NZ211465A - 3-mercapto-1,2,4-triazacycloalkadiene derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £11465 2 1 1465 NG SRA^SS /,«0 / ' lO / ' i/- ue. f-' .. £ -y .. r .Tfii<j*3 ::-,./ci; cation F.;«d. -v;-y C'rr • r ■ 05.10.^9 ,...ccOP^rv!.|cm.'.

. MU- 27 NOV publication Da'.c: ... •• P.O. Journal, No: - \ / 1987 .1 Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "3-mercapto-l,2,4-triazacycloalkadiene derivatives" WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement fanowe<f hY page f A.) - iA- 21 i'ibij } 4-14798/+ 3-mercapto-1,2,4-triazacycloalkadiene der ivatives The invention relates to 3-mercapto-l,2,4-triazacycloalkadiene derivatives of the fornnula I Rj-N-N, V \-s< 0,n-R3 =N' (I) j I in which the radicals and Rj, independently of one another, represent an aryl or optionally N-oxidised heteroaryl radical that is unsubstituted or substituted by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidised etherified raercapto, free or aliphatically substituted amino, nitro and/or tri- « 7" - ^28SEPW e 2 i 14 fluoromethyl, n represents 0, 1 or 2, and r3 represents an aliphatic hydrocarbon radical substituted by an optionally esterified or amidated carboxy group, cyano or, in a position higher than the a-position, by one or two optionally esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidised mercapto group or by an oxo group, and of their salts.

Heteroaryl radicals are, for example, monocyclic 5-raembered heteroaryl radicals containing an oxygen or sulphur atom and optionally also a nitrogen atom or monocyclic 6-membered heteroaryl radicals containing one or two nitrogen atoms, such as furyl, for example 2-furyl, thienyl, for example 2-thienyl, thiazolyl, for example 2-thiazolyl, pyridyl, for example 2-, 4- or, especially, 3-pyridyl or 3-(1-oxidopyridyl), or pyrimidyl, for example 2- or 4-pyrimidyl or 2-(1-oxido-pyrimidyl).

Aryl radicals are aryl radicals having up to and including 10 carbon atoms, for example monocyclic aryl radicals, such as phenyl.

Aryl and heteroaryl radicals can contain one or more than one, for example one, two or three, of the mentioned substituents, which may be identical or different.

Etherified hydroxy is, for example, lower alkoxy or vicinally bonded lower alkylenedioxy or lower alkylidenedioxy, but may also be lower alkenyloxy or lower alkynyloxy. 2JS4 m Esterified hydroxy as a substituent of R1 or R2 is, for example, hydroxy esterified by a mineral acid or an organic carboxylic acid, such as halogen or lower alkanoyloxy, also benzoyloxy optionally substituted as indicated, for example by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl.

Optionally oxidised etherified mercapto is, for example, lower alkylthio, lower alkanesulphinyl or lower alkanesulphonyl.

Aliphatically substituted amino substituents are, for example, amino that is mono- or di-substituted by lower alkyl, such as N-mono- or N,N-di-lower alkyl-amino, but may also be 4- to 7-membered alkyleneamino or 3-aza-, 3-oxa- or 3-thia-alkyleneamino.

Esterified carboxy represents, for example, aliphatically esterified carboxy, such as lower alkoxy-carbonyl.

Amidated carboxy is, for example, unsubstituted or aliphatically substituted carbamoyl, such as carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, but may also be 4- to 7-membered N,N-lower alkylenecarbamoyl or N,N-(3-aza-, 3-oxa- or 3-thia-)-lower alkylenecarbamoyl.

Aliphatic hydrocarbon radicals are, for example, lower alkyl radicals, and also lower alkenyl or lower alkynyl radicals. As substituents of Rj, which represents especially substituted lower alkyl, there come into consideration, for example, hydroxy optionally esterified by an organic carboxylic acid, for example lower alkanoyloxy, or aliphatically etherified hydroxy, for example lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally oxidised etherified mercapto, such as lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl, lower alkyl-enedithio, optionally esterified or amidated carboxy, such as carboxy, lower alkoxycarbonyl, carbamoyl or 2 1 146 #» .

N-mono- or N,N-di-lower alkylcarbamoyl, cyano and oxo. Radicals R3 are accordingly, for example: carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- and N,N-di-lower alkyl-carbamoyl-lower alkyl, cyano-lower alkyl, or mono- or di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, mono- or di-lower alkoxy-lower alkyl, lower alkylene-dioxy-lower alkyl, mono- or di-lower alkylthio-lower alkyl, lower alkanesulphinyl-lower alkyl or lower alkanesulphonyl-lower alkyl, lower alkylenedithio-lower alkyl or oxo-lower alkyl carrying the hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkylenedithio, lower alkanesulphinyl, lower alkanesulphonyl or oxo group(s), respectively, in a position higher than the a-position.

Hereinbefore and hereinafter, "lower" organic radicals and compounds should preferably be understood as meaning those containing up to and including 7, especially up to and including 4, carbon atoms.

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, and also pentyl, hexyl or heptyl.

Lower alkenyl is, for example, vinyl, but is preferably lower alkenyl bonded via a saturated carbon atom, such as allyl, methallyl or but-2-enyl.

Lower alkynyl is, for example, ethynyl, but is preferably lower alkynyl bonded via a saturated carbon atom, such as propargyl or but-2-ynyl.

Lower alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, also pentyloxy, hexyloxy or heptyloxy.

Lower alkenyloxy is, for example, allyloxy, and lower alkynyloxy is, for example, propargyloxy.

Lower alkylenedioxy is, for example, methylene-dioxy, ethylenedioxy, 1,3-propylenedioxy, 2,3- 2 1 14 butylenedioxy or 1,3-(2,2-dimethyl)-propylenedioxy; lower alkylidenedioxy is, for example, ethylidene-dioxy or isopropylidenedioxy.

Lower alkanoyloxy is, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, also formyloxy or pivaloyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio or tert.-butylthio, also pentylthio, hexylthio or heptylthio.

Lower alkylenedithio is, for example, ethylenedithio, 1,3-propylenedithio or 1,3-(2,2-diraethyl)-propylenedithio.

Lower alkanesulphinyl is, for example, methane-, ethane-, 1- or 2-propane-, butane- or isobutane-sulphinyl.

Lower alkanesulphonyl is, for example, methane-, ethane-, 1- or 2-propane-, butane- or isobutane-sulphonyl.

Mono- or di-lower alkylamino is, for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino or butylamino. 4- to 7-membered alkyleneamino or 3-aza-, 3-oxa-or 3-thia-alkyleneamino is, for example, pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino or 4-methyl- or 4-ethyl-piperazino. 4- to 7-membered N,N-lower alkylene- or N,N-(3-aza-, 3-oxa- or 3-thia-)-lower alkylene-carbamoyl-lower alkyl is, for example, pyrrolidino-, piperidino-, morpholino-, thiomorpholino- or piperazino- or 4-methyl-or 4-ethyl-piperazino-carbonylmethyl.

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

Carbamoyl-lower alkyl or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl is, for example, carbamoyl-methyl, 1- or 2-carbamoylethyl or 2-(2-carbamoyl)-propyl or N-methyl-, N-ethyl- or N,N-dimethyl-carbamoyl methyl, 1- or 2-(N-methyl-, N-ethyl- or N,N-dimethyl-carbamoyl)-ethyl or 2-[2-(N-methyl-, N-ethyl- or N,N-dimethyl-carbamoyl)]-propyl.

Cyano-lower alkyl 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-propoxy- or 2-isopropoxy-, 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-diethoxy-propyl, 2-(1-dimethoxy-2-methyl)-propyl or 4,4-dimethoxy-butyl.

Lower alkylenedioxy-lower alkyl is, for example, 2,2-ethylenedioxy- or 2,2-propylenedioxy-ethyl or 3,3-or 2, 3-ethylenedioxypropyl, also 2-(1-ethylenedioxy-2-methyl)-propyl.

Lower alkanoyloxy-lower alkyl is, for example, 1-or 2-acetoxyethyl, 1- or 2-pivaloyloxysthyl, 1-acetoxyprop-2-yl, 1-pivaloyloxyprop-2-yl, 1-acetoxy-2-methylprop-2-yl or 1-pivaloyloxy-2-methylprop-2-yl or 3 acetoxypropyl.

Mono- or di-lower alkylthio-lower alkyl is, for example, 2-methylthio-, 2-ethylthio-, 21!' 2-pcopylthio-, 2-isopropylthio-# 2,2-dimethylthio- or 2.2-diethylthio-ethyl, 3-methylthio- or 3-ethylthio-propyl or 3,3-bis(methylthio)-, 3,3-bis(ethylthio)-, 2.3-bis(methylthio)- or 2,3-bis(ethylthio)-propyl or 4, 4-bis(methylthio)-butyl.

Lower alkanesulphinyl-lower alkyl is, for example, 2-methanesulphinyl-, 3-ethanesulphinyl-, 2-propane-sulphinyl- or 2-(2-propanesulphinyl)-ethyl or 3-methanesulphinyl- or 2-ethanesulphinyl-propyl.

Lower alkanesulphonyl-lower alkyl is, for example, 2-methanesulphonyl-, 3-ethanesulphonyl-, 2-propane-sulphonyl- or 2-(2-propanesulphonyl)-ethyl or 3-methane sulphonyl- or 3-ethanesulphonyl-propyl.

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

Mono- or di-hydroxy-lower alkyl is, for example, hydroxymethyl, 1- or 2-hydroxyethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 2-hydroxyprop-2-yl, 1-hydroxy-2-methylprop-2-yl, 4-hydroxy- or 2,4-dihydroxy-butyl, 5-hydroxy-, 2,5-dihydroxy- or 3,5-dihydroxy-pentyl.

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

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

Salts of compounds of the formula I are especially pharmaceutically acceptable salts, either pharmaceutically acceptable acid addition salts with strong acids, such as mineral acids, for example salts with hydrohalic acids, especially hydrochloric or hydrobromic acid, that is to say hydrohalides, especially hydrochlorides and hydrobromides, or sulphuric acid salts, that is to say hydrogen sulphates 2 11 and sulphates, and salts with suitable organic acids, such as dicarboxylic acids or organic sulphonic acids, for example maleates, fumarates, malates, tartrates or methanesulphonates, and N-cyclohexylsulphamates, or internal salts of compounds of the formula I in which R3 contains carboxy, or pharmaceutically acceptable metal salts thereof, such as alkali metal or alkaline earth metal salts, or ammonium salts with ammonia or suitable organic amines, such as mono-, di- or tri-lower alkylamines, for example diethylamine, mono-, di-or tri-hydroxy-lower alkylamines, for example triethanolamine or 2-dimethylaminoethanol, or hetero-aliphatic amines, for example morpholine.

The compounds of the formula I have valuable pharmacological properties. In particular they exhibit marked antinociceptive activity and an inhibitory action on the synthesis of prostaglandin, as well as a marked anti-inflammatory action. Thus, they prove to have an excellent action in mice in the phenyl-£-benzoquinone-induced writhing syndrome according to J. Pharmacol, exp. Therap. 125, 237 (1959), in a dosage range of approximately from 3 to 50 mg/kg p.o..

They also exhibit, in doses upwards from approximately 25 mg/kg p.o., a marked inhibitory action on experimental carrageenin paw oedema in rats, (Di Pasquale et al^., Agents and Actions, 5^, 256, [1975]), and, on topical administration in a concentration upwards from approximately 20 mg/ml, a marked inflammation-inhibiting action in experimental croton oil oedema in the ears of rats (TONELLI et^ al., Endocrinology 11_, 625 [1965]).

In addition, JLn vitro in a concentration range of approximately from 2 to 30 vimol/1 they exhibit a marked inhibitory action on the synthesis of prostaglandin from arachidonic acid, demonstrated in 2 ! \<Uj16 r 9 the test procedure according to Prostaglandins 1_, 123 (1974).

