DD234006A5 - PROCESS FOR PREPARING NEW 3-MERCAPTO-1,2,4-TRIAZACYCLOALKADIA DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 3-mercapto-1,2,4-triazacycloalkadienderivate for use as a medicament. The aim of the invention is the provision of new compounds with analgesic properties, in particular for the treatment of painful-inflammatory diseases of the rheumatic type. According to the invention, 3-mercapto-1,2,4-triazacycloalkadiene derivatives of the formula I in which, for example: R 1 and R 2 independently of one another are unsubstituted or substituted aryl or optionally N-oxidized heteroaryl radicals, n is 0, 1 or 2 and R 3 is a substituted aliphatic hydrocarbon radical and their salts are prepared in such a way by z. B. from a compound of formula II, wherein one of Y1 and Y2 is a leaving group Y and the other is a hydrogen atom and Y3 and Y4 together represent an additional bond, or split off from a salt thereof with the introduction of an additional bond HY.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel 3-mercapto-i, 2,4-triazacycloalkadienderivate with valuable pharmacological properties, in particular with pronounced antinociceptive effect, with an inhibitory effect on the prostaglandin synthesis as well as with significantly anti'inflammatorischer effect.

The compounds according to the invention are used as medicaments, for example for the treatment of painful inflammatory diseases, especially chronic diseases of the rheumatic type, such as chronic arthritis.

Characteristics of the known technical solutions There are no known details of which compounds have hitherto been used for the treatment of painful inflammatory diseases, especially chronic diseases of the rheumatic type, such as chronic arthritis.

There is also no information available about processes for the preparation of 3-mercapto-1,2,4-triazacycloalkadienderivaten.

Object of the invention

The aim of the invention is to provide novel compounds with valuable pharmacological properties that are suitable for the treatment of painful inflammatory diseases, especially chronic diseases of the rheumatic type.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new S-mercapto-i ^^ - triazacycloalkadienderivate of formula I.

_й2 _ / ^

in which the radicals R ₁ and R ₂ independently of one another are the aryl or unsubstituted or unsubstituted or by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidized etherified mercapto, free or aliphatic substituted amino, nitro and / or trifluoromethyl -oxidierte Heteroarylreste mean, η is O, 1 or 2 and R _{3 is} a d- h h an optionally esterified or amidated carboxy group, cyano or in higher than the α-position by one or two optionally esterified or etherified hydroxy group (s), a or * represents etherified mercapto group (s), an oxidized mercapto group or an oxo group substituted aliphatic hydrocarbon radical, and their salts.

Heteroaryl radicals are, for example, monocyclic, an oxygen or sulfur atom and optionally in addition a nitrogen atom-containing 5-membered or one or two nitrogen atoms containing 6-membered heteroaryl, such as FuryI, for example 2-furyl, thienyl, z. B. 2-thienyl, thiazolyl, ζ. B. 2-thiazolyl, pyridyl, ζ. В. 2-, 4- or especially 3-pyridyl or 3- (1-Oxidopyric / I), or pyrimidyl, z. B. 2- or 4-pyrimidyl or 2- (1-0xidopyrimidyl).

Aryl radicals are aryl radicals of up to and including 10 carbon atoms (C atoms), for example monocyclic aryl radicals, such as phenyl.

Aryl or heteroaryl radicals may be one or more than one, e.g. B. one, two or three, identical or different of said substituents.

Etherified hydroxy is, for example, lower alkoxy or vicinal bound lower alkylenedioxy or lower alkylenedioxy, but may also be lower alkenyloxy or lower alkynyloxy.

Esterified hydroxy as a substituent of R ₁ or R ₂ is, for example, hydroxy esterified with a mineral acid or an organic carboxylic acid, such as halogen, lower alkanoyloxy, also optionally as indicated, e.g. B. by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, substituted benzoyloxy.

-4- 741 23

Optionally oxidized etherified mercapto is, for example, lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl. Aliphatic substituted amino substituents are, for example, mono- or disubstituted amino through lower alkyl, such as N-mono- or Ν, Ν-Diniederallcylamino, but can also 4- to 7-membered alkylene or 3-aza-, 3-oxa- or 3-Thiaalkylenamino

his.

For example, esterified carboxy means aliphatically esterified carboxy, such as lower alkoxycarbonyl. Amidated carboxy is, for example, unsubstituted or aliphatically substituted carbamyl, such as carbamyl, N-mono- or N.N-di-lower alkylcarbamyl, but can also 4- to 7-membered Ν, Ν-lower alkylene or N, N- (3-Aza-, 3-0xa- or

3-Thianiederalkylencarbamyl be.

Aliphatic hydrocarbon radicals are, for example, lower alkyl, furthermore lower alkenyl or lower alkynyl radicals. When Substituents of R3, which is in particular substituted lower alkyl, for example, optionally with a

organic carboxylic acid esterified hydroxy, ζ. B- lower alkanoyloxy, or aliphatically etherified hydroxy, ζ. B. lower alkoxy,

Lower alkenyloxy, lower alkylenedioxy, optionally oxidised etherified mercapto, such as lower alkylthio, lower alkanesulphinyl, Niederalkausulfouyl, Niederalkylendithio, optionally esterified or amidated carboxy, such as carboxy, lower alkoxycarbonyl, Carbamyl or M-mono- or Ν, Ν-Diniederalkylcarbamyl, cyano and oxo into consideration. Rete R ₃ are accordingly

for example, carboxy-lower alkyl, Niederalkoxycarbonylniederalkyl, carbamyl-lower alkyl, N-mono- and

N.N-di-lower alkylcarbamyl-lower alkyl, cyano-lower alkyl or the hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylenedioxy,

Miederalkytthio-, Niederaltylendittuo-, KtederalkansulfArtvl-, Niederalkaasulf onyl- or Qxagruppe (n \ in higher than the α-position-bearing mono- or dihydroxy lower alkyl, lower alkanoyloxy, lower mono- or di-lower alkoxy,

Lower alkylenedioxychol-lower alkyl, mono- or lower-lower alkylthio, lower alkanesulphinyl or lower alkanesulphonyl-lower alkyl, Lower alkylene dithio-lower alkyl or oxo-lower alkyl. Above and below, "lower" organic radicals and compounds are preferably to be understood as meaning those to and

with 7, especially up to and containing 4, carbon atoms (C atoms).

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, furthermore pentyl, hexyl

or heptyl.

Lower alkenyl is, for example, vinyl, but preferably lower alkenyl bonded via a saturated carbon atom, such as allyl.

Methallyl or but-2-enyl.

Lower alkynyl is, for example, ethynyl, but preferably lower alkynyl bonded via a saturated carbon atom, such as propargyl

or but-2-ynyl.

Lower alkoxy is, for example, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, secondary butoxy or Tertiary butoxy, furthermore pentyloxy, hexyloxy or heptyloxy. Lower alkenyloxy is z. B. allyloxy, lower alkynyloxy, z. B. Propargyloxy. Lower alkylenedioxy is, for example, methylenedioxy, ethylenedioxy, 1,3-propylenedioxy, 2,3-butylenedioxy or

1,3- (2,2-dimethyl) -propylendioxy; Lower alkylidenedioxy z. B. Aethylidendioxy or Isopropylidendioxy.

Lower alkanoyloxy is, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, furthermore formyloxy or pivaloyloxy. Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio or Tertiarybutylthio, also pentyrthio, 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-iodo-propane, butane or isobutanesulfonyl. Mono- or di-lower alkylamino is, for example, ethylamino, dimethylamino, ethylamino, diethylamino, propyiamino or Butylamino.

4- to 7-membered alkyleneamino or 3-aza-, 3-0xa- or 3-thiaalkyleneamino is, for example, pyrrolidino, piperidino, morpholine ",

Thiomorpholine or piperazino or 4-methyl or 4-ethylpiperazino.

4 to 7-membered Ν, Ν-lower alkylene or N, N- (3-aza, 3-oxa or 3-thia) -niederalkylencarbamylniederalkyl example

Pyrrolidino, piperidino, morpholino, thiomorpholine or piperazino or 4-methyl or 4-Aethylpiperazinocarbonylmethyl. Carboxyniederalkyl is for example carboxymethyl, 1- or 2-carboxy it hy 1,1-, 2- or 3-carboxypropyl, 2- {2-carboxy) propyl or

4-carboxybutyl, furthermore 2- (2-carboxy) -butyl.

Lower alkoxycarbonyl-lower alkyl is, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, 1- or

2-methoxycarbonylethyl, 1- or 2-ethoxycarbonylethyl, 1-, 2- or 3-methoxycarbonylpropyl, 1-, 2- or 3-ethoxycarbonylpropyl, 2- (2-methoxycarbonyl) - or 2- (2-ethoxycarbonyl) -propyl or 4-ethoxycarbonyl or 4-methoxycarbonylbutyl, furthermore 2- (2-methoxycarbonyl) or 2- (2-ethoxycarbonyl) -butyl.

Carbamyl-lower alkyl or N-mono- or N, N-di-lower alkylcarbamyl-lower alkyl is, for example, carbamylmethyl, 1- or

2-carbamylethyl or 2- (2-carbamyl) -propyl or N-methyl-, N-ethyl- or Ν, Ν-dimethylcarbamylmethyl, 1- or 2- (N-methyl-,

N-ethyl or N, N-dimethylcarbamyl) -ethyl or 2- [2- (N-methyl, N-ethyl or N, N-dimethylcarbamyl)] -propyl. Cyanoloweralkyl is, for example, cyanomethyl, 1-cyanoethyl or 2- (2-cyano) -propyl. Mono- "the Diniederalkoxyniederalkyl is, for example, 2-methoxy, 2-ethoxy, 2-propyloxy or 2-tsopropylox / -, 2,? - Dimethoxy-

or 2,2-diethoxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or 3,3-dimethoxy, 3,3-diethoxy, 2,3-dimethoxy or 2,3-diethoxypropyl, 2- (1 - Dimethoxy-2-methyl) -propyl or 4,4-dimethoxy-butyl.

Lower alkylenedioxy-lower alkyl is, for example, 2, "2-ethylenedioxy- or 2,2-propylenedioxy-ethyl or 3,3- or

2,3-ethylenedioxy-propyl, also 2- (1-ethylenedioxy-2-methyl) -propyl.

Lower alkanovoxylic ylkyldishkyl is, for example, 1- or 2-aetoxyethylthhanol, t- or 2-phenylalcohol, t-acetoxypropyl-1-yl, 1-pivaloyloxypropyl (2), 1-acetoxy-2-methyl-propyl (2) or 1-pivaloyloxy-2 -methyl-propyl- (2) or 3-acetoxypropyl.

Mono- or di-lower alkylthio-lower alkyl is, for example, 2-methyltio, 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-ethanesulfinyl-propyl.

-5- 74123

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 alkylenedithio-lower 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, hydroxymethyl, 1- or 2-hydroxyethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 2-hydroxy-propyl- (2), 1-hydroxy-2-methyl-propyl- (2) , 4-hydroxy- or 2,4-dihydroxybutyl, 5-hydroxy, 2,5-dihydroxy or 3,5-dihydroxypentyl.

Oxoniederalkyl means, for example, 2-Oxoäthyl, 2- or 3-oxopropyl or 2-, 3- or 4-oxobutyl, further corresponding oxopentyl, oxohexyl or oxoheptyl or formyl.

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

Salts of compounds of formula I are especially pharmaceutically acceptable salts, on the one hand pharmaceutically acceptable acid addition salts with strong acids, such as mineral acid, eg. As salts with hydrohalic acids, especially hydrochloric or hydrobromic acid, ie hydrohalides, especially hydrochlorides and hydrobromides, or sulfuric acid, ie

Hydrogen sulfates and sulfates, as well as salts with suitable organic acids, such as dicarboxylic acids or organic sulfonic acids,

z. Maleate, fumarates, maleates, tartrates or methanesulfonates, and N-cyclohexylsulfaminates, on the other hand, internal salts of compounds of formula I, wherein R _{3 has} carboxy, or pharmaceutically acceptable metal, such as alkali or alkaline earth metal salts or ammonium salts with ammonia or suitable organic Amines, such as mono-, di- or Triniederalkylaminen, z. B. diethylamine, mono-, di- or Trihydroxyniederalkylaminen, z. Triethanolamine or 2-dimethylaminoethanol, or heteroaliphatic amines, e.g. B. morpholine.

The compounds of the formula I have valuable pharmacological properties. In particular, they show a pronounced antinociceptive activity and an inhibitory effect on prostaglandin synthesis, as well as a marked anti-inflammatory effect. Thus, they are found in the mouse in the phenyl-p-benzoquinone-induced writhing syndrome according to J. Pharmacol, ѳхр.

