IE48738B1 - Novel mercaptoimidazole derivatives - Google Patents

Description

The present invention provides substituted 2mercaptoimidazoles of the formula wherein at least one of the radicals R^ and Rp is a mono5 cyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6-membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or C-substxtuted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is Ν-substituted by lower alkyl, lower alkoxy-lower alkyl or hydroxy-Icwer alkyl or is an N-oxide thereof, and a radical R^ or R2 different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl,lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, R^ is hydrogen or lower alkyl, n is 0, 1 or 2, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members,or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the a-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl with the proviso that heteroaryl radicals and/or R^ are different from 5-membered heteroaryl radicals containing one sulfur atom and from 6-membered heteroaryl radicals containing one nitrogen atom, or radicals R3 are different from hydrogen, if R^ is lower alkyl substituted in the 2-, 3- or 4-position by a hydroxyl group and with the further proviso that, in .. 48738 a compound of the formula I, in which n is 1 or 2, heteroaryl radicals Rg and/or Rg differ from 5-membered heteroaryl radicals containing one sulfur atom or one' oxygen atom, and from 6-membered heteroaryl radicals containing one nitrogen atom, if R^ is lower alkyl substituted by one or two hydroxyl groups, by a lower alkoxy group or by phenyl which is unsubstituted or substituted as indicated above, or is an unsubstituted lower alkynyl, the radicals qualified by lower containing up to and including 7 carbon atoms, or an acid addition salt thereof.

In this specification lower organic radicals and compounds are to be understood as meaning those which contain not more than 7 and in particular not more than 4 carbon atoms.

-Msrbered heteroaryl radicals which contain one oxygen or sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or 6-membered heteroaryl radicals which contain at least one nitrogen atom, are banded via a C atan. Exanples are, in particular, furyl, for exanple 2-furyl, thienyl, for example 2-thienyl, thiazolyl, for example l,3-thiazol-2or -4-yl, imidazolyl, for example imidazol-2- or -4-yl, triazolyl, for example 1H- or 2H-l,2,3-triazol-4- or-5-yl or 1H- or 2H-l,2,4-triazol-3- or -5-yl, tetrazolyl, for example lH-tetrazol-5-yl, pyridyl, for example 2-, 3- or 4-pyridyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, or triazinyl, for example l,3,5-triazin-2-yl or 1,2,4-triazin-3-yl. Substituents of the said heteroaryl groups are, for example, on carbon atoms, lower alkyl, lower alkoxy, halogen, substituted or unsubstituted amino and/or trifluoromethyl and/or, on nitrogen atoms, if desired lower alkyl, lower alkoxy-lower alkyl and/or hydroxy-lower alkyl, and also N-oxides thereof.

Substituted or unsubstituted aryl groups and also aryloxy and arylthlo groups are, for example, phenyl, phenoxy and phenylthio groups which are unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, substituted or unsubstituted amino, trifluoromethyl and/or nitro.

Substituted amino groups are monosubstituted or preferably disubstituted amino groups in which the substituents are, for example, lower alkyl,or alkylene which has 5 or 6 ring members and can be interrupted by a nitrogen, oxygen or sulfur atom, such as lower alkylamino, dilower alkylamino and 3-aza-, 3-oxa- or 3-thia-alkyleneamino with, in each case, 5 or 6 ring members. In addition to methylamino and ethylamino, examples are in particular dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino and N'-lower alkyl-piperazino, for example N'-methylpiperazino.

Lower alkyl, lower alkenyl or lower alkynyl which is unsubstituted or substituted by phenyl is, for example, lower alkyl having 1 to 4 C atoms, phenyl-lower alkyl, such as 1- or 2-phenyl-lower alkyl having 7 to 10 C atoms, for example benzyl or 2-phenylethyl, lower alkenyl having 2 to 4 C atoms, for example vinyl, allyl or methallyl, phenyl-lower alkenyl having 8 to 10 C atoms, for example styryl, lower alkynyl having 2 to 4 C atoms, for example ethynyl or propargyl, or phenyl-lower alkynyl having 8 to C atoms, for example phenylethynyl.

Lower alkyl substituted by hydroxy in a position higher than the α-position (hydroxy-lower alkyl) is, for example, mono- or dihydroxy-lower alkyl, has in particular 2 to 4 C atoms and is, for example, 2-hydroxyethyl, 2- or 3-hydroxy15 propyl or 2,3-dihydroxypropyl.

Lower alkyl substituted by lower alkoxy in a position higher than the α-position (lower alkoxy-lower alkyl) has, for example, 1 to 4 C atoms in each alkyl moiety and is, for example, 2-methoxyethyl, 2-ethoxyethyl or 2- or 3-methoxypropyl.

Lower alkyl substituted by lower alkylthio in a position higher than the α-position (lower alkylthio-lower alkyl) has, for example, 1 to 7 C atoms in the alkylthio and is, for example, 2-methylthioethyl.

Lower alkyl, substituted in a position higher than the α-position by a phenoxy or phenylthio group which Is itself optionally substituted as indicated above, has, for example, to 7 C atoms in the alkyl moiety and is, for example, 2-phenoxyethyl or 2-phenylthio ethyl.

Lower alkyl has, for example, 1 to 7 C atoms and Is, for example, methyl, ethyl, propyl, isopropyl or η-, iso-, sec.- or tert.-butyl or, less preferentially, one of the isomeric pentyl, hexyl or heptyl groups.