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

The invention relates especially to compounds of the formula I in which the radicals R1 and R2, independently of one another, represent an aryl radical having from 6 up to and including 10 carbon atoms or a monocyclic 5-membered heteroaryl radical having an oxygen or sulphur atom and optionally also a nitrogen atom or a monocyclic optionally N-oxidised 6-membered heteroaryl radical having one or two nitrogen atom(s), which radicals may be unsubstituted or substituted by lower alkyl, lower alkoxy or, at vicinal cauon atoms, lower alkyl (id) enedioxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl, amino, mono- or di-lower alkylamino and/or by trif luoromethyl, ri represents 0, 1 or 2, and R3 represents carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl, cyano-lower alkyl, or mono- or di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, mono- or di-lower alkoxy-lower alkyl, lower alkylenedioxy-lower alkyl, lower alkylenedithio-lower alkyl, mono- or di-lower alkylthio-lower alkyl, lower alkanesulphinyl-lower alkyl, lower alkanesulphonyl-lower alkyl or oxo-lower alkyl carrying the hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkylenedithio, lower alkanesulphinyl, lower alkanesulphonyl or oxo group(s), respectively iiMtnn-. position higher than the a-position, and their salts.

The invention relates more especially to compounds of the formula I in which the radicals R1 and R2, independently of one another, represent phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulphonyl, di-lower alkylamino and/or by trifluoromethyl, or 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, that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or by hydroxy, ri represents 0, 1 or 2, and R3 represents carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- or N#N-di-lower alkyl-carbamoyl-lower alkyl or hydroxy-lower alkyl, mono- or di-lower alkoxy-lower alkyl, lower alkylenedioxy-lower alkyl, lower alkylidenedioxy-lower alkyl or oxo-lower alkyl carrying the hydroxy, lower alkoxy, lower alkylenedioxy, lower alkylidenedioxy or oxo group(s), respectively, in a position higher than the o-position, and their salts, especially their pharmaceutically acceptable salts.

The invention relates very especially to compounds of the formula I in which the radicals R1 and R2# independently of one another, represent phenyl that is unsubstituted or substituted by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, lower alkylthio having up to and including 4 carbon atoms, such as methylthio, or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, ji represents 0, and R3 represent carboxy-lower alkyl having up to and ^ including 4 carbon atoms in the lower alkyl moiety[jM 1*2 8 SEP 1967 9^ 211465 -n- and carrying the carboxy group in the a-position, such as carboxymethyl, 1-carboxyethyl or 2-(2-carboxy)-propyl, and their salts, especially their pharmaceutically acceptable salts.

The invention relates more especially to compounds of the formula I in which and R^ represent : 3 a phenyl radical substituted by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, which is bonded especially in the o-position, ri represents 0, 1 or 2, and represents carboxy- or lower alkoxycarbonyl-lower alkyl having up to and including 4 carbon atoms in the lower alkyl moiety or in the lower alkyl and lower alkoxy moiety, as the case may be, and carrying the carboxy or lower alkoxy-carbonyl group, respectively, in the a-position, such as carboxymethyl, 1-carboxyethyl, methoxy- or ethoxy-carbonylmethyl or 2-(2-carboxy)-propyl, or hydroxy-lower alkyl having from 2 up to and including 4 carbon atoms, such as 2-hydroxyethyl or 3-hydroxypropyl, oxo-lower alkyl having from 2 up to and including 4 carbon atoms, such as 2-oxoethyl or 3-oxopropyl, or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl each having up to and including 4 carbon atoms in each alkyl(ene) moiety, such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2,2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-ethylenedioxyethyl, carrying the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group, respectively, in a position higher than the exposition, and their salts, especially their pharmaceutically acceptable salts.

The invention relates more especially to compounds of the formula I in which the radicals R-i and R,, .

/Ten r independently of one another, represent phenyl ' ** O,, U 2 8 SEP 1987 211465 12 that is unsubstituted or substituted by lower alkoxy having.up to and including 4 carbon atoms, such as methoxy, lower alkylthio having up to and including 4 carbon atoms, such as methylthio, or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, n_ represents 0, and represents hydroxy-lower alkyl having from 2 up to and including 4 carbon atoms, such as hydroxyethyl or 3-hydroxypropyl, oxo-lower alkyl having from 2 up to and including 4 carbon atoms, such as 2-oxoethyl or 3-oxopropyl, or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl each having up to and including 4 carbon atoms in each alkyl(ene) moiety, such as 2-methoxyethyl, 2,2-dimethoxymethyl, 2,2-dimethoxyethyl, 3,3-dimethoxypropyl or 2,2-ethylenedioxyethyl, carrying the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group, respectively, in a position higher than the a-position, and their salts, especially their pharmaceutically acceptable salts.

The invention relates very especially to compounds of the formula I in which R^ and R£ represent a phenyl radical substituted by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, which is bonded especially in the jd-position, ti represents 0, 1 or 2, and R3 represents carboxy-lower alkyl having up to and including 4 carbon atoms in the lower alkyl moiety and carrying the carboxy group in the a-position, such as carboxymethyl, 1-carboxyethyl or 2-(2-carboxy)-propyl, and their salts, especially their pharmaceutically acceptable salts.

The invention relates specifically to the novel *!> $ <1 /I &so L' |j compounds of the formula I mentioned in the Examples and to their pharmaceutically acceptable salts, to processes for their manufacture, to pharmaceutical preparations containing them and to their use.

The compounds of the formula I can be manufactured according to methods known per se, for example as follows: in a compound of the formula R1-N-N (II) in which one of the radicals Y-| and Y2 represents a removable radical Y and the other represents a hydrogen atom, and Y3 and Y4 together represent an additional bond, or in which Y4 represents a removable radical Y and Y3 represents hydrogen, and Y-| and Y2 represent an additional bond, or in a salt thereof, HY is removed with the introduction of an additional bond and, if necessary, an isomeric mixture obtainable according to the process is separated into the components and the isomer of the formula I is isolated and, if desired, a compound obtainable according to the process is converted into a different compound of the formula I and/or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process is converted into the free compound or into a different salt.

Removable radicals Y are, for example, optionally esterified or etherified hydroxy or mercapto groups, and also amino, ammonio and sulphonium groups. There comes into consideration as esterified hydroxy, for example, hydroxy esterified by an inorganic acid or by an organic carboxylic acid, such as halogen, for example chlorine or bromine, or lower alkanoyloxy, for example acetoxy. Etherified hydroxy groups are, for example, lower alkoxy groups, for example methoxy or ethoxy. Esterified mercapto groups are, for example, mercapto groups esterified by a lower alkanecarboxylic acid, such as acetylthio. Etherified mercapto groups and sulphonium groups are, for example, lower alkylthio and di-lower alkylsulphonium groups, such as methyl-thio, ethylthio and dimethylsulphonium. Amino groups are, in addition to groups R-j-NH-, for example, di-lower alkyl- or alkylene- or aza-, oxa- or thia-lower alkylene-amino groups, for example dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or thiomorpholino, and also anilino. Ammonium groups are, for example, tertiary ammonium groups corresponding to the amino group mentioned above or quaternary ammonium groups, such as tri-lower alkylammonio or pyridinio.

The removal of HY takes place in customary manner either spontaneously or by means of gentle heating, for example at approximately from 40 to 200°C, if necessary in the presence of an auxiliary and/or an inert solvent. As auxiliaries there come into consideration, for example, acidic agents, such as mineral acids or their anhydrides or acidic salts, for example hydrohalic acids, especially hydrochloric, hydrobromic or hydriodic acid, sulphuric acid, alkali metal hydrogen sulphates, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride, phosphorus oxychloride or phosphorus tribromide, organic sulphonic acids, such as j>- 2 11 " ) toluenesulphonic acid, or carboxylic acids and their anhydrides, such as lower alkanoic acids and their anhydrides or halides, for example acetic acid, acetic anhydride or acetyl chloride, and also buffered acid°*---^ solutions, for example phosphate or acetate buffer, hydrohalides of nitrogen-containing bases, for example ammonium or pyridinium chloride.

In many cases, however, it is also possible to use basic condensation agents, such as hydroxides, carbonates or lower alkoxides of alkali metals or alkaline earth metals, for example sodium, potassium or calcium hydroxide, sodium or potassium carbonate or sodium methoxide, and also organic nitrogen-containing bases, such as tri-lower alkylamines, for example triethylamine, or aromatic tertiary bases, such as pyridine.

The starting materials of the formula II are preferably manufactured jji situ, for example by cyclising a compound, or a salt thereof, of the formula Ra - NH - C(Y5) (Y6) - Rb (III) in which either RA represents a group of the formula -NH-N=C(SR^)- and R0 represents a group R£, or R^ represents a group of the formula R2-C (=NH)-N (R-j) -and Rg represents a group -SR3, and Y5 and Yg, independently of one another, each represents a radical Y, such as optionally esterified or etherified hydroxy, etherified mercapto or optionally substituted amino, or together represent oxo, thioxo or optionally substituted imino, such as lower alkylimino, optionally substituted anilo or groups of the formula =N-R-j .

The cyclisation of compounds of the formula III is effected in customary manner, under neutral, acidic or basic conditions, if necessary in the presence of one 1 1 16 of the mentioned acidic or basic agents, in the presence of an inert solvent or diluent, while heating, for example in a temperature range of approximately from 40 to 200°C, preferably approximately from 60 to 140°C, and/or under an inert gas, such as nitrogen.

There are several possible methods of forming compounds of the formula III. For example, compounds of the formula III in which RA represents a group of the formula -NH-N=C(ZR^) - and RQ represents a group R2 and Y5 and Yg together represent oxo are obtained, for example, by reacting a compound of the formula R-,-NH-N=C (SR3) -NH2 (IV), [which can readily be obtained, for example, by reacting an imino compound of the formula Y-C(=NH)-SR3 (V) in which Y has the meaning indicated and represents especially lower alkoxy, halogen or amino, or an isothiocyanate of the formula NEC-SR3 (Va), or an acid addition salt, for example a hydrohalide, thereof, for example in ethanol, with a substituted hydrazine of the formula R1~NH-NH2 (VII)] or a salt thereof, with a compound of the formula Y'-C(Y^)(Yg)-R2 (IX) in which Y^ and Yg have the meanings indicated and Y1 represents a group Y or, if Y5 and Yg together represent oxo, a group of the formula R2-C(=0)-0-, in customary manner, for example in the presence of a basic condensation agent.

Compounds of the formula III in which RA represents a group of the formula R2~C(=NH)-N(R^)-, Y5 + Yg = oxo and RB represents an R3S group are obtained, for example, by reacting a compound of the formula R2-C(=NH)-Y (XVI), or a hydrohalide thereof, with a compound of the formula R^NH-NH-C (Y5) (Yg)-SR3 (XVII) in which Y represents esterified or etherified hydroxy, for example halogen or lower alkoxy, and Y5 + Yg represent especially oxo, for example in a lower alkanol, such as ethanol.

In general, however, the intermediate of the formula III will not be isolated since, according to some important process variants, the synthesis of end products of the formula I via intermediates of the formulae III and II can be effected without intermediates being isolated. According to one important process variant, for example, compounds of the formulae R1-NH-NH2 (VII) and R2"C (Y£) (Y£) -NH-C (Y£) (Yg) -SR3 (XVIII) in which Y^, Yg, Y|! and Yg, independently of one another, each has one of the meanings given for Y, or Y,I + Yg and/or Y|! + Yg represent oxo, thioxo or optionally substituted imino, for example imino, lower alkylimino, anilo or an imino radical of the formula R-j-N=, it being possible for compounds of the formula XVIII also to be in tautomeric form, for example of the formula R2~C(Y^) (Yg)-N=C (Y)-SR3 (XVI Ila) or R2-C(Y)=N-C(Y£)(Yg)-SR3 (XVIIIb). The reaction is effected in customary manner, for example in the presence of one of the mentioned acidic or basic condensation agents, if necessary in the presence of an inert solvent or diluent, while heating, for example in a temperature range of approximately from 40° to 200°C, preferably approximately from 60° to 140°C, and/or under an inert gas, such as nitrogen.