Therap. 125, 237 (1959) in the dose range of about 3-50 mg / kg p. o. as excellent effective.

They also show at doses from about 25 mg / kg p. o. A marked inhibitory effect on experimental rat carragenic paw edema (Di Pasquale et al: Agents and Actions S, 256 [1975]) and in experimental rat ear croton oil edema (TONELLI et al .: Endocrinology 77, 655 (1965)) when applied topically in a concentration from about 20 mg / ml a significant anti-inflammatory effect.

Furthermore, they show in vitro in the concentration range of about 2 to 30 μΜ / L a significant inhibitory effect on prostaglandin synthesis from arachidonic acid, detected in the experimental design of prostaglandins 7,123 (1974).

Accordingly, the compounds of formula I are excellently suitable as active ingredients of pharmaceutical preparations for the treatment of painful inflammatory diseases, especially chronic diseases of the rheumatic type, such as chronic arthritis.

The invention relates in the first place to the preparation of compounds of the formula I in which the radicals R ₁ and R ₃ independently of one another are unsubstituted or lower alkyl, lower alkoxy or vicinal C atoms lower alkyl (id) endioxy, hydroxy, halogen, Niederalkonoyloxy, Niederalkylthio , Lower alkanesulfinyl, lower alkanesulfonyl, amino, mono- or di-lower alkylamino and / or trifluoromethyl-substituted aryl or monocyclic aryl or monocyclic, an oxygen or sulfur atom and optionally additionally a nitrogen atom having 5-membered or optionally N-oxidized one or two nitrogen atom (s) having mean 6-membered heteroaryl, η is 0.1 or 2, and R ₃ carboxy, Niederaikoxycarbonylniederalkyl, Carbamylniederalkyl, N-mono- and N, N-Diniederalkylcarbamylniederalkyl, cyano-lower alkyl or hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylenedioxy , Lower alkylthio, lower alkylenedithio, lower alkanesulfi nyl-, lower alkanesulfonyl or oxo group (s) in higher than the α-bearing mono- or Dihydroxyniederalkyl, Niederalkanoyloxyniederalkyl, mono- or Diniederalkoxyniederalkyl, Niederalkylendioxyniederalkyl, Niederalkylendithioniederalkyl, mono- or di-lower alkylthione, Niederalkansulfinylniederalkyl, Niederalkansulfonylniederalkyl or oxo-lower alkyl, and their salts ,

More particularly, the invention relates to the preparation of compounds of formula I wherein R ₁ and R _{2 are} independently phenyl or unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halo, lower alkanoyloxy, lower alkylthio, lower alkanesulfonyl, di-lower alkylamino and / or trifluoromethyl lower-alkyl, lower-alkoxy, halogen or hydroxy-substituted furyl, such as 2-furyl, thienyl, such as 2-thienyl, pyridyl, such as 2-, 3- or 4-pyridyl, or 1-oxidopyridyl, such as 2-, 3- or 4 - (1-Oxido) -pyridyl, mean, η is 0, 1 or 2 and R _{3 is} lower alkoxycarbyl, lower alkoxycarbonyl, lower carbamyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl-lower alkyl or the hydroxy, lower alkoxy, lower alkylenedioxy, lower alkylidenedioxy or oxo group (s) in higher than the α-position hydroxiloweralkyl, mono- or di-lower alkoxy-lower alkyl, lower-alkylenedioxy-lower alkyl, lower-alkylidenedioxy-lower alkyl or oxone iederalkyl, and their salts, in particular their pharmaceutically acceptable salts.

The invention relates in particular to the preparation of compounds of the formula I in which the radicals R ₁ and R ₂ independently of one another unsubstituted or by lower alkoxy with up to and 4 C atoms, such as methoxy, lower alkylthio with up to and 4 C atoms, such as Me 'hyithio, or halogen of / mum number to and 1 ... 135, such as fluorine or chlorine, substituted phenyl, η is 0, and R _{3 is} the carboxy or lower alkoxycarbonyl group in α-position carboxy or Niederalkoxycarbonylniederalkyl with bis and with 4 carbon atoms in the lower alkyl and optionally lower alkoxy, such as carboxy methyl, 1-carboxyethyl, methoxy or ethoxycarbonylmethyl or 2- (2-carboxy) propyl, and their, in particular pharmaceutically acceptable, salts.

The invention relates in the first place to the preparation of compounds of the formula I in which R ₁ and R ₂ are substituted by lower alkoxy having up to and 4 C atoms, such as methoxy, which is bonded in particular in the p position, phenyl, η is 0, 1 or 2 and R _{3 is} the carboxy or lower alkoxycarbonyl group in α-position bearing carboxy- or Niederalkoxycarbonylniederalkyl with up to 4 carbon atoms in the lower alkyl and optionally lower alkoxy, such as carboxymethyl, 1-carboxyethyl, methoxy or Aethoxycarbonylmethyl or 2- (2-carboxy) -propyl, or the hydroxy, oxo, lower alkoxy or Niederalkylenedioxygruppe in higher than the α-position bearing Hydroxiliederalkyl with 2 to and 4 C-atoms, such as 2-hydroxyethyl or 3-hydroxypropyl, oxo-lower alkyl with 2 to and 4 C atoms, such as 2-oxoethyl or 3-oxopropyl, or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl, each having up to and including 4 C atoms in each alkyl (s), such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2,2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-Aethylendioxyäthyl, and their, in particular pharmaceutically acceptable, salts.

The invention relates above all to the preparation of novel compounds of the formula I in which the radicals R ₁ and R _{2 are} independently of one another

-6- 74123

unsubstituted or substituted by lower alkoxy with up to and with 4 C-atoms, such as methoxy, lower alkylthio with up to and 4 C atoms, such as methylthio, or halogen of the atomic number to and 35, such as fluorine or chlorine, substituted phenyl, η is 0 and R _{3 is} the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group in higher than the α-position bearing Hydroxyniederalkyl with 2 to and 4 C-atoms, such as hydroxyethyl or 3-hydroxypropyl, Oxoniederalkyl with 2 to 4 C and Atoms, such as 2-oxoethyl or 3-oxopropyl, or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl, each having up to and including 4 carbon atoms in each alkyl (s), such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2, 2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-Aethylendioxyäthyl, and their, in particular pharmaceutically acceptable, salts.

The invention relates in particular to the preparation of compounds of the formula I in which R ₁ and R ₂ are phenyl radicals substituted by lower alkoxy having bis-C 4 -C atoms, such as methoxy, which is bonded in particular in the p position, η is 0, 1 or 2 and R _{3 is} the carboxy or lower alkoxycarbonyl group in α-position bearing carboxy- or Niederalkoxycarbonylniederalkyl with bis and with 4 C atoms in the lower alkyl and optionally lower alkoxy) such as carboxymethyl, 1-Carboxyäthyl, methoxy or Aethoxycarbonylmethyl or 2- (2-carboxy) -propyl, and their particular pharmaceutically acceptable salts. The invention relates in particular to the preparation of the novel compounds of the formula I mentioned in the examples and their pharmaceutically acceptable salts, to processes for their preparation, to pharmaceutical compositions containing them and to their use.

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

wherein one of Y ₁ and Y _{2 is} a leaving group Y and the other is hydrogen and Y ₃ and Y ₄ together represent an additional bond, or wherein Y _{4 is} a leaving group Y and Y _{3 is} hydrogen and Y ₁ and Y ₂ represent an additional bond, or split off from a salt thereof with the introduction of an additional bond HY, if necessary separate an isomer mixture obtainable according to the process into the components and isolate the isomer of the formula I and, if desired, convert a compound obtainable according to the process into another compound of the formula I and / or or a free compound obtainable in accordance with the process into a salt or a salt obtainable according to the process into the free compound or into another composition.

Cleavable radicals Y are, for example, optionally esterified or etherified hydroxy or mercapto groups, furthermore amino, ammonium and sulfonium groups. As esterified hydroxy is, for example, with an inorganic acid or with an organic carboxylic acid esterified hydroxy into consideration, such as halogen, z. As chlorine or bromine, or lower alkanoyloxy, z. B. acetoxy. Etherified hydroxy groups are, for example, lower alkoxy groups, eg. Methoxy or ethoxy. Esterified mercapto groups are, for example, mercapto groups esterified with a lower alkanecarboxylic acid, such as acetylthio. Etherified mercapto groups or sulfonium groups are, for example, lower alkylthio or di-lower alkylsulfonium groups, such as methylthio, ethylthio or dimethylsulfonium. In addition to groups R ₁ -NH-, amino groups are, for example, di-lower alkyl or alkylene or aza-, oxa- or thia-lower-alkylene-amino groups, eg. As dimethylamine, diethylamino, pyrrolidino, piperidino, morpholino or Thiomorpholine », further anilino. Ammonium groups are, for example, tertiary ammonium groups corresponding to the abovementioned amino group or quaternary ammonium groups, such as tri-lower alkylammonio or pyridinio. The elimination of HY takes place in the usual way spontaneously or by gentle heating, for. B. to about 40 to 200 ⁰ C, if necessary in the presence of an auxiliary and / or an inert solvent. As auxiliaries are, for example, acidic agents such as mineral acids or their anhydrides or acidic salts, eg. As hydrohalic acids, especially hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, Alkalimetallhydrogensulfate, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride, Phoxphoroxychlorid or phosphorus tribromide, organic sulfonic acids, such as p-toluenesulfonic acid, or carboxylic acids or their anhydrides, such as lower alkanoic acids and their anhydrides or halides, e.g. As acetic acid, acetic anhydride or acetyl chloride, further buffered acid solutions, eg. B. phosphate or acetate buffer, hydrohalides of nitrogen bases, ζ. Β. Ammonium or pyridinium chloride, into consideration.

In many cases, it is also possible to use basic condensing agents, such as hydroxides, carbonates or lower alkanolates of alkali or alkaline earth metals, eg. For example, sodium, potassium or calcium hydroxide, sodium or potassium carbonate or sodium, use, further organic nitrogen bases, such as Triniederalkylamine, z. B. Triethylamin, or aromatic Tertiärbasen, such as pyridine. The starting materials of formula II are preferably prepared in situ, for example by reacting a compound of the formula

R _A -NH-C (Y _s ) (Y _e ) -R ₈ (IM)

wherein either R _{A is} a group of the formula R ₁ -NH-N = C (SR ₃ ) - and R _{8 is} a group R ₁ or R _{A is} a group of the formula R ₂ -Cf = NH) -N (R ₁ ) - and R _{8 represents} a group -SR ₃ and Y ₅ and Y ₈ independently of one another radicals Y, such as optionally esterified or etherified hydroxy, etherified mercapto or optionally substituted amino or together oxo, thioxo or optionally substituted imino, such as lower alkylimino, optionally substituted anilo or Represent groups of the formula = NR _{1 #} , or a salt thereof cyclized.

The cyclization of compounds of formula III is carried out in customary, under neutral, acidic or basic conditions, if necessary in the presence of one of said acidic or basic agents, in the presence of an inert solvent or diluent, with heating, for. B. in the temperature range of about 40-200 ⁰ C, preferably from about 60-140 ⁰ C, and / or inert gas, such as nitrogen.