Lower alkoxy has, for example, 1 to 7 C atoms and is, for example, methoxy, ethoxy, propoxy, isopropoxy or η-, sec.-, iso- or tert.-butoxy or, less preferentially, one of the isomeric pentyloxy, hexyloxy or heptyloxy groups.

Lower alkylthio has, for example, 1 to 7 C atoms and is, for example, methylthio, ethylthio, propylthio, isopropylthio or butylthio or, less preferentially, pentylthio, hexylthio or heptylthio.

Halogen is preferably halogen with an atomic number of not more than 35, such as fluorine, chlorine or bromine.

Salts of compounds of the formula I are in particular pharmaceutically usable acid addition salts with strong acids, such as a mineral acid, for example salts with hydrogen halide acids, in particular hydrochloric acid or hydrobromic acid, i.e. hydrohalides, in particular hydrochlorides and hydrobromides, or sulfuric acid salts, i.e. bisulfates and sulfates.

The invention relates in particular to substituted 2-mercaptoimidazoles of the formula I in which R^, R2, R3 and R^ have the meanings indicated hereinbefore under formula I and n denotes 0, and pharmaceutically usable salts, in particular pharmaceutically usable acid addition salts, thereof, processes for their preparation, pharmaceutical preparations containing these compounds or pharmaceutically usable acid addition salts thereof, and the compounds defined above for use as pharmaceuticals.

The compounds of the formula I have valuable pharmacological properties. In particular, they have a pronounced anti-inflammatory, anti-nociceptive and/or anti-thrombotic activity as well as an inhibitory action 5 on the prostaglandin synthesis. Thus, they prove to have an excellent effect in rats in the kaolin paw oedema test according to Helv. Phydiol. Acta 25, 156 (1967) in the dosage range of about 15 to 150 mg/kg, and also in the Carrageneen paw oedema test according to Di Pasquale et al Agents and Actions 5, 256 (1975) in the dosage range of about 20 to 200 mg/kg, when administered perorally, in a single dose, additionally also in the adjuvaus-arthritis of the rat on four single doses of about 10 to 60 mg/kg p.< and in mice in the writhing syndrome induced by phenyl-p15 benzoquinone, according to J. Pharmacol, exp. Therap. 125, 237 (1959), in the dosage range of about 30 to 300 mg/kg p.o. and in the emboly of the rabbit lung which had been induced by dosage of arachidonates in a dose range of about 0,1 to 3 mg/kg p.o..

Furthermore, in the concentration range of about to 30 ml/1, they inhibit in vitro the prostaglandin synthesis from arachidonic acid, demonstrated in the test arrangement according to Prostaglandins 7, 123 (197^).

The compounds of the formula I are therefore out25 standingly suitable as active ingredients in pharmaceutical preparations for the treatment of inflammatory diseases , in particular chronic inflammation of the rheumatic type, such as chronic arthritis.

Accordingly, the invention also relates to compounds of the formula wherein at least one of the radicals Rg and Rg is a monocyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thia-alkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is N-substituted by lower alkyl, lower alkoxy-lower alkyl or hydroxy-lower alkyl or is an N-oxide thereof, and a radical Rg or Rg different therefrom is a phenyl group wich is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-axa-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, R3 is hydrogen or lower alkyl, n is 0, 1 or 2, and R4 is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the α-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkyl487 38 amino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, with the proviso that, in a compound of the formula I, in which n is 1 or 2, heteroaryl radicals Ry and/or r2 differ from 5-membered heteroaryl radicals containing one sulfur atom or one oxygen atom, and from 6-membered heteroaryl radicals containing one nitrogen atom, if R^ is lower alkyl substituted by one or two hydroxyl groups, a lower alkoxy group or by phenyl which is un10 substituted or substituted as indicated above, or is unsubstituted lower alkynyl, and their pharmaceutically usable acid addition salts for use in the therapeutic treatment of the animal or human body, pharmaceutical preparations containing them and their use as medicaments and also preparation of the medicaments by non-chemical methods.

The invention relates primarily to those compounds wherein in the formula I at least one of the radicals Ry and R2 is furyl, thienyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or triazinyl and the ring carbon atoms of said radicals Ry and R2 may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa or 325 thiaalkyleneamino, each containing 5 or 6 ring members, and the ring nitrogen atoms of pyrimidinyl, triazinyl or pyridyl radicals may also be an oxygen atom, and a radical Ry or R2 different therefrom is phenyl which may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number 30 of up to and including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, R^ is hydrogen or lower alkyl, n Is 0, 1 or 2, and Rj is a lower alkyl, lower alkenyl or lower alkynyl radical which has not more than 7 C-atoms and is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or is a lower alkyl radical which has not more than 7 C-atoms and is substituted in a position higher than the α-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, nitro, amino, lower alkyleneamino and/or alkyleneamino or 3-aza*, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and their acid addition salts, preferably pharmaceutically usable acid addition salts as well as pharmaceutical preparations containing these compounds and their use.

The invention relates in particular to compounds of the formula I in which one of the radicals R^ and R2 is a substituted or unsubstituted pyridyl group and the other is a substituted or unsubstituted phenyl or pyridyl group. Rg is hydrogen or lower alkyl having 1 to 4 C atoms, such as methyl, n is 0 and R^ is lower alkyl having 1 to 7 C atoms which is unsubstituted or substituted by phenyl or, in a position higher than the α-position, by hydroxyl, lower alkoxy or lower alkylthio having 1 to 4 C atoms, phenoxy or phenylthio, or is a lower alkenyl or lower alkynyl radical having 2 to 4 C atoms which is unsubstituted or substituted by phenyl, it being possible for pyridyl, phenyl, phenoxy or phenylthio groups to be substituted by lower alkyl having 1 to 4 C atoms, such as methyl, lower alkoxy having 1 to 4 C atoms, such as methoxy or ethoxy, halogen having an atomic number of not more than 35, such as chlorine, nitro, amino or N,N-di-lower alkylamino having 1 to 4 C atoms in each alkyl moiety, such as dimethylamino, and their salts as well as pharmaceutical preparations containing these compounds and their use.