Preferred methods of synthesising compounds of the formula I directly, which take place via the intermediates of the formula III and II, are: reacting compounds of the formula VII with compounds of the formula XVIII (Y' and YI = oxo, Y" and Y!I = thioxo) 6 5 6 or XVIIIa (Y' and Yl = oxo, Y = reactive esterified 3 O hydroxy, for example halogen, or etherified hydroxy, for example lower alkoxy, or di-lower alkylamino) under weakly acidic conditions, for example in the presence of an organic carboxylic acid, such as acetic acid, an ammonium/mineral acid salt, for example pyridinium 1 1465 chloride in acetic acid, or an acidic buffer system, such as an acetate or phosphate buffer; and condensing compounds of the formulae XVI and XVII, for example in ethanol at approximately from 10 to 50°C and subsequently effecting cyclisation at approximately from 80° to 160°C, for example in boiling xylene.

A. method that also takes place via intermediates of the formulae II and III is the formation of I-R1-R3-5-R2-IH-I,2,4-triazoles by reacting acylated thiosemicarbazides of the formula R2-C(=0)-NH-C(=S)-NH-NH-R1 (XXIII) with compounds of the formula R3-Y (XXIV) in which R3 has the meaning indicated and Y represents reactive esterified hydroxy, or with aliphatic epoxides.

The compounds of the formula I can also be manufactured by condensing compounds of the formulae R,-N-N 1 X —Yn R2 N and Y12 - R3 (XXXII) (XXXI) in which Y^-j represents a mercapto group optionally present in salt form and Y12 represents reactive esterified hydroxy, or Y-|-| represents sulphonyl and Y-|2 represents a mercapto group optionally present in salt form, to form the corresponding compound of the formula I in which 11 represents 0, and, if necessary or if desired, carrying out one or more of the mentioned additional reactions.

Sulphonyl is, for example, lower alkanesulphonyl, for example methane- or ethane-sulphonyl, or optionally substituted benzenesulphonyl, for example benzene-, £-toluene- or jD-bromobenzene-sulphonyl, and also fluorosulphonyl. 211465 As salt forms of the mercapto group there come into consideration, for example, metal salt forms thereof, such as alkali metal or alkaline earth metal salt forms, if ji is 1 or 2, also the ammonium salt ° forms with ammonia or organic amines. Such salts are preferably produced Jji situ by the action of an equivalent amount of the relevant base on the free mercapto reactant and are used without isolation.

The condensation is effected in customary manner, preferably in an inert solvent, if necessary while cooling or heating, for example in a temperature range of approximately from 0 to 100°C, in a closed vessel and/or under an inert gas, such as nitrogen. As inert solvents there come into consideration especially polar solvents, such as lower alkanols, di-lower alkyl ketones, N,N-di-lower alkylalkanecarboxylic acid amides or N-lower alkyl lactams or di-lower alkyl sulphoxides. If necessary, the operation is carried out with catalysts, if Y-|2 represents etherified hydroxy, for example, in the presence of dilithium palladium tetrachloride.

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

Thus, compounds of the formula XXXI in which represents mercapto can be obtained, for example, by cyclising a compound of the formula R^-NH-NH-C(=S)-NH-C(=0)-R2 (XXXIV) [which can be obtained, for example, by reacting a thiosemicarbazide of the formula R1-NH-NH-C(=S)-NH2 (XXXV) with a compound of the formula R2-C(=0)-Y (IXb, Y = halogen, or R2-C(=0)-0-)] in customary manner. Compounds of the formula XXXI in which Y^ represents mercapto are also obtained by reacting a compound of the formula R-j-NH-NH2 (VII) with thiophosgene or an alkali metal thiocyanate and then with a compound of the formula IXb.

The compounds of the formula I can also be manufactured by condensing compounds of the formulae in which one of the radicals Y-j-j and Y^ represents a metallic radical and the other represents a group -S(0)n-Y-|2 in which Y13 represents halogen, and, if necessary or if desired, carrying out one or more of the mentioned additional reactions.

R3 in this case represents an aliphatic hydrocarbon radical substituted by etherified hydroxy and/or mercapto groups.

Metallic radicals are, for example, groups of the formulae -M1, -MI3-^2 or -MII-Hal, in which M1 represents a metal atom from group 1h of the Periodic Table of Elements, for example lithium or sodium, and M11 represents a metal atom from groups 2A and 2B, for example magnesium, cadmium or zinc, and Hal represents a halogen atom.

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

The reaction is effected in customary manner, preferably in an inert solvent, if necessary while cooling or heating, and/or under an inert gas, such as nitrogen, for example in a temperature range of from -80° to approximately +60°C, preferably from approximately -25° to approximately +40°C. In a preferred form of this process, a compound of the formula XXXI in which Y^ is a halosulphenyl group is used as starting material and is reacted at approximately from -10° to +10°C in tetrahydrofuran or ■Y11 (XXXI) and Y12~R3 (XXXII) or R3~S-S-R3 (XXXIIa) v-=N / 2 1 1465 hexamethylphosphoric acid triamide with a compound of the formula XXXII in which Y-^ represents an alkali metal atom or a halogen/alkaline earth group. In another preferred form, for example, a compound of the formula XXXI in which Y-j q represents an alkali metal atom is reacted with a compound of the formula R3-S-S-R3 (XXXIIa).

Starting materials of the formula XXXI in which Y-j -j represents a group of the formula -S-Y-j3 in which Y-|3 is halogen are obtained, for example, by halogenating a compound of the formula XXXI in which Y-j-j represents mercapto in customary manner, for example by reaction with chlorine, for example in tetrachloromethane, optionally after prior treatment with iodine.

Compounds of the formula XXXI in which Yq-j represents a metallic radical can be manufactured, for example, by reacting a compound of the formula XXXI in which Y^1 represents hydrogen [which can be obtained, for example, by reaction of compounds of the formulae R2-C(=0)-NH-CHO (XXXVI) and R1-NH-NH2 (VII)] with an organometal compound, such as an alkali metal or alkaline earth metal hydrocarbon compound, for example with butyllithium, phenylsodium or butyl-magnesium bromide. It is also possible, however, to start from a compound of the formula XXXI in which Y^ represents halogen, and to react this compound with an alkaline earth metal, for example magnesium. h further process for the manufacture of compounds of the formula I is characterised in that a compound of the formula 211465 Rj^-N-N r2-.=n "Yll (XXXI) in which Y^ is mercapto, or a salt thereof, is reacted with a vicinal epoxy derivative derived from a compound of the formula R3-H (XXXVII) to form a compound of the formula I in which R3 contains a hydroxy group in the 8-position and r\ is 0, and, if necessary or if desired, one or more of the mentioned additional reactions is carried out.

As salts of compounds of the formula XXXI there come into consideration, for example, the metal salts thereof, preferably alkali metal or alkaline earth metal salts.

Vicinal epoxides derived from compounds of the formula XXXVII are, for example, vicinal aliphatic epoxides, such as a,8-epoxy-lower alkanes.

The reaction is effected in customary manner, for example in an inert solvent, such as a lower alkanol, or a tertiary amide, for example in hexamethyl-phosphoric acid triamide, if necessary in the presence of a condensation agent; for example, when using free mercaptans of the formula XXXI, in the presence of a basic agent that is capable of salt formation, such as an alkali metal alcoholate or hydroxide, for example sodium methoxide or sodium hydroxide, while cooling or heating and/or under an inert gas, such as nitrogen.

A further process for the manufacture of compounds of the formula I is characterised in that a compound of the formula ■R -N-N (XXXI) in which is mercapto, or a salt thereof, is reacted with a compound of the formula R^-H (XXXVIII) in which R^ represents an aliphatic radical that is derived from R3 and has a C-C double bond or C-C triple bond at least in the ct,B-position, to form a compound of the formula I in which R3 is a, 8-saturated or a,8-singly unsaturated and ji is 0, and, if necessary or if desired, one or more of the mentioned additional reactions is carried out.

As salts of mercaptans of the formula XXXI there come into consideration especially the metal salts thereof, preferably alkali metal or alkaline earth metal salts.

As compounds of the formula XXXVIII there come into consideration, for example: carboxy-lower alkenes, lower alkoxycarbonyl-lower alkenes, carbamoyl- or N- . lower alkyl-, N,N-di-lower alkyl-, N,N-lower alkylene-or N,N-(3-aza-, 3-oxa- or 3-thia-)-lower alkylene-carbamoyl-lower alkenes, or mono- or di-lower alkoxy-lower alkenes, lower alkylenedioxy-lower alkenes, lower alkanoyloxy-lower alkenes, mono- or di-lower alkylthio-lower alkenes, lower alkanesulphinyl- or lower alkanesulphonyl-lower alkenes, lower alkylenedithio-lower alkenes, mono- or di-hydroxy-lower alkenes and oxo-lower alkenes carrying the lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl, hydroxy, lower 2 1 1465 alkanoyloxy, lower alkylenedithio or oxo group(s), respectively, in a position higher than the 8-position.

The reaction is effected in customary manner, f-ar.. example in an inert solvent, such as a tertiary amide, for example in dimethylformamide or N-methylpyrroli-done, if necessary in the presence of a condensation agent, while cooling or heating and/or under an inert gas, such as nitrogen. As condensation agents there come into consideration, when using mercaptans of the formula XVI, for example, organic nitrogen-containing bases, such as di- or tri-lower alkylamines, for example diisopropylamine or triethylamine, or alkylene-or aza-, oxa- or thia-alkylene-amines, for example pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine.

The novel compounds of the formula I can also be manufactured as follows: in a compound of the formula R1-N-N r2-.=n' i-S'(O) -R" n 3 (I XL) in which R^ represents a radical that can be converted into a group R^, R^ is converted into the desired group R3 and, if necessary or if desired, one or more of the mentioned additional reactions is carried out.

Radicals that can be converted into radicals R3 are, for example, radicals R3 containing a carboxy group and optionally substituted by a further carboxy group, especially 1,1-dicarboxy-lower alkyl or 1-carboxy-2-oxo-lower alkyl radicals or radicals of the formula -C(=0)-0-R3. The conversion of these radicals into radicals R3 is carried out by removal of carbon dioxide.

The removal of carbon dioxide can be effected in customary manner, for example by the action of an acid, such as by treatment with a protonic acid, such as a mineral acid, for example hydrochloric or sulphuric acid, advantageously in a solvent or diluent, if necessary while heating, for example at from approximately 50° to approximately 250°C.

Thus, compounds of the formula IXL in which R^ represents a 1-carboxy-2-oxo- or 1,1-dicarboxy-lower alkyl radical can be converted into compounds of the formula I in which R3 represents a 1-carboxy- or 2-oxo-lower alkyl radical by heating with aqueous acid solutions, for example with equal parts of approximately 15% hydrochloric acid and acetic acid, at approximately from 60 to 100°C.

It is also possible to convert compounds of the formula IXL in which R3 represents a radical of the formula -C(=0)-0-R3 into the corresponding compounds of the formula I, for example by heating with a mineral acid, for example with hydrogen chloride in tetrahydrofuran, with carbon dioxide being removed.

Other radicals R3 that can be converted into groups R3 are, for example, radicals R3 containing at least one hydroxy group etherified by an a-phenyl-lower alkanol or at least one carboxy group esterified by an a-phenyl-lower alkanol, or containing at least one hydroxy group esterified by a carboxylic acid, such as a halogenated lower alkanoic acid or by carbonic acid or a semiester or semiamide thereof, such as optionally substituted benzyloxy, optionally halogenated lower alkanoyloxy or lower alkoxy- 26 carbonyloxy, benzyloxycarbonyloxy, di-lower alkylcarbamoyloxy or carbonyldioxy. As such radicals there come into consideration, for example: optionally substituted mono- or di-benzyloxy-lower alkyl, optionally halogenated mono- or di-lower alkanoyloxy-lower alkyl, mono- or di-lower alkoxycarbonyloxy-lower alkyl, benzyloxycarbonyl-lower alkyl or carbonyldioxy-lower alkyl carrying the benzyloxycarbonyloxy, optionally halogenated lower alkanoyloxy or lower alkoxy-carbonyloxy group(s) or the carbonyldioxy group, respectively, in a position higher than the a-position, radicals. The conversion of these radicals into is effected for example, by reduction by treatment with a suitable reducing agent.