For the preparation of compounds of formula III, several modes of formation are available. Thus, compounds of the formula III in which R _{A is} a group of the formula R ₁ -NH-N =C (ZR ₃ ) -, and R _{B is} a group R ₂ and Y ₅ and Y ₆ together are oxo, for example, by a compound of the formula R ₁ -NH-N =C (SRs) -NH ₂ (IV) obtained, for example, by reacting an imino compound of the formula Y-Cf = NH) -SR ₃ (V), where Y has the meaning given and particularly

-7- 74123

Lower alkoxy, halogen or amino, or an isothiocyanate of the formula N = C-SR ₃ (Va) or an acid addition salt, for. As hydrohalide, thereof, z. In ethanol, with a substituted hydrazine of the formula R ₁ -NH-NH ₂ (VII), or a salt thereof with a compound of the formula Y'-C (Y ₅ ) (Y _e ) -R ₂ ( IX) in which Y ₅ and Y _{9 have} the meanings indicated and Y 'represents a group Y or, if Y ₅ and Y ₈ together represent oxo, represents a group of the formula R ₂ -C (= O) -O-, in the usual way, for. B. in the presence of a basic condensing agent, brings to reaction. Compounds of the formula III in which R _{A is} a group of the formula R ₂ -C f = NH) -N (R ₁ ) -, Y ₅ + Y, = oxo and R _{B is} an R ₃ S group, are obtained, for example, by a compound of the formula R ₂ -Cf = NH) -Y (XVI) or a hydrohalide thereof with a compound of the formula R ₁ -NH-NH-C (Y ₅ ) (Ye) -SR ₃ (XVII), in which Y esterified or etherified hydroxy, ζ. B. halogen or lower alkoxy, and Y ₅ + Y, in particular for oxo, are reacted with each other, for. B. in a lower alkanol, such as ethanol. In general, however, one will not isolate the intermediate of formula III, because the synthesis of end products of formula I via intermediates of formulas III and II can be carried out according to some important process variants without the isolation of intermediates. An important process variant according to z. B. Compounds of the formulas R ₁ -NH-NH ₂ (VII) and R ₂ -C (Y ₅ ) (Yi) -NH-C (Y?) (Y "') - SR ₃ (XVIII), wherein Y ₅ , Y ₆ , Y ₅ 'and Y' _e 'independently of one another have one of the meanings given for Y or Y ₅ + Y, and / or Y ₅ + Y', 'oxo, thioxo or optionally substituted imino, z. As imino, lower alkylimino, anilo or those of the formula R ₁ -N =, where compounds of formula XVIII in tautomeric form, for. Of the formulas R ₂ -C (Y ₅ ) (Y 1) - N = C (Y) -SR ₃ (XVIIIa) or R ₂ -C (Y) = NC (Y ' _S ') (Y ',' ) -SR ₃ (XVIIIb) can be reacted with each other. The reaction is carried out in a customary manner, for example in the presence of one of said acidic or basic Kondensationsmitteis, if necessary in the presence of an inert solvent or diluent, with heating, for. B. in the temperature range of about 40-200 ⁰ C, preferably from about 60-140 ⁰ C, and / or under inert gas, such as nitrogen. Preferred embodiments of these intermediate intermediates of the formulas III and II are direct syntheses of compounds of the formula I are the reaction of compounds of the formula VII with compounds of the formula XVIII (Y ₅ and a = oxo, Y ₅ and Y ',' = thioxo ) or XVIIIa (Y ₅ and YJ = oxo, Y reactive esterified hydroxy, ζ B. halogen, or etherified hydroxy, ζ B. B. lower alkoxy, or di-lower alkylamino) under weakly acidic conditions, for. In the presence of an organic carboxylic acid such as acetic acid, an ammonium mineral acid salt, e.g. For example, of pyridinium chloride in acetic acid, or an acidic buffer system, such as an acetate or phosphate buffer, the condensation of compounds of formulas XVI and XVII, z. B. in ethanol at about 10-50 ⁰ C, and subsequent cyclization at about 80-160 ⁰ C, z. B. in boiling xylene. Also via intermediates of the formulas II and III, the formation of JR ₁ -R ₃ -OR ₂ -IH-1,2,4-triazoles proceeds by reaction of acylated thiosemicarbazides of the formula

R ₂ -C (= O) -NH-C (= S) -NH-NH-R, (XXIII) with compounds of the formula R ₃ -Y (XXIV) in which R _{3 has} the meaning given and Y is reactive esterified hydroxy means, or with aliphatic epoxides. The compounds of formula I can be further prepared by reacting compounds of formula

VfVv

_ I -У 11

and Y - R (XXXII),

wherein Y _{11 is} a mercapto group optionally present in salt form and Y _{12 is} reactive esterified hydroxy or

Y ₁ , sulfonyl and Y _{12 represents} an optionally present in salt form mercapto, mercapto group, with each other

to the corresponding compound of formula I, wherein η is 0, condensed and, if desired, one or more of said additional reactions is carried out.

Sulfonyl is, for example, lower alkanesulfonyl, e.g. As methane, or Aethansulfonyl, or optionally substituted Benzenesulfonyl, e.g. B. benzene, p-toluene or p-bromobenzenesulfonyl, further fluorosulfonyl. As the salt form of the mercapto group, for example, their metal salt forms such as alkali metal or Alkaline earth metal salt forms, provided that η is 1 or 2, and also their ammonium salt forms with ammonia or organic amines in Consideration. Such salts are preferably by the action of the equivalent amount of the respective base on the free Mercapto reaction component generated in situ and used without isolation. The condensation takes place in customary, preferably in an inert solvent, if necessary with cooling or Heating, z. B. in the temperature range of about 0 to 100 ⁰ C, in a closed vessel and / or under inert gas, such as nitrogen. Suitable inert solvents are, in particular, polar solvents, such as lower alkanols, dilower alkyl ketones, N.N-di-lower alkylalkanecarboxamides or N-lower alkyllactams or di-lower alkylsulfoxides. if necessary

one works with catalysts, provided that Y _{12 is} etherified hydroxy, z. In the presence of dilithium palladium tetrachloride.

The starting materials of the formula XXXI can be prepared by methods known per se. Thus, to provide compounds of formula XXXI, wherein Y _{11 is} mercapto, z. B. be obtained by a Compound of formula R, -NH-NH-C (= S) -NH-C (= O) -R ₂ (XXXIV) accessible for example by reacting a Thiosemicarbazides of the formula R, -NH-NH-Cf = S) -NH ₂ (XXXV) with a compound of the formula R ₂ -C (= O) -Y (IXb, Y = halogen

or R ₂ -C (= O) -O-), usually cyclized. Compounds of formula XXXI in which Y ₁₁ is mercapto can be further obtained by reacting a compound of formula R ₁ -NH-KM ₂ (VII) with thiophosgene or a Alkalirohodanid and then with a compound of formula IXb ^1.

The compounds of formula I can be further prepared by reacting compounds of the formulas

-Y (XXXI) and Y-R or R-S-S-R. (XXXIIa)

R ₂ ~ «= N Li S 5 i

wherein one of Y ₁₁ and Y _{12 is} a metallic radical and the other is a group -S (O) _n -Y ₁₃ in which Y _{13 is} halo, condensed together and, if desired, one or more of said additional reactions.

R ₃ is an unsubstituted or substituted by etherified hydroxy and / or mercapto aliphatic Hydrocarbon radical. Metallic radicals are, for example, groups of the formulas -M ¹ , -M "/ 2 or -M" -Hal, in which M ^{1 is} a metal atom of group 1A, eg. B. Lithium or sodium, and M "is a metal atom of Groups 2A and 2B of the Periodic Table of the Elements, for example magnesium, Cadmium or zinc, and Hai represents a halogen atom.

-8- 74123

Halogen is, for example, chlorine, bromine or iodine. The reaction is carried out in a customary manner, preferably in an inert solvent, if necessary with cooling or Heating and / or under inert gas, such as nitrogen, for example in the temperature range from -80 to about +60 ⁰ C, preferably from

about -25 to about +40 ⁰ C. In a preferred embodiment of this process is, for example, a compound of formula XXXI from wherein Y ₁₁ is a Halogensulfenylgruppe, and sets them at about -10 to +10 ⁰ C in tetrahydrofuran, or

Hexamethylphosphoric triamide with a compound of formula XXXII in which Y _{12 is} an alkali metal atom or a Halogen-alkaline earth group means. In another preferred embodiment, for example, a compound of Formula XXXI, wherein Y _{11 represents} an alkali metal atom, with a compound of the formula R ₃ -SSR ₃ (XXXIIa) to. Starting materials of the formula XXXI, wherein Y _{11 is} a group of the formula -SY ₁₃ and Y _{13 is} halogen, are obtained, for example, by

a compound of formula XXXI, wherein Y _{11 is} mercapto, halogenated in the usual manner, for example by reaction with

Chlorine, z. In tetrachloromethane, optionally after previous treatment with iodine. Compounds of the formula XXXI in which Y _{11 is} a metallic radical can be prepared, for example, by reacting

a compound of formula XXXI, wherein Y _{11 is} hydrogen, which may be prepared, for example, by reaction of compounds of the

Formulas R ₂ -C (^ O) -NH-CHO (XXXVI) and R ₁ -NH-NH ₂ (VII) is accessible, with an organometallic compound, such as a Alkali metal or alkaline earth metal hydrocarbon compound, e.g. With butyllithium, phenylsodium or butylmagnesium bromide,

implements. But one can also from a compound of formula XXXI, wherein Y _{11 is} halogen, starting, and this with a

Alkaline earth metal, e.g. B. implement magnesium. A further process for the preparation of compounds of the formula I is characterized in that a compound of the

formula

R ₂ -I- /

wherein Y _{11 is} mercapto, or a salt thereof with a vicinal derived from a compound of the formula R ₃ -H (XXXVII)

Reacting epoxy derivative to a compound of formula I, wherein R ₃ in the β-position has a hydroxy group and η is 0, and

required or if desired, one or more of said additional reactions is carried out.

As salts of compounds of formula XXXI, for example, their metal salts, preferably alkali metal or Alkaline earth metal salts into consideration. Vicinal epoxides derived from compounds of formula XXXVII are, for example, vicinal aliphatic epoxides such as

α, β-Epoxyniederalkane.

The reaction is carried out in a customary manner, for example in an inert solvent such as a lower alkanol, or a

tertiary amide, ζ. B. in hexamethylphosphoric triamide, if necessary in the presence of a condensing agent, for example starting from free mercaptans of the formula XXXI a capable of salting basic agent, such as a

Alkali metal alcoholates or hydroxides, ζ. From sodium methoxide or sodium hydroxide, with cooling or heating

and / or under inert gas, such as nitrogen.

A further process for the preparation of compounds of the formula I is characterized in that a compound of the

formula

R ^ -NN _x

) ~ ^Γ _η (XXXI),

wherein Y _{11 is} mercapto, or a salt thereof with a compound of the formula R ₃ -H (XXXIII), wherein R _{3 is} an R _3- derived, at least in α, β-position a CC double or C-C triple bond having aliphatic radical means to a

Compounds of formula I, wherein R _{3 is} α, β-saturated or α, β-monounsaturated and π 0, and required or

if desired, one or more of said additional reactions is carried out.

Suitable salts of mercaptans of formula XXXI are in particular their metal salts, preferably alkali metal or Alkaline earth metal salts into consideration. Suitable compounds of the formula XXXVIII are, for example: carboxy-lower alkenes, lower-alkoxycarbonyl-lower alkenes, Carbamyl or N-lower alkyl, N, N-di-lower alkyl, Ν, Ν-lower alkylene or N, N- (3-aza-, 3-oxa- or

3-thia) -lower alkylenecarbamyl-lower alkenes, the lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkanesulphinyl,

Lower alkanesulfonyl, hydroxy, lower alkanoyloxy, Niederalkylendithio or oxo group (s) in higher than the ß-position bearing Mono- or di-lower alkoxy-lower alkenes, lower-alkylenedioxy-lower alkenes, lower alkanoyloxy-lower alkenes, mono- or di-lower alkyno Di-lower alkylthio-lower alkenes, lower-alkanesulfinyl or lower-alkanesulfonyl-lower alkenes, lower-alkylenedithione-lower alkenes, mono-

or dihydroxy-lower alkenes and oxo-lower alkenes.

The reaction is carried out in customary manner, for example in an inert solvent, such as a tertiary amide, ζ. In Dimethylformamide or N-methylpyrrolidone, if necessary in the presence of a condensing agent, with cooling or Heating and / or under inert gas, such as nitrogen. As condensing agent, starting from mercaptans of the formula XVI

for example, organic nitrogen bases, such as di- or Triniederalkylamine, z. As diisopropylamine or triethylamine, or alkylene or. Aza-, Oxa- or Thiaalkyleneamines, e.g. As pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine, into consideration.

The novel compounds of formula I can be further prepared by reacting in a compound of formula

R. -N-I

-NN ₄ I ^ -S (O) _n -R ^ (IXL),

wherein Rj is a radical convertible into a group R ₃ , R _{3 is converted} into the desired group R ₃ and required or, if desired, one or more of said additional reactions is carried out.

Radicals which can be converted into radicals R ₃ are, for example, radicals R ₃ substituted by an optionally additional carboxy group, in particular 1,1-dicarboxynolower or 1-carboxy-2-oxo-lower alkyl radicals or radicals of the formula -C (= 0) -O-R ₃ , The conversion of these radicals into radicals R ₃ takes place by elimination of carbon dioxide.

-9- 741 23

The elimination of carbon dioxide can be carried out in a customary manner, for example by acid action, such as treatment with a protic acid, such as a mineral acid, for. As hydrochloric or sulfuric acid, advantageously in a solvent or diluent, if necessary, with heating, for. B. to about 50 to about 250 ⁰ C.

