DD234005A5 - PROCESS FOR THE PREPARATION OF NEW 1,2,4-TRIAZACYCLOALKADIEN DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 1,2,4-Triazacycloalkadienderivaten for use as a medicament. The aim of the invention is the provision of new compounds for the treatment of painful-inflammatory diseases of the rheumatic type. According to the invention 1,2,4-Triazacycloalkadienderivate of formula I are prepared wherein the radicals R1 and R2 independently unsubstituted or by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidized veraethertes mercapto, free or aliphatic substituted amino, nitro and or trifluoromethyl-substituted aryl or optionally N-oxidized heteroaryl groups and R3 is an unsubstituted, at least 2 C-atoms or by a cyano group, a possibly esterified or amidated carboxy u. a. They are prepared, for example, by reacting a compound of the formula I in which one of the radicals 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 a salt thereof with the introduction of an additional bond HY splits off.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel 1,2,4-Tnazacycloalkadienderivate with valuable pharmacological properties, in particular with antinociceptive, anti-inflammatory effect and inhibitory effect on the rostaglandinsynthese.

Lie compounds according to the invention are used as medicaments, in particular for the treatment of painful inflammatory diseases, especially chronic pain conditions of the rheumatic type, such. B.

hronic arthritis.

Characteristic of the known technical solutions.

There is no information available on which compounds have hitherto been used for the treatment of painful inflammatory diseases, especially chronic pain conditions of the rheumatic type.

Object of the invention

The aim of the invention is to provide novel compounds with valuable pharmacological properties that can be used for the treatment of painful inflammatory 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 1,2,4-Triazacycloalkadienderivate the formula

5- "3

R ₂ -.- N ^

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 groups and R _{3 is} an unsubstituted, having at least 2 C atoms or by a cyano group, a possibly esterified or amidated carboxy group, one or two optionally esterified or etherified hydroxy group (s), one or two etherified mercapto group (s) , an oxidized etherified mercapto group or an oxo group substituted, optionally interrupted by thia or Oxa aliphatic or an unsubstituted cycloaliphatic hydrocarbon radical, and their salts.

Heteroaryl radicals are, for example, monocyclic, an oxygen or sulfur atom and optionally in addition a nitrogen atom having 5-membered or one or two nitrogen atoms containing 6-membered heteroaryl, such as furyl, z. B.

2-furyl, thienyl,

z. B. 2-thienyl, thiazolyl, ζ. B. 2-thiazolyl, optionally N-oxidized pyridyl, ζ. B. 2-, 4- or especially 3-pyridyl or 3- (1-Oxidopyridyl), or pyrimidyl, ζ. B. 2-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, aliphatically etherified hydroxy, such as lower alkoxy or vicinal bound lower alkylenedioxy or lower alkylidenedioxy.

Esterified hydroxy as a substituent of R ₁ or R ₂ is z. B. with a mineral acid or an organic carboxylic acid esterified hydroxy, such as halogen or Niederalkanoyloxy, further optionally as indicated for aryl, z. B. by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, substituted benzoyloxy.

Optionally oxidised etherified mercapto as a substituent of R ₁ or R ₂ istz. Lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl.

Aliphatic substituted amino substituents are, for. B. by lower alkyl N-mono- or N, N-disubstituted amino, such as mono- or di-lower alkylamino, or secondarily 4- to 7-membered alkylene or 3-aza, 3-oxa or 3-thia-alkyleneamino.

Aliphatic hydrocarbon radicals are, for example, lower alkyl radicals or secondarily lower alkenyl or lower alkynyl radicals. Examples of suitable substituents, in particular of lower alkyl, are hydroxy, hydroxy esterified with an organic carboxylic acid, ζ. Β. Lower alkanoyloxy, or aliphatic etherified hydroxy, e.g. Lower alkoxy, lower alkylenedioxy or lower alkylidoxy, lower alkylthio, lower alkanesulphinyl, lower alkanesulfonyl F, lower alkylenedithio-carboxy, lower alkoxycarbonyl or free or N-mono-, Ν, Ν-di-lower alkylated or by 4- to 7-membered alkylene or 3-aza, 3-oxa or 3-thia-alkylene disubstituted carbamyl, cyano and oxo into consideration. Accordingly, radicals R ₃ are, for example, lower alkyl, furthermore lower alkenyl and lower alkynyl, mono- or dihydroxy-lower alkyl, mono- or di-lower alkanoyloxy-lower alkyl, mono- or lower-alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower-alkoxy-lower alkoxy-lower alkyl, hydroxy-lower alkylthione-lower alkyl, lower alkoxy-lower alkylthione-lower alkyl, lower-alkylenedioxy-lower alkyl, lower-alkylidenedioxy-lower alkyl, lower or lower di-lower alkylthio, lower alkanesulfinyl or Niederalkansulfonylniederalkyl, Niederalkylendithioniederalkyi, Oxoniederaikyl, Carboxiliederalkyl, Niederalkoxycarbonylniederalkyl, Cyanoloweralkyl, carbamyl-lower alkyl or N-mono- or Ν, Din-Diniederalkylcarbamylniederalkyl, further 4- to 7-membered Ν, Ν-lower alkylene or N, N- (3-aza- , 3-oxa or S-thiaj-lower alkylene carbamyl lower alkyl.

Cycloaliphatic hydrocarbon radicals are, for example, monocycloaliphatic hydrocarbon radicals having 3 to 8, in particular having 5 to 7 ring members, such as corresponding cycloalkyl radicals.

Above and below, "lower" organic riding and compounds are preferably to be understood as meaning those containing up to and including 7, especially up to and including 4, carbon atoms (C atoms).

Lower alkyl R ₃ is, for example, a lower alkyl having 3 to and containing 7 C atoms, bonded via a secondary or tertiary C atom, such as 2-propyl (isopropyl), 2-butyl (secondary butyl), 2- (2-methyl) -propyl ( Tertiarybutyl), 2-pentyl, 3-pentyi, 2- (3-methyl) -butyl, 2- (2-methyl) -butyl, 2-hexyl, 3-hexyl, 2- (2,3-dimethyl) -butyl , 3-heptyl or 3- (2,3-dimethylpentyl or, secondarily, primary lower alkyl having 2 to and having 7 C atoms, such as ethyl, 1-propyl, 1-butyl, 1-pentyl, 1-hexyl or 1 Other lower alkyl as R ₃ 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 alkyl bound 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 alkylenedioxy is, for example, methylenedioxy, ethylenedioxy, 1,3-propylenedioxy, 2,3-butylenedioxy or

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

For example, viiederalkanoyloxy is acetoxy, propionyloxy, butyryloxy, isobutyryloxy, fener formyloxy or pivaloyloxy.

Corset alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio or tert-butylthio, furthermore pentylthio, hexylthio or heptylthio.

Miederalkylendithio is, for example, ethylenedithio, 1,3-propylenedithio or 1,3- (2,2-dimethyl) -propylenedithio.

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

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

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

4- to 7-membered alkyleneamino or 3-aza-, 3-0xa- or 3-thiaalkyleneamino is, for example, pyrrolidino, piperidino, morpholino, rhiomorpholino or piperazino or 4-methyl- or 4-ethylpiperazino.

- to 7-membered Ν, Ν-alkylene or N, N- (3-aza-, 3-0xa- or 3-thia) -alkylencarbamylniederalkyl is, for example, pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino or 4-methyl or 4-ethylpiperazinocarbonylmethyl.

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

Carbamyl-lower alkyl or N-mono- or Ν, Ν-di-lower alkylcarbamyl-lower alkyl is, for example, carbamylmethyl, 1- or 2-carbamylethyl or 2- (2-carbamyl) -propyl, 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- or di-lower alkoxy-lower alkyl is, for example, 2-methoxy, 2-ethoxy, 2-propyloxy or 2-isopropyloxy, 2,2-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 or 4,4-dimethoxy-butyl, as well as methoxy, ethoxy, dimethoxy, propyloxy or isopropyloxymethyl.

Lower alkylenedioxy-lower alkyl is, for example, 2,2-ethylenedioxy- or 2,2-propylenedioxy-ethyl or 3,3- or 2,3-ethylenedioxy-propyl, likewise ethylenedioxy- or propylenedioxymethyl.

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

Mono- or di-lower alkanoyloxy-lower alkyl is, for example, 1- or 2-acetoxyethyl, 1- or 2-pivaloyloxyethyl, 1-acetoxypropyl - (2), 1-pivaloyloxypropyl- (2), 1-acetoxy-2-methyl-propyl- (2) or 1-pivaloyloxy-2-methyl-propyl- (2) or 3-acetoxy- or 2,3-diacetoxypropyl, but may also be pivaloylo'xymethyl or acetoxymethyl.

Mono- or di-lower alkylthio-lower alkyl is, for example, 2-methylthio, 2-ethylthio, 2-propylthio or 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, as well as methylthio, ethylthio, bis (methylthio), propylthio or isopropylthio-methyl.

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

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

Lower alkylenedithio-lower alkyl is, for example, 2,2-ethylenedithio or 2,2-propylenedithioethyl or 3,3- or 2,3-ethylenedithio-propyl, likewise ethylenedithio or propylenedithio-methyl.

Mono- or Dihydroxyniederalkyl 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.

Hydroxyniederalkoxyniederalkyl means, for example 2- (2-Hydroxyäthoxy) -, 2- (3-hydroxypropyloxy) - or 2- (2,3-Dihydroxyäthoxy) -ethyl or 3- {2-Hydroxyäthoxy) - or 3- (3-hydroxypropyloxy) - propyl, as well as 2-hydroxyethoxy- or 3-hydroxypropyloxymethyl.

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

Hydroxyniederalkylthioniederalkyl means, for example, 2- (2-hydroxyethylthio) -, 2- (3-hydroxypropylthio) - or 2- (2,3-dihydroxypropylthio) -ethyl or 3- (2-Hydroxyäthylthio) - or 3- (3-hydroxypropylthio) - propyl, as well as 2-hydroxyethylthio or 3-hydroxypropylthiomethyl.

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

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

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. B. salts with hydrohalic acids, especially hydrochloric or hydrobromic acid, d. H. Hydrohalides, especially hydrochlorides and hydrobromides, or sulfuric acid salts, d. H.

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

z. Maleinate, Furmarate, Maleate, tartrates or methanesulfonates, and N-Cyclohexylsulfaminate, on the other hand, internal salts of compounds of formula I, wherein R _{3 is} carboxy, or their 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 on the mouse in the phenyl-p-benzoquinone-induced writhing syndrome according to J. Pharmacol, exp. Therap. 125, 237 (1959) in the dose range of about 4-40 mg / kg p. o. as excellent effective.

They also show at doses of about 10 to 100 mg / kg p. o. a marked inhibitory effect on experimental carrageenan paw soil of the rat, Di Pasquale et al. Agents and Actions 5, 256, 1975.