As reducing agent for the reduction of a-phenyl-lower alkoxy and a-phenylalkoxy groups there comes into consideration, for example, hydrogen in the presence of a hydride, the operation advantageously being carried out in an inert solvent, if necessary at elevated pressure and/or while cooling or heating. Hydroxy groups esterified by carboxylic acids, including a-phenyl-lower alkoxycarbonyloxy groups, can be reduced, for example, by means of di-light metal hydrides, for example with lithium aluminium hydride. 2-halo-lower alkoxycarbonyloxy, for example 2,2,2-trichloro- or 2-iodo-ethoxycarbonyloxy, aroylmethoxy'-carbonyloxy or 4-nitrobenzyloxycarbonyloxy can be removed, for 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. Aroylmethoxycarbonyloxy can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitro-benzyloxycarbonyloxy can be cleaved also by treatment with an alkali metal dithionite, for example sodium 2 f 1 dithionite.

Other radicals R!j are radicals that can be solvolysed to groups R3, for example radicals R^ that contain one or two halogen atom(s) , *' a bivalent functionally modified oxo group, for example imino, a functionally modified carboxy group other than esterified and amidated carboxy according to the definition given at the beginning, such as an iminoether grouping, an amidino grouping optionally substituted as indicated for amidated carboxy, or halocarbonyl or optionally substituted phenoxycarbonyl, for example phenoxy-, ja-nitrophenoxy- or 2,4-dinitrophenoxy-carbonyl, or at least one acyloxy group derived from an alkanecarboxylic acid substituted by halogen or aryl or derived from a carbonic acid semiester, at least one silyloxy group or an arylenedioxy group, such as a 1,2-phenylenedioxy group, two geminally bonded aryloxy groups, such as phenoxy groups, or a vicinally bonded lower alkylidene- or mono-or di-aryl-lower alkylidene-dioxy group.

Removable 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 substituted in the 1- or 2-position, especially tert.-lower alkoxycarbonyloxy, benzyloxycarbonyloxy which can optionally be substituted by lower alkyl, especially tert.-butyl, lower alkoxy, hydroxy, halogen and/or by nitro, or optionally correspondingly substituted di-phenylmethoxycarbonyloxy. Such radicals are 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetoxy, tert.-butoxycarbonyloxy, 4-nitrobenzyloxy-carbonyloxy, phenacyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, for example 2,2,2-trichloroethoxy-carbonyloxy, 2-bromoethoxycarbonyloxy or 2- 2 1 146 iodoethoxycarbonyloxy, or 2-(tri-substituted silyl)-ethoxycarbonyloxy, in which the substituents, independently of one another, each represents an optionally substituted, for example lower alkyl-, lower alkoxy-, aryl-, halogen- or nitro-substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having, for example, up to 15 carbon atoms, such as corresponding optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxy-carbonyloxy, such as 2-trimethylsilylethoxycarbonyloxy or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyloxy, or 2-triarylsilylethoxycarbonyloxy, such as 2-triphenyl-silylethoxycarbonyloxy.

A silyloxy group is especially tri-lower alkyl-silyloxy, especially trimethylsilyloxy, also dimethyl-tert.-butyl-silyloxy.

Radicals R^ containing a halogen atom, at least one of the mentioned acyloxy groups, at least one silyloxy group, an arylenedioxy group, two geminally bonded aryloxy groups or a vicinally bonded lower alkylidene- or mono- or di-aryl-lower alkylidene-dioxy group can be converted by solvolysis into aliphatic radicals Rj containing hydroxy, such as mono- or di-hydroxy-lower alkyl; radicals R^ containing a halogen atom can also be converted by solvolysis into radicals Rg substituted by etherified or organically esterified hydroxy or by etherified mercapto, such as lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl or lower alkylthio-lower alkyl; radicals R^ containing two halogen atoms or a functionally modified oxo group can be converted by solvolysis into radicals R3 that contain oxo or are substituted by etherified or organically esterified hydroxy, such as oxo-lower 2 114 alkyl, di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl, and radicals containing a functionally modified carboxy group can be converted by solvolysis into optionally esterified or amidated carboxy R^, such as carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or optionally aliphatically N-substituted carbamoyl-lower alkyl.

The solvolysis of radicals R|j containing groups that can be solvolysed to hydroxy is effected, for example, by hydrolysis (treatment with water), alcoholysis (treatment with an alcohol), mercaptolysis (reaction with a mercaptan), by reaction with an organic carboxylic acid or a salt thereof, or by ammonolysis or aminolysis (treatment with ammonia or an organic amine)„ By hydrolysis it is possible, for example, to convert radicals R^ that contain a halogen atom, at least one of the mentioned acyloxy groups, at least one silyloxy group, an arylenedioxy group, two geminally bonded aryloxy groups or a vicinally bonded lower alkylidene- or mono- or di-aryl-lower alkylidene-dioxy group into radicals R3 substituted by hydroxy, such as mono- or di-hydroxy-lower alkyl; to convert radicals R^ containing two halogen atoms or a bivalent functionally modified oxo group into radicals R3 containing oxo, such as oxo-lower alkyl; to convert functionally modified carboxy-lower alkyl R^ into carboxy-lower alkyl, and to convert functionally modified carboxy-lower alkyl radicals R'^ containing an iminoether grouping or an optionally aliphatically N-substituted amidine grouping into esterified or amidated carboxy-lower alkyl R3.

The hydrolysis is carried out in customary manner, if necessary in the presence of a hydrolysing agent and/or in the presence of an inert solvent, while 2 1 *> cooling or heating and/or under an inert gas. Hydrolysing agents are, for example, acidic or alkaline agents. Acidic agents are, for example, mineral acids, hydrohalic acids, for example hydrochloric, hydrobromic or hydriodic acid, or oxyacids of sulphur or phosphorus, or acidic salts thereof, such as sulphuric acid, potassium hydrogen sulphate or phosphoric acid, or organic carboxylic or sulphonic acids, for example lower alkanoic acids, such as acetic acid, trifluoroacetic acid or chloroacetic acid, or jd-toluenesulphonic acid. Basic agents are, for example, hydroxides or carbonates of alkali metals or alkaline earth metals, such as potassium, sodium or calcium hydroxide, and potassium or sodium carbonate. Inert solvents are, for example, polar, water-miscible solvents, such as alcohols, for example methanol or ethanol, lower alkylene ethers, such as dioxan, di-lower alkyl ketones, such as acetone, tertiary amides, for example dimethylformamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide, or di-lower alkyl sulphoxides, for example dimethyl sulphoxide.

By alcoholysis it is possible, for example, to convert aliphatic radicals R!j containing one or two halogen atom(s) or bivalent functionally modified oxo into aliphatic hydrocarbon radicals R^ substituted by etherified hydroxy, such as mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl, or to convert aliphatic radicals R'^ containing halocarbonyl into radicals R-j containing esterified carboxy, such as lower alkoxycarbonyl, and in radicals R^, hydroxy groups esterified by organic carboxylic acid are freed by transesterification. The alcoholysis is effected in customary manner, for example in the presence of a basic agent and, in the case of transesterification, also in the presence of an acidic agent, if necessary 211465 while cooling or heating and/or under an inert gas, such as nitrogen. As acidic and basic agents there come into consideration, for example, those mentioned, and as basic agents also metal alcoholates, such as alkali metal or alkaline earth metal lower alkoxides, for example sodium methoxide.

By mercaptolysis it is possible, for example, to convert radicals Rjj containing one or two halogen atom(s) or bivalent functionally modified oxo into radicals R3 substituted by etherified mercapto, such as lower alkylthio-lower alkyl or lower alkylenedithio-lower alkyl. The mercaptolysis is effected in customary manner, for example in the presence of a basic condensation agent or by using the mercaptan component in salt form, such as in the form of an alkali metal salt.

In a modification of this process, it is also possible to convert a mercapto-substituted lower alkyl radical R!j into lower alkylthio-lower alkyl by reaction with any of the reactive esters of a lower alkanol, such as a lower alkyl halide or dimethyl sulphate.

Aliphatic radicals R3 having a halogen atom can also be converted into radicals R3 containing organically esterified hydroxy, such as lower alkanoyloxy-lower alkyl, by reaction with a salt of a carboxylic acid, such as a lower alkanoic acid alkali metal salt.

By aminolysis or ammonolysis it is possible, for example, to convert aliphatic radicals R3 containing halocarbonyl into aliphatic hydrocarbon radicals R3 substituted by amidated carboxy, such as optionally aliphatically N-substituted carbamoyl-lower alkyl radicals, advantageously in the presence of a basic condensation agent. It is also possible by aminolysis, however, to free the hydroxy group from the mentioned acyloxy groups. 32 Halo-lower alkyl can, however, also be first converted into the isothiouronium derivative by reaction with thiourea and then converted into lower alkylthio-lower alkyl by hydrolysis and alkylation. 2-substituted silylethoxycarbonyl can advantageously be cleaved by treatment with an alkali metal fluoride, for example with potassium fluoride.

The conversion by solvolysis of radicals containing halogen into the mentioned radicals R3 other than mono- or di-hydroxy-lower alkyl is customarily carried out in the presence of a basic condensation agent, such as an alkali metal hydroxide, or a tertiary organic nitrogen-containing base, such as a tri-lower alkylamine, or a heteroaromatic base, such as pyridine, or by using the component corresponding to the radical to be introduced in the form of a salt, such as an alkali metal or alkaline earth metal salt.

The starting materials can be manufactured according to methods known per se, for example by removing HY from compounds of the formula in which Y-j, Y2, Y-j and Y4 have the meanings given under formula II, and, if desired, oxidising the thio group, or by reacting compounds of the formulae Y 3 (XL) 2 1 1465 Rj-N-N r2-.=n \—Y H (xxxi) and Y12-R^ (XLI) in which one of the radicals Y^ and Y12 represents a reactive esterified hydroxy group and the other represents a mercapto group present in salt form.

Compounds of the formula I that can be obtained according to the process or according to other procedures not mentioned above can, if desired, be converted into other compounds of the formula I in a manner known per se. If necessary, an isomeric mixture obtainable according to the process can be separated into the pure isomers and, if desired, a compound obtainable according to the process can be converted into a different compound of the formula I, and/or a free compound obtainable according to the process can be converted into a salt, or a salt obtainable according to the process can be converted into the free compound.

Thus, for example, optionally etherified or esterified hydroxy groups can be converted into one another.

If, for example, at least one of the radicals R1, R2 and R^ contains a hydroxy group, this group can be etherified in customary manner. Thus, hydroxy as a constituent of R^ can be converted into a corresponding lower alkoxy group by using a lower alkylating agent, such as a lower alkanol, for example methanol, in the presence of an acid, such as a 211465 mineral acid, for example sulphuric acid, or in the presence of a dehydrating agent, such as dicyclohexyl carbodiimide, and hydroxy in a radical R-j or R2 can be converted into a corresponding lower alkoxy group, for example, in the presence of bases, such as alkali metal hydroxides or carbonates, for example sodium hydroxide or potassium carbonate, with the aid of di-lower alkyl sulphates or diazo-lower alkanes. Conversely, ethers, such as lower alkoxy groups, as substituents of R-j or R2 can be removed, for example by treatment with acids, such as with Lewis acids, for example boron tribromide, or mineral acids, for example hydrogen iodide.

Furthermore, hydroxy can be esterified, for example converted into lower alkanoyloxy, for example by reaction with a corresponding lower alkanecarboxylic acid, such as acetic acid, or a reactive derivative, such as a symmetrical anhydride, thereof or an anhydride with a hydrohalic acid, if necessary in the presence of a condensation agent: when using anhydrides, for example, in the presence of a basic condensation agent, such as an alkali metal hydroxide or carbonate, or a tertiary nitrogen-containing base, for example a tri-lower alkylamine or pyridine, and when using an acid, for example, in the presence of an acid, such as a protonic acid, for example hydrochloric, sulphuric or phosphoric acid or a sulphonic acid, or a Lewis acid, for example boron trifluoride etherate.