Thus, compounds of formula IXL, wherein R ' ₃ ' is a 1-carboxy-2-oxo or 1,1-Dicarboxyniederalkylrest, by heating with aqueous acid solutions, for. B. with equal parts of about 15% hydrochloric acid and acetic acid to about 60-100 ⁰ C, convert into compounds of formula I, wherein R _{3 is} a 1-carboxy or 2-Oxoniederalkylrest.

Furthermore, compounds of formula IXL, wherein R ' ₃ ' is a radical of the formula -C (= O) OR ₃ , z. B. by heating with a mineral acid, eg. B. with hydrogen chloride in tetrahydrofuran, with elimination of carbon dioxide in the corresponding compounds of formula I.

Further radicals R _{3 which} can be converted into groups R ₃ are, for example, at least one hydroxyl group or esterified carboxy group etherified with a C 1 -phenyl-lower alkanol or at least one hydroxyl group esterified with a carboxylic acid, such as a halogenated lower alkanoic acid or carbonic acid or a half ester or half-amide thereof, as appropriate substituted benzyloxy, optionally halogenated lower alkanoyloxy or lower alkoxycarbonyloxy, benzyloxycarbonyloxy, di-lower alkylcarbamyloxy or carbonyldioxy, having radicals R ₃ . Examples of suitable compounds are: the benzyloxy, benzyloxycarbonyloxy, optionally halogenated lower alkanoyloxy or lower alkoxycarbonyloxy group (s) or the carbonyldioxy group in higher than the α-position bearing, optionally substituted mono- or Dibenzyloxyniederalkyl, optionally halogenated mono- or Diniederalkanoyloxyniederalkyl or Mono- or lower-alkoxycarbonyloxy or carbonyl-dioxy-lower alkyl and benzyloxycarbonyl-lower alkyl. The conversion of the same into R ₃ takes place, for example, reductively by treatment with a suitable reducing agent.

Suitable reducing agents for the reduction of oc-Phenylniederalkoxy and o-phenylalkoxy groups, for example, hydrogen in the presence of a hybrid, which is advantageous in an inert solvent, if necessary at elevated pressure and / or cooling or heating works. With carboxylic acids esterified hydroxy groups, and ct-Phenylniederalkoxycarbonyloxygruppen, for example, by Dileichtmetallhydriden, z. B. with lithium aluminum hydride can be reduced.

2-halo-lower alkoxycarbonyloxy z. For example, 2,2,2-trichloro or 2-Jodäthoxycarbonyloxy, Aroylmethoxycarbonyloxy or 4-Nitrobenzyloxycarbonyloxy z. B by treatment with a suitable chemical Reduktionsmitel, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid cleaved. Aroylmethoxycarbonyloxy may also be prepared 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. As sodium dithionite, are cleaved. Further radicals R ₃ are to a group R ₃ solvolyzable radicals, for example radicals R ₃ , the 1 or 2 halogen atom (s), a bivalent functionally modified oxo group, for. Imino, a different carboxy group from esterified and amidated carboxy as defined at the outset, such as an imino ether moiety, a substituted amidino grouping optionally substituted for amidated carboxy, halocarbonyl or optionally substituted phenoxycarbonyl, e.g. For example, phenoxy, p-nitrophenoxy or 2,4-dinitrophenoxycarbonyl, or at least one of a substituted by halogen or aryl alkanecarboxylic acid or a carbonic acid half ester Derived acyloxy group, at least one silyloxy or Aryklendioxy-, such as 1,2-Phenylendioxygruppe, two geminal bonded aryloxy, such as phenyloxy or a vicinal bound lower alkylidene or mono- or Diarylniederalkylidendioxygruppe have. Cleavable acyloxy are, for example Haiogenniederalkanoyloxy, such as 2-haloacetoxy, in the 1-position of the lower alkyl or branched 1- or 2-position suitably substituted lower alkoxycarbonyloxy, especially tert-Niederalkoxycarbonyloxy, Benzyloxycarbonyloxy which optionally lower alkyl, especially tert-butyl, lower alkoxy, hydroxy , Halogen and / or nitro, or optionally substituted diphenylmethoxycarbonyloxy. Such radicals are 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetoxy, tert-butyloxycarbonyloxy, 4-nitrobenzyloxycarbonyloxy, phenacycloxycarbonyloxy, 2-halo lower alkoxycarbonyloxy, e.g. B. 2,2,2-Trichloräthoxycarbonyloxy, 2-Bromäthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy, or 2- (trisubstituted silyl) -äthoxycarbonyloxy, wherein the substituents independently of one another are each an optionally substituted, for. B. by lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical with z. B. up to 15 carbon atoms, such as corresponding, optionally substituted lower alkyl, phenyl, lower alkyl, cycloalkyl or phenyl, z. B. 2-Triniederalkylsilyläthoxycarbonyloxy, such as 2-trimethylsilylethoxycarbonyloxy or 2- (di-n-butyl-methyl-silyl) -äthoxycarbonyloxy, or 2-Triarylsilyläthoxycarbonyloxy, such as 2-Triphenylsilyläthoxycarbonyloxy.

A silyloxy group is primarily tri-lower alkylsilyloxy, especially trimethylsilyloxy, furthermore dimethyl-tert-butylsilyloxy. A halogen atom, at least one of said acyloxy groups, at least one silyloxy group, an arylenedioxy group, two geminally bound aryloxy groups or a vicinally bonded lower alkylidene- or mono- or diaryl-lower alkylidenedioxy group-containing radicals R ' ₃ may have solvolytically hydroxy-containing aliphatic radicals R ₃ , such as mono- or Dihydroxynlederalkyl, a halogen atom-containing radicals R ₃ further in etherified by tert or ether tert tert hydroxy or etherified mercapto substituted radicals R ₃ , as Niederalkoxyniederalkyl, Niedb.aiKanoyloxyniederalkyl or Niederalkylthioniederalkyl, two halogen atoms or a functionally modified oxo group having R ₃ solvolytic in Oxo-containing or by etherified or organically esterified hydroxy-substituted radicals R ₃ , such as oxo-lower alkyl, Diniederalkoxyniederalkyl or Niederalkylendioxyniederalkyl, and a functionally modified carboxy group having radicals R ₃ solvolytically in ge optionally esterified or amidated carboxy R ₃ , such as carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or optionally aliphatic N-substituted carbamyl-lower alkyl are converted.

The solvolysis of the groups R ₃ 'having hydroxy-solvizable groups is effected, 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 ammonia - or aminolysis (treatment with ammonia or an organic amine).

By hydrolysis, for example, a halogen atom, at least one of said acyloxy groups, at least one silyloxy, Arylendioxygruppe, geminally bound aryloxy or a vicinally bound Niederalkyliden- or mono- or Diarylniederalkylidendioxygruppe having radicals R ₃ in hydroxy-substituted radicals R ₃ , such as Mono- or Dihydroxyniederalkyl, two halogen atoms or a bivalent functionally modified oxo group containing radicals R ₃ in Oxo having radicals R ₃ , such as oxoloweralkyl, functionally modified carboxy-lower alkyl R ₃ in carboxy-lower alkyl and a

-ю- 741 23

Iminoäthergruppierung, an optionally aliphatic N-substituted Amidingruppierung having functionally modified Carboxyniederalkylreste R, convert into esterified or amidated carboxy-lower alkyl R ₃ . The hydrolysis is carried out in a conventional manner, if necessary in the presence of a hydrolysis agent, and / or an inert Solvent, with cooling or heating and / or under inert gas. Hydrolyzing agents are, for example, acidic or alkaline Medium. Acid agents are, for example, such as mineral acids, hydrohalic acids, eg. As chlorine, bromine or Hydroiodic acid, or oxygen acids of sulfur or phosphorus or their acid salts, such as sulfuric acid, Kaliumhydrogensulfat or phosphoric acid, or organic carboxylic or sulfonic acids, eg. B. 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, or potassium or sodium carbonate. inert

Solvents are, for example, polar, water-miscible solvents such as alcohols, eg. Methanol or ethanol, Niederalkylenäther such as dioxane, Diniederalkylketone such as acetone, tertiary amides, eg. As dimethylformamide, N-methylpyrrolidone, or Hexamethylphosphoric triamide, or di-lower alkyl sulfoxides, e.g. For example, dimethyl sulfoxide. By alcoholysis, for example, one or two halogen atom (s) or bivalent functionally modified oxo having

aliphatic radicals R ' ₃ ' in etherified hydroxy-substituted aliphatic hydrocarbon radicals R ₃ , such as mono- or

Diniederalkoxyniederalkyl, Niederalkylendioxyniederalkyl or halocarbonyl-containing aliphatic radicals R ₃ 'in esterified Carboxy-containing radicals R ₃ , such as lower alkoxycarbonyl, converted and esterified in radicals R ₃ with organic carboxylic acid Hydroxy groups are released by transesterification. The alcoholysis is carried out in the usual manner, for example in the presence of a

basic in the transesterification of an acidic agent, if necessary with cooling or heating and / or under inert gas, such as nitrogen. As acidic or basic agents come z. As those mentioned, as basic agents also metal alkoxides, such as alkali metal or Erdalkalimetallniederalkanolate, z. For example, sodium methoxide.

For example, one or two halogen atoms (e) or bivalent functionally modified oxo can be obtained by mercaptolysis

having R ₃ in etherified mercapto-substituted radicals R ₃ , such as Niederalkylthioniederalkyl or

Lower alkylenedithione-lower alkyl. The mercaptolysis is carried out in the usual manner, for. In the presence of a basic Condensation agent or by using the mercaptan component in salt form, such as alkali metal salt. In a variant of this process, one can also use a mercapto-substituted lower alkyl radical R ₃ by reaction with all

reactive esters of a lower alkanol, such as a lower alkyl halide or dimethyl sulfate, in lower alkylthio-lower alkyl.

Aliphatic radicals R ₃ having a halogen atom can also be obtained by reaction with a salt in a carboxylic acid, such as Niederalkansäurealkalimetallsalz, in organically esterified hydroxy having radicals R ₃ , such as Niederalkanoyloxyniederalkyl.

be transferred.

By amino or ammonolysis can be, for example, halocarbonyl-containing aliphatic radicals R ₃ in by amidated Carboxy-substituted aliphatic hydrocarbon radicals R ₃ , such as optionally aliphatic N-substituted Carbamylniederalkylreste, convert, advantageously in the presence of a basic condensing agent. But you can through Aminolysis also release the hydroxy group from the mentioned acyloxy. However, halo-lower alkyl can also be converted by reaction with thiourea first in the Isothiouroniumderivat and

subsequently converted by hydrolysis and alkylation in Niederalkylthioniederalkyl. 2-Substituted

Silylethoxycarbonyloxy can be advantageously obtained by treatment with an alkali metal fluoride, e.g. B. with potassium fluoride, split. The solvolytic conversion of halogen-containing radicals R ₃ in the above, of mono- or Dihydroxyniederalkyl

Various radicals R ₃ are usually carried out in the presence of a basic condensing agent, such as an alkali metal hydroxide, or a tertiary organic nitrogen base, such as a Triniederalkylamins or a heteroaromatic base, such as pyridine, or by mixing the component to be introduced corresponding component in the form of a set, such as Alkali or

Alkaline earth metal salt used. The starting materials can be prepared by methods known per se, for example by elimination of HY Compounds of the formula

(XL)

wherein Y ₁ , Y ₂ , Y ₃ and Y _{4 have} the meanings given under the formula II, and if desired oxidation of the thio group or by reacting compounds of the formulas

, "" Υ,. (XXXI) and Y ₁ -R "(XLI),

R ₂ - »IT ^ll - ³

wherein one of Y ₁₁ and Y _{12 is} a reactive esterified hydroxy group and the other one is in salt form

Mercapto group means. According to the method or according to other methods not mentioned above, available compounds of formula I can

if desired, be converted into other compounds of the formula I in a manner known per se. If necessary, a mixture of isomers obtainable by the process can be separated into the pure isomers and, if desired, a process according to the available compound can be converted into another compound of the formula I and / or a free compound obtainable according to the process in a salt or a salt obtainable according to the process can be converted into the free compound.