Furthermore, they show in vitro in the concentration range of about 0.1 to 1.5 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 1 are excellently suitable as active ingredients of pharmaceutical preparations for the treatment of painful inflammatory diseases, especially chronic pain conditions of the rheumatic type, such as those of chronic arthritis.

The invention relates in the first place to compounds of the formula I in which the radicals R ₁ and R ₂ independently of one another are unsubstituted or lower alkyl or lower alkoxy or vicinal C atoms lower alkyl (id) endioxy. Hydroxy, halogen, lower alkanoyloxy, but also unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted benzoyloxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, mono- or di-lower alkylamino, furthermore 4- to 7-membered alkylene or 3-aza, 3 Oxa or 3-Thiaalkylenamino, nitro and / or trifluoromethyl substituted 6 to and having 10 C-atoms aryl or an oxygen or sulfur atom and optionally additionally having a nitrogen atom-containing 5-membered or optionally N-oxidized one or two nitrogen atom (s) having 6-membered heteroaryl radicals and R _{3 is} lower alkyl having at least 2 C atoms, 3- to 8-membered cycloalkyl, mono- or dihydroxy-lower alkyl, mono- or di-lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, lower-alkoxy-lower alkoxy-lower alkyl, hydroxy-lower alkylthione-lower alkyl, lower-alkoxy-lower alkylthione-lower alkyl, mono- or lower-alkoxy-lower alkyl, lower-alkylenedioxy-lower alkyl, Lower alkylene dithionieroderalkyl, mono- or di-lower alkylsilylthioieroderalkyl, lower alkanesulphinyl-lower alkyl, lower alkanesulphonyl-lower alkyl, oxo-lower alkyl, lower alkoxycarbonyl-lower alkyl, cyano-lower alkyl, lower carbamyl, N-mono- or Ν, Din-di-lower alkylcarbamyl-lower alkyl, further 4- to 7-membered Ν, Ν-lower alkylene or N, N- ( 3-aza, 3-oxa or 3-thia) -lower alkylenecarbamyl-lower alkyl, and their salts.

The invention relates in particular to compounds of the formula I in which the radicals R ₁ and R ₂ independently of one another are unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulfonyl, di-lower alkylamino and / or trifluoromethyl, phenyl or unsubstituted or 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, and R _{3 is} lower alkyl having at least 2 C atoms, mono- or dihydroxy-lower alkyl, mono- or lower-alkoxy-lower alkyl, lower-alkylenedioxy-lower alkyl, lower-oxo-lower alkylthio-lower alkyl, lower-alkoxycarbonyl-lower alkyl, cyano-lower alkyl, carbamoyl-lower alkyl, N-mono- or Ν, Din-di-lower alkylcarbamyl-lower alkyl , and their salts, in particular their pharmaceutically acceptable salts. The invention relates, in particular, to compounds of the formula I in which the radicals R 1 and R ₂ independently of one another are unsubstituted or lower alkoxy having up to and including 4 C atoms, such as methoxy, lower alkylthio having up to and including 4 C atoms, such as methylthio, or halogen the atomic number to and with 35, such as fluorine or chlorine, substituted phenyl, optionally N-oxidized pyridyl, such as 3-pyridyl or unsubstituted thienyl, such as 2-thienyl, and R _{3 is} a secondary or tertiary carbon atom bonded lower alkyl to 3 to and with 7 C atoms, such as isopropyl or tertiary butyl, the cyano or Niederalkylthiogruppe in α-position bearing Cyanoniederalkyl with bis and with 4 C atoms in the lower alkyl, such as cyanomethyl or 2-cyanopropyl (2), or Niederalkylthioniederalkyl each with to and with 4 C atoms, such as alkylthiomethyl, or hydroxy-lower alkyl having up to and containing 4 C atoms, such as hydroxyethyl, hydroxymethyl, 2-hydroxypropyl (2) or 1-hydroxy-2-methyl-propyl- (2), lower alkanoyloxy-lower alkyl having up to and including 7 carbon atoms in the lower alkanoyloxy part and up to and including 4 carbon atoms in the lower alkyl part, such as 1-pivaloyloxy-2-methyl-propyl (2), oxo-lower alkyl having up to and including 4 carbon atoms, such as acetyl or 2-Oxoäthyl, or Diniederalkoxyniederalkyl or Niederalkylendioxyniederalkyl each having up to and 4 C atoms in each alkyl (en) part, such as 2,2-dimethoxyethyl, 3,3-dimethoxypropyl, dimethoxymethyl or 2,2-Aethylendioxyäthyl, and their, especially pharmaceutically acceptable salts.

The invention more particularly relates to compounds of the formula I in which R ₁ and R ₂ are phenyl substituted by lower alkoxy having up to and 4 C atoms, such as methoxy, or R, pyridyl and R _{2 are} phenyl and R _{3 is} a tertiary C ₁ Atom-bonded lower alkyl having up to and including 7 C atoms, such as tert-butyl, the carboxy, cyano, lower alkoxycarbonyl, lower alkylthio, Hydroxiliederalkylthio-, Oxoniederalkylthio-, Diniederalkoxyniederalkylthio or Niederalkylendioxyniederalkylthiogruppe in α-position bearing carboxy-lower alkyl, such as carboxymethyl or 1- Carboxyethyl, cyano-lower alkyl, such as cyanomethyl or 2-cyanopropyl- (2), neideralkoxycarbonyl-lower alkyl, such as 2-ethoxycarbonylpropyl- (2), lower alkylthionierderalkyl, such as ethylthiomethyl, ω-hydroxy-lower alkylthionierdereralkyl, co -oxoloweralkylthionierderalkyl, di-lower alkoxy-lower alkylthionierderalkyl or lower alkylenedioxy-lower alkylthionierderalkyl, with a total of up to and including 7 C Atoms such as 2-hydroxyethylthio, 2-ox oäthylthio-, 2,? - Dimethoxyäthylthio- or 2,2-Aethylendioxyäthylthiomethyl, hydroxy lower alkyl having up to and with 7 carbon atoms, such as 2-hydroxypropyl (2) or 1-hydroxy-2-methyl-propyl (2) , and their, especially pharmaceutically acceptable salts. The invention relates, first and foremost, to compounds of the formula I in which R ₁ and R ₂ are phenyl which is substituted by lower alkoxy having bis-4-carbon atoms and R _{3 is} lower-alkyl, containing up to and including 7 carbon atoms, bonded via a tertiary carbon atom. such as tert-butyl, the cyano, lower alkylthio or di-lower alkoxy-lower alkylthio group in α-position-bearing cyano-lower alkyl having a total of up to and containing 7 carbon atoms, such as cyanomethyl or 2-cyanopropyl- (2), lower alkylthionierderalkyl having in total up to and containing 7 carbon atoms, such as ethylthiomethyl, di-lower alkoxy-lower alkylthio-lower alkyl having in total to and having 7 carbon atoms or hydroxy-lower alkyl having up to and containing 7 carbon atoms such as 2-hydroxypropyl (2) or i-hydroxy-2-methyl-propyl (2), and their, in particular pharmaceutically acceptable salts.

The invention relates in particular to the new 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 compounds of the formula I can be prepared by methods known per se, for example by reacting a compound of the formula

in one of the radicals Y, and Y _{2 is} a leaving group Y and the other is a hydrogen atom and Y ₃ and Y ₄ together represent a line 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, an isomer mixture obtainable by the process is separated into the components and the isomer of the formula I is solubilized and, if desired, a compound obtainable according to the process is converted into another compound of the formula I or 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.

Vbspaltbare radicals Y are, for example, optionally esterified or etherified hydroxy or mecapto groups, further amino, mmonio 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. keto-ethoxy. Etherified hydroxy groups are, for example, lower alkoxy groups, eg. Methoxy or ethoxy. Esterified / lercapto groups are, for example, mercapto groups esterified with a lower alkanecarboxylic acid, such as acetylthio. Etherified / lercapto groups or sulfonium groups are, for example, lower alkylthio or di-lower alkylsulfonium groups, such as / ethylthio, ethylthio or dimethylsulfonium. In addition to groups R ₁ -NH-, amino groups are, for example, di-lower alkyl or ethylene glycol or aza-, oxa- or thia-lower alkylene amino groups, eg. As dimethylamine diethylamino, pyrrolidino, piperidino, / lorpholino or thiomorpholino, further anilino. Ammonium groups are, for example, the abovementioned amino group mtsprechende tertiary ammonium groups or quaternary ammonium groups, such as Triniederalkylammonio or Pyridinio. The elimination of HY is carried out in the usual way spontaneously or by gentle heating, for. B. to about 40 to 100 ⁰ C, if necessary in the presence of an auxiliary and / or an inert solvent. As auxiliaries are, for example, aure agents such as mineral acids or their anhydrides or acidic salts, eg. As hydrohalic acids, especially hydrochloric, hydrobromic, sulfuric acid, Alkalimetallhydrogensulfate, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, 'phosphorus trichloride, phosphorus oxychloride or phosphorus tribromide, organic sulfonic acids such as p-toluenesulfonic acid, or their anhydrides such as lower alkanoic acids and their anhydrides or Halides, e.g. As acetic acid, acetic anhydride ider acetyl chloride, further buffered acid solutions, eg. B. phosphate or acetate buffer, hydrohalides of nitrogen bases, ζ. Β. ammonium or pyridinium chloride, into consideration.

However, it is also possible to use basic condensation agents, such as hydroxides, carbonates or lower alkanolates of alkali or alkaline earth metals, eg. As sodium, potassium or calcium hydroxide, sodium or potassium carbonate or sodium, use, further organic nitrogen bases, such as Triniederalkylamine, z. B. Tiräthylamin, or aromatic Tertiärbasen, such as yridin

 Starting materials of the formula I are preferably prepared in situ, for example by reacting a compound of the formula

R _A -NH-C (Y ₅ ) (Y _e ) -R _B (IM)

rorin either R _{A is} a group of the formula R ₁ -NH-N = C (R ₃ ) and R _{B is} a group R ₂ or R _{A is} a group of the formula I ₂ -Cf = NH) -N (R ₁ ) - and R _{8 represents} a group R ₃ and Y ₅ and Y ₆ independently of one another radicals Y, such as optionally esterified the etherified hydroxy, etherified mercapto or optionally substituted amino or together oxo, thioxo the optionally substituted imino, such as lower alkylimino, optionally substituted anilo or groups Formula ¹ NR ₁ , or a cyclic thereof.