Furthermore, free carboxy as a constituent of R-j can be esterified to form an esterified carboxy group in customary manner, for example by treatment with a diazo-lower alkane or tri-lower alkyloxonium, tri-lower alkylcarboxonium or di-lower alkylcarbonium salt, such as hexachloroantimonate or hexafluorophosphate, or 2 1 146 it ' V especially by reaction with the corresponding alcohol or a reactive derivative, such as a carboxylic, phosphorous, sulphurous or carbonic acid ester, for example a lower alkanecarboxyl ic acid ester, tri-lower'"^ alkylphosphite, di-lower alkylsulphite, or a pyro-carbonate, or a mineral acid ester or sulphonic acid ester, for example a hydrochloric or hydrobromic acid ester or a sulphuric, benzenesulphonic, toluene-sulphonic or methanesulphonic acid ester, of the corresponding alcohol, or an olefin derived therefrom.

The reaction with the corresponding alcohol itself can advantageously take place in the presence of an acidic catalyst, such as a protonic acid, for example hydrochloric or hydrobromic, sulphuric, phosphoric, boric, benzenesulphonic and/or toluenesulphonic acid, or a Lewis acid, for example boron trifluoride etherate, in an inert solvent, especially in an excess of the alcohol used, and, if necessary, in the presence of a water-binding agent and/or with removal by distillation, for example azeotropic distillation, of the water of reaction, and/or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol can be carried out in customary manner, when starting from a carboxylic, phosphorous, sulphurous or carbonic acid ester, for example, in the presence of an acidic catalyst, such as one of those mentioned above, in an inert solvent, such as an aromatic hydrocarbon, for example in benzene or toluene, or in an excess of the alcohol derivative used or the corresponding alcohol. When starting from a mineral acid ester or sulphonic acid ester, the acid to be esterified is advantageously used in the form of a salt, for example the sodium or potassium salt, and the operation is, if necessary, carried out in the presence of a basic condensation agent, such as an inorganic 2 1 f- 4 & base, for example sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen-containing base, for example triethylamine or pyridine, and/or in an inert solvent, such as one of the above-mentioned tertiary nitrogen-containing bases or a polar solvent, for example in dimethylformamide, and/or at elevated temperature.

The reaction with an olefin can be effected, for example, in the presence of an acidic catalyst, for example a Lewis acid, for example boron trifluoride, a sulphonic acid, for example D-toluenesulphonic acid, or especially a basic catalyst, for example sodium or potassium hydroxide, advantageously in an inert solvent, such as an ether, for example in diethyl ether or tetrahydrofuran.

A free carboxy group can also be converted into an amidated carboxy group by reaction with ammonia or with an amine having at least one hydrogen atom in customary manner, the ammonium salt formed intermediately being dehydrated, for example by azeotropic distillation with benzene or toluene or by dry heating.

The above-described conversions of free carboxy groups into esterified or amidated carboxy groups can, however, also be carried out by first converting a compound of the formula I in which R3 contains carboxy into a reactive derivative in customary manner, for example into an acid halide by means of a halide of phosphorus or sulphur, for example by means of phosphorus trichloride or tribromide, phosphorus pentachloride or thionyl chloride, or, by reaction with a corresponding alcohol or amine, into a reactive ester, that is to say an ester having electron-attracting structures, such as the ester with phenol, thiophenol, _£-nitrophenol or cyanomethyl alcohol, or into a reactive amide, for example the amide derived 2 15 if " u from imidazole or 3,5-dimethylpyrazole, and then reacting the resulting reactive derivative in customary manner, for example as described hereinbelow for the transesterification or conversion into one another of'-esterified and amidated carboxy groups, with a corresponding alcohol, ammonia or the corresponding amine having at least one hydrogen atom, to form the desired group.

An esterified carboxy group can be converted in customary manner into a free carboxy group, for example by hydrolysis in the presence of a catalyst, for example a basic or acidic agent, such as a strong base, for example sodium or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric acid, or into an amidated carboxy group, for example by reaction with ammonia or the corresponding amine having at least one hydrogen atom.

An esterified carboxy group can also be trans-esterified to form a different esterified carboxy group in customary manner, for example by reaction with a metal salt, such as the sodium or potassium salt, of a corresponding alcohol or with the alcohol itself in the presence of a catalyst, for example a strong base, for example sodium or potassium hydroxide, or a strong acid, such as a mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric acid, or an organic sulphonic acid, for example £-toluenesulphonic acid, or a Lewis acid, for example boron trifluoride etherate.

An amidated carboxy group can be converted into a free carboxy group in customary manner, for 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, for example sodium or potassium hydroxide or carbonate, or a strong acid, ^ <f] /! ,7 JL S i 4o such as a mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric acid.

Cyano can be hydrolysed to carbamoyl or carboxy by hydrolysis, for example under basic conditions, or can be converted into esterified or amidated carboxy by reaction with an alcohol or with ammonia or a primary or secondary amine in the presence of an acid, such as hydrochloric acid, and by subsequent hydrolysis. Conversely, carbamoyl can be dehydrated to form cyano by heating, if necessary in the presence of a water-binding agent, for example phosphorus pentoxide or polyphosphoric acid, or an N,N-disubstituted carbodi-imide, for example N,N-dicyclohexyl carbodiimide.

Furthermore, carboxy-lower alkyl radicals of the formula -CmH2m~C00H, which may be in an ester, anhydride or salt form, can be reduced to the corresponding oxo-lower alkyl radicals of the formula ~cm+1H2m+1or hydroxy-lower alkyl radicals of the formula -Cm+1H2m+2-OH' — each case representing a number from 1 up to and including 7, for example from 1 up to and including 4.

The reduction is effected in customary manner, for example by reaction with a hydride transfer agent that transfers hydrogen in anionic form to the carbon atom in the a-position, for example with a light metal or di-light metal hydride, for example with boron hydride etherate or, preferably, lithium aluminium hydride, advantageously in an ether, such as a di-lower alkyl or lower alkylene ether, for example in diethyl ether, tert.-butoxymethane or tetrahydrofuran, or by means of sodium borohydride or sodium cyanoborohydride, advantageously in alcoholic solution. It is also possible to use reducing agents that transfer nonvalent metals or atomic hydrogen. These principles are employed, for example, in metallic reduction, which can 2 1 i465 be effected by the action of finely divided metals, for example zinc powder, and also in reduction with nascent hydrogen, which can be produced, for example, by the action of acids on base metals, such as acetic acid orf"-zinc, iron and hydrochloric acid, or the action of water on sodium amalgam. By using the reducing agents mentioned there are preferably obtained compounds of the formula I in which R-j represents a hydroxy-lower alkyl radical. Salt forms of carboxy are, for example, basic 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 other ester forms there come into consideration lactone forms, for example y-lactone forms, the presence of which in the w-position and in a position lower than the (u>-2)-position results in the formation of radicals R3 having two hydroxy groups. The reduction can, however, also be halted at the oxo stage by using selective reducing agents. Such reducing agents are, for the reduction of carboxy optionally present in salt form, for example, mono- or di-lower alkylborohydrides, for example 2-(2,3-dimethylbutyl)-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-containing bases, such as quinoline, and, for the reduction of ester forms, for example, electronegatively substituted aluminium or alkali metal aluminium hydrides, for example N-methylpiperazinoaluminium hydride or sodium 2 1 «» ') bis(2-methoxyethoxy)-aluminium hydride, and also dibutylaluminium hydride.

Conversely, in compounds of the formula I, groups R- of the formula -C .nH„ .o-0H can be oxidised to 3 m+1 2m+2 groups R^ of the formula and groups R^ of the formula -C Hn -CH^OH or -C -CH=0 can be m 2m 2 m 2m oxidised to those of the formula CmH2m~COOH, tr in each case representing an integer from 1 up to and including 7, for example from 1 up to and including 4. The oxidation of groups of the formula -CnH-lH2m+2-°H to those o£ the £°™ula -cm+lH2m+1=0 is effected, for example, by treatment with an oxidising agent customary for the oxidaton of primary and secondary alcohols to aldehydes or ketones, respectively, such as non-oxidising metal compounds, for example chromyl chloride in pyridine, chromium trioxide in 2,5-dimethylpyrazole, pyrilinene salts, nitrosonium tetrafluoroborate or the complexes of chlorine or methanesulphonic acid anhydride and dimethyl sulphoxide, and the like, but especially by treatment with an aliphatic or cycloaliphatic ketone, such as an oxo-lower alkane, for example acetone, or a cycloalkanone, for example cyclohexanone, in the presence of an aluminium alcoholate, for example aluminium isopropoxide.

The oxidation of groups of the formulae -C H- -CHo0H and -C H~ -CH=0 to those of the formula m zm 2. m zm ~CmH2m~C00H effected, for example, by treatment with an oxidising agent customary for the oxidation of alcohols and aldehydes, such as oxidising heavy metal compounds, for example manganese(IV) and manganese(VII), chromium(VI), lead(IV) or bismuth(III) compounds, especially potassium permanganate, chromium trioxide or chromic acid or alkali metal chromates. Peroxysulphuric acid, for example Caro's acid, is also y Q 21146 suitable; if the oxidation is carried out in an alcohol, the corresponding ester is obtained by esterification of the acid formed initially.

It is also possible in compounds of the formula-to N-oxidise radicals of the formula -S(0)n- in which ri represents 0 to the corresponding sulphinyl or sulphonyl radicals in which ji represents 1 or 2, and to N-oxidise radials -S(0)n~ in which _n represents 1 to the corresponding sulphonyl radical in which ii represents 2, and/or to N-oxidise heteroaryl radicals R1 and/or R2 having at least one free ring nitrogen atom, such as pyridyl radicals. The oxidation is preferably effected by the action of a suitable oxidising agent, advantageously in a solvent that is inert towards this oxidising agent, if necessary while cooling or heating, for example in a temperature range of approximately from -30° to +100°C, preferably at approximately from 0° to 60°C, in a closed vessel and/or under an inert gas, such as nitrogen. Suitable oxidising agents are, for example, peroxy compounds, such as hydrogen peroxide, organic hydroperoxides, for example tert.-butyl hydroperoxide, organic peracids, such as aromatic or aliphatic percarboxylic acids, for example m-chloroperoxybenzoic acid, peroxyacetic acid or permonophthalic acid, oxidising heavy metal compounds, such as chromium(VI) or manganese(IV) or manganese(VII) compounds, for example chromium trioxide, chromic acid, manganese dioxide or potassium permanganate, oxidising inorganic oxyacids, such as oxyacids of nitrogen, of halogens or chalcogens, or anhydrides or salts thereof, for example nitric acid, dinitrogen tetroxide, selenium dioxide or sodium metaperiodate, and also ozone. Suitable solvents are, for example, halogenated hydrocarbons, such as haloalkanes, for example carbon tetrachloride, 2iC ^ I i400 chloroform or methylene chloride, or carboxylic acids, such as alkanoic acids, for example acetic acid, or anhydrides thereof.

In a preferred form of this oxidation process it is possible to oxidise, for example, thioethers of the formula I in which n is 0 and/or a radical R-j, R2 and/or a heteroaryl-aliphatic radical R3 contains an unsubstituted ring nitrogen atom by reaction with an organic peracid, for example with m-chloroperbenzoic acid, in a haloalkane, for example in chloroform, to form the corresponding sulphinyl compounds or in tetrahydrofuran to form the corresponding sulphonyl compounds, in which ji is 1 or 2, respectively.

In a different preferred form, thioethers of the formula I in which £ is 0 can be oxidised selectively by treatment with sodium metaperiodate, preferably in a haloalkane, for example in carbon tetrachloride or chloroform, to form the corresponding sulphoxides in which ri and/or m represent(s) 1, or to oxidise these with hydrogen peroxide in acetic acid to form sulphones in which n is 2 and, if desired, to oxidise the nitrogen atom.

Conversely, in compounds of the formula I in which n_ represents 1 or 2 and/or heteroaryl radicals R-j and/or R2 are N-oxidised, the sulphinyl or sulphonyl group can be reduced and/or the oxy group at the N-oxidised ring nitrogen atom can be removed by reduction. The reduction is effected by treatment with customary reducing agents, for example with nascent or catalytically activated hydrogen, such as iron or zinc and acid, such as hydrochloric acid, or with hydrogen in the presence of Raney nickel, advantageously in an inert solvent, such as a lower alkanol or with light metal hydrides or di-light metal hydrides, for example with alkali metal aluminium or alkali metal 2 1 14£3 borohydrides, for example sodium borohydride or lithium aluminium hydride, advantageously in an inert solvent, such as an ether, for example diethyl ether or tetra-hydrofuran, or, for the selective reduction of N-oxi9e-~^ groups, with a phosphorus(III) compound, such as a phosphine, for example triphenylphosphine or tri-n-butylphosphine, or a phosphorous acid ester, such as a tri-lower alkylphosphite, for example trimethyl or triethyl phosphite.

