and amidated carboxy according to the definition given at the outset

modified carboxyl groups, such as an iminoether grouping,

an optionally substituted amidino grouping indicated for amidated carboxy, halocarbonyl or optionally substituted phenoxycarbonyl, e.g. phenoxy-, p-nitrophenoxy- or 2,4-dinitrophenoxycarbonyl or at least one acyloxy group derived from a halogen- or aryl-substituted alkanecarboxylic acid or a carboxylic acid half-ester, at least one silyloxy group or an arylenedioxy-, such as 1,2-phenylenedioxy group,

two geminally bonded aryloxy-, such as phenyloxy groups or a vicinally bonded lower alkylidene- or mono- or diaryl-lower alkylidenedioxy groups.

Cleavable acyloxy groups are, for example, halogen-lower alkanoyloxy, such as 2-haloacetoxy, branched in the 1-position of the lower-alkyl residue or 1- or 2-position suitably substituted lower alkoxycarbonyloxy, especially tert.-lower alkoxycarbonyloxy, benzyloxycarbonyloxy which may optionally be substituted with lower alkyl, especially tert. -butyl, lower alkoxy, hydroxy, halogen and/or nitro or optionally similarly substituted diphenylmethoxycarbonyloxy.

Such residues are 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro or 2,2,2-trichloroacetoxy, tert-butyloxycarbnyloxy, 4-nitrobenzyloxycarbonyloxy, phenacycyclooxycarbonyloxy, 2-halogenloweralkoxycarbonyloxy, e.g. e.g. 2,2,2-trichloro-ethoxycarbonyloxy, 2-bromomethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or 2-(trisubstituted silyl)-ethoxycarbonyloxy, in which substituent independently of each other respectively means an optionally substituted, e.g. by lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue with e.g. up to 15 C atoms, as corresponding, optionally substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, e.g. 2-trilower alkylsilyethoxycarbonyloxy, such as 2-trimethylsilylethoxycarbonyloxy or 2-(di-n-butylmethylsilyl)ethoxycarbonyloxy or 2-tri-arylsilylethoxycarbonyloxy, such as 2-triphenylsilylethoxycarbonyloxy.

A silyloxy group is primarily trilower alkylsilyloxy, especially trimethylsilyloxy, further dimethyl-tert-butylsilyloxy.

A halogen atom, at least one of the aforementioned acyloxy groups, at least one silyloxy group, an arylenedioxy group, two geminally bonded aryloxy groups or a vicinally bonded lower alkylidene resp. mono- or diaryllower alkylidenedioxy group-containing residues can be solvolytically transferred to hydroxy-containing aliphatic residues R^, such as mono- or dihydroxylower alkyl, a halogen atom-containing residue R^' further transferred in etherified or organically esterified hydroxy or etherified mercapto substituted residues R^, such as lower alkyl lower alkyl, lower alkanoyloxy lower alkyl or lower alkylthio lower alkyl . or amidated carboxy R 1 , such as carboxyl lower alkyl, lower alkoxycarbonyl lower alkyl or optionally aliphatic N-substituted carbamyl lower alkyl.

The solvolysis of the hydroxy solvolyzable group-containing residues R^' takes place, 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 means of hydrolysis, for example, residues R^' containing a halogen atom, at least one of the aforementioned acyloxy groups, at least one silyloxy group, an arylenedioxy group, two geminally bonded aryloxy groups or a vicinally bonded lower alkylidene resp. mono- or diaryllower alkylidenedioxy group is transferred to hydroxy-substituted residues R^, as mono- or dihydroxylower alkyl, two halogen atoms or a bivalent functionally modified oxo group-containing residue R^', is transferred to oxo-containing residues R^, as oxolaverealkyl, functionally modified carboxyloweralkyl R^ ' is transferred to carboxyl lower alkyl as well as an iminoether group, an optionally aliphatic N-substituted amidine group containing functionally modified carboxyl lower alkyl residue R^, is transferred to esterified or amidated carboxyl 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 acid, halogenated hydrogen acids, e.g. hydrochloric, bromic or hydroiodic acid or oxygen acids of sulfur or phosphorus resp. their acid salts, such as sulfuric acid, potassium hydrogen sulphate or phosphoric acid or organic carboxylic or sulphonic acids, e.g. lower alkanoic acid, such as acetic acid, trifluoroacetic acid or chloroacetic 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, resp. 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 dilave alkyl sulphoxides, e.g. dimethyl sulfoxide.

In alcoholysis, for example, aliphatic residues R^ such as

has one or two halogen atoms or bivalent functionally modified oxo, are transferred to etherified hydroxy substituted aliphatic hydrocarbon residues R^, such as mono- or dilavereal oxylaverealkyl, aliphatic residues R^' which have lower alkylenedioxylaverealkyl or halocarbonyl, are transferred into esterified carboxy-containing residues R^, which lower alkoxycarbonyl and in residues R^' with organic carboxylic acid

esterified hydroxy groups are released by transesterification. The alcoholysis takes place in the usual way, for example in the presence of a base during transesterification or also an acidic agent, if necessary during cooling or heating, and/or under an inert gas, such as nitrogen. As sour resp. basic agents there are e.g. considering the aforementioned, as basic agents, further metal alcoholates, such as alkali metal or alkaline earth metal avereal alkanolates, e.g. sodium methanolate.

During mercaptolysis, one can for example transfer residues R^' which have one or two halogen atoms or bivalent functionally modified oxo to etherified mercapto-substituted residues R^, such as lower alkylthiolower alkyl or lower alkylenedithiolower alkyl. Mercaptolysis takes place in the usual way, e.g. in the presence of a basic condensing agent or using the mercapto components in salt form, such as as an alkali metal salt.

In a modification of this method, one can also convert a mercapto-substituted lower alkyl residue R^' by reaction with all reactive esters of a lower alkanol, such as a lower alkyl halide or dimethyl sulfate, into a lower alkylthio lower alkyl.

A halogen atom-containing aliphatic residue R 1 can also be transferred

by reaction with a salt of a carboxylic acid, such as a lower alkanoic acid alkali metal salt, to. organically esterified hydroxy-containing residues R^, such as lower alkanoyloxylaverealkyl.