The cyclization of compounds of formula III is carried out in a customary manner, under neutral, acidic or basic conditions, if necessary in the presence of one of said acidic or basic agents, in the presence or absence of an inert solvent or diluent, with heating, e.g. B. in the temperature range of about 40-200 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 Formula III wherein R _{A is} a group of the formula R ₁ -NH-N = C (R ₃ ) - and R _{B is} a group R ₂ and Y ₅ and Y ₆ together form oxo, for example, by a compound of formula R ₁ -NH-N = C (R ₃ J-NH ₂ (IV), for example, by reacting in imino compound of the formula YC (= NH) -R ₃ (V), wherein Y has the meaning given, and in particular lower alkoxy, alogene or amino, or an acid addition salt, for example hydrohalides, thereof, for example in ethanol, or of a riazine derivative of the formula

(VI)

a substituted hydrazine of the formula R ₁ -NH-NH ₂ (VII) or by decomposing a 5-R ₃ -tetrazole in the presence of an amine of formula R ₁ -NH ₂ (VIII) is readily accessible, or a salt thereof with a A compound of the formula Y'-C (Y _s ) (Y ₆ ) -R ₂ (IX) in which Y ₅ and Y _{6 have} the meanings indicated and Y 'is a group Y or, if Y ₅ and Y ₆ together are oxo is a lower alkoxycarbonylmethyl, lower alkanoyloxy, 1-imidazolyl or a phthaliminooxy group or a group of the formula 2-C (= 0) -0-, in the usual manner, for. But in the presence of a basic condensing agent, lan can also be an amide of the formula R ₂ -C (= 0) -NH ₂ (X) with an orthocarboxylic acid derivative of the formula R ₃ -C (Y ₅ ) (Y ₆ JY (XI, Y ₅ Y ₆ = etherified hydroxy or mercapto or halogen Y = disubstituted amino, in particular di-lower alkylamino) to give a compound of the formula R ₂ -C (Y ₅ ) (Y ₆ JN = C (Y) -R ₃ ( XII, Y ₅ + Y ₆ = oxo, Y = substituted amino, ζ. Β. Didniederalkylamino) implement,

B. in dimethylformamide at about 30-160 ⁰ C, and this then under acidic conditions, eg. In acetic acid at about) -100 ° C, with a hydrazine of the formula R ₁ -NH-NH ₂ (VII) condense.

Compounds of the formula III in which R _{A is} a group of the formula R ₂ -Cj = NH) - (R ₁ ) -, Y ₅ + Y ₆ = oxo and R _{8 is} an R ₃ group, are obtained, for example, by reacting a A compound of the formula R ₂ -C (NHNH) -Y (XIII) or a hydrohalide thereof with a compound of the formula R ₁ -NH-NH-C (Y ₅ ) (Y ₆ JR ₃ (XIV) in which Y is esterified or etherified hydroxy, ζ, Halogen, halogen or lower alkoxy, and Y ₅ + Y _{6 are} in particular oxo, are reacted with one another, for example in a lower alkanol, such as ethanol However, in general, the intermediate of formula III is not isolate, because the synthesis of end products of the formula

I via intermediates of the 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 ) (Y ₆ ) -NH-C (= O) -R ₃ (XV), wherein Y ₅ + Y ₅ and oxo or optionally substituted imino of the formula R ₁ -N =, reacting with one another. The reaction is carried out in customary manner, for example in the presence of one of the abovementioned acidic or basic condensing agent, 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 Ausfürhrungsformen this via intermediately formed intermediates of the formulas III or II extending direct syntheses of compounds of formula I are the reaction of compounds of formula VII with compounds of formula XV (Y ₅ and Y 'β = oxo) under weakly acidic conditions, eg. In the presence of an organic carboxylic acid such as acetic acid, an ammonium mineral acid salt, e.g. From pyridinium chloride in acetic acid, or an acidic buffer system such as an acetate or phosphate buffer, the condensation of compounds of formulas XIII and XIV, e.g. B. in ethanol at about 10-50 ⁰ C, and subsequent cyclization at about 80-160 ° C, z. B. in boiling xylene, as well as reaction of an amidrazone of the formula IV with an acid anhydride of the formula IX (Y 'eg halogen, lower alkanoyloxy or R ₂ COO-, Y ₅ + Y ₆ = oxo or thio) and subsequent base treatment, for , B. with sodium or potassium hydroxide.

Likewise via intermediates of the formulas II and III, the reaction of compounds of the formula R ₁ -NH-NH ₂ (VII) with a compound of the formula YC (Y ₅ ) (Y ₆ JR ₃ (Xl) and then with a nitrile of the formula R ₂ -CN (XVI). According to another variant example may be an amidrazone of formula R ₁ -N (NH ₂ JC (R ₂ = NH J (XVH) at elevated temperatures, eg. in the melt at about 100 230 ⁰ C, for. example, at about 190-210 ° C, or in a high boiling organic solvent, for. example, in boiling xylene or dimethylformamide, condensing with a compound of formula XV. also, while intermediate an intermediate of formula

II formed, which then reacts further under HY-cleavage according to the invention.

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

^ -Rj (XVIII), '

in which R ' _{3 is} a radical convertible into a group R ₃ , R _{3 converted} into the desired group R ₃ and required or, if desired, performs one or more of the said subsequent reactions.

In residues R ₃ which can be converted radicals R ₃ are, for example, by an optionally additional carboxy-substituted radicals R _3, in particular 1,1-Dicarboxyniederalkyl- or 1-carboxy-2-oxo-lower alkyl, or radicals of the formula -C (= 0) -0- R ₃ . The conversion of these radicals into radicals R ₃ takes place by elimination of carbon dioxide.

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

Thus, compounds of formula XVIII wherein R _{3 is} a 1-carboxy-2-oxo-lower alkyl radical can be prepared by heating with aqueous acid solutions, e.g. B. with equal parts of about 15% hydrochloric acid and acetic acid to about 60-100 ⁰ C, in compounds of formula I, wherein R _{3 represents} a 2-Oxoniederalkylrest.

Furthermore, compounds of the formula XVIII in which R _{3 is} a radical of the formula -C (= O) -O-R ₃ can be prepared by heating with a mineral acid, ζ. B. with hydrogen chloride in tetrahydrofuran, under carbon dioxide elimination indie corresponding compounds of formula I.

Further radicals R _{3 which} can be converted into groups R ₃ are, for example, radicals reducible to radicals R ₃ , such as carboxy groups present in an ester, anhydride or salt form, and 1 or 2 hydroxy group (s) etherified with a-phenyl-lower alkanol or 1 or 2 a halogenated lower alkanoic acid or carbonic acid or a half-ester or half-amide of the same esterified hydroxy group (s) having radicals R ₃ '.

Carboxy groups present in an ester form are, for example, carboxy groups esterified with an aliphatic, cycloaliphatic, araliphatic or aromatic alcohol, such as lower alkoxycarbonyl, e.g. B. methoxy or ethoxycarbonyl, optionally substituted in the phenyl moiety Benzoyloxymethoxycarbonyl, 2-Halogenniederalkoxycarbonyl, z. B. 2,2,2-trichloro or 2-Jodäthoxycarbonyl, 3- to 8-, especially 5 to 7-membered cycloalkoxycarbonyl, z. B. cyclopentyloxycarbonyl or cyclohexyloxycarbonyl, optionally substituted Phenylniederalkoxycarbonyl-, in particular a-Phenylniederalkoxycarbonyl-,

z. B. benzyloxycarbonyl or optionally substituted phenyloxycarbonyl.

Carbohydrate in an anhydride form is, in particular, carboxy groups anhydrided by a hydrohalic acid, in particular chlorocarbonyl.

In a salt form present carboxy is in particular in an alkali metal or alkaline earth metal or ammonium salt form, for. B.

as sodium, potassium or ammonium salt.

1 or 2 aliphatic hydrocarbon radical etherified with an o-phenyl-lower alkanol etherified or esterified with a halogenated lower alkanoic acid or carbonic acid or a half ester or half-amide thereof, as substituents, in particular halo-lower alkanoyloxy, lower alkoxycarbonyloxy, optionally substituted benzylcarbonyloxy, diloweralkylcarbam / ioxy or carbonyldioxy and are, for example, optionally substituted mono- or Dibenzyloxyniederalkyl, mono- or di (halo-lower alkanoyloxy) lower alkyl, carbonyldioxyniederalkyl, mono- or di (lower alkoxycarbonyloxy) lower alkyl or optionally substituted Benzyloxycarbonyloxyniederalkyl.

As phenyl substituents of optionally substituted phenyl-containing radicals of the type mentioned z. B.

Lower alkyl, lower alkoxy, halogen and / or nitro into consideration.

For example, for the reduction of carboxy (to hydroxymethyl) present in an anhydride form and for the reductive cleavage of cc-phenyl-lower alkoxy or ct-phenyl-lower alkoxycarbonyl groups, hydrogen may be used in the presence of a hydrogenation catalyst such as palladium carbon.

If desired, carboxy groups which are present in an ester, anhydride or salt form can furthermore be reduced to hydroxymethyl by reaction with a hydride carrier or to a-oxo-lower alkyl radicals or x-branched ot-hydroxy-lower alkyl radicals by reaction with an alkoxide carrier.

Ms hydride are, for example, light metal or Dileichtmetallhydride, such as aluminum hydride, .ithiumaluminiumhydrid, lithium borohydride, lithium (triethyl) borohydride, for the reduction of chlorocarbonyl further ^ atriumborhydrid, into consideration. Suitable alkoxide transfer agents are, for example, metal derivatives, in particular alkali metal or alkaline earth metal derivatives of lower alkanes, such as lower alkyl, in particular methyl lithium, or lower alkyl magnesium halides. For the reduction of Chlorcarbonyi to cc-Oxoniederalky! Also particularly suitable are lower alkyl zinc and cadmium halides, which are advantageously prepared in situ from the corresponding lower alkyl magnesium halide and zinc or cadmium halide. The reaction with the said hydride or Alkidüberträgem can be carried out in customary manner, for example in an aliphatic or cycloaliphatic ether, such as diethyl ether, Tertiärbutyloxymethan, tetrahydrofuran or dioxane, if necessary, with cooling or heating, advantageously under inert gas.

Halo-lower alkoxycarbonyloxy, z. For example, 2,2,2-trichloro or 2-Jodäthoxycarbonyloxy, Benzoylmethoxycarbonyloxy or l-Nitrobenzyloxycarbonyloxy z. Example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid, cleaved off. Aroylmethoxycarbonyloxy may also be treated by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 1-nitrobenzyloxycarbonyloxy also by treatment with an alkali metal, e.g. As sodium dithionite, are cleaved. Other radicals R ₃ are solvable to a group R ₃ radicals, for example, 1 or 2 halogen atom (s), a bivalent ^: unctionally modified oxo group, eg. Imino, a carboxy group other than esterified and amidated carboxy as defined hereinabove as well as cyano, such as an iminoether moiety, optionally as indicated for amidated carboxy substituted amidino moiety, halocarbonyl or optionally substituted phenoxycarbonyl, e.g. Phenoxy, p-nitrophenoxy or 2,4-dinitrophenoxycarbonyl, or at least one acyloxy group derived from an alkanecarboxylic acid or a carbonic monoester substituted by halogen or optionally substituted phenyl, at least one silyloxy group or a 1,2-phenylenedioxy group, two geminally bonded ' henyloxygruppen or a vicinal bound mono- or Diphenylniederalkylidendioxy- or mono- or Diphenylniederalkylidendithiogruppen have.