The invention preferably relates to compounds of the formula I in which one of the radicals or Rp is pyridyl and the other is phenyl and these radicals inde5 pendently of one another can be substituted by lower alkyl having 1 to 4 C atoms, such as methyl, lower alkoxy having 1 to 4 c atoms, such as methoxy or ethoxy, halogen having an atomic number of not more than 35, such as chlorine, and/or N,N-di-lower alkylamino having 1 to 4 C atoms in lo each alkyl moiety, such as dimethylamino, but are preferably unsubstituted, R^ is hydrogen or lower alkyl having to 4 c atoms, such as methyl, n is 0 and R^ is lower alkyl having 1 to 4 C atoms, such as methyl, ethyl, propyl, isopropyl or butyl, lower alkenyl having 2 to 4 C atoms, 15 such as allyl, phenyl-lower alkyl which has 1 to 4 C atoms in the alkyl moiety and is unsubstituted or substituted by lower alkyl having 1 to 4 C atoms, such as methyl, lower alkoxy having 1 to 4 C atoms, such as methoxy or ethoxy, and/or halogen having an atomic number of not more than 2o 35, such as chlorine, hydroxy-lower alkyl which has 1 to 4 C atoms and carries the hydroxyl group or groups in a position higher than the α-position, such as 2-hydroxyethyl, or lower alkoxy- or lower alkylthio-lower alkyl which has 1 to 4 C atans in each alkyl moiety and carries the alkoxy or alkylthio group in a position higher than the α-position, such as 2metboxyethyl or 2^nsthylthioethyl, and their acid addition salts as well as pharmaceutical preparations containing these compounds and their use.

The invention relates in particular to compounds of the formula I in which one of the radicals and Rp is unsubstituted pyridyl, such as 3-pyridyl, or thienyl, such as 2-thienyl, and the other is unsubstituted phenyl or phenyl substituted by lower alkyl having 1 to 4 C atoms, such as methyl, lower alkoxy having 1 to 4 C atoms, such as methoxy, and/or halogen having an atomic number of not more than 35, such as chlorine and in particular fluorine, R^ is hydrogen or, less preferentially, lower alkyl having 1 to 4 C atoms, such as methyl, n is 0, 1 or and R^ is lower alkyl having 1 to 4 C atoms, such as ethyl, and their salts as well as pharmaceutical preparations containing these compounds and their use.

The invention relates especially to compounds of the formula I in which one of the radicals and R2 is unsubstituted pyridyl, such as 3-pyridyl, and the other is unsubstituted phenyl or, less preferentially, phenyl substituted by lower alkyl having 1 to 4 C atoms, for example methyl, lower alkoxy having 1 to 4 C atoms, for example methoxy, or halogen, for example chlorine or bromine, R3 is hydrogen or lower alkyl having 1 to 4 C atoms, for example methyl or ethyl, n is 0 and R^ is hydrogen, lower alkyl having 1 to 4 C atoms, for example methyl or ethyl, or hydroxy-lower alkyl which has 2 to 4 C atoms and carries the hydroxyl group in a position higher than the α-position, for example 2-hydroxyethyl, and their acid addition salts as well as pharmaceutical preparations containing these compounds and their use.

The invention relates very particularly to compounds of the formula I in which one of the radicals R^ and R2 is pyridyl, such as 3-pyridyl, and the other is phenyl, R3 is hydrogen, n is 0 or 1 and R^ is lower alkyl having 1 to 4 C atoms, such as ethyl, and their acid addition salts as well as pharmaceutical preparations containing these compounds and their use.

The invention relates specifically to the compounds of the formula I named in the examples, and their aoid addition salts.

The invention furthermore relates to a process for the preparation of compounds of the formula wherein at least one of the radicals R^ and R2 is a monocyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 65 membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thia-alkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is N-substituted by lower alkyl, lower alkoxy-lower alkyl or hydroxy-lower alkyl or is an N-oxide thereof, and a radical R^ or R2 different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, Rj is hydrogen or lower alkyl, n is 0, 1 or 2, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the ατ-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, and their acid addition salts.