For example, it is possible to convert etherified or esterified hydroxy groups into one another. Includes, for example, at least one of the radicals R _1, R ₂ and R ₃ a hydroxy group on, this can in the usual manner

etherified. Thus, hydroxy as a component of R ₃ can be reacted with a lower alkylating agent such as a lower alkanol, e.g. Methanol,

-I- 74123

in the presence of an acid, such as a mineral acid, e.g. For example, sulfuric acid, or a dehydrating agent such as dicyclohexylcarbodiimide, and hydroxy at a radical R ₁ or R ₂ z. In the presence of bases such as alkali metal hydroxides or carbonates, e.g. As sodium hydroxide or potassium carbonate, converted by means of Diniederalkylsulfaten or Diazoniederalkanen in corresponding lower alkoxy groups. Conversely, ethers, such as lower alkoxy groups can be split off as substituents of R ₁ or R ₂ , for example by treatment with acids, such as with Lewis acids, for. B. boron tribromide or mineral acids, eg. B. of hydrogen iodide.

Furthermore, hydroxy can be esterified, z. B. in Niederalkanoyloxy, for example by reaction with a corresponding lower alkanecarboxylic acid such as acetic acid, or a reactive derivative such as a symmetrical anhydride thereof or an anhydride with a hydrohalic acid, if necessary in the presence of a condensing agent, starting from anhydrides z. As a basic condensing agent, such as an alkali metal hydroxide or carbonate or a tertiary nitrogen base, ζ. B. a Triniederalkylamins or pyridine, and starting from an acid, for. In the presence of an acid, such as a protic acid, e.g. For example, hydrochloric, sulfuric, phosphoric or sulfonic acid, or a Lewis acid, for. B. boron trifluoride etherate.

Furthermore, one can free carboxy as a component of R ₃ in usually z. Example, by treatment with a Diazoniederalkan or Triniederalkyloxonium-, Triniederalkylcarboxonium- or Diniederalkylcarboniumsalz, such as hexachloroantimonate or hexafluorophosphate, or especially by reaction with the corresponding alcohol or a reactive derivative such as a carboxylic, phosphorous, sulfuric or carbonic acid ester, eg. B. a Niederalkancarbonsäureester, Triniederatkylphosphit, Diniederalkylsulfit or pyrocarbonate, or a mineral acid or sulfonic acid esters, eg. As the hydrochloric or hydrobromic acid or sulfuric acid, benzenesulfonic or toluenesulfonic or methanesulfonic, the corresponding alcohol or an olefin derived therefrom to esterify to an esterified carboxyl group. The reaction with the corresponding alcohol itself can advantageously be carried out in the presence of an acidic catalyst, such as a protic acid, for. As of hydrochloric or hydrobromic, sulfuric, phosphoric, boron, benzenesulfonic and / or Toiuolsulfonsäure, or a Lewis acid, for. As boron trifluoride etherate, in an inert solvent, in particular an excess of the alcohol used and, if necessary, in the presence of a water-binding agent and / or under distillative, z. B. 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 a conventional manner, starting from a carboxylic, phosphorous, sulfuric or carbonic acid ester, for example in the presence of an acid catalyst, such as one of the above, in an inert solvent, such as an aromatic Hydrocarbon, z. B. in benzene or toluene, or an excess of the alcohol derivative or the corresponding alcohol. Starting from a mineral acid or sulfonic acid ester, the acid to be esterified is advantageously used in the form of a salt, eg. As the sodium or potassium salt, and if necessary in the presence of a basic condensing agent, such as an inorganic base, for. As sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, ζ. Β. of triethylamine or pyridine, and / or in an inert solvent such as one of the above tertiary nitrogen bases or a polar solvent, e.g. B. in dimethylformamide and / or at elevated temperature.

The reaction with an olefin can be carried out, for example, in the presence of an acid catalyst, for. B. a Lewis acid, for. B. boron trifluoride, a sulfonic acid, eg. B. of p-Toloulsulfonsäure, or especially a basic catalyst, for. As sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, for. In diethyl ether or tetrahydrofuran. A free carboxyl group may further by reacting with ammonia or at least one hydrogen atom-containing amine in usually, with dehydration of the intermediate ammonium salt formed, for. B. by azeotropic distillation with benzene or toluene or dry heating, be converted into an amidated carboxyl group.

However, the above-described transformations of free esterified or amidated carboxyl groups can also be carried out by first reacting a compound of formula I in which R ₃ contains carboxy in a conventional manner in a reactive derivative, for example by means of a halide of phosphorus or sulfur, for , Example, by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, in an acid halide or by reaction with a corresponding alcohol or amine in a reactive ester, ie esters with electron-attracting structures, such as the esters with phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol, or a reactive amide, ζ. B. derived from imidazole or 3,5-dimethylpyrazole amide, transferred and the resulting reactive derivative then in the usual manner, for. B. as described below for the transesterification or mutual conversion of esterified and amidated carboxyl groups, reacted with a corresponding alcohol, ammonia or the corresponding at least one hydrogen atom-containing amine to the desired group. An esterified carboxyl group can in the usual way, for. By hydrolysis in the presence of a catalyst, for example a basic or acidic agent such as a strong base, e.g. As sodium or potassium hydroxide, or a mineral acid, eg. As hydrochloric acid, sulfuric acid or phosphoric acid, the free carboxyl group or z. B. converted by reaction with ammonia or the corresponding, at least one hydrogen atom-containing amine into an amidated carboxyl group. An esterified carboxyl group can also be in customary, z. Example, by reaction with a metal, such as the sodium or potassium salt, a corresponding A ^ .ohols or with this itself in the presence of a catalyst, for example a strong base, for. As sodium or potassium hydroxide, or a strong acid, such as a mineral acid, eg. As hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic sulfonic acid, eg. B. of p-toluenesulfonic acid, or a Lewis acid, for. B. from Brotrifluorid etherate, be transesterified to another esterified carboxyl group.

An amidated carboxyl group may be prepared in a conventional manner, e.g. Example, 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, ζ. As sodium or potassium hydroxide or carbonate, or a stronger acid, such as a mineral acid, for. B. of hydrochloric acid, sulfuric acid or phosphoric acid are converted into the free carboxyl group.

Cyano can be hydrolytically, z. B. under basic conditions, hydrolyzed to carbamyl or carboxy or converted 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 in esterified or amidated carboxy. Conversely, carbamyl may be prepared by heating, if necessary in the presence of a water-binding agent, e.g. As of phosphorus pentoxide or of polyphosphoric acid, or of an N, N-disubstituted carbodiimide, ζ. B. of Ν, Ν-Dicyclohexycarbodiimid be dehydrated to cyano.

-12- 74123

In addition, carboxy-lower alkyl radicals of the formula -C _1n H _21n -COOH present in an ester, anhydride or salt form may optionally be added to the corresponding oxo-lower alkyl radicals of the formula -C _{1n +} 1Hj _{1n + 1} = O or hydroxy-lower alkyl radicals of the formula -C _{1n + 1} H _{21n + 2} -OH, where m is a number from 1 to and 7, z. B. from 1 to 4 and means. The reduction is carried out in a customary manner, for example by reaction with a hydride carrier, which transfers hydrogen to the α-position carbon atom in anionic form, for example with a light metal or Dileichtmetallhydrides, z. B. with borohydride etherate or preferably lithium aluminum hydride, advantageously in an ether, such as a Diniederalkyl- or Niederalkylenäther, z. As in diethyl ether, tert-butyl oxymethane or tetrahydrofuran, or by means of sodium borohydride, advantageously in alcoholic solution. Also applicable are reducing agents which transfer zerovalent metals or atomic hydrogen. These principles are used for example in the metallic reduction, by the action of finely divided metals, eg. As zinc powder, can be effected, equally in the reduction with nascent hydrogen, the z. B. by acid action on base metals, such as acetic acid on zinc, iron and hydrochloric acid or water action on sodium amalgam can be produced. The abovementioned reducing agents preferably give compounds of the formula I in which R ₃ denotes a hydroxy-lower alkyl radical. Salt forms of carboxy are, for example, base salt forms, such as alkali metal or alkaline earth metal salt forms, but may also be ammonium salt forms with ammonia or organic amines. Anhydride forms are, for example, mixed anhydride forms with hydrohalic acids, but may also be mixed anhydride forms with organic carboxylic acids such as lower alkanoic acids. Ester forms are, for example, lower alkyl ester forms, but may also be other organic ester forms such as optionally substituted phenyl ester forms. As further ester forms Lactonformen, z. B. y-Lactomformen, into consideration, in their presence in the ω-position and in a lower than the (u-2) position two hydroxyl groups having radicals R _{3 are} formed. However, the reduction can also be stopped at the oxo level by using selective reducing agents. Such are for the reduction of optionally present in salt carboxy example mono- or di-lower alkyl borohydrides, eg. For example, 2- (2,3-dimethyl-butyl) borohydride, for the reduction of anhydride forms, for example, hydrogen in the presence of palladium or hydrocyanic acid in the presence of tertiary aromatic nitrogen bases, such as quinoline, and for the reduction of ester forms, for example, electronegatively substituted aluminum or alkali metal aluminum hydrides, e.g. N-methylpiperazinoaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride, but also dibutylaluminum hydride.

Conversely, in compounds of the formula I groups R _{3 of} the formula -C _{m + 1} H _{2m + 2} -OH to groups R _{3 of} the formula -C _{1n +} ! H _{21n + 1} = O and groups R _{3 of} the formulas -C _1n Hj _1n -CH ₂ OH or -C _1n H _21n -CH = O to oxidize those of the formula -C _m H _2m -COOH, where m is an integer from 1 to and with 7, z. B. from 1 to and 4, printed.

The oxidation of groups of the formula -C _{m +} H _{2m + J} -OH to those of the formula -C _{n + 1} H _{21n + 1} = O takes place, for example, by treatment with an oxidation of primary and secondary alcohols to form aldehydes or ketones conventional oxidizing agents, such as non-oxidizing metal compounds, e.g. As chromyl chloride in pyridine, chromium trioxide in 2,5-dimethylpyrazole, Pyrilinensalzen, Nitrosoniumtetrafluorborat or the Kernplexen of chlorine or methanesulfonic anhydride and dimethyl sulfoxide, and others, but especially by treatment with an aliphatic or cycloaliphatic ketone, such as an Oxoniederalkan, z. Acetone, or a cycloalkanone, e.g. As cyclohexanone, in the presence of an aluminum alcoholate, for. B. of aluminum isopropoxide.

The oxidation of groups of the formulas -C _m H _2m -CH ₂ OH or -C _m H _2m -CH = O to those of the formulas -C _m H _2m -COOH takes place, for example, by treatment with one for the oxidation of alcohols and aldehydes conventional oxidizing agents, such as heavy metal oxidizing compounds, e.g. B. manganese IV and manganese VII, chromium VI, lead IV or bismuth III compounds, in particular with potassium permanganate, chromium trioxide or chromic acid or alkali metal chromates. Also suitable is peroxy sulfuric acid, for. B. Caro's acid, wherein in carrying out the oxidation in an alcohol by esterification of the primary acid formed the corresponding ester is obtained.

Furthermore, in compounds of the formula I, radicals of the formula -S (O) _n -, in which η is 0, to the corresponding sulfinyl or sulfonyl radicals, in which η is 1 or 2, radicals -S (O) _n -, wherein η is t, to the corresponding sulfonyl radicals, wherein η is 2, and / or heteroaryl radicals R ₁ and / or R ₂ - with at least one free ring nitrogen atom, such as pyridyl, N-oxidize. The oxidation is preferably carried out by the action of a suitable oxidizing agent, advantageously in a solvent inert thereto, if necessary with cooling or heating, for. Example, in the temperature range of about -30 ° to +100 "C, preferably at about 0 ° to 60" C, in a closed vessel and / or under inert gas, such as nitrogen. Suitable oxidizing agents are, for example, peroxy compounds, such as hydrogen peroxide, organic hydroperoxides, z. For example, tert-butyl hydroperoxide, organic peracids, such as aromatic or aliphatic percarboxylic acids, eg. B.

m-chloroperoxybenzoic acid, peroxyacetic acid or permonophthalic acid, oxidizing heavy metal compounds, such as chromium-Vl or manganese-IV or manganese-VII compounds, eg. As chromium trioxide, chromic acid, manganese dioxide or potassium permanganate, oxidizing inorganic oxygen acids such as oxygen acids of nitrogen, halogens or chalcogens, or their anhydrides or salts, eg. For example, nitric acid, dinitrogen tetroxide, selenium dioxide or Natriummetaperjodat, also ozone. Suitable solvents include halogenated hydrocarbons, such as haloalkanes, z. As carbon tetrachloride, chloroform or methylene chloride, or carboxylic acids such as alkanoic acids, eg. As acetic acid, or their anhydrides.