Cleavable acyloxy groups are, for example, halo-lower alkanoyloxy, such as 2-haloacetoxy, lower alkoxycarbonyloxy branched in the 1-position of the lower alkyl radical or suitably 1- or 2-position, in particular: tert-alkoxycarbonyloxy, arylmethoxycarbonyloxy having one or two phenyl radicals, which are preferably optionally substituted by lower alkyl, especially tertiary-lower alkyl such as tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g. Chloro, and / or siitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyloxy or substituted diphenylmethoxycarbonyloxy, benzoylmethoxycarbonyloxy, wherein the benzoyl group is preferably substituted by halogen, such as bromine. Such radicals are for. For example, 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetoxy, tert-butyloxycarbonyloxy, l-Nitrdbenzyloxycarbonyloxy, Phenacyloxycarbonyloxy, 2-Halogenniederalkoxycarbonyloxy, z , B. 2,2,2-Trichloräthoxycarbonyloxy,! -Bromäthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy, or 2-Triniederalkylsilyäthoxycarbonyloxy, such as! -Trimethylsilyläthoxycarbonyloxy or 2- (di-n-butyl-methyl-silyl) -äthoxycarbonyloxy, further 2-Triphenylsilyläthoxycarbonyloxy. A silyloxy group is primarily an organic silyloxy group wherein the silicon is preferably lower alkyl, especially methyl, further lower alkoxy, e.g. B. methoxy, and / or halogen, for. As chlorine, as a substituent. Corresponding silyloxy groups are primarily tri-lower alkylsilyloxy, especially trimethylsilyloxy, furthermore dimethyl-tert-butyl-silyloxy, lower alkoxy-lower alkylhalo-silyloxy, e.g. Methoxy-methyl-chloro-silyloxy, or di-lower alkyl-halosilyloxy, e.g. B. dimethyl-chloro-silyloxy.

At least one of said acyloxy groups, at least one silyloxy group, a 1,2-phenylenedioxy group, two geminally bonded phenyloxy groups or a vicinally bonded mono- or diphenyl-lower alkylidenedioxy or mono- or diphenyl-lower alkylidenedithio group-containing radicals R ₃ may have solvolytically hydroxy-containing aiiphatic radicals R ₃ , as mono- or Dihydroxyniederalkyl, a halogen atom-containing radicals R ₃ further in etherified by etherified or organically esterified hydroxy or etherified mercapto äiiphatische R ₃ , such as Niederalkoxyniederalkyl, Niederalkanoyloxyniederalkyl) of Niederalkylthioniederalkyl, two halogen atoms or a functionally modified oxo group having radicals R ₃ iolvolytically in Oxo-containing or substituted by etherified or organically esterified hydroxy-substituted radicals R ₃ , such as Dxoloweralkyl, Diniederalkoxyniederalkyl or Niederalkylendioxyniederalkyl, and a functionally modified carboxy iufweisend Residues R _{3 are} solvolytically converted into optionally esterified or amidated carboxy R ₃ , such as carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or optionally aliphatically N-substituted carbamyl-lower alkyl. The solvolysis of the R ₃ solvolyzable groups R ₃ is carried out, 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, at least one of said acyloxy groups, at least one silyloxy group, a 2-phenylenedicxy group, two geminally bound phenyloxy groups or a vicinally bonded mono- or diphenyl-lower alkylidenedioxy or mono- or diphenyl-lower alkylidenedithio group-containing radicals R ₃ in hydroxy-substituted aliphatic R ₃ , such as mono- or Dihydroxyniederalkyl, two halogen atoms or a bivalent functionally modified oxo group having radicals R ₃ 'in Oxo having Äiiphatische R ₃ , such as Oxoniederalkyi, functionally modified Carboxiliederalkyl R ₃ in carboxy-lower alkyl and a Iminoäthergruppierung or an optionally äiiphatische N-substituted Amidino-substituted functional carboxy-lower alkyl radicals R ₃ in esterified JZW. transfer 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. Hydrolysing agents are, for example, acidic or alkaline agents. Acid agents are, for example, such as mineral acids, hydrohalic acids, eg. For example, chloro, bromo or hydriodic acid, or oxygen acids of sulfur or phosphorus or their acid salts, such as sulfuric acid, <aliumhydrogensulfate or phosphoric acid, or organic carboxylic or sulfonic acids, eg. B. lower alkanoic acid, such as acetic acid, crifluoroacetic 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. For example, dimethylformamide, N-methylpyrrolidone, or hexamethylphosphoric triamide, or Diniederalkylsulfoxide, z. For example, dimethyl sulfoxide.

By alcoholysis, for example, one or two halogen atoms 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 having aliphatic radicals R ₃ in esterified carboxy, such as lower alkoxycarbonyl, containing radicals R ₃ transferred and in groups R ₃ esterified with organic carboxylic acid hydroxy groups are liberated by transesterification. The alcoholysis is carried out in a customary 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.

By mercaptolysis, for example, one or two halogen atoms or bivalent functionally modified oxo having aliphatic radicals R ₃ in substituted by etherified mercapto aliphatic hydrocarbon radicals R ₃ , as Niederalkylthioniederalkyl, or Hydroxyniederalkylthioniederalkyl convert. The mercaptolysis is carried out in customary, z. In the presence of a basic condensing agent or by using the mercaptan component in salt form, such as an alkali metal salt.

One or two halogen atoms having aliphatic radicals R ₃ can also be converted by reaction with a salt of a carboxylic acid, such as a Niederalkansäurealkalimetallsatz, in organic esterified hydroxy radicals R ₃ , such as mono- or di-lower alkanoyloxyniederalkyl.

By amino or aminolysis can be, for example, halocarbonyl-containing aliphatic radicals R ₃ in substituted by amidated carboxy aliphatic hydrocarbon radicals R ₃ , such as optionally aliphatic N-substituted carbamyl lower alkyl, convert, preferably in the presence of a basic condensing agent. However, it is also possible to liberate the hydroxyl group from the cited acyloxy groups by aminolysis.

However, halo-lower alkyl can also be converted into cyano-lower alkyl by reaction with hydrocyanic acid or an alkali metal cyanide. 2-substituted Silyläthoxycarbonyl can be advantageously by treatment with an alkali metal fluoride, for. B. with potassium fluoride, split.

Furthermore, R ₃ 'may also be in salt form, for. Example, as alkali metal salt form, present mercapto mean that by reaction with a reactive ester, for example a hydrogen halide ester such as hydrochloric, hydrobromic or hydriodic acid ester, or a sulfonic acid ester such as p-toluenesulfonic, optionally by 1 or 2 free, esterified or etherified Hydroxy groups, 1 or 2 etherified mercapto groups or oxidized etherified mercapto substituted aliphatic alcohol can be converted into an optionally correspondingly substituted, interrupted by thia aliphatic radical R ₃ .

The starting materials can be prepared by methods known per se, for example by removal of HY from compounds of the formula

Vf <A

wherein Y ₁ , Y ₂ , Y ₃ and Y _{4 have} the meanings given under the formula II.

Compounds of formula XVIII wherein R ₃ 'is optionally carboxy present in an ester, anhydride or salt form can be further prepared by reacting an aminomalonic acid diester in the usual way by means of a compound of the formula R ₂ -C (= O) -CI (XX) N-acylated, the reaction product α-coupled with a diazotised amine of the formula R ₁ -NH ₂ (VIII) and the resulting azo compound by base treatment, eg. B. action of sodium, with elimination of an esterified carboxy group cyclized. From the obtained ester can then hydrolytically produce the free acid or a salt thereof and from this by means of thionyl chloride.

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

N _x Y

wherein Y, and Y _{2 is} hydrogen and Y ₃ and Y _{4 is} an additional bond or hydrogen or Y, and Y _{2 is} an additional bond and Y ₃ and Y _{4 are} hydrogen, dehydrogenated.

The dehydrogenation is carried out in a conventional manner by treatment with a dehydrating oxidizing agent, advantageously in a solvent or diluent, if necessary with cooling or heating, for. B. at about 0 to 200 ⁰ C. Suitable oxidizing agents are, for example, oxygen, such as atmospheric oxygen, if necessary in the presence of a silver, manganese, iron or cobalt catalyst, peroxy compounds, such as hydrogen peroxide, metal peroxides, z. As nickel peroxide, percarbonic acid and its salts or organic peracids, eg. As m-chloroperbenzoic acid, phthalic acid or peracetic acid, or their salts, oxidizing oxygen acids or their salts or anhydrides, such as hypohalous acids and their salts, for. For example, sodium hypochlorite, halogen acids and their salts, eg. As iodic acids, periodic acids, potassium iodate, sodium periodate or potassium chlorate, nitric acid or nitrous acid and their salts and anhydrides, eg. As potassium nitrate, sodium nitrite, nitrogen oxide, dinitrogen trioxide or nitrogen dioxide, or oxidizing heavy metal compounds such as chromium-Vl, chromium-IV, manganese-IV, manganese-VII, silver-Il, copper-Il, mercury-II , Vanadium V or bismuth II compounds, e.g. As sodium dichromate, potassium dichromate, chromium trioxide, manganese dioxide, potassium permanganate, silver-ll-oxide, copper-ll-oxide, mercury oxide or

Vismutoxid. Inert solvents are, for example, inert solvents, such as water, ketones, z. For example, acetone, carboxylic acids, eg. As acetic acid, halogenated hydrocarbons, aromatic, iraliphatic or heteroaliphatic hydrocarbons, eg. As carbon tetrachloride, or aromatics or heteroaromatics, eg. B. ienzol. Toluene, xylene or pyridine, or mixtures thereof.

) The above starting materials of the formula II are preferably prepared in situ by reacting under oxidizing conditions such as inter-air access or in the presence of ferric chloride, preferably in xylene at about 100 ° C. to boiling point, a compound of formula R ₁ -NH- N = (R ₃ J-NH ₂ (IV), obtainable for example by decomposition of a 5-R ₃ -tetrazole in the presence of an amine of formula R ₁ -NH ₂ (VIII) or condensation of compounds of the formulas R ₁ -NH- NH ₂ (VII) and YC (= NH) -R ₃ (V, Y = etherified hydroxy), condensed with a compound of the formula R ₂ CH = O (XXI).

By way of example or according to other methods not mentioned above, compounds of the formula I can be converted into other compounds of the formula I, if desired, in a manner known per se. If necessary, a isomer mixture obtainable in accordance with the process can be separated into the pure isomers and, if desired, a compound obtainable according to the process can be converted into another compound of the formula I and / or a free compound according to the method can be converted into a salt or a salt obtainable according to the process into the free compound. For example, it is possible to convert optionally 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 reräthern in the usual way. Thus, hydroxy as a component of R ₃ can be reacted with a lower alkylating agent such as a lower alkanol, e.g. Methanol, η the presence of an acid such as a mineral acid, e.g. For example, sulfuric acid, or a dehydrating agent, such as Jicyclohexylcarbodiimid, 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 mtsprechende lower alkoxy. Conversely, ethers, such as lower alkoxy groups as substituents of R,) zw. Cleave R ₂ , for example by treatment with acids, such as with Lewis acids, eg. B. boron tribromide or mineral acids, eg. B. On hydrogen iodide.