The compounds of the formula I and their salts can be prepared by methods known per se, for example by a) reacting compounds of the formulae (ill) in which one of the radicals X and Y is mercapto, which can be in the form of a salt, and the other is a radical which is replaceable by etherified mercapto, with the proviso that, in compounds of the formula (II), in which X is mercapto which may be in salt form, heteroaryl radicals Ry and/or R2 differ from 5-membered heteroaryl radicals containing a sulfur atom and from 6-membered heteroaryl radicals containing a nitrogen atom, or radicals R^ differ from hydrogen, if in compounds of the formula (III) Y is reactive esterified hydroxy and R^ is lower alkyl monosubstituted in the 2-, 3- or 4-position by hydroxy, with one another, or b) reacting compounds of the formulae II and III, wherein one of the radicals X and Y is a group of the formula —S(0)n—Vj, wherein Yy is a reactive esterified hydroxyl group or, if n is 0, an etherified mercapto group, or if n is 1 or 2, an etherified hydroxyl group, and the other is a metal radical Y2, with one another, or (c) reacting a compound of the formula II, wherein X is the mercapto group, with a lower alkene which is unsubstituted or substituted as indicated for lower alkyl R4, or d) reacting a compound of the formula II, wherein X is a sulfinic or sulfonic acid group in salt form, with a compound of the formula III, wherein Y is a reactive esterified hydroxyl group, or e) reacting a compound of the formula (VI) wherein one of the radicals RQ is a group Eg and the other 5 is a group Rg and Xg is a reactive esterified hydroxyl group, or an acid addition salt thereof, with a N—Rg—S—R^ isothiourea, or f) rearranging a compound of the formula wherein Χθ is lower alkylthio which is unsubstituted or substituted by phenyl which may itself be substituted as for Rg and Rg, or an acid addition salt thereof, and, if desired, in a compound of the formula I obtained by one of process variants a) to f) and in which n is 0, and Rg, Rg, Rg and R^ are as defined above, with the proviso that, in compounds of the formula I obtained by process variant a) by reacting compounds of the formulae (II) and (m), in which X is mercapto which may be in salt form and Y is reactive esterified hydroxy, heteroaryl radicals R^ and/or R2 differ from 5-membered heteroaryl radicals containing a sulfur atom or an oxygen atom, or from 6-membered heteroaryl radicals containing a nitrogen atom, if R^ is a lower alkyl radical which is substituted by one or two hydroxyl groups, a lower alkoxy group or by phenyl which is unsubstituted or substituted as indicated, or is an unsubstituted lower alkynyl radical, oxidising the thio group to the sulfinyl or sulfonyl group, and/or in a compound obtained by one of process variants a) to f), wherein R^ and/or R2 contain at least one N, N-oxidising said nitrogen atom, or in a compound obtained by one of process variants b) or f), in which n is 1 or 2, reducing the sulfinyl or sulfonyl group to the thio group, and/or in a compound obtained by one of process variants a) to f), in which R^ and R2 contain a N-oxidised nitrogen atom, reducing said nitrogen atom to a group ^N, N-lower alkylating a compound of the formula I, in which R3 is hydrogen, or in a compound of the formula I optionally introducing additional C-substituents into radicals R^, R2 and/or into phenyl, phenoxy or phenylthio groups as constituents of R^, and/or converting a free compound into an acid addition salt or an acid addition salt into the free compound or into another salt.

Mercapto or sulfinic acid groups in the form of a salt are, for example, in the form of an alkali metal salt or ammonium salt, for example mercapto or sulfinic acid groups in the form of the sodium, potassium or ammonium salt.

Radicals X and Y which are replaceable by etherified mercapto are, for example, halogen atoms, for example chlorine, bromine or iodine, and radicals X which are replaceable by the group -SR^ are, furthermore, sulfonyl groups, in particular sulfonyl groups derived from organic sulfonic acids, for example methanesulfonyl, ethanesulfonyl, benzenesulfonyl, g-bromobenzenesulfonyl or £-toluenesulfonyl. Radicals Y which are replaceable by l-R3-4-R^-5-R2-imidazol2-ylthio are, furthermore, reactive esterified hydroxyl groups other than halogen, such as hydroxyl groups esterified with sulfuric acid or with an organic acid, for example with methane-, ethane-, benzene-, g-braicbenzene- or £-toluene-sulfonic acid. Reactive esterified hydroxyl groups YandY^ are, for example, halogen atoms, such as chlorine, bromine or iodine, or sulfonyloxy groups, preferably sulfonyloxy groups of the formula -SC^-R/p in groups Y of the formula -S(O)n-Y1( in which n is 2. Etherified mercapto groups Y^ in groups X of the formula ~S(O)n-Y^ in which n is 0 are, for example, l-R3-4-R1=5-R2-imidazol-2-ylthio radicals and in groups Y of the formula S(O)n-Y-j_ in which n is 0 are, for example, those of the formula -SR^. Etherified hydroxyl is, for example, hydroxyl etherified with an aromatic alcohol, such as a substituted or unsubstituted phenol, in groups of the formula -S(O)n-Y^ in which n is 1, and also lower alkoxy. Metal radicals Y, are, for example, those of the formulae -mF, -11^/2 tt τ or -M -Hal, in which M is an alkali metal atom, for example lithium or sodium, and M11 is an alkaline earth metal atom, for example magnesium, cadmium or zinc.

The reaction according to process variants a) - d can be carried out in a conventional manner, especially in the manner known frcm the literature for analogous reactions, if necessary in the presence of a catalytic agent, and in the case of the reaction of mercapto compounds of the formula II with alkenes or phenylalkenes, for example in the presence of acid agents, 25 such as Lewis acids, for example of iron-II salts or boron trifluoride, or of peroxides,for examplecf di-tert.butyl peroxide, or under the action of UV light, for example with a wavelength of about 200 to 350 urn.

When carrying out the said reactions, the reaction is in 3o each case preferably carried out in a solvent, and when compounds of the formulae II and III in which one of the radicals X and Y is a metal radical and the other is a group of the formula -S(O)n-Yj_ are used as the starting materials, and also in the case of the reaction of mer35 capto compounds of the formula II with alkenes or phenylalkenes of the formula III, is carried out, for example, in ether, tetrahydrofuran or dioxan, or in the case of the reaction of mercaptans or mercaptides or sulfonic acid salts of the formula II with reactive esters, for example halides, of the formula III is carried out, for example, in an alcohol, for example in methanol, ethanol, ethylene glycol or ethylene glycol monooethyl ether, the reactions in each case advantageously being carried out under an inert gas atmosphere, for example under nitrogen, and if necessary at elevated temperature, for example at the boil.