In a preferred embodiment of this oxidation process, for example, thioethers of the formula I in which η is 0, and / or a radical R ₁ , R ₂ and / or a heteroarylaliphatic radical R _{3 has} an unsubstituted ring substance, by reaction with an organic peracid, for , With m-chloroperbenzoic acid, in a haloalkane, e.g. B. in chloroform, to the corresponding sulfinyl or in tetrahydrofuran to the corresponding sulfonyl compounds in which η is 1 or 2, oxidize. In another preferred embodiment, thioethers of formula I, wherein η is 0, may be prepared by treatment with sodium metaperiodate, preferably in a haloalkane, e.g. In carbon tetrachloride or chloroform, selectively to the corresponding sulfoxides in which η and / or m is 1, or with hydrogen peroxide in acetic acid to sulfones, where η is 2, and, if desired, oxidizing nitrogen atom.

Conversely, in compounds of the formula I in which η is 1 or 2 and / or heteroaryl radicals R ₁ and / or R _{2 are} N-oxidized, it is possible to reduce the sulfinyl or sulfonyl group and / or the oxy group on the N-oxidized ring nitrogen remove reductively. The reduction is carried out by treatment with conventional reducing agents, for. B. 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, advantageously in an inert solvent such as a lower alkanol or with light metal hydrides or Dileichtmetallhydriden, z. With alkali metal aluminum or alkali metal borohydrides, e.g. B. with sodium borohydride or lithium aluminum hydride, advantageously in one

-13- 74123

inert solvents, such as an ether, e.g. As diethyl ether or tetrahydrofuran, or for the selective reduction of groups

N-oxides having a phosphorus-III compound, such as a phosphine, e.g. B. triphenylphosphine or tri-n-butylphosphine, or a Phosphoric acid esters, such as a Triniederalkylphosphit, z. B. with trimethyl or Triäthylphosphit. Furthermore, it is possible to introduce into the radicals R, and / or R ₂ optionally additional C substituents. So you can in the usual way

halogenate, z. B. by reaction with chlorine or bromine in the presence of iron or by means of N-chlorosuccinimide. Furthermore, one can in the usual way, for. B. by reaction with an alkyl halide, alkanol or alkene in the presence of aluminum trichloride alkylate. Furthermore, you can in the usual way, for. Example by means of nitric acid / sulfuric acid, nitrate, the nitro group, z. B. with

Tin-II-chloride to amino and reduce this by means of sodium nitrite and tetrafluoroboric acid by fluorine, by means of hydrochloric acid, Replace sodium nitrite and copper l-chloride (bromide) with chlorine (bromine) or with sodium nitrite and potassium iodide with iodine or

by means of sodium nitrite and a Niederalkylmercaptans in Niederalkylthio or by means of sodium nitrite in hydroxy.

In the radicals R ₃ can also geminal bound di-lower alkoxy, di-lower alkylthio, Niederalkylendioxy and Hydrolyze Niederalkylendithio to oxo, preferably acid catalysis. It is also possible to add esterified hydroxy, such as lower alkanoyloxy or optionally substiuiertes benzoyloxy radicals R ₃

hydrolyze the corresponding hydroxy-containing residues, for. B. as above for the hydrolysis of compounds of

Formula IXL indicated. If compounds of the formula I containing isomer mixtures are obtained in the process according to the invention, these can be

as well as stereoisomer mixtures obtainable according to the invention are usually separated into the components.

Thus, such isomer mixtures, for. B. mixtures of stereoisomers and diastereomers according to the invention on the basis of Differences in the physical properties of the components by conventional physical separation methods, such as crystallization, Chromatography, distillation or phase distribution techniques into which components are separated. Enantiomeric mixtures, such as racemates, can be obtained by crystallization from optically active solvents, chromatography

optically active solids, microorganisms or reaction with an optically active auxiliary compound in

Diastereomeric mixtures, e.g. With an optically active acid in mixtures of diastereomeric acid addition salts, and separation

the same into the diastereomers from which the enantiomers can be released in the usual manner in the

Enantiomers are cleaved. For this purpose, common optically active acids are, for. B. D- or L-tartaric acid, Di-o-toluenoic, malic, mandelic, camphorsulfonic or quinic acid. Furthermore, obtained free compounds can be converted in a conventional manner into acid addition salts, for. B. by Reacting a solution of the free compound in a suitable solvent or solvent mixture with one of

the aforementioned acids or with a solution thereof, or with a suitable anion exchanger.

Obtained salts can be converted in a conventional manner into the free compounds, for. B. by treating a

basic end product with an acid or an acidic end product with a base, such as an alkali metal hydroxide, a

Metal carbonate or bicarbonate, or ammonia, or with a suitable anion exchanger. Salts obtained can be converted in a conventional manner into other salts, for. B. by treatment of a salt

a suitable metal salt, such as a sodium, barium or silver salt, in a suitable solvent in which a nucleating inorganic salt is insoluble and thus precipitates out of the reaction mixture, into other acid addition salts.

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

include solvents used.

Due to the close relationship between the new compounds in free form and in the form of their salts are in the previous

and below, among the free compounds or their salts, appropriate and appropriate, if appropriate, the corresponding

To understand salts or free compounds. The invention also relates to those embodiments of the method in which one of an on any process step

as intermediates available compounds and performs the missing process steps, or wherein a

Starting material formed under the reaction conditions or in the form of a derivative thereof, optionally a salt,

is used.

In the process of the present invention, preference is given to using those starting materials which are initially described as

lead particularly valuable connections described. New starting materials and processes for their preparation also form an object of the present invention.

In the pharmaceutical preparations according to the invention, which compounds of the formula I or pharmaceutically acceptable Salts thereof are those for enteral as well as oral or rectal, and parenteral administration and

topical application to warm-blooded animals containing the pharmacological agent alone or together with a pharmaceutically acceptable carrier. The dosage of the drug depends on the warm-blooded species, the

Age and the individual condition, as well as the mode of administration. Normaifall for an approximately 75 kg warm-blooded animal when administered orally an approximate daily dose of about 50-500 mg,

advantageously distributed in several equal parts.

The new pharmaceutical preparations contain z. From about 10% to about 80%, preferably from about 2% to about 60% of the Active ingredient. According to the invention pharmaceutical preparations for enteral or parenteral administration are z. B. such in Dosage unit forms such as dragees, tablets, capsules or suppositories, also ampoules. These are known per se Way, z. Example by means of conventional mixing, granulation, coating, solution or lyopilation. That's the way to do it

pharmaceutical preparations for oral use obtained by combining the active ingredient with solid carriers, possibly granulated a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable HilfsSteffen, processed into tablets or dragee cores.

Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations

and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch pastes under

Use z. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone,

and / or, if desired, disintegrants 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 regulating and Lubricant, z. As silica, talc, staric acid or salts thereof, such as magnesium or calcium stearate, and / or Polyethylene glycol. Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, where

u. a concentrated sugar solutions, which may be Arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or

-I- 74123

Titanium dioxide contain, salmon solutions in suitable organic solvents or solvent mixtures or, for the production

of enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or

Hydroxypropylmethylcellulose phthalate used. The tablets or dragee coatings may contain dyes or pigments, e.g. For identification or identification

different doses of active substance, to be attached.

Other oral pharmaceuticals include gelatin capsules and soft, closed capsules Gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of granules, eg. B.

in admixture 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 ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

As rectally applicable pharmaceutical preparations come z. B. Suppositories into consideration, which consists of a combination of Active ingredient consist of a suppository base. As suppository base are z. B. natural or

synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkenols. Further, you can also

Gelatine rectal capsules containing a combination of the active ingredient with a matrix; when Basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question. For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. B. one

water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, suitable lipophilic solvents or vehicles such as fatty oils, e.g. As sesame oil, or synthetic fatty acid esters, eg. For example, ethyl oleate or

Triglycerides used, or aqueous injection suspensions containing viscosity increasing agents, e.g. B. Sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers. As topically applicable pharmaceutical preparations are primarily cream, ointments, pastes, foams, tinctures and Solutions in question containing from about 0.5 to about 20% of the active ingredient. Cream are oil-in-water emulsions containing more than 50% water. The oily base is primarily used Fatty alcohols, e.g. For example, lauryl, cetyl or stearyl alcohol, fatty acids, eg. As palmitic or stearic, liquid to solid waxes, z. B. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. When Emulsifiers come surface-active substances with predominantly hydrophilic properties in question, as appropriate

nonionic emulsifiers, e.g. Fatty acid esters of polyhydric alcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of

Fatty alcohol sulfates, e.g. As sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which is usually in the presence

of fatty alcohols, e.g. As cetyl alcohol or stearyl alcohol used. Additives to the water phase are u. a. Means which the

Deteriorate drying of the cream, z. For example, polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, further Preservatives, fragrances, etc. Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% water or aqueous Phases included. As the fatty phase come primarily hydrocarbons, eg. Vaseline, paraffin oil and / or hard paraffin in Question, the preferred hydroxy compounds for improving the water-binding capacity, such as fatty alcohols or Esters thereof, e.g. As cetyl alcohol or wool wax alcohol or wool wax. Emulsifiers are corresponding lipophilic Substances, such as sorbitan fatty acid ester (Spans), z. B. sorbitan oleate and / or sorbitan isostearate. Additions to the water phase are

u. a. Humectants, such as polyalcohols, eg. As glycerol, propylene glycol, sorbitol and / or polyethylene glycol, and

Preservatives, fragrances etc. Fatty ointments are anhydrous and contain as a basis in particular hydrocarbons, eg. As paraffin, Vaseline and / or liquid Paraffins, further natural or partially synthetic fats, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. B.

hydrogenated peanut or castor oil, and fatty acid partial esters of glycerol, ζ. B. glycerol mono- and distearate, and z. B. in the

Related to the ointments mentioned, the water absorbency enhancing fatty alcohols, emulsifiers and / or

Additions.

Pastes are cream and ointments with secretion-absorbing powder components, such as metal oxides, eg. As titanium oxide or zinc oxide, further Talc and / or aluminum silicates, which have the task of binding existing moisture or secretions. Foams are administered from pressurized containers and are Arosol-form liquid oil-in-water emulsions, wherein

halogenated hydrocarbons, such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane, are used as blowing agents. As the oil phase used u. a. Hydrocarbons, eg. As paraffin oil, fatty alcohols, eg. Cetyl alcohol,

Fatty acid esters, e.g. As isopropyl myristate, and / or other waxes. As emulsifiers u u. a. Mixtures of such with

predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). Add to that the usual additives, such as preservatives,

Tinctures and solutions usually have an aqueous-ethanolic base, the u. a. Polyalcohols, for. Glycerin, glycols,

and / or polyethylene glycol, as a humectant to reduce evaporation, and refatting substances, such as

Fatty acid esters with low polyethyleneglycols, d. H. soluble in aqueous mixture, lipophilic substances as a substitute for the Skin with ethanol-removed fatty substances, and, if necessary, other auxiliaries and additives are added. The preparation of the topically usable pharmaceutical preparations is carried out in a conventional manner, for. B. by loosening or Suspending the active ingredient in the base or in a part thereof, if necessary. When processing the drug as a solution

this is usually solved by the emulsification in one of the two phases; when processed as a suspension, he is after the

Emulsification mixed with one part of the base and then added to the rest of the formulation. The present invention also relates to the use of the compounds of formulas I and the salts thereof Compounds with salt-forming properties, preferably for the treatment of inflammation, primarily of inflammatory

chronic diseases of the rheumatic type, especially chronic arthritis.

embodiment The invention is explained in more detail below with reference to some examples. The following examples illustrate the invention described above; however, they are not to be included in their scope in any way

limit. Temperatures are given in degrees centigrade, pressures in mbar.

-15- 74123

Example 1: 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. To Adding 2.5 ml of bromoacetaldehyde dimethyl acetal in 30 ml of methanol is heated at 70 ° for 6 hours under reflux. The Reaction solution is diluted with 150 ml of water and extracted three times with methylene chloride. The combined extracts are with Water, dried over sodium sulfate, filtered and evaporated. The residue gives off after crystallization Methanol, the 1,5-bis (p-methoxyphenyl) -3- (2,2-dimethoxyethylthio) -1H-1,2,4-triazole, mp. 107-108 °. The starting material may, for. B. be prepared as follows:

5.8 g of p-Methoxyphenylhydrazin hydrochloride and 2.6 g of ammonium thiocyanate with 20 ml of ethanol for 20 hours with stirring and

Reflux heated to boiling. After cooling, it is filtered off with suction, washed with water and ethanol and then dried

the p-Methoxyphenylthiosemicarbazid, mp 194-196 °.