It is also possible to introduce optionally additional C-substituents into the radicals R-j and/or R2. Thus halogenation can be carried out in customary manner, for example by reaction with chlorine or bromine in the presence of iron or by means of N-chlorosuccinimide. Alkylation can also be carried out in customary manner, for example by reaction with an alkyl halide, alkanol or alkene in the presence of aluminium trichloride. Furthermore it is possible in customary manner to effect nitration, for example by means of nitric acid/sulphuric acid, to reduce the nitro group to amino, for example with tin(II) chloride, and to replace this amino by fluorine by means of sodium nitrite and tetrafluoroboric acid, by chlorine (bromine) by means of hydrochloric acid, sodium nitrite and copper(I) chloride (bromide), or by iodine by means of sodium nitrite and potassium iodide, or to convert this amino into lower alkylthio by means of sodium nitrite and a lower alkylmercaptan, or into hydroxy by means of sodium nitrite.

In radicals R-j it is also possible to hydrolyse geminally bonded di-lower alkoxy, di-lower alkylthio, lower alkylenedioxy and lower alkylenedithio to oxo, preferably by acid catalysis.

Radicals R^ containing esterified hydroxy, such as lower alkanoyloxy or optionally substituted 2 1 ^ * y 44 benzoyloxy, can be hydrolysed to the radicals containing corresponding hydroxy, for example as indicated above for the hydrolysis of compounds of the formula IXL.

If, in the processes according to the invention, isomeric mixtures containing compounds of the formula I are obtained, these mixtures can be separated into the components in customary manner, as can also stereoisomeric mixtures obtainable according to the invention.

Thus, such isomeric mixtures, for example mixtures of stereoisomers and diastereoisomers according to the invention, can be separated into their components on the basis of the differences between the physical properties of the components by customary physical separation processes, such as crystallisation, chromatography, distillation or phase distribution processes.

Enantiomeric mixtures, such as racemates, can be separated into the enantiomers by crystallisation from optically active solvents, by chromatography over optically active solids, by the action of microorganisms or by reaction with an optically active auxiliary compound to form diastereoisomeric mixtures, for example, using an optically active acid, to form mixtures of diastereoisomeric acid addition salts, and separation thereof into the diastereoisomers from which the enantiomers can be freed in the appropriate customary manner. Optically active acids customary for this purpose are, for example, D- or L-tartaric acid, di-o-toluyltartaric acids, malic acid, mandelic acid, camphorsulphonic acid or quinic acid.

Resulting free compounds can be converted into acid addition salts in a manner known per se, for example by reacting a solution of the free compound in 2 1 146 a suitable solvent or solvent mixture with one of the above-mentioned acids or with a solution thereof, or with a suitable anion exchanger.

Resulting acid addition salts can be converted into the free compounds in a manner known per se, for example by treatment of a basic end product with an acid or by treatment of 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.

Resulting salts can be converted into different salts in a manner known per se, for example by treatment of a salt with a suitable metal salt, such as a sodium, barium or silver salt, in a suitable solvent in which an inorganic salt being formed is insoluble and therefore separates out from the reaction mixture, into other acid addition salts.

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

As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter the free compounds or their salts should be understood as meaning optionally also the corresponding salts and free compounds, respectively, where appropriate and exped ient.

The invention relates also to those forms of the process in which compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or a starting material is formed under the reaction conditions or is used in the form of a derivative thereof, optionally a salt.

In the process of the present invention it is 2 1 1465 preferable to use those starting materials which result in the compounds described at the beginning as being especially valuable. The present invention relates also to novel starting materials and to processes for their manufacture.

The pharmaceutical preparations according to the invention, which contain compounds of the formula I or pharmaceutically acceptable salts thereof, are for enteral, such as oral or rectal, and parenteral administration and for topical administration to (a) warm-blooded animal(s) and contain the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warmblooded animal, age and individual condition and on the method of administration.

In a normal case, the estimated daily dose for a warm-blooded animal weighing approximately 75 kg is, in the case of oral administration, approximately 50 - 500 mg, advantageously divided into several equal partial doses.

The novel pharmaceutical preparations contain, for example, from approximately 10% to approximately 80%, preferably from approximately 20% to approximately 60%, of active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets, capsules or suppositories, and also ampoules. These are manufactured in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating 2 1146 n t> » " n a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragee cores.

Suitable carriers are, especially, fillers, such"*-^ as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions that may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the manufacture of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl-methylcellulose phthalate.

Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

Further orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatine, and also soft sealed capsules consisting of 2 1146 - 48 gelatine and a plasticiser, such as glycerine or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.

There come into consideration as rectally administrable pharmaceutical preparations, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable as suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal capsules that contain a combination of the active ingredient and a base material; suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilisers. 2 1 '146 Suitable as topically administrable pharmaceutical preparations are especially creams, ointments, pastes, foams, tinctures and solutions that contain from approximately 0.5 to approximately 20% of active ingredient.

Creams are oil-in-water emulsions that contain more than 50% water. There are used as oily base especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable as emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerine fatty acid esters or polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents that reduce the drying-out of the creams, for example polyalcohols, such as glycerine, sorbitol, propylene glycol and/or polyethylene glycols, also preservatives, perfumes, etc..

Ointments are water-in-oil emulsions that contain up to 70%, but preferably from approximately 20% to approximately 50%, water or aqueous phases. Suitable as the fatty phase are especially hydrocarbons, for example petroleum jelly, paraffin oil and/or hard 2 'i "i 4 o paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, humectants, such as polyalcohols, for example glycerine, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives, perfumes, etc..

Fatty ointments are anhydrous and contain as base especially hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut or castor oil, also fatty acid partial esters of glycerine, for example glycerine mono- and di-stearate, and also, for example, the fatty alcohols increasing the water-absorption capacity, emulsifiers and/or additives mentioned in connection with the ointments.

Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, also talc and/or aluminium silicates, the purpose of which is to bind any moisture or secretions present.

Foams are administered from pressurised containers and are liquid oil-in-water emulsions in aerosol form; halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, are used as propellants. There are used as the oily phase, inter alia hydrocarbons, for example paraffin oil, fatty alcohols, 2114 for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. There are used as emulsifiers, inter alia mixtures of emulsifiers having predominantly hydrophilic properties, such as polyoxyethylenesorbitan fatty acid esters (Tweens), and emulsifiers having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). The customary additives, such as preservatives, etc., are also added.

Tinctures and solutions generally have an aqueous-ethanolic base to which there are added, inter alia, polyalcohols, for example glycerine, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives.

The manufacture of the topically administrable pharmaceutical preparations is carried out in a manner known per se, for example by dissolving or suspending the active ingredient in the base or, if necessary, in a part thereof. When processing the active ingredient as a solution, it is generally dissolved in one of the two phases before emulsification; when processing the active ingredient as a suspension, it is mixed with part of the base after emulsification and then added to the rest of the formulation.

The present invention relates also to the use of the compounds of formula I, and salts of such compounds having salt-forming properties, preferably for the treatment of inflammation, especially chronic inflammatory disorders of the rheumatic type, 2 1146 especially chronic arthritis.

The following Examples illustrate the invention described above but are not intended to limit the scope thereof in any way. Temperatures are given in degrees Centigrade, and pressures in mbar. 2 1 1 S* O Example 1 4.4 g (0.014 mol) of 1,5-bis(£-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole are dissolved in 8 ml of 2N sodium hydroxide solution. After the addition of °... 2.5 ml of bromoacetaldehyde dimethyl acetal in 30 ml of methanol, the whole is heated at 70° under reflux for 6 hours. The reaction solution is diluted with 150 ml of water and extracted three times with methylene chloride. The combined extracts are washed with water, dried over sodium sulphate, filtered and concentrated by evaporation. After crystallisation from methanol the residue yields 1,5-bis(£-methoxyphenyl)-3-(2,2-dimethoxyethylthio)-1H-1,2,4-triazole having a melting point of 107-108°.

The starting material can be manufactured, for example, as follows: While stirring, 5.8 g of £-methoxypheny1-hydrazine hydrochloride and 2.6 g of ammonium thio-cyanate are heated at boiling under reflux with 20 ml of ethanol for 20 hours. After cooling, filtration with suction, washing with water and ethanol and subsequent drying, jo-methoxyphenylthiosemicarbazide having a melting point of 194-196° is obtained. 6.1 g of £-methoxyphenylthiosemicarbazide are suspended in 40 ml of pyridine and, at -10°, 5.8 g of £-methoxybenzoy1 chloride are added dropwise in such a manner that the internal temperature does not exceed -5°. The reaction mixture is then stirred at room temperature for 20 hours and then poured onto 300 ml of ice-cold 2N hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and methanol and dried. ,N^-bis (jd-methoxyphenyl)-thiosemicarbazide having a melting point of 154-159° is obtained. 1 3 7.5 g of N -(4-methoxyphenyl)-N -benzoylthio- 2 i 14 semicarbazide are heated at boiling under reflux with 75 ml of 2N sodium hydroxide solution for 3 hours. The resulting clear solution is cooled, and 75 ml of 2N hydrochloric acid are added. A crystalline precipitate is obtained which is filtered with suction, washed with water and ethanol and dried. The resulting 1,5-bis-(£-methoxyphenyl)-3-mercapto-1H—1,2,4-tr iazole melts at 173-174°.

Example 2 In a manner analogous to that described in Example 1, starting from 2.2 g (0.007 mol) of 1,5-bis(jD-methoxypheny1)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide solution and 1.53 g of bromoacetic acid methyl ester there is obtained 1, 5-bis (j3-methoxypheny 1) -3-methoxycarbony1-methylthio-1H-1,2,4-triazole having a melting point of 78-79° (from petroleum ether).

Example 3 In a manner analogous to that described in Example 1, starting from 1.5 g (0.005 mol) of 1,5-bis(jD-methoxyphenyl)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide solution and 0.75 g of 3-bromopropionic acid there is obtained, after acidification of the reaction solution with dilute hydrochloric acid, 1, 5-bis (jD-methoxypheny 1)-3- (2-carboxyethylthio)-1H-1,2,4-triazole having a melting point of 85-86° (from ethanol/water).

Example 4 In a manner analogous to that described in Example 1, starting from 3.1 g (0.01 mol) of 1,5-bis(£-methoxypheny1)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide solution and 'j c*1 .■? Z I HO 1.8 g of 3-bromopropionaldehyde ethylene acetal there is obtained 1, 5-bis (jo-methoxyphenyl)-3-(3, 3-ethylene-dioxypropylthio)— 1H — 1,2,4-triazole having a melting point of 94-96° (from ether).

Example 5 2.5 g (0.0062 mol) of 1, 5-bis (jo-met hoxyphenyl)-3-(2,2-dimethoxyethylthio)-1H—1,2,4-tr iazole are dissolved in a mixture of 20 ml of acetic acid, 10 ml of water and 5 ml of sulphuric acid and the resulting solution is kept at 20° for 20 hours. The solution is then diluted with 200 ml of water and extracted twice with ethyl acetate. The combined extracts are washed several times with water, dried over sodium sulphate, filtered and concentrated by evaporation. After crystallisation from ether there is obtained 1, 5-bis (jD-methoxyphenyl) -3 - (2-oxoethylthio)-lH-1,2,4-triazole having a melting point of 88-89°.

Example 6 While stirring, 2.5 g (0.0065 mol) of 1,5-bis-(jo-methoxyphenyl) -3- (methoxycarbonylmethylthio) - 1H-1,2,4-triazole are heated under reflux with 7 ml of 1N sodium hydroxide solution for 1 1/2 hours. 7 ml of 2N hydrochloric acid are added to the cooled solution. The crystals that are deposited are filtered, washed with water and dried. The resulting 1,5-bis(jo-methoxypheny1)-3-carboxymethylthio-1H—1,2,4-triazole melts at 184-185°.