A preferred embodiment of the above process variants a) and d), respectively, oarprises, for exanple, reacting a 2-mercapto- or 2-sulfoimidazole derivative of the formula II, which can be in the form of one of the said salts, in a lower alkanol, for example in methanol or ethanol, with a hydrochloric acid, hydrobromic acid, hydriodic acid or sulfuric acid ester of the formula II.

In a preferred embodiment of process variant b>, for exanple, a compound of the formula II in which X is a metal radical Y2, preferably lithium, and preferably differs from hydrogen, is reacted, for example in an open-chain or cyclic aliphatic ether, for example in diethyl ether, tert.-butyl methyl ether, tetrahydrofuran or dioxan, with a compound of the fonnula III in which Y is a group of the formula -S-S-R^, halogen-S-R^ or -S(0)2-°“s(°)2“R4· Some of the starting materials are known.

Novel starting materials can be prepared by methods known per se.

The compounds of the formula II in which X is mercapto, which have been cited as starting materials, i.e. l-Rj-4-R^-5-R2~2-mercapto-imidazoles and l-Rj-^-Rj-S-Rg-imidazoline-thiones, in which R^ , R2 and R-j are as defined initially under the formula I, can be prepared, for example, by subjecting a compound of the fonnula _ ' IK /X1 (IV) in which Xg is a group of the formula -NH-C(=S)-NHR^ and Xg is hydroxyl, or Xg is a group of the formula -NR3-C(=S)-NHg and Xg is hydroxyl, or a tautomer thereof, which can be in a ketalised form, to intramolecular cyclisation.

Tautomers of compounds of the formula IV are preferably the ketones tautomeric to the enols which have the formula IV. These enols can be ketalised with lower alkanols or lower alkanediols, for example with methanol, ethanol, ethylene glycol or 1,3-propylene glycol.

The intramolecular cyclisation can be carried out in a conventional manner, especially in the manner described in the literature for analogous reactions, for example in a solvent, such as water or an alcohol, for example in water, ethanol, butanol, ethylene glycol or ethylene glycol monomethyl ether, if necessary in the presence of an acid condensing agent, such as an inorganic acid, for example hydrochloric acid, and/or at elevated temperature, for example at the boil. 2o The starting materials of the formula IV, in turn, can be obtained by methods known per se and are advantageously prepared in situ and cyclised without isolation. For this purpose, the starting material used is preferably a compound of the formula Rg-C0-CH(NHR3)-Rg (IVa) or an acid addition salt thereof and this is reacted with thiocyanic acid or a metal thiocyanate. A compound of the formula IV is formed as an intermediate and this cyclises according to the invention. A particularly advantageous reaction is that of a hydrohalide, for example the hydrochloride, of a compound of the formula IVa with an alkali metal thiocyanate or ammonium thiocyanate, suedss with sodium thiocyanate or potassium thiocyanate, in aqueous solution, if necessary with warming to 60 to 100°C.

A variant of this process comprises reacting a compound of the formula Rg-CH(NHg)-CO-Rg (IVb), or an acid addition salt thereof, with an isothiocyanate of the formula R-j-N=C=S (IVc), in an analogous manner.

The starting materials of the formula IV can also be prepared by reacting a compound of the formula Rq-CO-CHOH-R0 (IVd), or a compound of the formula Ro-CO-CH(halogen)-R^ (iVf) obtainable by a-halogenation, for example with bromine in acetic acid, of a compound of the formula RQ-C0-CH2-Ro (IVe), in which formulae one of the groups Ro is the radical R^ and the other is the radical R2, in a conventional manner with a thiourea compound of the formula RjNH-CS-NH2 (iVg) or a compound which produces the latter in situ, for example a Rjammonium thiocyanate. At elevated temperatures, for example at 100-250°, the compound of the formula IV which is first formed oyolises in the manner according to the invention. If R^ and R2 are different and R^ is not hydrogen, it is possible, depending on the reactivities of the individual component of the formula IVc and/or on the reaction conditions, to obtain both or only one of the possible isomers, i.e. a l-R^-4-R^-5-R2-2(3H)-imidazoline2-thione and/or a l-R3~4-R2-5-R^-2(3H)-imid.azoline-2thione, and these isomers can, if necessary, be separated in a conventional manner, for example by fractional crystallisation or by chromatography.

The starting materials of the formula IVa, in turn, can be prepared in a manner known per se, for example by converting a compound of the formula R^-CO-CHg-Rg to the oxime, converting the oxime with toluenesulfonyl chloride in pyridine to the oxime-ester, subjecting the latter to the Neber's oxime/amine-ketone rearrangement and, if desired, introducing a radical R^ into the resulting compound of the formula R1-C0-CH(NH2)-R2, for example by reaction with a lower alkyl bromide or lower alkyl iodide.

Starting materials of the formula IVb can be prepared in an analogous manner, using a compound of the formula R^-CH2-C0-R2 as the starting material.

Starting materials of the formula IVd in which R^ and R2 are identical radicals RQ can also be prepared by autocondensation of an aldehyde of the formula RQ-CHO (IVh), for example effected with potassium cyanide in ethanol/water or tetrabutyl-ammonium cyanide in water.