6.1 g of p-methoxyphenylthiosemicarbazide are suspended in 40 ml of pyridine and added dropwise at -10 ° 5.8 g of p-methoxybenzoyl chloride so that the internal temperature does not rise above -5 °. Then it is stirred for 20 hours at room temperature and the

Reaction mixture poured onto 300 ml of ice-cold 2N hydrochloric acid. The resulting precipitate is filtered off with suction, with Washed water and methanol and dried. This gives N ', N ³ -Bis (p-methoxyphenyl) thiosemicarbazide, mp. 154-159 °.

7.5 g of N '- (4-methoxyphenyl) -N ³ -benzoyl-thiosemicarbazide are mixed with 75 ml of 2-n. Sodium hydroxide solution for 3 hours under reflux for

Boil boiling. The resulting clear solution is cooled and treated with 75 ml of 2-n. Hydrochloric acid added. You get one

crystalline precipitate, which is filtered off, washed with water and ethanol and dried. The resulting 1,5-bis (p-methoxyphenyl) -3-mercapto-1H-1,2,4-triazole melts at 173-174 °.

Example 2: In an analogous manner as described 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 appropriate amount of caustic soda and 1.53 g

Bromessigsäuremethylester the!, S-Bisfp-methoxyphenylJ-S-methoxycarbonylmethylthio-i H-1,2,4-triazole, mp. 78-79 ° (from Petroleum ether). Example 3: In an analogous manner as described in 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 sodium hydroxide solution and 0.75 g of 3-bromopropionic acid, after acidification of the reaction solution with dilute hydrochloric acid, the Bis (p-methoxyphenyl) -3- (2-carboxyethylthio) -1H-1,2,4-triazole of mp. 85-86 ° (from ethanol / water).

Example 4: In an analogous manner as described in Example 1, starting from 3.1 g (0.01 mol)

1,5-bis (p-methoxyphenyl) -3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide solution and 1.8 g

S-Bromopropionaldehyde acetal the 1,5-bis (p-methoxyphenyl) -3- (3,3-ethylenedioxypropylthio) -1H-1,2,4-triazole, mp. 94-96 °

(from ether).

Example 5: 2.5 g (0.0062 mol) of 1,5-bis (p-methoxyphenyl) -3- (2,2-dimethoxyethylthio) -1H-1,2,4-triazole are dissolved in a mixture of

Dissolved 20 ml of acetic acid, 10 ml of water and 5 ml of sulfuric acid and stored at 20 ° for 20 hours. It is diluted with 200 ml of water and extracted twice with ethyl acetate. The combined extracts are washed several times with water, over

Dried sodium sulfate, filtered and evaporated. After crystallization from ether, this is obtained

1,5-bis (p-methoxyphenyl) -3- (2-oxoethylthio) -1H-1,2,4-triazole of mp. 88-89 °.

Example 6: 2.5 g (0.0065 mol) of I.B-bis-p-methoxyphenylj-S-methoxycarbonylmethylthioj-iH-1,2,4-triazole are mixed with 7 ml

1N sodium hydroxide solution for V / ₂ hours with stirring and reflux. The cooled solution is displaced with 7 ml of 2N hydrochloric acid. The deposited crystals are filtered, washed with water and dried. The obtained 1,5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole melts at 184-185 °.

Example 7: In an analogous manner as described in Example 5 is obtained from 1.8 g

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 the 1,5-bis (p-methoxyphenyl) -3- (3-oxopropylthio) -1H-1,2,4-triazole from

Mp. 103-105 ° (from ether). Examples: 1.1 g (0.003 mol) of J, 5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole and 0.5 ml of thionyl chloride in 30 ml of toluene

are heated with stirring to 60-70 ° until a clear solution is formed. Then, the solvent is distilled off under reduced pressure and the residue is redissolved in toluene. This solution is added to a stirred solution of 1.2 g cooled to 0 °

Dimethylamine in 50 ml of toluene was added dropwise. Subsequently, the temperature of the solvent is allowed to rise to room temperature. It is then evaporated under reduced pressure and the residue is partitioned between ethyl acetate and water. To

After repeated washing with water, the organic phase is dried with sodium sulfate, filtered and evaporated. To

Crystallization of the residue from ethanol gives the I.S-Bisfp-methoxyphenyll-S-N ^ -Dimethylcarbamoylmethylthio-i H-1,2,4-triazole, mp. 173-175 °. (Yield 30%). Analog, but using ammonia instead of dimethylamine, you get the

1,5-bis (p-methoxyphenyl) -3-carbamoylmethylthio-1H-1,2,4-triazole, mp 170-172 °.

Example 9: A solution of 3.0 g (0.0078 mole) of bis-bis-p-methoxyphenyl O-S-methoxycarbonylmethylthio-i H-1,2,4-triazole in 50 ml Dichloromethane is added in portions with 2.0 g of 90% m-chloroperbenzoic acid. After 3 days stirring at room temperature

the solvent is distilled off under reduced pressure. The residue is chromatographed from 100 g K "" gel 60 (230-400 mesh, Merck) using a pressure of 0.6 bar and toluene-ethyl acetate (4: 1, y / w) as eluant. The one you want

Product containing fractions are combined and evaporated. You get that IS-Bisip-methoxyphenyl O-S-methoxycarbonylmethanesulfinyl-iH-1,2,4-triazole as colorless oil, IH-NMR spectrum (CDCl ₃ , TMS): Singlet 2H at δ = 4.37 ppm, which is in the fractions last obtained. From the middle fractions one obtains

the 1,5-bis (p-methoxyphenyl) -3-methoxycarbonylmethanesulfonyl-1H-1,2,4-triazole 1H-NMR spectrum (CDCl ₃ , TMS): singlet 2 H at δ = 4.41 ppm as a colorless oil.

Example 10: 1.5 g (0.00375 mol) of 1,5-bis (p-methoxyphenyl) -3-methoxycarbon ·! -Methanesulfinyl-1H-1,2,4-triazole are mixed with 40 ml of 1-n Sodium hydroxide solution stirred for 20 hours. The solution, after treatment with animal charcoal, is 4.1 ml of 1-n. Hydrochloric acid

added and then extracted with methylene chloride. The extracts are dried with sodium sulfate, filtered and evaporated under reduced pressure. The residual, oily I.S. Bisfp methoxyphenyll S-carboxymethanesulfinyl-i H-1,2,4-triazole is calculated in the calculated amount of 1.0-n. Dissolved sodium hydroxide and the solution is lyophilized. The lyophilisate is slurried with a little isopropanol and filtered with suction. This gives the sodium salt of

bS-Bisfp-methoxypheny O-S-carboxymethanesulfinyl-IH-I ^ atriazole, as dihydrate, which melts from 135 ° with decomposition.

In an analogous manner, starting from 1, S-Bisip-methoxyphenylJ-S-methoxycarbonylmethansulfonyl-i H-1,2,4-triazole the Sodium salt of 1, S-Bisfp-methoxyphenylJ-S-carboxymethanesulfonyl-i H-1,2,4-triazole, which melts from 133 ° with decomposition.

-16- 74123

Example 11: 7.5 g (0.0226 mol) of N '- (4-methoxyphenyl) -N ³ -benzoylthiosemicarbazide and 2.7 g of sodium chloroacetate are mixed with 75 ml

2-n. Sodium hydroxide solution heated to boiling for 3 hours under reflux. The resulting clear solution is cooled and treated with 75 ml of 2-n. Hydrochloric acid added. A crystalline precipitate is obtained, which is filtered off with suction, washed with water and ethanol. The thus prepared 1,5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole melts at 184-185 °.

Example 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. Sodium hydroxide dissolved. To

Adding 1.3 g of bromomalonic acid, the resulting solution is allowed to stand at room temperature for 24 hours. It is then adjusted with concentrated hydrochloric acid to pH 1 and then heated for 1 hour with stirring and reflux to boiling. To

After cooling and standing, the precipitated 1,5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole is filtered off;

Mp. 184-185 °.

Example 13: In an analogous manner as 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 sodium hydroxide solution and also chloroacetonitrile, 1,5-bis (p-methoxyphenyl) -3-cyanomethylthio-1H- 1,2,4-triazole as an oil.

Example 14: In a manner analogous to that described in Examples 1 and 6, the reaction of

1,5-bis (p-methoxyphenyl) -3-mercapto-1H-1,2,4-triazole with the calculated amount of 2-bromopropionic acid ethyl ester the 1,5-bis (p-methoxyphenyl) -3- (1-athoxycarbonylethylthio) 1 H-1,2,4-triazole, mp. 80-82 ° and from this the 1,5-bis (p-methoxyphenyl) -3- (1-carboxyethylthio) -1H-1,2,4-triazole of the m. 148-150 °.

Example 15: 1.76 g (0.005 mol) of 1,5-bis (p-methoxyphenyl) -3-cyanomethylthio-1H-1,2,4-triazole are added with 10 ml of acetic acid and 10 ml

36% hydrochloric acid for 12 hours under reflux. Then, the reaction mixture under reduced pressure to

Dry evaporated. The residue is crystallized from chloroform-ethanol mixture. You get that

1,5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole of mp. 184-185 °.

Example 16: 1.76 g (0.05 mol) of 1,5-bis (p-methoxyphenyl) -3-cyanomethylthio-1H-1,2,4-triazole are saturated with 20 ml

methanolic hydrochloric acid with stirring in the pressure tube for 10 hours at 100 °. It is then evaporated to dryness, the residue extracted several times with diethyl ether, the extracts are filtered and partially evaporated. After addition of petroleum ether, the I.s-bis-bis-diphenoxyphenyl J-S-methoxycarbonymethylthio-iH-1,2,4-triazole, mp. 78-79 °, crystallizes.

Example 17: To a solution of 0.45 g (0.005 mol) of thioglycolic acid in 5 ml of dimethylformamide is added 0.54 g of sodium methylate

entered. The mixture is stirred at room temperature for 1 hour, then 1.8 g (0.005 mol) of 1,5-bis (p-methoxyphenyl) -3-methylsulfonyl-1 H-1,2,4-triazole entered. The mixture is then heated for 24 hours with stirring to 100 °. The solvent is distilled off under reduced pressure and the residue with 5 ml of 2-n. Hydrochloric acid Puts. It is extracted several times with dichloromethane, the extracts are dried over sodium sulfate, filtered and evaporated. The remaining crude 1,5-bis (p-methoxyphenyl) -3-carboxymethylthio-1H-1,2,4-triazole crystallizes from chloroform-ethanol with the mp. 184-185 °.

Example 18: To 1.93 g (0.01 mol) of 4-methoxybenzoylisothiocyanate (C.A. 44 2515 b) in 50 ml of benzene is added 1.10 g Dropped mercaptoacetic acid methyl ester. Then it is stirred for 5 hours at room temperature. The solvent is absorbed

distilled off under reduced pressure. Then, 1.40 g of 4-methoxyphenylhydrazine and 100 ml of benzene are added. After 4 hours

Stirring and refluxing on a water separator, the solvent is distilled off under reduced pressure. By Crystallization of the residue from diethyl ether with the addition of petroleum ether to obtain the

bS-Bisfp-methoxyphenyll-S-methoxycarbonylmethylthio-i H-1,2,4-triazole, mp. 78-79 °.

Example 19: In a manner analogous to that described in Examples 1 to 18, the following are also obtained:

1,5-bis (p-chlorophenyl) -3- (2,2-dimethoxyethylthio) -1H-1,2,4-triazole of mp 117-118 °, 1,5-bis (p-chlorophenyl) - 3- (2-oxoethylthio) -1H-1,2,4-triazole, mp. 96-100 °, 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 mp 140-142 °.

Example 20: Tablets containing 25 mg of active ingredient, e.g. B. 3- (2,2-dimethoxyethylthio) -1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole,

can be prepared as follows.

Ingredients (for 1000 tablets): Active ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5 g Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q. s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the Active ingredient which mixes lactose, talc, magnesium stearate and half of the starch. The other half of the strength will be in

40 ml of water are suspended and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, through a

Driven screen with 1.2 mm mesh size and compressed to both sides concave tablets of about 6 mm in diameter. Example 21: Chewable tablets containing 30 mg of active ingredient, e.g. B. 3- (2,2-dimethoxyethylthio) -1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole,

can z. B. be prepared as follows:

Composition (for 1000 tablets): Active ingredient 30.0 g

Mannitol 267.0 g

Lactose 179.5 g

Talc 20.0 g

Glycine 12.5 g

Stearic acid 10.0 g Saccharin 1.0 g

5% gelatin solution q. s.