In the case of amino or ammonolysis, one can for example transfer halocarbonyl-containing aliphatic residues R^' to amidated carboxy-substituted aliphatic hydrocarbon residues R^, such as optionally aliphatic N-substituted carbamyl lower alkyl residues, advantageously in the presence of a basic condensing agent.

However, aminolysis can also release them

said acyloxy groups the hydroxy group.

However, halolower alkyl can also be transferred by reaction with thiourea firstly to the isothiouronium derivative and then by hydrolysis and alkylation to lower alkylthio-lower alkyl. 2-Substituted silylethoxycarbonyloxy can advantageously be cleaved by treatment with an alkali metal fluoride, e.g. with potassium fluoride.

The solvolytic transfer of halogen-containing residues R^' in the aforementioned, from mono- or dihydroxylower alkyl different residues R^ usually takes place in the presence of a basic condensing agent, such as an alkali metal hydroxide, or a tertiary organic nitrogen base, such as a trilower alkylamine or a heteroaromatic base., as of pyridine or by applying it to the residue to be introduced corresponding component in the form of a salt, such as an alkali or alkaline earth metal salt.

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

in which Y-^, , Y^ and Y4 have the meanings indicated under formula II, and if desired, oxidation of the thio group or by reaction of compounds with the formulas

in which one of the residues Y1 and Y12 denotes a reactive esterified hydroxy group and the other a mercapto group present in salt form.

Compounds of formula I obtained according to the method or according to other methods not mentioned above can, if desired, in a manner known per se, be converted into other compounds of formula I. If necessary, an isomer mixture obtained according to the method can be divided into the pure isomers and if desired, a compound obtained according to the method is transferred into another compound of formula I and/or a free compound obtained according to the method is transferred into a salt or a salt obtained according to the method is transferred into the free compound.

Thus, for example, etherified or esterified hydroxy groups can be transferred into each other.

If, for example, at least one of the residues R^, R2 and R^ has a hydroxy group, then this can be etherified in the usual way. Thus, 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 a dehydrating agent, such as dicyclohexylcarbodiimide and hydroxy on 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, by means of dilower alkyl sulfates or diazolarealkanes, are transferred in corresponding lower alkoxy groups. Furthermore, ethers, such as lower alkoxy groups, can be used as substituents of R^ resp. R2av cleavage, for example by treatment 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 to lower alkanoyloxy, for example by reaction with a corresponding lower alkane carboxylic acid, such as acetic acid, or a reactive derivative, such as a symmetrical anhydride thereof or an anhydride with a halohydrogen 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 tri-lower alkylamine or of pyridine, and starting from an acid, e.g. in the presence of 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 carboxy as a component of R^ can normally

way e.g. by treatment with a diazolaveralkane or triloweralkyloxonium, triloweralkylcarboxonium or diloweralkylcarbonium 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 carbonic acid ester, e.g. a lower alkane carboxylic acid ester, trilower alkyl phosphite, dilower alkyl sulfite or pyrocarbonate or

a mineral acid or sulphonic acid ester, e.g. chloro or bromohydrogen acid or sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid ester of the corresponding alcohol or an olefin derived from it esterified to an esterified carboxyl group.

The reaction with the corresponding alcohol itself can preferably take place in the presence of an acidic catalyst, such as protonic acid, e.g. of chlorine or hydrogen bromine, sulphur, phosphorus,

boronic, benzenesulfonic and/or toluenesulfonic acid, or a Lewis acid, e.g. of boron trifluoride etherate, in an inert solvent, especially an excess of the alcohol used and, if necessary, in the presence of a water-binding agent and/or under distillation, e.g. azeotropic removal of the water of reaction and/or at elevated temperature.

The reaction with a reactive derivative of 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 the above, in an inert solvent, as an aromatic hydrocarbon, such as in benzene or toluene, or an excess of the alcohol derivative used or of a corresponding alcohol. Starting from mineral acid or sulphonic acid esters, the acid to be esterified is added, preferably in the form of a salt, e.g. of the sodium or potassium salt, and working, if necessary, in the presence of a basic condensing agent, such as an inorganic base, e.g. of sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, e.g. of 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.

The reaction with an olefin can, for example, take place in the presence of

of an acid catalyst, e.g. a Lewis acid, e.g. of boron trifluoride, a sulphonic acid, e.g. of p-toluenesulfonic acid or above all of a basic catalyst, e.g. sodium or potassium hydroxide, preferably in an inert solvent, such as an ether, e.g. in diethyl ether or tetrahydrofuran.

A free carboxyl group can further by reaction with ammonia or an amine which has at least one hydrogen atom in a similar manner during dehydration of the intermediately formed ammonium salt, e.g. by azeotropic distillation with benzene or toluene or dry heating, is transferred to an amidated carboxyl group.

However, the above-mentioned conversions of free to esterified or amidated carboxyl groups can also be carried out so that a compound of formula I, which contains carboxy, primarily on. in the usual way is transferred in a reactive derivative, for example by means of a halide of phosphorus or sulphur, e.g. by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, to an acid halide or by reaction with a corresponding alcohol or an amine, is transferred to a reactive ester, i.e. ester with electron-withdrawing structures, such as esters with phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol or a reactive amide, e.g. the amide derived from imidazole or 3,5-dimethylpyrazole. and then the reactive derivative formed is reacted in the usual way, such as e.g. below for transesterification or mutual conversion of esterified and amidated carboxyl groups, with a corresponding alcohol, ammonia or the corresponding at least one hydrogen atom-containing amine to the desired group.

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

An esterified carboxyl group' can further in the usual way, e.g. by reaction with a metal salt, such as the sodium or potassium salt of a corresponding alcohol or with this itself 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 acid, sulfuric acid or phosphoric acid, or an organic sulphonic acid, e.g. of p-toluenesulfonic acid or a Lewis acid, e.g. of boron trifluoride etherate, is transesterified to another esterified carboxyl group.

An amidated carboxyl group can, 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. hydrochloric acid, sulfuric acid or phosphoric acid is converted to the free carboxyl group.