The compounds of the formula II in which X is mercapto can also be obtained by heating a corresponding imidazole derivative of the formula which is unsubstituted in the 2-position, in tetramethylene sulfone with sulfur to about 15O-25O°C, for example to about 200°C. io Starting materials of the formula II in which X is a metal radical Y2 are preferably prepared in situ, for example by reacting a compound of the formula V with a metal-organic compound of the formula R-Y2 (VI), in which R is an aliphatic radical, preferably lower alkyl, for example with butyl-lithium or methyl- or butyl-magnesium bromide. Compounds of the formula II in which Y2 is a z n-halogen or Cd-halogen group can then be obtained from the magnesium-organic compounds thus obtainable, by reaction with zinc chloride or cadmium dichloride, The starting materials of the formula V can, in turn, be prepared by heating a compound of the formula R0-CO-CH(halogen)-R0 (iVf), in which one of the radicals Rq is a group Ry and the other is a group Rg, with formamide, preferably at the boil. The compounds of the formula IVf can, in turn, be obtained by reacting a compound of the formula Ry-CH=O or R2-CH=0 (Va) in the presence of a di-lower alkylamine hydrochloride, for example dimethylamine hydrochloride, with an alkali metal cyanide, treating the resulting 2-Ry- or 2-R2-di-lower alkylamino30 acetonitrile (Vb) in dimethylformamide with sodium hydride and then with a compound of the formula R2- or Ry-CHghalogen (Vc), hydrolysing the condensation product by heating for several hours in a mixture of concentrated hydrochloric acid and chloroform and halogenating the resulting compound of the formula Ro-CO-CH2-RQ(IVe), for example by means of bromine in acetic acid or copper-II bromide in ethyl acetate.

Starting materials of the formula II in which X is a free or esterified sulfo group or a sulfo group in the form of an anhydride, such as sulfo, lower alkoxy- or phenoxy-sulfonyl or a sulfonyloxysulfonyl group, can be obtained, for example, by oxidising the mercapto group in a compound of the formula II in which X is mercapto to the sulfo group and, if desired, halogenating this, for example with phosphorus pentachloride, and converting the halogenosulfonyl group to esterified sulfo with an alcohol, for example a lower alkanol or phenol, or to an anhydride in the conventional manner, for example by reaction with a sulfonic acid salt. Sulfinic acid esters of the formula II can also be prepared analogously, the oxidation of the mercaptan being stopped at the sulfinic acid stage. Compounds of the formula II In which X is a group -S-S-R^ can be obtained by mild oxidation of mercaptans of the formula II, for example by means of ironill chloride or atmospheric oxygen.

In process variant e), the ocnpounds of the formula VI in which and/or R2 is a basic group can also be in the form of an acid addition salt.

The reaction according to process variant e) is carried out in a conventional manner, preferably by liberating the N-S^-S-R^-isothiourea, and optionally the compound of the formula VII, in situ from a N-R^-S-R^-isothiuronium salt/ such as an alkosulfate or halide, for example bromide or chloride, and a compound of the formula VI which may be in the form of a salt, for example by the action of a base, such as an alkali metal hydroxide or alkali metal carbonate, for example sodium hydroxide or carbonate or potassium io hydroxide or carbonate, or a nitrogen base, for example ammonia, a tri-lower alkylamine, such as triethylamine or Ν,Ν-diisopropylethylamine, or pyridine, 3 equivalents of base being required if the starting materials of the formula VI are in the form of a saltsand otherwise 2 equivalents of base being required, the reaction advantageously being carried out in a solvent, such as a lower alkanol, for example in methanol, ethanol, butanol or amyl alcohol, if necessary at elevated temperature, for example at the boil.

The starting materials of the formula VI can be prepared by methods known per se, for example by reacting a compound of the formula Ry-CH=O or R2-CH=0 (Va) in the presence of a di-lower alkylamine hydrochloride, for example dimethylamine hydrochloride, with an alkali metal cyanide, treating the resulting 2-Ry- or 2-R2-di-lower alkylaminoacetonitrile (Vb) in dimethylformamide with sodium hydride and then with a compound of the formula R2- or Ry-CH2~halogen (Vc), hydrolysing the condensation product by heating for several hours in a mixture of con3o centrated hydrochloric acid and chloroform and halogenating the resulting compound of the formula Ro-C0-CH2-RQ (IVe), for example by means of bromine in acetic acid or The compounds of the formula I have valuable pharmacological properties. In particular, they have a pronounced anti-inflammatory, anti-nociceptive and/or anti-thrombotic activity as well as an inhibitory action on prostaglandin synthesis. Thus, they prove to have an excellent effect in rats in the kaolin paw oedema test according to Helv. Phydiol. Acta 25, 156 (1967) in the dosage range of about 15 to 150 mg/kg, and also in the Carrageneen paw oedema test according to Di Pasquale et al., Agents and Actions 5, 256 (1975) in the dosage range of about 20 to 200 mg/kg, when administered perorally, in a single dose, additionally also in the adjuvaus-arthritis of the rat on four single doses of about 10 to 60 mg/kg p.o. and in mice in the writhing syndrome induced by phenyl-p15 benzoquinone, according to J. Pharmacol, exp. Therap. 125, 237 (1959), in the dosage range of about 30 to 300 mg/kg p.o. and in the emboly of the rabbit lung which ι had been induced by dosage of arachidonates in a dose range of about 0.1 to 3 mg/kg p.o..