Furthermore, hydroxy can be esterified, z. B. in Niederalkanoyloxy, for example by reaction with antsprechenden Niederalkancarbonsäure, 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. A basic condensing agent such as an alkali metal hydroxide of the carbonate or a tertiary nitrogen base, ζ. Example, a Triniederalkylamins or pyridine, and starting from an acid,:. In the presence of an acid, such as a protic acid, e.g. For example, hydrochloric, sulfuric, phosphoric or sulfonic acid, or iisher Lewis acid, z. B. boron trifluoride etherate.

^: erner one can free carboxyl as a component of R ₃ in a conventional manner, for. B. by treatment with a Diazoniederalkan or "riniederalkyloxonium-, Triniederalkylcarboxonium- or Diniederalkylcarboniumsalz such as Hexachloroantimonat or lexafluorophosphat, or especially by reaction with the corresponding alcohol or a reactive derivative, such as sinem carbonic, phosphorous, sulfuric or carbonic acid esters, eg B. a Niederalkancarbonsäureester, Triniederalkylphosphit,) iniederalkylsulfit or pyrocarbonate, or a mineral acid or sulfonic acid esters, eg., The hydrochloric or hydrochloric acid, benzenesulfonic or toluene sulfonic or methanesulfonic, the mtsprechenden alcohol or an olefin derived therefrom, esterification to an esterified carboxyl group.) The reaction with the corresponding alcohol itself can advantageously be carried out in the presence of an acid catalyst, such as a "rotohensäure, z. B. of hydrochloric or hydrobromic, sulfuric, phosphoric, boron, benzenesulfonic and / or toluenesulfonic acid, or line Lewis acid, z. 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, intfernung the reaction water and / or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol can be carried out in a customary manner, starting from a carboxylic, phosphorous, sulfuric or carbonic acid ester, for example in the presence of an acidic catalyst, such as one of the abovementioned, in an inert solvent, such as aromatic hydrocarbon, e.g. As η benzene or toluene, or an excess of the alcohol derivative or the corresponding alcohol. Starting from linem mineral acid or sulfonic acid ester, the acid to be esterified is advantageously used in the form of a salt, for. As the sodium salt potassium, and if necessary in the presence of a basic condensing agent, such as an inorganic Sase, z. As sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, ζ. Β. pn triethylamine or pyridine, and / or in an inert solvent such as one of the above tertiary nitrogen bases or lines of polar solvent, e.g. B. in dimethylformamide and / or at elevated temperature.

iyano can be hydrolyzed in a conventional manner to carbamyl or carboxy or with intermediate formation of an imino ether or midin moiety which can subsequently be hydrolyzed, even without isolation, to an esterified or amidated carboxy group, with an alcohol or ammonia or a primary or secondary Amine be implemented.

Ine free carboxyl group can further by reacting with ammonia or having at least one hydrogen atom ^ in the usual manner, with dehydration of the intermediate ammonium salt formed, for. B. by azeotropic distillation with ienzol 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 the formula I in which R ₃ contains carboxy in a conventional manner into an operable derivative, for example by means of a halide of phosphorus or sulfur, z. Example, by means of phosphorus trichloride ider 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, i-nitrophenol or cyanomethyl alcohol, or a reactive amide, ζ. As that of imidazole or 3,5-dimethylpyrazole! derived amide, transferred and the resulting reactive derivative then in the usual manner, for. B. as described below for the transesterification or iesided conversion of esterified and amidated carboxyl groups, with a corresponding alcohol, ammonia ider the corresponding at least one hydrogen atom-containing amine to the desired group, an esterified carboxyl group, as well as a Trihalogenmethylgruppe, in a conventional manner, z. 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 [alium hydroxide, or a mineral acid, eg. As hydrochloric acid, sulfuric acid or phosphoric acid, in the free carboxyl group,

esterified? Carboxy furthermore ζ. 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 may further in the usual manner, for. Example, by reaction with a metal salt, such as the sodium or potassium salt, a corresponding alcohol 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. Of p-toluenesulfonic acid, or a Lewis acid, e.g. of bread trifluoride etherate, to 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 strong acid, such as a mineral acid, for. B. of hydrochloric acid, sulfuric acid or phosphoric acid in the free carboxyl unsubstituted carbamyl further by dehydration, z. B. by means of a carbodiimide or phosphorus pentoxide or polyphosphoric or sulfuric acid, are converted into cyano.

In addition, carboxy-lower alkyl radicals of the formula -C _n H _2n -COOH which are present in an ester, anhydride or salt form may optionally be substituted by oxo-lower alkyl radicals of the formula -C _{n + 1} H _{2n +} I = O in the oxo or hydroxy group or Hydroxyniederalkylreste the formula -C _{n + 1} H _{2n + 2} -OH reduce.

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, tertiary butoxymethane or tetrahydrofuran, or by means of sodium borohydride or sodium cyanoborohydride, 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. B: of zinc powder can be effected equally in the nascent hydrogen reduction which can be produced, for example, by acid action on base metals such as acetic acid on zinc, iron and hydrochloric acid or water action on sodium amalgam. 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-Lactonformen, into consideration, in their presence in the ω-position and in a lower than the (tu-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. As further reducing agents for the reduction of optionally existing in a salt, anhydride or ester form Carboxyzu oxo or hydroxy groups come Alkidüberträger which transfer to the α-C atom a lower alkyl radical in anionic form, for. B. Compounds of aliphatic hydrocarbons of the formula R ₀ -H (XXVI) with metals, eg. B. Compounds of the formula R ₀ -M ¹ , R ₀ -M "Hal or (R _O ) ₂ M", wherein M ^{1 is} a metal atom of group 1 A and M "is a metal atom of groups 2A and 2B of the Periodic Table And M is preferably sodium or lithium and M is preferably magnesium or cadmium The reduction with these reducing agents, in which carboxy groups present in a salt, anhydride or ester form are converted into tertiary hydroxyl groups, is carried out in a conventional manner. for example, in an inert solvent, such as a di-lower alkyl or lower alkylene ether, for example in diethyl ether or tetrahydrofuran, if necessary with cooling or heating and / or under an inert gas such as nitrogen, Again, the reduction of optionally in a salt, anhydride or If desired, the carboxy compound present in the ester form can be stopped at the oxy stage by mixing mild reducing agents, for example a cadmium or halocadmium compound or a cadmium or halocadmium compound Halogenmagnesiumverbindung in the presence of a cadmium halide, used or at low temperatures, for. B. below -25 ⁰ C, works. Conversely, in compounds of the formula I groups R _{3 of} the formula -C _{n + 1} H _{2n + 2} -OH to groups R _{3 of} the formula -C _{n + 1} H _{2n + 1} = O and groups R _{3 of} the formula -C _n H _2n -CH ₂ OH or -C _n H _2n -CH = O to oxidize those of the formula C _n H _2n -COOH. The oxidation of groups of the formula -C _{n + 1} H _{2n + 2} -OH in those of the formula -C _{n + 1} H _{2n + 1} = O takes place for example by treatment with a for the oxidation of primary and secondary alcohols to aldehydes or Ketones conventional oxidizing agents, such as non-oxidizing metal compounds, eg. B. chromyl chloride in pyridine, chromium trioxide in 2,5-dimethylpyrazole, Nitrosoniumtetrafluorborat or the complexes of chlorine or methanesulfonic anhydride and dimethyl sulfoxide, and others, but all by treating with an aliphatic or cycloaliphatic ketone, such as eir.-jm Oxoniederalkan, z , As acetone, or a cycloalkanol ζ. As cyclohexanone, in the presence of an aluminum alcoholate, for. B. of aluminum isopropoxide. The oxidation of groups of the formulas -C _n H _2n -CH ₂ OH or -C _n H _2n -CH = O to those of the formula -C _n H _2n -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, which is obtained by carrying out the oxidation in an alcohol by esterification of the primary acid of the corresponding ester.

In addition, compounds of the formula I in which R _{3 has} vicinal C-esterified hydroxy groups, such as lower alkanoyloxy, can be prepared by oxidative acyloxyation of the double bond in corresponding nonaromatic double bond (s) containing compounds of the formula I. The oxidative Acyioxyiierung carried out for example by treatment with a heavy metal salt of an organic carboxylic acid, for. B. with lead tetraacetate, or with a silver salt of an organic carboxylic acid in the presence of halogen, eg. B. with silver acetate in the presence of iodine or bromine.

Furthermore, compounds of the formula I in which R _{3 has} an optionally esterified or amidated carboxy group or cyano and in α-position to this at least one hydrogen, by reaction with a tertiary ammonium base, such as

"etrabutylammonium hydroxide, or a metal base such as an alkali metal or alkaline earth metal hydride or amide," "eg. with sodium hydride or sodium amide, .ct-deprotonated and subsequently with a reactive ester of a lower alkanol such as a lower alkyl halide, lower alkyl sulfonate, e.g. p-toluenesulfonate, or Diniederalkylsulfat, α-mono- or, if desired, also t, a-diniederalkylieren.