Example 7 In a manner analogous to that described in Example 5, from 1.8 g of 1, 5-bis (]D-methoxyphenyl)-3-(3, 3-ethylenedioxypropylthio)-1H-1,2,4-triazole there is obtained, after hydrolysis with a mixture of 20 ml of acetic acid, 10 ml of water and 5 ml of sulphuric acid and after working up, 1, 5-bis (]3-methoxyphenyl)-3-(3-oxopropylthio)-1H-1,2,4-triazole having a melting point of 103-105° (from ether) .

Example 8 1.1 g (0.003 mol) of 1,5-bis(£-methoxyphenyl)-3-carboxymethylthio-1H-1,2,4-triazole and 0.5 ml of thionyl chloride in 30 ml of toluene are heated at 60-70°, while stirring, until a clear solution is formed. The solvent is then distilled off under reduced pressure and the residue is dissolved in toluene again. This solution is added dropwise to a stirred solution, cooled to 0°, of 1.2 g of dimethyl-amine in 50 ml of toluene. The temperature of the solution is then allowed to rise to room temperature. The solution is then concentrated by evaporation under reduced pressure and the residue is partitioned between ethyl acetate and water. After washing several times with water, the organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. After crystallisation of the residue from ethanol there is obtained 1,5-bis(£-methoxyphenyl)-3-N,N-dimethyl-carbamoylmethylthio-1H-1,2,4-triazole having a melting point of 173-175°. (Yield 30%).

In an analogous manner but using ammonia instead of dimethylamine, 1, 5-bis (]D-methoxyphenyl) -3-carbamoylmethylthio-1H-1,2,4-triazole having a melting point of 170-172° is obtained.

Example 9 2.0 g of 90% m-chloroperbenzoic acid are added in portions to a solution of 3.0 g (0.0078 mol) of 1,5-bis(£-methoxyphenyl)-3-methoxycarbonylmethylthio-1H-1,2,4-triazole in 50 ml of dichloromethane. After ft & d. I i 4 o 5 «l >) stirring for 3 days at room temperature, the solvent is distilled off under reduced pressure. The residue is chromatographed over 100 g of silica gel 60 (230-400 ... mesh, Merck) using a pressure of 0.6 bar and toluene/-ethyl acetate (4:1, v/v) as eluant. The fractions containing the desired product are combined and concentrated by evaporation. There is thus obtained 1,5-bis-(]D-methoxypheny 1) -3-methoxy car bony lmethanesulph iny 1-1H—1,2,4-triazole in the form of a colourless oil, 1H-NMR spectrum (CDCl^, TMS) singlet 2H at <5 = 4.37 ppm, which is found in the fractions obtained last. 1, 5-bis (jD-methoxypheny 1)-3-methoxycarbony 1-methanesulphony1-1H-1,2,4-triazole is obtained from the middle fractions, 1H-NMR spectrum (CDCI3, TMS): singlet 2H at ^ =4.41 ppm in the form of a colourless oil.

Example 10 1.5 g (0.00375 mol) of 1,5-bis(£-methoxyphenyl)-3-methoxycarbonylmethanesulphinyl-lH-1,2,4-triazole are stirred with 40 ml of 1N sodium hydroxide solution for 20 hours. After treatment with animal charcoal, 4.1 ml of 1N hydrochloric acid are added to the solution and the whole is then extracted with methylene chloride. The extracts are dried with sodium sulphate, filtered and concentrated by evaporation under reduced pressure.

The oily 1, 5-bis (jD-methoxyphenyl)-3-carboxymethane-sulphinyl-1H-1,2,4-triazole that remains is dissolved in the calculated amount of 1N sodium hydroxide solution and the solution is lyophilised. The lyophilisate is made into a slurry with a small quantity of isopropanol and then filtered with suction.

There is thus obtained the sodium salt of 1,5-bis-(£-methoxyphenyl)-3-carboxymethanesulphiny1-1H-1,2,4-triazole, in the form of a dihydrate, which melts 2 l i from 135° with decomposition.

In an analogous manner, starting from 1,5-bis(p-methoxypheny1)-3-methoxycarbonylmethanesulphony1-1H-1,2,4-triazole there is obtained the sodium salt of 1,5-bis(£-methoxypheny1)-3-carboxymethanesulphony1-1H-1,2,4-triazole which melts from 133° with decomposition.

Example 11 7.5 g (0.0226 mol) of N^-(4-methoxyphenyl)-N^-benzoyIthiosemicarbazide and 2.7 g of sodium chloro-acetate are heated at boiling under reflux with 75 ml of 2N sodium hydroxide solution for 3 hours. The resulting clear solution is cooled, and 75 ml of 2N hydrochloric acid are added. A crystalline precipitate is obtained which is filtered with suction and washed with water and ethanol. The 1,5-bis(£-methoxypheny1)-3-carboxymethylthio-1H—1,2,4-triazole so obtained melts at 184-185°.

Example 12 2.2 g (0.007 mol) of 1, 5-bis (jD-methoxypheny 1)-3-mercapto-1H-1,2,4-triazole are dissolved in 15 ml of 2N sodium hydroxide solution. After the addition of 1.3 g of bromomalonic acid, the resulting solution is left to stand at room temperature for 24 hours. The solution is adjusted to pH 1 with concentrated hydrochloric acid and then, while stirring, heated at boiling under reflux for 1 hour. After cooling and leaving to stand, the 1, 5-bis (js-methoxypheny 1)-3-carboxymethylthio-lH-1,2,4-triazole that has separated out is filtered off; m.p. 184-185°.

Example 13 In a manner analogous to that described in Example 1 14 1, from 2.2 g (0.007 mol) of 1, 5-bis (jo-methoxypheny 1)-3-mercapto-1H-1,2,4-triazole and the corresponding amount of sodium hydroxide solution and chloro-acetonitrile there is obtained 1, 5-bis (p-methoxy-phenyl)-3-cyanomethylthio-1H-1,2,4-triazole in the form of an oil.

Example 14 In a manner analogous to that described in Examples 1 and 6, by reacting 1,5-bis (]D-methoxy-phenyl)-3-mercapto-1H-1,2,4-triazole with the calculated amount of 2-bromopropionic acid ethyl ester there is obtained 1, 5-bis (jo-methoxyphenyl)-3-(1-ethoxycarbonylethylthio) — 1H—1,2,4-triazole having a melting point of 80-82° and, from this, 1,5-bis-(£-methoxyphenyl)-3-(1-carboxyethylthio)-1H-1,2,4— triazole having a melting point of 148-150°.

Example 15 1.76 g (0.005 mol) of 1,5-bis(£-methoxyphenyl)-3-cyanomethylthio-lH-1,2,4-triazole are heated under reflux with 10 ml of acetic acid and 10 ml of 36% hydrochloric acid for 12 hours. The reaction mixture is then concentrated to dryness by evaporation under reduced pressure. The residue is crystallised from a chloroform/ethanol mixture. 1, 5-bis (jo-methoxy-phenyl)-3-carboxymethylthio-1H-1,2,4-triazole having a melting point of 184-185° is obtained.

Example 16 While stirring, 1.76 g (0.05 mol) of 1,5-bis(jo-methoxyphenyl)-3-cyanomethylthio-1H-1,2,4-tr iazole are heated at 100° with 20 ml of saturated methanolic hydrochloric acid in a pressure tube for 10 hours. The mixture is then concentrated to dryness by evaporation 21 ; 465 and the residue is extracted several times with diethyl ether and the extracts are filtered and partly concentrated by evaporation. After the addition of petroleum ether, the 1, 5-bis (jD-methoxyphenyl)-3-methoxycarbonyl-methylthio-1H-1,2,4-triazole crystallises, melting point 78-79°.

Example 17 0.54 g of sodium methoxide is added to a solution of 0.45 g (0.005 mol) of thioglycolic acid in 5 ml of dimethylformamide. The mixture is stirred for 1 hour at room temperature and then 1.8 g (0.005 mol) of 1, 5-bis (]D-methoxypheny 1) -3-methy 1 sulphonyl- 1H-1,2,4-triazole are added. The mixture is then heated, while stirring, at 100° for 24 hours. The solvent is distilled off under reduced pressure, and 5 ml of 2N hydrochloric acid are added to the residue. Extraction is carried out several times with dichloromethane and the extracts are dried over sodium sulphate, filtered and■concentrated by evaporation. The crude 1,5-bis(£-methoxyphenyl)-3-carboxymethylth io-1H-1,2,4-triazole that remains crystallises from chloroform/ethanol and has a melting point of 184-185°.

Example 18 1.10 g of mercaptoacetic acid methyl ester are added dropwise to 1.93 g (0.01 mol) of 4-methoxy-benzoy1isothiocyanate (C.A. 44, 2515 b) in 50 ml of benzene. The mixture is then stirred at room temperature for 5 hours. The solvent is distilled off under reduced pressure. 1.40 g of 4-methoxyphenyl-hydrazine and 100 ml of benzene are then added. After boiling under reflux, while stirring, for 4 hours on a water separator, the solvent is distilled off under reduced pressure. Crystallisation of the residue from y » " t^i A i i 4 diethyl ether with the addition of petroleum ether yields 1, 5-bis(£-methoxyphenyl)-3-methoxycarbonyl-methylthio-1H-1,2,4-triazole having a melting point o€..„ 78-79°.

Example 19 In a manner analogous to that described in Examples 1 to 18, there are also obtained: 1, 5-bis (js-chloropheny 1) -3- (2, 2-dimethoxyethylthio) -1H-1,2,4-triazole having a melting point of 117-118°, 1, 5-bis (]D-chloropheny 1) - 3- (2-oxoethy lthio) - 1H-1,2,4-triazole having a melting point of 96-100°, 1-(3-pyr idyl)-5-pheny1-3-(2-hydroxyethylthio)-1H—1,2,4-triazole in the form of an oil, and 1,5-bis(jo-met hoxyphenyl)-3-(2-hydroxyethylthio)-1H-1,2,4-triazole having a melting point of 140-142°.

Example 20 Tablets containing 25 mg of active ingredient, for example 3-(2,2-dimethoxyethylthio)-1,5-bis(£-methoxy-phenyl)-lH-1,2,4-triazole, can be manufactured as follows: Constituents (for 1000 tablets): active ingredient 25.0 g lactose 100.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5.0 g magnesium stearate 1.8 g demineralised water q.s.

Manufacture: All the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active i 11 $ <£s» (t ti H u ingredient, the lactose, the talc, the magnesium stearate and half the starch are mixed together. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water, and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35°, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter that are concave on both sides.

Example 21 Tablets for chewing containing 30 mg of active ingredient, for example 3-(2,2-dimethoxyethylthio)-1,5-bis(jo-methoxyphenyl)-1H—1,2,4-triazole can be manufactured, for example, as follows: Composition (for 1000 tablets): active ingredient . .0 g mannitol 267. ,0 g lactose 179. . 5 g talc . .0 g glycine 12. .5 g stearic acid . ,0 g sacchar ine 1. .0 g % gelatine solution q< . s.

Manufacture All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose are mixed together, granulated with the addition of gelatine solution, forced through a sieve of 2 mm mesh width, dried at 50° and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the saccharine are 2 1 1 carefully mixed; the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets o£ . approximately 10 mm diameter that are concave on both sides and have a breaking groove on the upper side.

Example 22 Tablets containing 100 mg of active ingredient, for example 3-(2, 2-d imethoxyethylthio) -1, 5-bis (jd-methoxyphenyl)-1H-1,2,4-triazole can be manufactured as follows: Composition (for 1000 tablets): active ingredient 100.0 g lactose 248.5 g corn starch 17.5 g polyethylene glycol 6000 5.0 g talc 15.0 g magnesium stearate 4.0 g demineralised water q.s.