Cyano can be transferred hydrolytically, e.g. under basic conditions, is hydrolyzed to carbamyl or carboxy, or by reaction with an alcohol or with ammonia or a primary or secondary amine in the presence of an acid, such as hydrochloric acid and subsequent hydrolysis is transferred to esterified or amidated carboxy. Conversely, by heating, if necessary, carbamyl in the presence of a water-binding agent, e.g. of phosphorus pentoxide or of polyphosphoric acid or an N,N-disubstituted carbodiimide, e.g. of N,N-dicyclohexycarbodiimide, is dehydrated to cyano.

Furthermore, carboxyl lower alkyl residues with formula can optionally be left in ester, anhydride or salt form

-C m H2„ m -COOH is reduced to the corresponding oxolavereal alkyl Jl residues with formula -C , nH„ ,„=0 resp. hydroxyl lower alkyl

m+1 2m+2r i j jresidues with formula -C ,,H0 ,„-0H, where m respectively means

m+1 2m+2 ^J

a number from 1 to 7 inclusive, respectively from 1 to 4 inclusive.

The reduction takes place in the usual way, for example by reaction with a hydride transfer agent, which transfers hydrogen in anionic form to the a-placed Kratom, for example with a light metal or dilite metal hydride, e.g. with boron hydride etherate or preferably lithium aluminum hydride, preferably in an ether, such 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, preferably in alcoholic solution. Equally applicable are reducing agents that transfer zero-valent metals or atomic hydrogen.

These principles are used, for example, by the metallic reduction, which can be effected by the impact of finely divided metals, e.g. of zinc powders, in the same way by the reduction with nascent hydrogen, as e.g. can be produced by acid action on base metals, such as by acetic acid on zinc, iron and hydrochloric acid or water action on sodium amalgam. With the aforementioned reducing agents, compounds of formula I are preferably obtained, in which R 1 denotes a hydroxyl lower alkyl residue. Salt forms of carboxy are thereby, for example, base salt forms, such as alkali or alkaline earth metal salt forms, but can also be ammonium salt forms with ammonia or inorganic amines. Anhydride forms are, for example, mixed anhydride forms with halogen hydrogen acids, but can also be mixed anhydride forms with organic carboxylic acids, such as lower alkanoic acids. Ester forms are, for example, 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 come into consideration, e.g. ylactone forms, by whose presence in the aj position; ag in a position lower than (co-2) residues R. are formed, which have two hydroxy groups. However, the reduction can also be maintained at the oxo stage, using selective reducing agents. Such are for the reduction of any carboxy present in salt form, for example mono- or dilave alkyl borohydrides, e.g. 2-(2,3-dimethylbutyl)-borohydride,. for 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 reduction of ester forms, for example electronegatively substituted aluminum or alkali metal aluminum hydrides, e.g. N-methylpiperazinoaluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride, however also dibutylaluminum hydride.

Conversely, in compounds of formula I, one can oxidize groups R3 with formula ~cm+]_H2m+2~OH ti]-9ruPPer R3 of formula ~cm+l<H>2m+l<=0>' and groups R3 with formula -CmH2m-CH20H resp. .

-C H~ -CH=0 to those with the formula C H~-COOH, as m resp.

m ^m m 2m ^ means an integer from 1 to 7, e.g. from 1 to 4 inclusive.

The oxidation of groups of formula -C ,,H_ ,_-0H to such

m+1 2m+2

with formula _<-'m4.]_H2m+l=<~) ^ore9ar, for example, by treatment with a for the oxidation of primary and secondary alcohols to aldehydes reps. ketones common oxidizing agents, such as non-oxidizing metal compounds, e.g. chromyl chloride in pyridine, chromium trioxide in 2,5-dimethylpyrazole, pyrilinene-

salts, nitrosonium tetrafluoroborate or of core complexes of chlorine resp. methanesulfonic anhydride and dimethylsulfoxide and further above all, however, by treatment with an aliphatic or cycloaliphatic ketone, such as an oxolave alkane, e.g. acetone or a cycloalkanone, e.g. cyclohexanone, in the presence of an aluminum alcoholate, e.g. of aluminum isopropanolate.

The oxidation of groups with the formula -C H2-CI^OH resp.

-C H_ -CH=0 to those with formula -C H0 -COOH takes place example- m 2m m 2m 3 r vis 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 resp. alkali metal chromates. Furthermore, peroxysulphuric acid is suitable, e.g. Carosic acid, since when the oxidation is carried out in an alcohol, a corresponding ester is obtained by esterification of the primarily formed acid.

Furthermore, compounds of formula I can be N-oxidized

the residues of formula -S(0) -, in which n means 0, to the corresponding sulfinyl or sulfonyl residues, in which n means 1

or 2, residues -S(O) n-, where n means 1, to the corresponding-

end sulfonyl residues, where n means 2, and/or heteroaryl residues R^ and/or R2 with at least one free ring nitrogen atom,

as pyridyl residues. The oxidation preferably takes place by the action of a suitable oxidizing agent, preferably in a solvent inert to these, if necessary, during cooling or heating, e.g. in the temperature range of approx. -30 to +100°C, preferably below approx. 0-60°C,

in a closed vessel and/or under inert gas, such as nitrogen.

Suitable oxidizing agents are, for example, peroxy compounds

els, such as hydrogen peroxide, organic hydroperoxides,

e.g. tert-butyl hydroperoxide, organic peracids, such as aromatic or aliphatic percarboxylic acids, e.g. m-chloroperoxybenzoic acids, peroxyacetic acid or permonophthalic acid, oxidizing heavy metal compounds, such as chromium-VI

or manganese IV or manganese-VII compounds, e.g. chrome

trioxide, chromic acid, manganese dioxide or potassium permanganate, oxidizing inorganic oxygen acids, such as oxygen acids of nitrogen, of the halogens or chalcogens, or their anhydrides or salts, e.g. nitric acid, dinitrogen tetraoxide, selenium dioxide or sodium metaperiodate, further ozone. Suitable solvents are, for example, halogenated hydrocarbons, such as haloalkanes, e.g. carbon tetrachloride, chloroform or methylene chloride or carboxylic acids, such as alkanoic acids, e.g. acetic acid or their anhydrides.