^: Ernerkann to introduce ₂ optional additional C-substituents in the radicals R ₁ and / or R. So you can logenogenieren in usually, z. By reaction with chlorine or bromine in the presence of iron or by means of N-chlorosuccinimide In addition, η may be conventionally ilkylated, for example by reaction with an alkyl halide, alkanol or alkene in the presence of aluminum trichloride usually by nitric acid / sulfuric acid nitrate, the nitro group, for example with 'inn-ll-chloride to reduce amino and these by means of sodium nitrate and tetrafluoroboric acid by fluorine, by means of hydrochloric acid, sodium nitrite and copper-l-chloride ( Bromine) by chlorine (bromine), or replaced by sodium nitrite and potassium iodide by iodine or Nittels sodium nitrite and a Niederalkylmercaptans in Niederalkylthio or by means of sodium nitrite in hydroxy ^.: Ner can be in oxo-containing radicals R ₃ Oxo reduce to hydroxy or reductively replaced by hydrogen, for example by the action of nascent hydrogen, for example produced by treatment of base metals with ³ rotonendon ator, z. Of zinc with hydrochloric or acetic acid, of amalgamated aluminum or sodium amalgam with water) of sodium with an alcohol such as methanol. The reductive substitution of oxo by hydrogen can also be accomplished by reaction with hydrazine in the presence of a metal base, e.g. Example of sodium or potassium hydroxide or an alkali metal alcoholate, vie of sodium in a high-boiling alcohol such as ethylene glycol, diethylene glycol or diethylene glycol monomethyl ether, preferably at elevated temperature, for. B. at about 150 to 250 ° C. Oxo may also be reduced to hydroxy in conventional manner, for example by reaction with a light metal hydride such as borane-tetrahydrofuran, diborane, or a difatty metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride or by reaction with a secondary alcohol such as isopropanol or cyclohexanol in the presence of an aluminum alcoholate. However, the reduction of oxo to hydroxy can also be carried out with simultaneous introduction of a hydrocarbon radical on the carbonyl carbon atom by reacting with a lower alkyl metal compound, eg. B. with a lower alkyl lithium or 'diederalkylmagnesiumhalogenid reacted. In an analogous manner, by aldol addition of a ketone or aldehyde to an äldehydic oxo group with reduction of the same to hydroxy, an oxo-containing β-position radical can be introduced. Oxo may be ^{: more} neat by treatment with an orthocarboxylic acid ester, e.g. As a Orthoameisensäureniederalkylester, or under dehydrating conditions and acid catalysis with a lower alkanol, Niederalkandiol, Niederalkylmercaptan or Miederalkyldimercaptan be converted into di-lower alkoxy, Niederalkylendioxy, Diniederalkylthio or Niederalkylendithio. In addition, in hydroxy-containing radicals R _3, the hydroxy group (s) can be replaced reductively by hydrogen, for example as indicated above for the reductive replacement of oxo by the action of hydrogen. Hydroxy may further be obtained by reaction with a halogenating agent such as thionyl chloride or phosphorus tribromide, or a sulfonic acid chloride such as a mkaned or optionally substituted benzenesulfonyl chloride, e.g. B. with p-toluenesulfonyl chloride, in halogen or sulfonyloxy, which then by reaction with a salt of hydrocyanic acid, such as ammonium or an alkali metal cyanide, Jurch cyano or by reaction with an unsubstituted or substituted as a cyano group, an optionally esterified or amidated Carboxy group, one or two optionally esterified or etherified hydroxy group (s), one or: white etherified mercapto group (s), an oxidized etherified mercapto group or an oxo group-containing aliphatic alcohol or mercaptan or a metal salt thereof by the missing part of an optionally correspondingly substituted , Jurch Oxa or Thia interrupted aliphatic hydrocarbon radical can be replaced. But it is also possible to treat the halogen atom by treatment with an alkali or alkaline earth metal by a metallic radical, for. B. in the lithium or sinen Halogenmagnesiumrest convert, which then by reaction with a reactive carbonic acid derivative, such as carbon dioxide, a halogen, z. As chloroformate or an optionally N-substituted carbamoyl chloride can be replaced by optionally esterified or amidated carboxy. It is also possible to convert hydroxyalkyl R ₃ to alkenyl by acid treatment with dehydration.

η the radicals R ₃ can also geminally bound Diniederalkoxy, Diniederalkylthio, Niederalkylendioxy and Niederalkylendithio to oxo or vicinal bound Niederalkylidendioxy exhibiting lower alkyl to Dihydroxyniederalkyl iydrolysieren, preferably acid-catalytically.

^{It is} possible to hydrolyze esterified hydroxy, such as lower alkanoyloxy or optionally substituted benzoyloxy, having radicals R ₃ : u to the corresponding hydroxyl-containing radicals, eg. As indicated above for the hydrolysis of compounds of ^: ormel XVIII.

If, in processes according to the invention, compounds of the formula I containing isomer mixtures are obtained, these, just like the stereoisomer mixtures obtainable according to the invention, can usually be separated into the components. 5o such isomer mixtures, e.g. Mixtures of stereoisomers or diastereomers due to the differences in the physical properties of the components by conventional physical separation methods, such as crystallization, chromatography, distillation or phase distribution method, split into the components.

inantiomer mixtures, such as racemates, can be prepared by crystallization from optically active solvents, chromatography on siccally active solids, action of microorganisms or reaction with an optically active auxiliary compound in ~, diastereomer mixtures, eg. B. with an optically active acid in mixtures of diastereomeric acid addition salts, and separation of the same into the diastereomers from which the enantiomers can be released in the usual manner in the cleaved inantiomer. For this purpose, common optically active acids are, for. For example, D- or L-tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acids or quinic acid.

^: erner obtained free compounds can be converted in a conventional manner in acid addition salts, for. Example by Jmsetzen a solution of the free compound in a suitable solvent or solvent mixture with one of the rarer acids or with a solution thereof, or with a suitable anion exchanger.

Erhalte acid addition salts can be converted in a conventional manner into the free compounds, for. 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. irhalte salts can be converted in a conventional manner into other salts, for. Example, by treating a salt with a suitable metal salt, such as a sodium, barium or silver salt, in a suitable solvent in which a forming inorganic salt is insoluble and thus excreted from the reaction mixture, are converted into other acid addition salts.

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

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and expedient in the preceding and following among the free compounds or their salts.

The invention also relates to those embodiments of the process which start from a compound obtainable as intermediates at any stage of the process and carry out the missing process steps, or a starting material formed under the reaction conditions or in the form of a derivative thereof, optionally a salt used.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. Processes for the preparation of new starting materials also form an object of the present experience.

The pharmaceutical preparations which contain compounds of the formula I or pharmaceutically acceptable salts thereof are those for enteral or oral or rectal, and parenteral administration and for topical application to warm-blooded animals (n) containing the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier material. The dosage of the active ingredient depends on the species of warm-blooded animals, age and individual condition, as well as the mode of administration.

Normally, an approximately daily dose of about 50-500 mg, advantageously distributed in several equal sub-doses, is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

The new pharmaceutical preparations contain z. From about 10% to about 80%, preferably from about 20% to about 60% of the active ingredient. According to the invention pharmaceutical preparations for enteral or parenteral administration are z. As in unit dose formers) such as dragees, tablets, capsules or suppositories, further ampoules. These are in a conventional manner, for. Example by means of conventional mixing, granulation, coating, solution or lyopilation. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, 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, eg. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. Corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the abovementioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt of it, like sodium alginate. Auxiliaries are primarily flow regulators and lubricants, eg. For example, 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 contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, salmon solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of 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, stabilizers also being added.

As rectally applicable pharmaceutical preparations come z. As suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base are z. As natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkenols. Further, gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; as basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbon in question.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. As a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvent or vehicle, such as fatty oils, ζ. As sesame oil, or synthetic fatty acid esters, ζ. As ethyloleate or triglycerides used, or aqueous injection suspensions, which viscosity-increasing substances, eg. 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, which contain from about 0.5 to about 20% of the active ingredient.

Cream are oil-in-water emulsions containing more than 50% water. As an oily basis are used primarily fatty alcohols, eg. 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. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, ζ. 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. For example, sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which is usually in the presence of fatty alcohols, eg. As cetyl alcohol or stearyl alcohol used. Additives to the water phase are u. a. Agents which reduce the drying of the cream, z. As polyols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, 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. As the fatty phase come primarily hydrocarbons, eg. As petroleum jelly, paraffin oil and / or hard paraffins in question to improve the water binding capacity preferably suitable hydroxy compounds, such as fatty alcohols or esters thereof, for. As cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic

Substances, such as sorbitan fatty acid ester (Spans), z. B. sorbitan oleate and / or sorbitan isostearate. Additives to the water phase are ι. a. Humectants, such as polyalcohols, ζ. For example, glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as onylation agents, fragrances, etc.

^: ettsalben are anhydrous and contain as a basis in particular hydrocarbons, eg. Paraffin, vaseline and / or liquid araffins, further natural or partially synthetic fats, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, ζ. Β.

iydrated peanut or castor oil, and fatty acid partial ester of glycerol, ζ. B. glycerol mono- and distearate, and z. As mentioned in connection with the ointments, the water absorbency enhancing fatty alcohols, emulsifiers and / or additives.

Asten are cream and ointments with sekretabsorbierenden powder ingredients, such as metal oxides, z. As titanium oxide or zinc oxide, further falk and / or aluminum silicates, which have the task of binding existing moisture or secretions.

Foams are administered from pressure vessels and are aerosolized liquid oil-in-water emulsions, with halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. For example, dichlorodifluoromethane and dichlorotetrafluoroethane, are used as the blowing agent. The oil phase used include hydrocarbons, eg. As paraffin oil, fatty alcohols, eg. Cetyl ^alcohol,: ettsäureester such. As isopropyl myristate, and / or other waxes. The emulsifiers used include mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly aliphatic properties, such as sorbitan fatty acid esters (Spans). Add to that the usual additives, such as preservatives,

"Inkturen and solutions usually have an aqueous-ethanolic basis, including polyalcohols, ζ. Β. Glycerol, glycols, ind / or polyethylene glycol, as humectants to reduce evaporation, and lubricating substances, such as ^: acid esters with low Polyäthylenglycolen, ie in aqueous mixture of soluble, lipophilic substances as a replacement for the skin with the ethanol withdrawn fatty substances, and, if necessary, other auxiliaries and additives are added.

) he preparation of the topically usable pharmaceutical preparations is carried out in a conventional manner, for. By dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When processing the active ingredient as a solution vird this is usually solved by the emulsification in one of the two phases; when processed as a suspension, it is mixed with part of the base after emulsification and then added to the remainder of the formulation.

The compounds of formulas I and the salts of such compounds having salt-forming properties are preferably used for the treatment of inflammations, primarily of inflammatory chronic diseases of the rheumatic type, in particular of chronic arthritis.

Uisführungsbeispiel

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade, pressures in mbar.

Example 1: 5.5 g (0.0124 mol) of N'-fp-methoxyphenyl-tert-butyl-pyramidrazone hydrochloride are dissolved in 20 ml of water and combined with 2 ml of 2N sodium hydroxide solution. The liberated base is extracted with ether. The extract is dried with sodium sulfate, filtered and evaporated. The resulting oil is heated to boiling with 20 ml of xylene (mixture of isomers) and 2.75 g of 4-methoxybenzaldehyde under reflux for 20 hours. It is then evaporated under reduced pressure and the residue from petroleum ether, recrystallized. The 1,5-bis (p-methoxyphenyl) -3-tert-butyl-1H-1,2,4-triazole is obtained in the form of colorless crystals of mp.

) N'-fp-methoxyphenyl I-tertiary-carbamidehydrazone hydrochloride used as the starting material may be prepared in the following manner:

', 6 g Pivaloimidsäuremethylesterhydrochlorid are dissolved in 40 ml of methanol and treated with a solution of 7.0 g (-Methoxyphenylhydrazin in 100 ml of methanol.) After standing for 24 hours at 20 ° is evaporated under reduced pressure The residue yields on trituration with ether the N ¹ - (p-methoxyphenyl) -tertiärbutyramidrazonhydrochlorid, which I decomposes when heated above 170 °.

EXAMPLE 2 A solution of 8.2 g (36 mmol) of N'-phenylterti-butyl-pyramidrazone hydrochloride in 50 ml of methanol is admixed with 6.66 ml of 1.4 molar sodium methylate solution in methanol, the separated sodium chloride is filtered off and the product is filtered off Filtrate evaporated under 'reduced pressure. The residue is refluxed with 100 ml of xylene and 3.4 ml of pyridine-2-aldehyde for 20 hours under reflux.