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

Claims (5)

21 - 64 - Example 23 In a manner analogous to that described in Examples 20 to 22 it is also possible to manufacture pharmaceutical preparations containing one of the compounds of the formula I mentioned in Examples 2 to 19, it being possible for compounds in which R3 represents carboxy also to be in the form of salts with bases, for example in sodium salt form. 211465 65 WHAT/T/WE CCA'IM 1S:- ■Patcnt Glaima 1. 3-Mercapto-1,2,4-triazacycloalkadiene derivatives of-the formula I R1-N-N \ r2-.=n (I) in which the radicals R^ and R2, independently of one another, represent an aryl or optionally N-oxidised heteroaryl radical that is unsubstituted or substituted by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidised etherified mercapto, free or aliphatically substituted amino, nitro and/or tri-fluoromethyl, radical substituted by an optionally esterified or amidated carboxy group, cyano or, in a position higher than the exposition, by one or two optionally esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidised mercapto group or by an oxrt n represents 0, 1 or 2, and represents an aliphatic hydrocarbon group 9 i "j a r- r ^11Hb u - 66 - and their salts. 2. Compounds according to claim 1 of the formula I in which the radicals R-j and R2, independently of one another, represent an aryl radical having from 6 up to and including 10 carbon atoms or a monocyclic 5-membered heteroaryl radical having an oxygen or sulphur atom and optionally also a nitrogen atom or a monocyclic optionally N-oxidised 6-membered heteroaryl radical having one or two nitrogen atom(s), which radicals may be unsubstituted or substituted by lower alkyl, lower alkoxy or, at vicinal carbon atoms, lower alkyl(id)enedioxy, hydroxy, halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl, amino, mono- or di-lower alkylamino and/or by trifluoromethyl, n_ represents 0, 1 or 2, and Rj represents carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl, cyano-lower alkyl, or mono- or di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, mono- or di-lower alkoxy-lower alkyl, lower alkylenedioxy-lower alkyl, lower alkylenedithio-lower alkyl, mono- or di-lower alkylthio-lower alkyl, lower alkanesulphinyl-lower alkyl, lower alkanesulphonyl-lower alkyl or oxo-lower alkyl carrying the hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylenedioxy, lower alkylthio, lower alkylenedithio, lower alkanesulphinyl, lower alkanesulphonyl or oxo group(s), respectively, in a position higher than the exposition, and their salts. 3. Compounds according to claim 1 of the formula I in which the radicals R-| and R2, independently of one another, represent phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,# ;|W ■ibj; \ 28SEP!W7V 21141> 5 67 halogen, lower alkanoyloxy, lower alkylthio, lower alkanesulphonyl, di-lower alkylamino and/or by trifluoromethyl, or furyl, thienyl, pyridyl or 1-oxidopyridyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or by hydroxy, n_ represents 0, 1 or 2, and R^ represents carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl, or hydroxy-lower alkyl, mono- or di-lower alkoxy-lower alkyl, lower alkylenedioxy-lower alkyl, lower alkylidenedioxy-lower alkyl or oxo-lower alkyl carrying the hydroxy, lower alkoxy, lower alkylenedioxy, lower alkylidenedioxy or oxo group(s), respectively, in a position higher than the a-position, and their salts. 4. Compounds according to claim 1 of the formula I in which the radicals R-j and R2, independently of one another, represent phenyl that is unsubstituted or substituted by lower alkoxy having up to and including 4 carbon atoms, lower alkylthio having up to and including 4 carbon atoms or by halogen having an atomic number of up to and including 35, n_ represents 0, and R^ represents carboxy-lower alkyl having up to and including 4 carbon atoms in the lower alkyl moiety and carrying the carboxy group in the a-position, and their salts. 5. Compounds according to claim 1 of the formula I in which R^ and R2 represent a^phenyl ;radical . ' : 1 substituted by lower alkoxy having up to and including 4 carbon atoms, n represents 0, 1 or 2, and R-j represents carboxy- or lower alkoxycarbonyl-lower alkvl> 28SEPI987™ 21146 68 having up to and including 4 carbon atoms in the lower alkyl moiety or in the lower alkyl and lower alkoxy moiety, as the case may be, and carrying the carboxy or lower alkoxycarbonyl group, respectively, in the exposition, or hydroxy-lower alkyl having from 2 up to and including 4 carbon atoms, oxo-lower alkyl having from 2 up to and including 4 carbon atoms or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl each having up to and including 4 carbon atoms in each alkyl(ene) moiety, and carrying the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group, respectively, in a position higher than the exposition, and their salts. 6. Compounds according to claim 1 of the formula I in which the radicals R-j and R2, independently of one another, represent phenyl that is unsubstituted or substituted by lower, alkoxy having up to and including 4 carbon atoms, lower alkylthio having up to and including 4 carbon atoms or by halogen having an atomic number of up to and including 35, n_ represents 0, and R-j represents hydroxy-lower alkyl having from 2 up to and including 4 carbon atoms, oxo-lower alkyl having from 2 up to and including 4 carbon atoms, or mono- or di-lower alkoxy-lower alkyl or lower alkylenedioxy-lower alkyl each having up to and including 4 carbon atoms in each alkyl(ene) moiety, and carrying the hydroxy, oxo, lower alkoxy or lower alkylenedioxy group, respectively, in a position higher than the a-position, and their salts. 7. Compounds according to claim 1 of the formula I in which R^ and R2 represent a phenyl radical substituted by lower alkoxy having up to and including^' 4 carbon atoms, n_ represents 0, 1 or 2, and R3 , cd114 6 o 59 represents carboxy-lower alkyl having up to and including 4 carbon atoms in the lower alkyl moiety and carrying the carboxy group in the a-position, and their salts. 8. 1,5-bis(p-methoxyphenyl)-3-(2,2-dimethoxyethyl-thio)-1H-1,2,4-triazole or a salt thereof. 9. 1,5-bis(p-methoxyphenyl)-3-methoxycarbonyl- methylthio-IH-1,2,4-triazole or a salt thereof. 10. 1,5-bis (p-methoxyphenyl)-3-(2-carboxyethyl-thio)-1H-1,2,4-triazole or a salt thereof. 11. 1,5-bis(p-methoxyphenyl)-3-(3,3-ethylenedioxy-propylthio)-1H-1,2,4-triazole or a salt thereof. 12. 1, 5-bis (_£-methoxyphenyl) -3- (2-oxoethylthio) -1H-1,2,4-triazole or a salt thereof. 13. 1, 5-bis (_p-methoxyphenyl) -3- (3 -oxopr opyl thio) -19-1,2,4-triazole or a salt thereof. 14. 1, 5-bis (j3-methoxyphenyl) -3-N, N-dimethyl-carbamoylmethylthio-lH-1,2,4-triazole or a salt thereof. 15. , 5-bis (jo-methoxyphenyl) -3-methoxycarbonyl-methanesalphonyl-1H-1,2,4-triazole or a salt thereof. 16. 1,5-bis(p-methoxyphenyl)-3-carboxymethy]

1,2,4-triazole or a salt thereof. > « r - 70 17. 1, 5-bis (p-methoxyphenyl) -3-methoxycarbonyl-methanesulphinyl-1H-1,2,4-triazole or a salt thereof. 18. 1,5-bis (p-methoxyphenyl)-3-carboxymethane-sulphinyl-lH-1,2,4-triazole or a salt thereof. 19. 1,5-bis(p-methoxyphenyl)-3-cyanomethylthio-IH-1, 2,4-triazole or a salt thereof. 20. 1,5-bis(p-chlorophenyl)-2-(2,2-dimethoxyethyl-thio)-1H-1,2,4-triazole or a salt thereof. 21. 1,5-bis(p-chlorophenyl)-3-(2-oxoethylthio) -1H-1,2,4-triazole or a salt thereof. 22. 1-(3-pyridyl)-5-phenyl-3-(2-hydroxyethylthio)-1H-1,2,4-triazole or a salt thereof. 23. 1,5-bis(p-methoxyphenyl)-3-carboxymethane-sulphonyl-1H-1,2,4-triazole or a salt thereof. 24. 1,5-bis(p-methoxyphenyl)-3-(1-ethoxycarbonyl-ethylthio)-1H-1,2,4-triazole or a salt thereof. 25. 1,5-bis (p-methoxyphenyl)-3-(1-carboxyathylthio) -1H-1,2,4-triazole or a salt thereof. 26. 1,5-bis(p-methoxyphenyl)-3-carbamoylmethylthio-1H-1,2, 4-triazole or a salt thereof. 27. 1,5-bis(p-methoxyphenyl)-3-(2-hydroxyethylthio) — 1H — 1,2,4-triazole or a salt thereof. 28. Pharmaceutical preparations containing a compound according to any one of patent claims 1, 2, 4, 7, 14, 2] 14 211465 - 71 - 15, 17 to 19 and 23 to 27 together with pharmaceutical adjuncts. . 29. Pharmaceutical preparations containing a compound according to any one of patent claims 3, 5, 6, 8 to 13, 16 and 20 to 22 together with pharmaceutical adjuncts. 30. A .process for. the manufacture -"of ;3—marcapto- ; -1,2,4-triazacycloalkadiene derivatives of the formula I in which the radicals R n_ R- ^ and R2/ independently of one another, represent an aryl or optionally N-oxidised heteroaryl radical that is unsubstituted or substituted by aliphatic hydrocarbon radicals, free, etherified or esterified hydroxy, optionally S-oxidised etherified mercapto, free or aliphatically substituted amino, nitro and/or tri- fluoromethyl, represents 0, 1 or 2, and represents an aliphatic hydrocarbon radical substituted by an optionally esterified or amidated carboxy group, i: I'-1 28 SEP 1987* - 72 - cyano or, in a position higher than the exposition, by one or two optionally esterified or etherified hydroxy group(s), one or two etherified mercapto group(s), an oxidised mercapto group or by an oxo group, and their salts, characterised in that a) in a compound of the formula R^N-N, V (II) -N SR. Y Y 12 in which one of the radicals Y-j and Y2 represents a removable radical Y and the other represents a hydrogen atom, and Y-j and Y^ together represent an additional bond, or in which Y^ represents a removable radical Y and Y3 represents hydrogen, and Y-j and Y2 represent an additional bond, or in a salt thereof, HY is removed with the introduction of an additional bond, or b) compounds of the formulae R1-N-N R, \ Y =N' 11 (XXXI) and Y12 - R3 (XXXII) <4. 'ii 1 4 ,> < r 73 in which Y-j-j represents a mercapto group optionally present in salt form and Y-|2 represents reactive esterified hydroxy, or Y-j-] represents sulphonyl and Y-j 2 represents a mercapto group optionally present in salt form, are condensed to form the corresponding compound of the formula i in which ii represents 0, or c) compounds of the formulae in which one of the radicals Y-j-j and Y-j2 represents a metallic radical and the other represents a group -S(0)n-Y-|3 in which Y13 represents halogen are condensed, or d) a compound of the formula in which Y^ is mercapto, or a salt thereof, is reacted with a vicinal epoxy derivative derived from a compound of the formula r3-h (xxxvii) to form a compound of the formula i in which R3 contains a hydroxy group in the 8-position and n_ is 0, or

2 - (XXXI) and Y12"R3 (XXXII) or R

3-S-S-R3 (XXXIIa) (XXXI) *> 'j ^ / 4 £ k Ko - 7

4 - e) a compound of the formula R.-N-n *11 r2-.=n- (XXXI) in which Y-j-j is mercapto, or a salt thereof, is reacted with a compound of the formula R^-H (XXXVIII) in which R3 represents an aliphatic radical that is derived from R3 and has a C-C double bond or C-C triple bond at least in the a,8-position, to form a compound of the formula I in which R3 is a, 8-saturated or a,8-singly unsaturated and ri is 0, or f) in a compound of the formula R1-N-N R2~ s(o)n R3 (ixc.) . =N' in which R3 represents a radical that can be converted into a group R3, R3 is converted into the desired group R3, and, if necessary, an isomeric mixture obtainable according to the process is separated into the components and the isomer of the formula I is isolated and, if desired, a compound obtainable according to the process is converted into a different compound of the formula I and/or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process is converted into the free compound or into a different salt. 211465 - 7

5 - 31. The:^focess"ac66rding ~to claim 30?- characterised in that compounds obtainable as intermediates at any stage of the process' are used as starting materials and the remaining process steps are carried out, or a starting material is formed under the reaction conditions or is used in the form of a derivative thereof, optionally a salt. BALDWIN, SON & CAREY FO 7. 4/GR/hpw* /ShiJfjL* attorneys for the applicants