In a preferred embodiment of these oxidation methods, one can, for example, oxidize thioethers of formula I, in which n means 0, and/or a residue R-^, R 2 and/or a heteroarylaliphatic residue R^ has an unsubstituted ring nitrogen atom, by reaction with an organic peracid, e.g. with m-chloroperbenzoic acid, to a haloalkane, e.g. in chloroform, to the corresponding sulfinyl resp. in tetrahydrofuran to the corresponding sulfonyl compounds, in which n is 1 or 2.

In another preferred embodiment, thioethers of formula I, in which n is 0, can be oxidized by treatment with sodium metaperiodate, preferably in a haloalkane, e.g.

in carbon tetrachloride or chloroform, selectively to the corresponding sulfoxides, in which n and/or m means 1, or oxidize these with hydrogen peroxide in acetic acid to sulfones, in which n is 2, and, if desired, a nitrogen atom.

Conversely, one can in compounds of formula I, in which n is

1 or 2 and/or heteroaryl residues R 1 and/or R 2 are N-oxidized, oxidize sulfinyl or the sulfonyl group and/or reductively remove the oxy group at the N-oxidized ring nitrogen. The reduction takes place by treatment with common reducing agents, e.g. with nascent or catalytically activated hydrogen, such as iron or zinc and acid, such as hydrochloric acid, or with hydrogen in the presence of Raney nickel, preferably in an inert solvent, such as a lower alkanol or with light metal hydrides resp. dilate metal hydrides, e.g. with alkali metal aluminum or alkali metal borohydrides, e.g. with sodium borohydride or lithium aluminum hydride, preferably in an inert solvent, such as an ether, e.g. diethyl ether or tetrahydrofuran, or for the selective reduction of group N-oxides with a phosphorus-III compound, such as a phosphine, e.g. triphenylphosphine or tri-n-butylphosphine, or a phosphoric acid ester, such as a trilower alkyl phosphite, e.g. with trimethyl or triethyl phosphite.

Furthermore, additional C-substituents can optionally be introduced into the residues R-1 and/or R2. 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. Furthermore, one can 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/sulphuric acid, reduce the nitro group e.g. with stannous chloride to amino, and replacing this with fluorine using sodium nitrite and tetrafluoroboric acid,

using hydrochloric acid, sodium nitrite and copper I chloride (-bromide) with chlorine (bromine), resp. by means of sodium nitrite and potassium iodide with iodine and by means of sodium nitrite and a lower alkyl mercaptan transfer to lower alkylthio resp. using sodium nitrite to hydroxy.

In the residues R^, one can further hydrolyze, preferably acid-catalytically, geminally bound dilavereal oxy, dilaverealkylthio, lower alkylenedioxy and lower alkylenedithio to oxo.

Furthermore, esterified hydroxy, such as lower alkanoyloxy or optionally substituted benzyloxy-containing residues R^ can be hydrolysed to the corresponding hydroxy-containing residues, e.g. as indicated above for the hydrolysis of compounds of formula IXL.

If compounds with formula I-containing isomer mixtures are obtained by the method according to the invention, these, like the stereoisomer mixtures obtainable according to the invention, can be divided into the components in the usual way.

Thus, such isomer mixtures, e.g. mixtures according to the invention stereoisomers and diastereomers divide into the components due to the differences in physical properties

of the components by common physical separation methods, such as crystallisation, chromatography, distillation and phase distribution methods.

Enantiomer mixtures, such as racemates, can by crystallization from 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 are liberated each time in the usual way, are resolved into the enantiomers. For this purpose optically active acids, e.g. D- or L-tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphor sulphonic acids or quinic acid.

Furthermore, free compounds formed can be transferred in a manner known per se to the 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 salts can be converted in a manner known per se

the free connections, e.g. by treatment with a basic final substance with an acid or an acid finisher 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

to other salts, e.g. by treating a salt with a specific metal salt, such as a sodium, barium or silver salt,

in a suitable solvent, in which an inorganic salt that forms is insoluble and thus separates from the reactant

sion mixture, is transferred to other acid addition salts.

The compounds, including their salts, can also be obtained in the form of the hydrates or contain the solvent used for crystallization.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the preceding and following with free compounds and their salts, it is also possible to understand the corresponding salts or free connections.

The invention also relates to the embodiments of the method, where one starts from a compound obtained as an intermediate in an arbitrary process step and carries out the missing process steps, or where a starting material is formed under the reaction conditions, or is used in the form of a derivative thereof, possibly a salt.

In the method according to the invention, such starting materials are preferably used, which lead to the compounds indicated at the outset as particularly valuable.

The pharmaceutical preparations, which contain compounds of formula I or pharmaceutically usable salts thereof, are those for enteral as well as oral or rectal and parenteral administration as well as for topical use on warm-blooded animals, and which contain the pharmacologically active substance alone or together with a pharmaceutically acceptable carrier material. The dosage of the active substance depends on the warm-blood type, age and individual condition, as well as on the method of application.

Normally, it is for approx. 75 kg heavy warm-blooded animal: for oral application to suggest an approximate daily dose of

about. 50-500 mg, preferably in several 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 for enteral or parenteral administration are e.g. such dosage unit forms as dragées, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se,

e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Thus, 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 adding suitable excipients for tablets or dragé 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 binder, such as starch glue using e.g. corn, wheat, rice and potato starch, gelatin, 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 flow regulators and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magne-

sium or calcium stearate, and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly gastric juice-resistant covers, as one e.g. uses concentrated sugar solutions, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/

or titanium dioxide, lacquer 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.

Dyes or pigments can be added to the tablets or dragé coatings, e.g. for the identification or characterization of different active substance doses.

Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The injectable capsules can contain the active substance in the form of a granule, e.g. 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, as stabilizers may possibly be added.

As rectally applicable pharmaceutical preparations come

it e.g. considering suppositories, which consist of a combination of active substance with a suppository base. As a suppository base material, it is suitable, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active substance with a base substance, as base substances there are e.g. namely 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, using suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and possibly also stabilizers.