After distilling off the XyIoIs obtained 1-phenyl-5 (3-pyridyl) -3-tert-butyl-1H-1,24-triazole in colorless crystals of mp.

43-144 ° (from petroleum ether).

) N'-phenyl-tertiary-butyl-pyridrazone hydrochloride used as the starting material can be obtained in the following manner:

• Ine solution of 12.1 g Pivaloimidsäuremethylester hydrochloride in 100 ml of methanol is added 8.6 g of phenylhydrazine and stored for 24 hours at 20 °. After evaporation under reduced pressure, the residue crystallized from 2-propanol. The J'-phenyl-tertiärbutyramidrazon hydrochloride is obtained in colorless crystals, mp. 237-239 °.

Example 3: 1.2 g (0.0052 mol) of N ¹ - (3-pyridyl) -tertiarybutyramidrazone hydrochloride are dissolved in 3 ml of absolute methanol, with 5.2 ml of -n. Sodium methylate solution in methanol and filtered from the precipitated sodium chloride. The filtrate is evaporated under reduced pressure, mixed with 20 ml of xylene (mixture of isomers) and 0.6 g of benzaldehyde and then heated to boiling for 20 hours under reflux. After Abdestiilieren of XyIoIs gives the 5-phenyl-1- (3-pyridyl) -3 ^ tertiärbutyl-1H-1,2,4-triazole ι colorless crystals of mp. 146-147 ° (from petroleum ether).

) N ¹ - (3-pyridyl) -terti-butyl-pyramidrazone hydrochloride used as starting material can be obtained in the following manner:

 Ine solution of 9.6 g Pivaloimidsäuremethylesterhydrochlorid in 40 ml of methanol is added with a solution of 6.9 g of 3-hydrazinopyridine τ 50 ml of methanol and stored for 24 hours at 20 °. Evaporation under reduced pressure crystallizes the residue from ether. The N '- (3-pyridyl) -tertiärbutyramidrazon hydrochloride, mp. 221-222 °.

Examples 4: 20.5 g (0.0897 mol) of N ¹ - {3-pyridyl) -tertiarybutyramidrazone hydrochloride are dissolved in 150 ml of methanol, admixed with 16.6 ml of a linear 5.4 molar solution of sodium methoxide in methanol, and filtered from the precipitated sodium chloride. The filtrate is evaporated under reduced pressure, treated with 200 ml of xylene (mixture of isomers) and 12.2 g of p-methoxybenzaidehyde and then heated under reflux for 20 hours to boiling. After distilling off the XyIoIs obtained the - (p-methoxyphenyl) -1- (3-pyridyl) -3-tertiärbutyl-1H-1,2,4-triazole in colorless crystals of mp. 115-116 ° (from petroleum ether).

Example 5: 15.2 g of methyl 1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3-carboxylate are dissolved in a mixture of 450 ml of tetrahydrofuran and 450 ml of methanol. While stirring, 10.5 g of sodium borohydride are added in portions over 10 minutes. After 2 hours, the reaction mixture is mixed with 500 ml of water and freed from the organic solvents under reduced pressure. The remaining aqueous solution precipitates an oil which is taken up in ethyl acetate. The ethyl acetate solution is dried over sodium sulfate, filtered and evaporated. The residue gives from isopropanol, the 1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3-methanol, mp. 108-109 °

 The starting material may, for. B. be prepared as follows:

70.3 g Aminomalonsäuredimethylester hydrochloride are heated with 65.4 g of 4-methoxybenzoyl chloride in 700 ml of methylene chloride for 48 hours with stirring and reflux. It is then cooled, filtered from undissolved material and the filtrate washed with water and potassium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue gives from isopropanol, the p-Methoxybenzoylaminomalonsäuredimethylester, mp. 114-115 °. 2.0 g of p-methoxyaniline are dissolved in a mixture of 16 ml of glacial acetic acid and 4 ml of concentrated hydrochloric acid, cooled to 0 ° and treated dropwise with an aqueous ömolaren solution of sodium nitrite. The reaction mixture is cooled to -10 ° and treated dropwise with a solution of 3.8 g of p-Methoxybenzoylaminomalonsäuredimethylester in 40 ml of acetone. Then, a solution of 22.8 g of potassium carbonate in 23 ml of water is added dropwise and stirred at 0-5 ° for half an hour. Then ethyl acetate is added to the reaction mixture. The organic phase is separated, washed with water, dried over sodium sulfate, filtered and evaporated. The residue gives from isopropanol, the p-methoxybenzoylamino-p-methoxyphenylazo-malonsäuredimethylester, mp. 139 ° (decomposition).

0.42 g of p-methoxybenzoylamino-p-methoxyphenylazo-malonate are suspended in 9 ml of methanol, treated with 0.15 ml of a 1 N sodium methylate solution in methanol and stirred at 20 ° for 3 hours. Thereafter, the resulting solution is cooled to 0 °, followed by crystallization. The crystals are filtered off with suction, washed with isopropanol and dried. The resulting 1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3-carboxylic acid methyl ester melts at 174-176 °. Example 6: 7.1 g (0.0216 mol) of 1,5-bis (p-methoxyphenyl) -3-chloromethyl-1 H-1,2,4-triazole are reacted with a solution of 4.6 g of ethylmercaptan in 80 ml of 1 N sodium methylate solution in methanol for 20 hours to reflux. The reaction solution is evaporated under reduced pressure and the residue is partitioned between water and ether. The ether phase is washed with brine, dried over sodium sulfate and evaporated. The residue provides from petroleum ether, the 3-ethylthiomethyl-1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole, mp. 89-90 °.

The 1,5-bis (p-methoxyphenyl) -3-chloromethyl-1H-1,2,4-triazole used as starting material can be prepared as follows: 6.0 g of 1,5-bis (p-methoxyphenyl) - 1H-1,2,4-triazole-3-methanol are dissolved in 20 ml of chloroform and added dropwise at 10-15 ° to a solution of 6.0 ml of thionyl chloride in 10 ml of chloroform. After 3 hours storage at 20 °, the volatiles are distilled off under reduced pressure at 30-40 ° bath temperature. The residue gives after crystallization from ether, the 1,5-bis (p-methoxyphenyl) -3-chloromethyl-1 H-1,2,4-triazole of mp. 90-9Γ.

Example 7

1.0 g of I.S-bis-p-methoxyphenyl J-IH-i ^^ - triazole-S-methyl-S-thiuronium chloride are dissolved in 10 ml of ethanol with 2.9 ml of 2-n. Sodium hydroxide solution and 1.27 g of 1-bromo-2,2-dimethoxyäthan heated for 4 hours under reflux to boiling. Then the ethanol is distilled off and the residue is partitioned between water and diethyl ether. The Ätherextrakt is washed with water, dried over sodium sulfate and evaporated. Kugelrohr distillation gives the

1- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3-ylmethylthio] -2,2-dimethoxy-ethane, Kp. = 17072 · 10- ² mbar, as a colorless oil ,

The starting material can be prepared as follows:

3.3 g of 1,5-bis (p-methoxyphenyl) -3-chloromethyl-1H-1,2,4-triazole are refluxed in 15 ml of ethanol with 0.84 g of thiourea for 20 hours under reflux. Upon cooling, this gives the

1,5-bis (p-methoxyphenyl) -1H-1 ^ -triazole-S-methyl-S-thiuronium hydrochloride in colorless crystals. Mp 209-211 °. (3.8 g = 94%

Example 8: 18.4 g of tetrabutylammonium hydrogensulfate are dissolved in 68 ml of 2-n. Dissolved sodium hydroxide solution and added at room temperature to a solution of 8.7 g of 1,5-bis (p-methoxyphenyl) -3-cyanomethyl-1 H-1,2,4-triazole and 19.3 g of methyl iodide in 50 ml of dichloromethane.

The mixture is stirred for 20 hours at room temperature. Then the dichloromethane phases are separated, washed with water, dried over sodium sulfate, filtered and evaporated. Crystallization of the residue from ethanol yields 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3] -2-methyl-propionitrile of mp 103-104 °.

Example 9 12.7 g of 1,5-bis- (p-methoxyphenyl) -3-chloromethyl-1H-1,2,4 are added with stirring to an ice-cooled suspension of 5.7 g of sodium cyanide in 50 ml of dimethyl sulphoxide Triazole added in portions. Subsequently, the reaction mixture is stirred for 2 hours at room temperature. After addition of 350 ml of water is extracted with diethyl ether. The extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The residue crystallizes from diethyl ether. The resulting 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3] acetonitrile melts at 76-78 °.

Example 10: 1,85 g of magnesium turnings are 10.6 _r: treated methyl iodide and 20 ml of diethyl ether. After dissolution of the metal, a solution of 10.2 g of methyl 1,5-3is (p-methoxyphenyl) -1H-1,2,4-triazole-3-carboxylate in 200 ml of tetrahydrofuran is added;

Slowly added dropwise stirring and then the reaction mixture heated to 50 ° for 2 hours. Then, the reaction mixture is cooled to 0 ° and treated dropwise with 100 ml of saturated ammonium chloride solution. Two phases are formed, the upper one of which is separated off and washed with saturated ammonium chloride solution. Then the tetrahydrofuran solution is dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from ether-hexane gives the 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3] -propan-2-ol, mp. 96-97 °.

Example 11: 2.75 g (0.0107 mol) of N ¹ - (p-methoxyphenyl) tertiarybutyramidrazone and 10 g of p-methoxybenzoyl chloride are heated to 120 ° with stirring for 12 hours. Thereafter, the reaction mixture is stirred with excess 10% sodium carbonate solution until all the excess acid chloride is decomposed. It is extracted several times with diethyl ether, the extracts are dried over sodium sulfate, filtered and the filtrate is evaporated. This gives the 1,5-bis (p-methoxyphenyl) -3-tert-butyl-1 H-1,2,4-triazole of the mp.

Analogously, from 1.2 g of N ¹ - (3-pyridyl) -tertiärbutyramidrazon the 5- (p-methoxyphenyl) -1- (3-pyridyl) -3-tertiärbutyl-1 H-1,2,4-triazole from Mp 115-116 °, and by reaction with the appropriate amount of benzoyl chloride, the 5-phenyl-1- (3-pyridyl) -3-tert-butyl-1 H-1,2,4-triazole, mp. 146-147 ° ,

Example 12: In a manner analogous to that described in Examples 1 to 11, it is also possible to prepare:

[1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3] -2-methyl-propionic acid ethyl ester, m.p. 106-107 °, - [1,5-bis (p-methoxyphenyl ) -1H-1,2,4-triazole-3] -2-methyl-propan-1-ol, m.p. 109-110 °, and - [1,5-bis (p-methoxyphenyl) -1H-1 , 2,4-triazol-3-yl] -2-methyl-1-pivaloyloxy-propane, m.p. 90-92 °.