Furthermore, in the concentration range of about 10 to 30 ml/1, they inhibit in vitro the prostaglandin synthesis from arachidonic acid, demonstrated in the test arrangement according to Prostaglandins 7, 123 (1974).

The compounds of the formula I are therefore out25 standingly suitable as active ingredients in pharmaceutical preparations for the treatment of inflammatory diseases, in particular chronic inflammation of the rheumatic type, such as chronic arthritis.

The invention relates primarily to compounds of 30 the formula I in which at least one of the radicals and R2 is substituted or unsubstituted furyl, thienyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or triazinyl and the other is substituted or unsubstituted phenyl, R3 is hydrogen or lower alkyl, n is 0, 1 or 2 and R^ is an aliphatic hydrocarbon radical which has not more than 7 carbon atoms and is unsubstl48738 2ό tuted or substituted by unsubstituted or substituted phenyl or, in a position higher than the α-position, by hydroxyl, lower alkoxy, such as methoxy or ethoxy, lower alkylthio, such as methylthio, or a substituted or un5 substituted phenoxy or phenylthio group, it being possible for ring carbon atoms in the said radicals Rg and Rg as well as phenyl, phenoxy and phenylthio groups to be substituted by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, halogen with an atomic number of not more than 35, such as chlorine, trifluoromethyl, nitro and/or amino which is unsubstituted or contains, as substituents, lower alkyl, such as methyl, or 4-membered to 7-membered alkylene, such as trimethylene or tetramethylene, which can be interrupted by nitrogen, oxygen or sulfur, and for ring nitrogen atoms of pyrimidinyl, triazinyl or, in particular, pyridyl radicals also to be substituted by oxy, and their acid addition salts, preferably pharmaceutically usable acid addition salts.

The invention relates in particular to compounds 2o of the formula I in which one of the radicals Rg and Rg is a substituted or unsubstituted pyridyl group and the other is a substituted or unsubstituted phenyl or pyridyl group. Rj is hydrogen or lower alkyl having 1 to 4 C atoms, such as methyl, n is 0 and R^ is lower alkyl having 1 to 7 C atoms which is unsubstituted or substituted by phenyl or, in a position higher than the α-position, by hydroxyl, lower alkoxy or lower alkylthio having 1 to 4 C atoms, phenoxy or phenylthio, or is a lower alkenyl or lower alkynyl radical having 2 to 4 C atoms which is unsub30 stituted or substituted by phenyl, it being possible for pyridyl, phenyl, phenoxy or phenylthio groups to be substituted by lower alkyl having 1 to 4- C atoms, such-as methyl, lower alkoxy having 1 to 4 C atoms, such as methoxy or ethoxy, halogen having an atomic number of not more than 35, such as chlorine, nitro, amino or N,Ndi-lower alkylamino having 1 to 4 C atoms in each alkyl moiety, such as dimethylamino, and their salts. copper-ll bromide in ethyl acetate.

The rearrangement according to process variant f) can be effected in a conventional manner, if necessary in the presence of a catalyst, such as a Lewis acid, for example aluminium trichloride, and advantageously in a solvent, for example in benzene, toluene, Ν,Ν-dimethylaniline, anisole, tetralin, chlorobenzene, pyridine or decalin.

The starting materials of the formula VII can be prepared in a manner known per se, for example by first reacting a compound of the formula R^-CO-CO-Rj (Vila) with thiourea, converting the resulting S-R^-5-R2~2thiohydantoin with phosphorus pentasulfide to the corresponding 5-R^-5-R2~di-thiohydantoin and further reacting the latter with a lower alkyl halide, which can be substituted as indicated for Xg.

In resulting compounds of the formula I it is possible, within the scope of the given definition, to introduce, convert or detach substituents.

Thus, for example, an organic radical Rg can be introduced in place of a hydrogen atom Rg by reaction with an agent which introduces the radical Rg. Such agents are, for example, reactive esters, such as hydrogen halide acid esters, for example hydrochloric, hydrobromic or hydriodic acid esters, organic sulfonic acid esters, for example methane-, ethane-, benzene-, p-bromobenzene- or p-toluenesulfonic acid, esters, or sulfuric acid esters of corresponding lower alcohols R^OH. The reaction with these agents is carried out in a conventional manner, for example in the presence of a basic condensing agent, such as an alkali metal hydroxide or alkali metal carbonate, for example sodium hydroxide or potassium hydroxide or sodium carbonate or potassium carbonate, an alcoholate, for example an alkali metal lower alkanolate, such as sodium methanolate, and also sodium hydride, advantageously in an inert solvent, for example in dimethylformamide or Nmethylpyrrolidone.

Furthermore, in compounds of the formula I, it is possible to carry out N-oxidation on radicals -SCO^-R^ in which n is 0 to the corresponding sulfinyl or sulfonyl radicals in which n is 1 or 2, of radicals =S(O)n-R^ in which n is 1 to the corresponding sulfonyl radicals in which n is 2 and/or of heteroaryl radicals R^ and/or Rp which have 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 which is inert towards this agent, if necessary with cooling or warming, for example in the temperature range of about -30° to +100°C, preferably at about 0° to 60°C, in a closed vessel and/or under 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 per-acids, 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 compounds 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 of chalcogens, or the anhydrides or salts there48738 of, for example nitric acid, dinitrogen tetroxide, selenium dioxide or sodium metaperiodate, and also ozone. Suitable solvents are, for example, halogenated hydrocarbons, such as halogenoalkanes, for example carbon tetrachloride, chloroform or methylene chloride, or carboxylic acids, such as alkanoic acids, for example acetic acid, or the anhydrides thereof.