As topically applicable pharmaceutical preparations, there are 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, which contain more than 50% water. Fatty alcohols are primarily used as oily bases, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitic or stearic acid, liquid to solid wax, e.g. isopropyl myrista, wool 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 ethyleneoxy adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene fatty alcohol ether or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, 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 creams, e.g. polyalcohols, e.g. glycerol, sorbitol, propylene glycol and/or polyethylene glycols, further preservatives, fragrances etc.

Ointments of water-in-oil emulsions containing up to 70%, preferably, however, from approx. 20% to approx. 50% water,

or aqueous phases. The fatty phase primarily refers to hydrocarbon substances, e.g. vaselines, paraffin oil and/or hard paraffins, which to improve the water-binding capacity preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, e.g. cetyl alcohol or wool wax alcohols, resp. wool wax. Emulsifiers are similar lipophilic substances, such as sorbitan fatty acid esters (Spans), e.g. sorbitan oleate and/or sorbitan isostearate. Additions to the water phase include humectants, such as polyalcohols, e.g. glycerol, propyl

lenglycol, sorbitol and/or polyethylene glycol, as well as preservatives, fragrances etc.

Fatty ointments are anhydrous and contain hydrocarbons in particular as a basis, e.g. initialed in,. • petroleum jelly 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 of glycerol, e.g. glycerol raono-and -distearate, as well as e.g. the fatty alcohols, emulsifiers and/or additives mentioned in connection with the ointments increasing water absorption.

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 has the task of binding the moisture or secretions present.

Foams are administered from pressurized containers and are liquid oil-in-water emulsions present in aerosol form, halogenated hydrocarbons, such as chlorofluorolower alkanes, e.g. dichlorodifluoromethane or dichlorotetrafluoroethane are used as propellants. As oil phases, e.g. hydrocarbons, f. e.g. paraffin oil, fatty alcohols, e.g. cetyl alcohol, fatty acid ester, fe.sk. isopropyl myristate and/or other wax. As emulsifiers, e.g. mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additions,

as preservatives etc.

Tinctures and solutions mostly have an aqueous-ethanolic basis, which e.g. has added polyalcohols,

as glycerol, glycols and/or polyethylene glycol, as a humectant to reduce evaporation and re-greasing substances, as fatty acid esters with low polyethylene

glycols, i.e. lipophilic substances soluble in an aqueous mixture as a substitute for the fatty substances that are removed from the skin with ethanol, and if necessary, other auxiliaries and additives.

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

The invention relates to the production of the compounds of formula I and the salts of such compounds with salt-forming properties, preferably for the treatment of inflammations, primarily inflamed chronic diseases of the rheumatic form, especially chronic arthritis.

The invention will be explained in more detail with the help of some examples, where the temperatures are indicated in °C and pressure in mbar.

Eczema gel_l

4.4 g (0.014 mol) of 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole are dissolved in 8 ml of 2n-sodium hydroxide solution. After adding 2.5 ml of bromoacetaldehyde dimethyl acetal in 30 ml of methanol, heat under reflux for 6 hours to 70°C. The reaction solution is diluted with 150 ml of water and extracted three times with methylene chloride. The combined extracts are washed with water, dried over sodium sulphate, filtered and evaporated. The residue gives, after crystallization from methanol, 1,5-bis(p-methoxyphenyl)-3-(2,2-dimethoxyethylthio)-1H-1,2,4-triazole of melting point 107-108°C.

The starting material can e.g. produced as follows:

5.8 g of p-methoxyphenylhydrazine hydrochloride and 2.6 g of ammonium rhodanide are heated with 20 ml of ethanol for 20 hours while stirring and refluxed to boiling. After cooling, suction, washing with water and ethanol and subsequent drying, p-methoxyphenylthiosemicarbazide is obtained, melting point 194-196°C.

6.1 g of p-methoxyphenylthiosemicarbazide are suspended in 40 ml

pyridine and at -10°C 5.8 g of p-methoxybenzoyl chloride are added dropwise so that the internal temperature does not rise above -5°C. It is then stirred for 20 hours at room temperature, and the reaction mixture is poured onto 300 ml of ice-cold 2n-chlorohydrogen acid.

The formed precipitate is filtered off, washed with water and methanol and dried. N"*", N^-bis(p-methoxy enyl)-thiosemicarbazide of melting point 154-159°C is obtained.

7.5 g of N 1 -(4-methoxyphenyl)-N 3-benzoyl-thiosemicarbazide are heated with 75 ml of 2n-sodium hydroxide solution for 3 hours under reflux until boiling. The clear solution formed is cooled and mixed with 75 ml of 2n-chlorohydrogen acid. A crystalline precipitate is obtained which is filtered off, washed with water and ethanol and dried. The thus prepared 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole melts at 173-174°C.

Ex<mp>el_2

In an analogous way as in example 1, starting from 2.2 g (0.007 mol) 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide and 1.53 g bromoacetic acid methyl ester, obtain 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole of melting point 78-79°C (from petroleum ether).

Eczema gel_3

Analogous to example 1, starting from 1.5 g (0.005 mol) 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of caustic soda and 0.75 g of 3-bromopropionic acid, after acidifying the reaction solution with dilute hydrochloric acid, obtain 1,5-bis(p-methoxyphenyl)-3-(2-carboxyethylthio)-1H-1,2,4-triazole of melting point 85-86°C (from ethanol/water).

Eczema gel_4

Analogous to example 1, when starting from 3.1 g (0.01 mol) 1,5-bis(p-methoxyphenyl)-7-3-mercapto-1H-1,2,4-triazole and the equivalent amount of sodium hydroxide and 1.8 g of 3-bromo-propionaldehyde ethylene acetal, obtain 1,5-bis(p-methoxyphenyl)-3-(3,3-ethylenedioxypropylthio)-1H-1,2,4-triazole of melting point 94-96 °C (from ether).