Example 13: Tablets containing 25 mg of active ingredient, eg. For example, 5-phenyl-1- (3-pyridyl) -3-tertiary-butyl-1H-1,2,4-triazole can be prepared as follows:

Components (for 1000 tablets): 25.0 g Virkstoff 100.7 g .actose 7.5 g Veizstärke 5.0 g Ethylethylene glycol 6000 5.0 g 'alkum 1.8 g / lagnesiumstearat q. s. mineralized water

Preparation: All solid ingredients are first driven through a sieve with 0.6 mm mesh size. Then the active substance, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 0 ml of water and this suspension is added to a boiling solution of the polyethylenglycol in 100 ml of water, and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, forced through a sieve with 1.2 mm mesh size and compressed to both sides concave tablets of about 6 mm diameter, η analogous manner can also tablets, each containing 25 mg of one of the examples 1, 2 and 4 to 11 mentioned compounds of formula I are prepared, these compounds may also be present in the form of salts. Example 14: Chewable tablets containing 30 mg of active ingredient, e.g. For example, 5-phenyl-1- (3-pyridyl) -3-tert-butyl-1H-1,2,4-triazole, z. B. are produced as follows:

Composition (for 1000 tablets):

Active ingredient 30.0 g

i / lannit 267.0 g

lactose 179.5 g

'alcum 20.0 g

Blycine 12.5 g

Stearic acid 10.0 g ·

saccharin 1.0 g

i% gelatin solution q. s.

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

In an analogous manner, it is also possible to prepare tablets containing in each case 30 mg of one of the compounds of the formula I mentioned in Examples 1, 2 and 4 to 11, these compounds also being able to be present in the form of salts.

ieispiei 15: tablets containing 100 mg of active ingredient, for. For example, 5-phenyl-1- (3-pyridyl) -3-tert-butyl-1H-1,2,4-triazole can be. B.

be made as follows:

Composition (for 1 000 tablets):

/ Active substance 100.0 g

lactose 248.5 g

Corn starch 17.5 g

Ethylethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium stearate 4.0 g

änt mineralized water q. s.

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

In the same way, it is also possible to prepare tablets containing in each case 100 mg of one of the compounds of the formula I mentioned in Examples 1, 2 and 4 to 11, these compounds also being able to be present in the form of salts.

Claims (19)

Invention claim: 1. A process for the preparation of novel 1,2,4-Triazacycloalkadienderivate the formula 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 Heteroaryigruppen and R _{3 is} an unsubstituted, having at least 2-carbon atoms or by a cyano group, an optionally esterified or amidated carboxy group, one or two optionally esterified or etherified hydroxy group (s), one or two etherified mercapto group (s), an oxidized etherified mercapto group or an oxo group substituted, optionally interrupted by thia or oxa aliphatic or an unsubstituted cycloaliphatic hydrocarbon radical, and their salts and optionally of analgesic pharmaceutical preparations vorvorn, characterized in that starting from a compound of formula I ι in which one of the radicals Y ₁ and Y _{2 is} a leaving group Y and the other is a hydrogen atom 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 or in a compound of the formula I. / -R _'3 (XVIII), R ₂ -.- N where R ' _{3 is} a radical convertible into a group R ₃ , R' _{3 is converted} into the desired group R ₃ or a compound of the formula T3 / \ UiJ. FU -.- N R, ^Y 1 ^Y 2. WOrJnY ₁ and Y _{2 are} hydrogen and Y ₃ and Y _{4 are} an additional bond or hydrogen or Y ₁ and Y _{2 is} an additional bond and Y ₃ and Y _{4 are} hydrogen, dehydrogenated, if necessary a mixture of isomers obtained according to the invention is separated into the components and the isomer of Formula I is isolated and, if desired, converts a compound obtainable by the process into another compound of the formula I and / or converts a free compound obtainable according to the process into a salt or a salt obtainable according to the process into the free compound or into another salt and if appropriate those prepared by this process Compounds in a manner known per se, alone or with carrier materials, binders, lubricants and other auxiliaries customary in the production of medicaments, optionally in combination with other pharmaceutically active substances having a similar action, in the form of tablets, capsules, pills, supposit orions, emulsions, injection solutions, inhalation solutions and other known drug formulations. 2. Ancestors according to item 1, characterized in that compounds of the 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) enoxy, hydroxy, halogen, Lower alkyloxy, but also unsubstituted or substituted by lower alkyl, lower alkoxy and / or halogen benzoyloxy, Niederalkylthio, Niederalkansufinyl, Niederalkansulfonyl, amino, mono- or di-lower alkylamino, further 4- to 7-membered alkylene or 3-aza-, 3-oxa- or 3 -Thianiederalkylenamino, nitro and / or trifluoromethyl-substituted 6 to and having 10 C-atoms aryl or an oxygen or sulfur atom and optionally additionally a nitrogen atom-containing 5-membered or optionally N-oxidized one or two nitrogen atom (s) having 6-membered Heteroaryl significant and R ₃ lower alkyl having at least 2 C-Stomen, mono- or Dihydroxyniederalkyi, mono- or Diniederalkanoyloxynie lower alkoxy lower alkylthio-lower alkyl, mono- or lower-alkoxy-lower alkyl, lower-alkylenedioxy-lower alkyl, lower-alkylenedithio-lower alkyl, lower or lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkyl, lower alkyl, lower alkoxycarbonyl-lower, lower alkyl, lower carbamyl, lower mono-or lower alkylcarbamoyl, further lower 4- to 7-membered Ν, Ν-lower alkylene or N, N- (3-aza, 3-oxa or 3-thia) -niederalkylencarbamylniederalkyl, or produces their salts. 3. The method according to item 1 or 2, characterized in that starting from a obtainable at any stage of the process as intermediates compounds and executes the missing process steps, or formed a starting material under the reaction conditions or in the form of a derivative thereof, optionally a salt used. 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 hydroxy-substituted furyl, thienyl, pyridyl or 1-Oxidopyridyl mean and R _{3 is} lower alkyl having at least 2 carbon atoms, mono- or Dihydroxyniederalkyl, mono- or di-lower alkoxyniederalkyl, Niederalkylendioxyniederalkyl, oxo-lower alkyl , Lower alkylthio-lower alkyl, carboxy-lower alkyl, lower-alkoxycarbonyl-lower alkyl, cyano-lower alkyl, carbamoyl-lower alkyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl-lower alkyl, or preparing their salts. 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 6 C Atoms or halogen of the atomic number to and with 35 substituted phenyl, optionally N-oxidized pyridyl or unsubstituted thienyl and R _{3 is} a secondary or tertiary carbon atom bonded lower alkyl to 3 to and having 7 carbon atoms, the cyano or Niederalkylthiogruppe in α-position bearing Cyanoniederalkyl with bis and with 4 C atoms in the lower alkyl or Niederalkylthioniederalkyl each having and 4 C-atoms or hydroxy lower alkyl with up to 4 carbon atoms, Niederalkanoyloxyniederalkyl with up to 7 carbon atoms in Niederalkanoyloxyteil and to and with 4 C atoms in the lower alkyl part of oxo-lower alkyl with up to and with 4 C-atoms or Diniederalkoxyniederalkyl or Niederalkylendioxyniederalkyl with each to and with 4 C atoms in each alkyl (en) part, or produces their salts. 6. The method according to item 1 or 2, characterized by reacting compounds of formula I, wherein R ₁ and R ₂ by lower alkoxy with up to and 4 C atoms substituted phenyl or R _{1 is} pyridyl and R _{2 is} phenyl and R ₃ Lower alkyl having up to and including 7 carbon atoms bonded via a tertiary carbon atom, the carboxy-lower alkyl, cyano-lower alkyl, lower-alkoxycarbonyl-lower alkyl containing carboxy-, cyano-, lower alkoxycarbonyl-, lower-alkylthio-, hydroxy-lower alkylthio-, oxo-lower alkylthio, di-lower alkoxy-lower alkylthio or lower alkylenedioxy-lower alkylthio group , Lower alkylthio-lower alkyl, ω-hydroxy-lower alkylthione-lower alkyl, ω-oxo-lower alkylthione-lower alkyl, lower-lower alkoxy-lower alkylthio-lower alkyl or lower-alkylenedioxy-lower alkylthio-lower alkyl having in total to and having 7 carbon atoms or hydroxy-lower alkyl having up to and including 7 carbon atoms, or preparing their salts. 7. The method according to item 1 or ί, characterized by reacting compounds of formula I, wherein R ₁ and R ₂ by lower alkoxy with up to and with 4-C atoms substituted phenyl and R ₃ via a tertiary carbon atom bonded lower alkyl with bis and with 7 carbon atoms, the cyano-, Niederalkylthio- or Diniederalkoxyniederalkylthiogruppe in α-position bearing Cyanoniederalkyl with a total up to and with 7 C-atoms, Niederalkylthioniederalkyl with a total up to and with 7 C-atoms, Diniederalkoxyniederalkylthioniederalkyl with a total to and with 7 C atoms or Hydroxiliederalkyl with up to 7 carbon atoms, or produces their salts. 8. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -3-tertiärbutyl-1H-1,2,4-triazole or a salt thereof. 9. The method according to item 1 or 2, characterized by preparing 1-phenyl-5- (3-pyridyl) -3-tert-butyl-1 H-1,2,4-triazole or a salt thereof. 0. Method according to item 1 or 2, characterized in that 5-phenyl-1- (3-pyridyl) -3-tert-butyl-1 H-1,2,4-triazole or a salt thereof is prepared. 1. The method according to item 1 or 2, characterized in that one
5- (p-methoxyphenyl) -1- (3-pyridyl) -3-tert-butyl-1H-1,2,4-triazole or a salt thereof. 2. The method according to item 1 or 2, characterized in that one prepares 1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3-methanol or a salt thereof. 3. The method according to item 1 or 2, characterized in that one
3-ethylthiomethyl-1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole or a salt thereof. 4. The method according to item 1 or 2, characterized by reacting 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3] propan-2-ol or a salt of it manufactures. 5. Process according to item 1 or 2, characterized in that 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3] acetonitrile or a salt thereof is prepared. 6. The method according to item 1 or 2, characterized in that one 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3] -2-methyl-propionitrile or a salt thereof. 7. The method according to item 1 or 2, characterized in that one 2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3] -2-methyl-propionic acid ethyl ester or a salt thereof. 8. The method according to item 1 or 2, characterized in that one
2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazole-3] -2-methylpropanol or a salt thereof. 9. The method according to item 1 or 2, characterized in that one
2- [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3-yl] -2-methyl-1-pivaloyloxypropane or a salt thereof. 0. Method according to item 1 or 2, characterized in that 1 - [1,5-bis (p-methoxyphenyl) -1H-1,2,4-triazol-3-yl-methylthio] -2,2-dimethoxyethane or a salt thereof.