-π- 74123

Preparation: All solid ingredients are first forced through a 0.25 mm mesh screen. The mannitol and lactose are mixed, granulated with the addition of gelatine solution, passed through a sieve of 2 mm mesh size, dried at 50 ° and again forced through a sieve of 1.7 mm mesh size. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose granules, the stearic acid and the talcum added, the whole thoroughly mixed and pressed to both sides concave tablets of about 10 mm diameter with breaking groove on the top.

Example 22: Tablets containing 100 mg of active ingredient, e.g. B. 3- (2,2-Dimethoxyethylthio) -1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 100.0 g

Lactose 248.5 g

Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium stearate 4.0 g

demineralised water q. s.

Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension added to a boiling solution of Pofyäthylenglykols in 260 ml of water and the mixture, if necessary with the addition of water, granulated. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and compressed on both sides concave tablets of about 6 mm in diameter.

Example 23: In an analogous manner as in Examples 20-22, pharmaceutical preparations containing in each case one of the compounds of formula I mentioned in Examples 2 to 19 can be prepared, wherein compounds in which R _{3 is} carboxy, also in the form of salts Bases, e.g. B. as the sodium salt may be present.

Claims (28)

-1 - 741 claim for invention: 1. A process for the preparation of novel S-mercapto-I ^ Atriazacycloalkadienderivate of formula I. (I) wherein the radicals R ₁ and R _{2 are} independently unsubstituted or substituted by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidized etherified mercapto, free or aliphatic substituted amino, nitro and / or trifluoromethyl substituted aryl or optionally N-oxidized heteroaryl mean, η is 0, 1 or 2, and R3 represents a carboxy group, cyano, optionally esterified or amidated, or cyano in higher than the α position by 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 radical, and their salts, characterized in that
a) from a compound of formula II Y ₁ Y ₂ wherein one of Y ₁ and Y j is a leaving group Y and the other is hydrogen and Y ₃ and Y ₄ together represent an additional bond, or wherein Y _{4 is} a leaving group Y and Y _{3 is} hydrogen and Y ₁ and Y] are one represent additional bond, or split off from a salt thereof with the introduction of an additional bond HY b) compounds of the formula vrv , , ... (XXXI) and Y ₁₀ -R, (XXXII), R ₂ -L / υ ^{12 3} wherein Y _{11 is} a mercapto group optionally present in salt form and Y _{12 is} reactive esterified hydroxy or Y _{11 is} sulfonyl and Y _{12 represents} a mercapto group optionally present in salt form, condensed together or to the corresponding compound of formula I, wherein η is 0, or
c) Compounds of the formulas MA 1 N. J) -Y ₁₁ (XXXI) and ^Y ₁₂ ~ ^R 3 wherein one of Y ₁₁ and Y _{12 is} a metallic group and the other is a group S (O) _n -Y ₁₃ in which Y _{13 is} halogen, fused together or
d) a compound of the formula MA : _n (XXXI), wherein Y _{11 is} mercapto, or a salt thereof with a derived from a compound of formula R ₃ -H (XXXVII) vicinal epoxy derivative to give a compound of formula I, wherein R ₃ in β-Stelli'ng has a hydroxy group and η 0 is, or e) a connection de. formula -Y ₁₁ (ΧΣΧΙ) wherein Y _{11 is} mercapto, or a salt thereof, with a compound of the formula R ₃ -H (XXXVIII), wherein R _{3 is} an aliphatic radical derived from R ₃ and having a C-C double or C-C triple bond at least in the cc, β position Rest means reacting to a compound of formula I, wherein R _{3 is} cc, ß-saturated or α, ß-monounsaturated and η is O, or f) in a compound of formula -2- 741 23 in which R ' ₃ ' is a radical convertible into a group R3, R ' ₃ ' converted into the desired group R ₃ , if necessary, an isomer mixture obtainable by the process is separated into the components and the isomer of the formula I is isolated and, if desired, a compound obtainable according to the method in a converts another compound of the formula I and / or converts a free compound obtainable by the process into a salt or a salt obtainable according to the process into the free compound or into another salt. 2. The method according to item 1, characterized in that one starts from an arbitrary process step as intermediates available compound and performs the missing process steps, or wherein a starting material is formed under the reaction conditions or in the form of a derivative thereof, optionally a salt used. 3. The method according to item 1 or 2, characterized by reacting compounds of formula I, wherein the radicals R ₁ and R _{2 are} independently unsubstituted or by lower alkyl, lower alkoxy or vicinal C-atoms lower alkyl (id) endioxy, hydroxy, Halogen, Niederalkanoyloxy, Niederalkylthio, Niederalkansulfinyl, Niederalkansulfonyl, amino, mono- or di-lower alkylamino and / or trifluoromethyl substituted 6 to and having 10 carbon atoms aryl or moncyclic, an oxygen or sulfur atom and optionally additionally having a nitrogen atom 5-membered or optionally N-oxidized one or two nitrogen atom (s) having mean ßgliedrige heteroaryl η stands for 0,1 or 2 and R ₃ carboxy, Niederalkoxycarbonylniederalkyl, Carbamylniederalkyl, N-mono- and Ν, Ν-Diniederalkylcarbamylniederalkyl, cyano-lower alkyl or hydroxy, Lower alkanoyloxy, lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkylenedithio, Ni ederalkansulfinyl-, lower alkanesulfonyl or oxo group (s) in higher than the α-bearing mono- or Dihydroxyniederalkyl, Niederalkanoyloxyniederalkyl, mono- or Diniederalkoxyniederalkyl, Niederalkylendioxyniederalkyl, Niederalkylendithioniederalkyl, mono- or di-lower alkylthione, Niederalkansulfinylniederalkyl, Niederalkansulfonylniederalkyl or oxo-lower alkyl, or salts thereof manufactures. 4. The method according to item 1 or 2, characterized by reacting compounds of formula I wherein the radicals R ₁ and R _{2 are} independently unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, Niederalkansulfonyl, Diniederalkylamino and / or Trifluoromethyl-substituted phenyl or unsubstituted or by lower alkyl, lower alkoxy, halogen or hydroxyl-substituted furyl, thienyl, pyridyl or 1 -Oxidopyridyl mean, η is 0,1 or 2 and R ₃ carboxy-lower alkyl, Niederalkoxycarbonytniederalkyl, carbamyl-lower alkyl, N-mono or Ν, Ν-di-lower alkylcarbamyl-lower alkyl, or the hydroxy, lower alkoxy, lower alkylenedioxy, Niederalkylidendioxy- or oxo group (s) in higher than the α-position hydroxiloweralkyl, mono or Diniederalkoxyniederalkyl, Niederalkylendioxyniederaikyl, Niederalkylidendioxyniederalkyl or oxo-lower alkyl, or the Salts produces. 5. The method according to item 1 or 2, characterized by reacting compounds of formula I, wherein the radicals R ₁ and R _{2 are} independently unsubstituted or by lower alkoxy with up to and with 4 C-atoms, lower alkylthio with up to and with 4 C Atoms or halogen of the atomic number up to and including 35, substituted phenyl, η is 0 and R _{3 represents} the carboxy or lower alkoxycarbonyl group in the α-position bearing carboxy- or Niederalkoxycarbonylniederalkyl with bis and with 4 C-atoms in the lower alkyl and optionally lower alkoxy , or their salts. 6. The method according to item 1 or 2, characterized in that compounds of formula I, wherein R ₁ and R ₂ by lower alkoxy with up to and 4 C atoms substituted phenyl radicals, η is 0.1 or 2 and R ₃ the carboxy or lower alkoxycarbonyl group in the α-position bearing carboxy or Niederalkoxycarbonylniederalkyl with up to and 4 C atoms in the lower alkyl and optionally lower alkoxy or the hydroxy, oxo, lower alkoxy or Niederalkylenedioxygruppe in higher than the α-position bearing Hydroxyniederalkyl with 2 to and 4 C atoms, oxo-lower alkyl having 2 to and 4 C atoms or mono- or di-lower alkoxy or lower alkylenedioxy lower alkyl each having up to 4 carbon atoms in each alkyl (en) part, or the salts thereof , 7. The method according to item 1 or 2, characterized by reacting compounds of formula I, wherein the radicals R ₁ and R _{2 are} independently unsubstituted or by lower alkoxy with up to and with 4 C-atoms, lower alkylthio up to and 4 C-atoms or halogen of the atomic number up to and including 35 substituted phenyl, η is 0 and R _{3 is} the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group in higher than the α-position-bearing hydroxy lower alkyl having 2 to and having 4 C atoms, Oxoniederalkyl with 2 to and 4 C atoms or mono- or di-lower alkoxy or lower alkylenedioxyniederalkyl each having up to 4 carbon atoms in each alkyl (en) part, or the salts thereof produces. 8. The method according to item 1 or 2, characterized in that compounds of formula I, wherein R ₁ and R ₂ by lower alkoxy with up to and 4 carbon atoms substituted phenyl radicals, η is 0.1 or 2 and R ₃ the carboxy or lower alkoxycarbonyl group in the α-position bearing carboxy or Niederalkoxycarbonylniederalkyl with bis and with 4 C atoms in the lower alkyl and optionally lower alkoxy part, or produces their salts. 9. The method according to item 1 or 2, characterized in that one
1,5-bis (p-methoxyphenyl) -3- (2,2-dimethoxyethylthio) -1H-1,2,4-triazole or a salt thereof. 10. The method according to item 1 or 2, characterized in that one
i ^ -Bislp-methoxyphenylj-S-methoxycarbonylmethylthio-i H-1,2,4-triazole or a salt thereof. 11. The method according to item 1 or 2, characterized in that one
1,5-bis (p-methoxyphenyl) -3- (2-carboxyethylthio) -1H-1,2,4-triazole or a salt thereof. 12. The method according to item 1 or 2, characterized in that one
1,5-bis (p-methoxyphenyl) -3- (3,3-ethylenedioxypropylthio) -1H-1,2,4-triazole or a salt thereof. 13. The method according to item 1 or 2, characterized in that one 1,5-bis (p-methoxyphenyl) -3- (2-oxoethylthio) -1H-1,2,4-triazole or a salt thereof. 14. The method according to item 1 or 2, characterized in that one
1,5-bis (p-methoxyphenyl) -3- (3-oxopropylthio) -1H-1,2,4-triazole or a salt thereof. 15. The method according to item 1 or 2, characterized in that one
IS-Bisip-methoxypheny O-SN.N-dimethylcarbamoyl-methylthio-iH-1,2,4-triazole or a salt thereof. 16. The method according to item 1 or 2, characterized in that one 1,5-bis (p-methoxyphenyl) -3-methoxycarbonylmethane-sulfonyl-1H-1,2,4-triazole or a salt thereof. 17. The method according to item 1 or 2, characterized in that one
IS-bis ^ -methoxyphenyl J-S-methoxycarbonyl-methanesulfinyl-i H-1,2,4-triazole or a salt thereof. -z- 74123 18. The method according to item 1 or 2, characterized in that one prepares I.S-Biste-methoxyphenyO-S-carboxymethansulfinyM H-1,2,4-triazole or a salt thereof. 19. The method according to item 1 or 2, characterized in that one prepares I.S-Bisip-methoxyphenylJ-S-carboxymethylthio-i H-1,2,4-triazole or a salt thereof. 20. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -3-cyanomethylthio-1H-1,2,4-triazole or a salt thereof. 21. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-chlorophenyl) -3- (2,2-dimethoxyäthylthio) -1H-1,2,4-triazole or a salt thereof. 22. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-chlorophenyl) -3- (2-oxoäthylthio) -1H-1,2,4-triazole or a salt thereof. 23. The method according to item 1 or 2, characterized by preparing 1- (3-pyridyl) -5-phenyl-3- (2-hydroxyethylthio) -1 H-1,2,4-triazole or a salt thereof. 24. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -3-carboxymethansulfonyl-1H-1,2,4-triazole or a salt thereof. 25. The method according to item 1 or 2, characterized in that one prepares I.S-Biste-methoxyphenylj-S-fi-ethoxycarbonyl-ethylthioJ-i H-1,2,4-triazole or a salt thereof. 26. The method according to item 1 or 2, characterized in that one 1,5-bis (p-methoxyphenyl) -3- (1-carboxyethylthio) -1H-1,2,4-triazole or a salt thereof. 27. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -3- (2-hydroxyethylthio) -1 H-1,2,4-triazole or a salt thereof. 28. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -3-carbamoylmethylthio-1 H-1,2,4-triazole or a salt thereof.