Example_el_5

2.5 g (0.0062 mol) of 1,5-bis(p-methoxyphenyl)-3-(2,2-dimethoxy-ethylthio)-1H-1,2,4-triazole are dissolved in a mixture of 20 ml of acetic acid , 10 ml of water and 5 ml of sulfuric acid and stored for 20 hours at 20°C. Dilute with 200 ml of water and extract twice with ethyl acetate. The combined extracts are washed several times with water, dried over sodium sulphate, filtered and evaporated. After crystallization from ether, 1,5-bis(p-methoxyphenyl)-3-(2-oxoethylthio)-1H-1,2,4-triazole with melting point 88-89°C is obtained.

Example 6_

2.5 g (0.0065 mol) of 1,5-bis(p-methoxyphenyl)-3-(methoxy-carbonylmethylthio)-U-1,2,4-triazole are heated with 7 ml of sodium hydroxide solution for 1 hour while stirring and refluxing. The cooled solution is mixed with 7 ml of 2n-chlorohydrogen acid.

The precipitated crystals are filtered, washed with water and dried. The 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole formed melts at 184-185°C.

Example_el_7

Analogously to example 5, 1.8 g of 1,5-bis(p-methoxyphenyl)-3-(3,3-ethylenedioxypropylthio)-1H-1,2,4-triazole after hydrolysis with a mixture of 20 ml of acetic acid, 10 ml of water and 5 ml of sulfuric acid after work-up obtain 1,5-bis(p-methoxyphenyl)-3-(3-oxopropylthio)-1H-1,2,4-triazole of melting point 103-105°C (from ether).

Example_el_8

1.1 g (0.003 mol) 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole and 0.5 ml thionyl chloride in 30 ml toluene are heated with stirring at 60-70° C until a clear solution has formed. Thereby, the solvent is distilled off under reduced pressure and the residue is dissolved again in toluene. This solution is added dropwise to a cooled to 0°C, stirred solution of 1.2 g of dimethylamine in 50 ml of toluene. The temperature of the solvent is then allowed to rise to room temperature. It is then evaporated under reduced pressure and the residue is distributed between ethyl acetate and water. After washing several times with water, the organic phase is dried with sodium sulphate, filtered and evaporated. After crystallization of the residue from ethanol, 1,5-bis(p-methoxyphenyl)-3-N,N-dimethylcarbamoylmethyl-thio-1H-1,2,4-triazole of melting point 173-175°C is obtained (yield 30%) .

Analogously, however, using ammonia instead of dimethylamine, 1,5-bis(p-methoxyphenyl)-3-carbamoyl-methylthio-1H-1,2,4-triazole is obtained, melting point 170-172°C.

Example<p>el_9

A solution of 3.0 g (0.0078 mol) 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole in 50 ml of dichloromethane is mixed portionwise with 2.0 g of 90% -ig m-chloroperbenzoic acid. After 3 days of stirring at room temperature, the solvent is distilled off under reduced pressure. The residue is chromatographed on 100 g of silica gel 60 (230-400 mesh, Merck) using a pressure of 0.6 bar and toluene-ethyl acetate (4:1, v/v) as eluent. The fractions containing the desired product are combined and evaporated. One thus obtains 1,5-bis(p-methoxyphenyl)-3-methoxy-carbonylmethane-sulfinyl-1H-1,2,4-triazole as a colorless oil, 1H-NMR spectrum (CDCl 3 , TMS): Singlet 2H at <5 >= 4.37 ppm, which is in the most recently obtained fractions. From the middle fractions, 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethanesulfonyl-1H-1,2,4-triazole is obtained 1H-NMR spectrum (CDCl-j, TMS): Singlet 2 H at 6 = 4 .41 ppm as a colorless oil.

Eczema<el_>10

1.5 g (0.00375 mol) of 1,5-bis(p-methoxyphenyl)-3-methoxycarbonyl-methanesulfinyl-1H-1,2,4-triazole is stirred with 40 ml of 1-n caustic soda for 20 hours. After treatment with animal charcoal, the solution is mixed with 4.1 ml 1-1 hydrochloric acid and then extracted with methylene chloride. The extracts are dried with sodium sulphate, filtered and evaporated under reduced pressure. The remaining, oily 1,5-bis(p-methoxyphenyl)-3-carboxymethanesulfinyl-1H-1,2,4-triazole is dissolved in the calculated amount of 1.0-n caustic soda and the solution is lyophilized. The lyophilisate is slurried with a little isopropanol and aspirated. The sodium salt of 1,5-bis(p-methoxyphenyl)-3-carboxymethanesulfinyl-1H-1,2,4-triazole is thus obtained as dihydrate, which melts from 135°C during cleavage.

In an analogous way, when starting from 1,5-bis(p-methoxy-phenyl)-3-methoxycarbonylmethanesulfonyl-1H-1,2,4-triazole, one will get the sodium salt of 1,5-bis(p-methoxyphenyl) -3-carboxymethanesulfonyl-1H-1,2,4-triazole, which melts from 133°C during cleavage.

Example_el_ll

7.5 g (0.0226 mol) N 1 -(4-methoxyphenyl)-N 3-benzoylthiosemicarbazide and 2.7 g sodium chloroacetate are heated with 75 ml 2-n sodium hydroxide solution for 3 hours under reflux to boiling. The clear solution formed is cooled and mixed with 75 ml of 2-n hydrochloric acid. A crystalline precipitate is obtained which is filtered off, washed with water and ethanol. The thus produced 1,5-bis-(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole melts at 184-185°C.

Eczema gel_12

2.2 g (0.007 mol) of 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole are dissolved in 15 ml of 2-n caustic soda. After adding 1.3 g of bromomalonic acid, the resulting solution is allowed to stand at room temperature for 24 hours. The mixture is then adjusted to pH 1 with concentrated hydrochloric acid and then heated for 1 hour while stirring and refluxed to boil. After cooling and resting from raf, the separated 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole, melting point 184-185°C, is evaporated.

Example_el_13

Analogous to that described in example 1, from 2.2 g (0.007 mol) 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of caustic soda and chlorocetonitrile, 1 ,5-bis(p-methoxyphenyl)-3-cyanomethylthio-1H-1,2,4-triazole as an oil.

Example<l>_<14>

Analogously to examples 1 and 6, by reacting 1,5-bis(p-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole with the calculated amount of 2-bromopropionic acid ethyl ester, 1,5-bis (p-methoxyphenyl)-3-(1-ethoxycarbonylethylthio)-1H-1,2,4-triazole of melting point 80-82°C and of this 1,5-bis(p-methoxyphenyl)-3-(1-carboxyethylthio) )-1H-1,2,4-triazole of melting point 148-150°C.

Example_el_15

1.76 g (0.005 mol) of 1,5-bis(p-methoxyphenyl)-3-cyanomethylthio-1H-1,2,4-triazole is heated with 10 ml of acetic acid and 10 ml of 36% hydrochloric acid for 12 hours under reflux . The reaction mixture is then evaporated to dryness under reduced pressure. The residue is crystallized from a chloroform-ethanol mixture. 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole of melting point 184-185°C is obtained.

Example_el_16_

1.76 g (0.05 mol). 1,5-bis(p-methoxyphenyl)-3-cyanomethylthio-1H-1,2,4-triazole is heated with 20 ml of saturated methanolic hydrochloric acid while stirring in a pressure tube for 10 hours at 100 °C. It is then evaporated to dryness, the residue is extracted several times with diethyl ether, the extracts are filtered and partially evaporated. After the addition of petroleum ether, 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole crystallizes, melting point 78-79°C.

Example_el_17

To a solution of 0.45 g (0.005 mol) thioglycolic acid i

5 ml of dimethylformamide is added to 0.54 g of sodium methylate. It is stirred at room temperature for 1 hour, then 1.8 g (0.005 mol) of 1,5-bis(p-methoxyphenyl)-3-methylsulfonyl-1H-1,2,4-triazole are introduced. It is then heated for 24 hours with stirring at 100°C. The solvent is distilled off under reduced pressure and the residue is mixed with 5 ml of 2-n hydrochloric acid. It is extracted several times with dichloromethane,

dry the extracts over sodium sulphate, filter and evaporate. The remaining crude 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole crystallizes from chloroform-ethanol with melting point 184-185°C.

Example_<18>

To 1.93 g (0.01 mol) of 4-methoxybenzoyl isothiocyanate (CA.

44 2515 b) drop 1.10 g of mercaptoacetic acid methyl ester into 50 ml of benzene. It is then stirred for 5 hours at room temperature. The solvent is distilled off under reduced pressure. 1.40 g of 4-methoxyphenylhydrazine and 100 ml of benzene are then added. After 4 hours of stirring and reflux under a water separator, the solvent is distilled off under reduced pressure. Crystallization of the residue from diethyl ether with the addition of petroleum ether gives 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole of melting point 78-79°C.

Exe<mp>_el_19

Analogous to examples 1-18, one further obtains: 1,5-bis(p-chlorophenyl)-3-(2,2-dimethoxyethylthio)-1H-1,2,4-triazole of melting point 117-118°C,

1,5-bis(p-chlorophenyl)-3-(2-oxoethylthio)-1H-1,2,4-triazole of melting point 96-100°C,

1-(3-pyridyl)-5-phenyl-3-(2-hydroxyethylthio)-1H-1,2,4-triazole as an oil, and

1,5-bis(p-methoxyphenyl)-3-(2-hydroxyethylthio)-1H-1,2,4-triazole of melting point 140-142°C.

Example_el_20

Tablets containing 25 mg of active substance, e.g. 3-(2,2-Dimethoxyethylthio)-1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole can be prepared as follows.

Ingredients (for 1000 tablets):

F£§ms.l:iiii22:

All solid ingredients are first passed through a sieve

with 0.6 mm mesh size. The active substance, lactose, talc, magnesium stearate and half of the starch are then mixed. The other starch half is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary, with the addition of water. The granulate is dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm and pressed into concave tablets of approx. 6 mm diameter.

Example_el_21

Chewable tablets containing 30 mg of active substance, e.g. 3-(2,2-dimethoxyethylthio)-1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole can e.g. produced as follows:

Composition (for 1000 tablets):

All solid ingredients are first run through a sieve with

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

Example_el_22

Tablets containing 100 mg of active substance, e.g. 3-(2,2-Dimethoxyethylthio)-1,5-bis(p-methoxyphenyl)-1H-1,2,4-triazole can be prepared as follows:

Composition (for 1000 tablets)

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 mixed well. The other starch half is suspended in 65 ml of water, and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water, and the mixture is granulated, if necessary, with the addition of water. The granulate is dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm and pressed into concave tablets of approx. 6 mm diameter.

Example_el_23_

In an analogous way as in examples 20-22, pharmaceutical preparations can also be prepared containing respectively one of the compounds of formula I mentioned in examples 2-19, the compounds, in which R3 is carboxy, can also be present in the form of salts with bases, e.g. e.g. as sodium salt.

Claims (10)

1. Process for the preparation of new 3-mercapto-1,2,4-triazacycloalkadiene derivatives of formula I in which the radicals R-1 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- or optionally N-oxidized heteroaryl residues, n means 0, 1 or 2, and R, means a by an optionally esterified or amidated carboxy group, cyano or in a higher position than α with one or two optionally esterified or etherified hydroxy groups, one or two etherified mercapto groups, an oxidized mercapto group or an oxo group substituted aliphatic hydrocarbon residue and their salts, characterized by ata) from a compound of formula in which one of the residues and Y2 means a cleavable residue Y and the other means a hydrogen atom, and Y^ and Y^ together mean an additional bond, or in which Y^ means a cleavable residue Y, and Y, means hydrogen, and Y-^ and Y2 means an additional bond, or from a salt thereof, is cleaved off during the introduction of an additional bond HY, orb) compounds of formula in which Y, , means a mercapto group optionally present in salt form, and Y^2 means reactive esterified hydroxy or Y^ means sulfonyl and Y^ means a mercapto group optionally present in salt form, are condensed with each other to corresponding compounds of formula I, in which n means 0 , orc) compounds with the formulas in which one of the residues Y^ and Y^2 means a metallic residue, and the other a group s(°)n~ Yi3' in which Y^ means halogen, condense with each other, ord) a compound of formula in which Y^ is mercapto or a salt thereof, is reacted with an epoxy derivative derived from a compound of formula R-j-H (XXX VII) to a compound of formula I, in which R 3 in the 6-position has a hydroxy group, and n means 0, or ) a compound with formula in which Y-j^ means mercapto or a salt thereof, is reacted with a compound of formula R^-H (XXXVIII), in which R^ means one derived from R^, at least in the a,3 position a C-C double or C-C triple bond aliphatic residue, to a compound of formula I, in which R^ is a,3-saturated or a,B-monounsaturated and n is 0, orf) in a compound of formula in which R^ means a residue transferable to a group R^, R3' is transferred in the desired group R^, if necessary, an isomer mixture obtained according to the method is divided into its components, and the isomer of formula I is isolated, and if desired, a compound obtained according to the method is converted into another compound of formula I and/or a free compound obtained according to the method is converted into a salt or a salt formed according to the method to the free compound or to another salt. 2. Process according to claim 1, characterized in that compounds of formula I and their salts are prepared, in which the radicals R 1 and R 2 independently of each other mean unsubstituted or with lower alkyl, lower alkoxy resp. on vicinal C atoms lower alkyl (id)endioxy. hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, mono- or di-lower alkylamines and/or trifluoromethyl substituted 6 to and including 10 C-atom-containing aryl resp. monocyclic, an oxygen or sulfur atom and possibly additionally a nitrogen atom-containing 5-membered resp. optionally N-oxidized one or two nitrogen atom-containing 6-membered heteroaryl residues, n means 0, 1 or 2, and means carboxyl lower alkyl, lower alkoxycarbonyl lower alkyl, carbamyl lower alkyl, N-mono- and N,N-di lower alkyl carbamyl lower alkyl, cyano lower alkyl or hydroxy-, lower alkanoyloxy-, lower alkoxy- , lower alkylenedioxy-, lower alkylthio-, lower alkylenedithio-, lower alkanesulfinyl-, lower alkanesulfonyl- or oxo group or groups in higher than a-position containing mono- or dihydroxy lower alkyl, lower alkanoyloxy lower alkyl, mono- or di-lower oxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylene dithio lower alkyl, mono- or di lower alkyl thiol lower alkyl, lower alkanesulfin lower alkyl, lower alkanesulfonyl lower alkyl or oxola lower alkyl. 3. Method according to claim 1, characterized in that compounds of formula I and their salts are prepared, in which the residues 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 resp. unsubstituted or with lower alkyl, lower alkoxy, halogen or hydroxy substituted furyl, thienyl, pyridyl resp. 1-oxidopyridyl, n means 0, 1 or 2, and means carboxyl lower alkyl, lower alkoxycarbonyl lower alkyl, carbamyl lower alkyl, N-mono- or N,N-dilower alkyl carbamyl lower alkyl or hydroxy-, lower alkoxy-, lower alkylenedioxy-, lower alkylidenedioxy-, respectively. oxo group or groups in a higher than α-position containing hydroxyl lower alkyl, mono- or dilavereal oxy lower alkyl, lower alkylenedioxy lower alkyl, lower alkylidenedioxy lower alkyl or oxola lower alkyl. 4. Method according to claim 1, characterized in that compounds of formula I or their salts are prepared, in which R-^ and R 2 mean phenyl radicals substituted with up to 4 carbon atoms, n means 0, 1 or 2, and R^ means carboxy or lower alkoxycarbonyl group in a -position containing carboxy-resp. lower alkoxycarbonyl lower alkyl with up to and including 4 C atoms in the lower alkyl and optionally lower alkoxy part or the hydroxy, oxo, lower alkoxy or lower alkylenedioxy groups in a higher than α-position hydroxyl lower alkyl with 2 to 4 C atoms, oxola lower alkyl with 2 to 4 C atoms or mono- or dilavereal oxy lower alkyl resp. lower alkylenedioxylave alkyl having respectively up to and including 4 C atoms in each alkyl(ene) moiety and their salts. 5. Method according to claim 1, characterized in that compounds of formula I or their salts are prepared, in which R 1 and R 2 mean phenyl radicals substituted with lower alkoxy with up to and including 4 C atoms, n means 0, 1 or 2, and means carboxy or lower alkoxycarbonyl group in the a-position containing carboxy-resp. lower alkoxycarbonyl lower alkyl with up to 4 C atoms in the lower alkyl and optionally lower alkoxy part. 6. Method according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-(2,2-dimethoxyethylthio)-1H-1,2,4-triazole or a salt thereof is produced. 7. Method according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole or a salt thereof is produced. 8. Method according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-(2-oxoethylthio)-1H-1,2,4-triazole or a salt thereof is produced. 9. Method according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole or a salt thereof is produced. 10. Method according to claim 1, characterized in that 1,5-bis(p-methoxyphenyl)-3-(2-carboxyethylthio)-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl )-3-(3,3-ethylenedioxypropyl-thio)-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-(3-oxopropylthio)-1H-1,2, 4-triazole, 1,5-bis(p-methoxyphenyl)-3-N,N-dimethylcarbamoylmethylthio-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethanesulfonyl-1H -1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-methoxycarbonylmethanesulfinyl-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-carbamylmethylthio-1 ,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-carboxymethyl-sulfinyl-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-cyano-methylthio -1H-1,2,4-triazole, 1,5-bis(p-chlorophenyl)-3-(2,2-dimethoxyethylthio)-1H-1,2,4-triazole, 1,5-bis(p- chlorophenyl)-3-(2-oxoethylthio)-1H-1,2,4-triazole, 1-(3-pyridyl)-5-phenyl-3-(2-hydroxyethylthio)-1H-1,2,4-triazole , 1,5-bis(p-methoxy-phenyl)-3-carboxymethanesulfonyl-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-(1-ethoxycarbonylethylthio)-1H,1 ,2,4-triazole, 1,5-b is(p-methoxyphenyl)-3-(1-carboxyethylthio)-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-carbonylmethylthio-1H-1,2,4-triazole, 1,5-bis(p-methoxyphenyl)-3-(2-hydroxyethylthio)-1H-1,2,4-triazole or respectively a salt thereof.