In a preferred embodiment of this oxidation process, it is possible, for example, to oxidise thioethers of the formula I in which n is 0 and/or one of the radicals Ry and/or Rg has an unsubstituted ring nitrogen atom /N by reaction with an organic per-acid, for example with m-chloroperbenzoic acid, in a halogenoalkane,'for example in chloroform, to the corresponding sulfinyl or sulfonyl compounds in which n is 1 or 2, and, if desired, at the nitrogen atom >N.

In another preferred embodiment, thioethers of the formula I in which n is 0 can be selectively oxidised by treatment with sodium metaperiodate, preferably in a halogenoalkane, for example in carbon tetrachloride or chloroform, to the corresponding sulfoxides in which n is 1, or the latter can be oxidised with hydrogen peroxide in acetic acid to sulfones in which n is 2, Conversely, in compounds of the formula I in which n is 1 or 2 and/or heteroaryl radicals Ry and/or R2 are N-oxidised, it is possible to reduce the group -S(O)-Ra or -S(0)2-R4 to the corresponding group S(O)Q-RA and/or to reduce N-oxidised ring nitrogen >N-0 to ^N.

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 hydrides or alkali metal borohydrides, for example with sodium borohydride or lithium aluminium hydride, advan48738 tageously in an inert solvent, such as an ether, for example diethyl ether or tetrahydrofuran, or, for selective reduction of ^N-0 groups, with a phosphorusIII compound, such as a phospine, for example triphenyl5 phosphine or tri-n-butylphosphine, or a phosphorous acid ester, such as a tri-lower alkyl phosphite, for example with trimethyl phosphite or triethyl phosphite.

Furthermore, it is possible, if desired, to introduce additional C substituents into the radicals and ϊ?2 and also into phenyl, phenoxy and phenylthio groups as constituents of R^, Thus, halogenation can be carried out in a conventional manner, for example by reaction with chlorine or bromine in the presence of iron or by means of N-chlorosuccinimide. Furthermore, alkylation can be carried out in a conventional manner, for example by reaction with a lower, alkyl halide, lower alkanol or lower alkene in the presence of aluminium trichloride.

Furthermore, nitration can be carried out in a conventional manner, for example by means of nitric acid/sulfuric 2o acid.

Furthermore, nitro groups can be reduced to amino in a conventional manner, such as with nascent hydrogen, for example with iron/hydrochloric acid.

Amino groups can also be substituted in a con25 ventional manner, for example alkylated by reaction with an alkylating agent, such as one of those mentioned, in the presence of a basic condensing agent.

Furthermore, resulting free compounds can be converted to acid addition salts in a manner known per se, for example by reacting a solution of the free compound in a suitable solvent or solvent mixture with one of the abovementioned acids or with a solution thereof, or with a suitable anion exchange resin.

Resulting acid addition salts can be converted to the free compounds in a manner known per se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or bicarbonate or ammonia, or with a suitable anion exchange resin.

Resulting acid addition salts can be converted to other acid addition salts in a manner known per se, for 5 example by treatment with an anion exchange resin or by treating a salt of an inorganic acid with a suitable metal salt, such as a sodium, barium or silver salt, of an acid in a suitable solvent, in which an inorganic salt which forms is insoluble and thus precipitates out of the reio action mixture.

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

Because of the close relationship between the 15 novel compounds in the free form and in the form of their salts, what is stated in this specification in respect of the free compounds or the salts thereof also applies by analogy to the corresponding salts and free compounds.

The invention also relates to those embodiments 20 of the process in which a compound obtainable as an intermediate at any process stage is used as the starting material and the missing process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative thereof, if desired in the form of a salt.

The starting materials used in the process of the present invention are preferably those which result in the compounds described initially as being particularly valuable.

The pharmaceutical preparations according to the invention, which contain compounds of the formula I or II or pharmaceutically usable salts thereof, are those which are intended for enteral, such as oral or rectal, and parenteral administration and for topical application to warm-blooded animals and which contain the pharmacological active ingredient on its own or together with a pharmaceutically usable carrier. The dosage of the active ingredient depends on the species of warm-blooded = 48738 animal, the age and the individual condition and also on the mode of administration. In the normal case, an approximate daily dose of about 30-300 mg, advantageously divided into several equal partial doses, is to he esti5 mated for a warm-blooded animal weighing about 75 kg, in the case of oral administration.

The novel pharmaceutical preparations contain, for example, from about 10?$ to about 80?$, and preferably from about 20% to about 60%, of the active ingredient.

Pharmaceutical preparations according to the invention for enteral and parenteral administration are, for example, those in the form of dosage units, such as sugar-coated tablets, tablets, capsules or suppositories, as well as ampoules. These are prepared in a manner known per se, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilising methods.

Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, granulating a resulting mixture if desired and processing the mixture or granules, if desired or if necessary after adding suitable adjuncts, to tablets or sugar-coated tablet cores.

Suitable carriers are, in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes^using, for example, maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or poly30 vinylpyrrolidone, and/or, if desired, disintegrators, such as the above starches, and also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are in particular glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are pro48738 vided with suitable coatings which can be resistant to gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, shellack in suitable organic solvents or solvent mixtures, or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to ifte tablets or the coatings of sugar-coated tablets, for example to identify or indicate different doses of active ingredient.

Further pharmaceutical preparations for oral administration are dry-filled capsules made of gelatin and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dryfilled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, 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 can also be added.

Pharmaceutical preparations for rectal administration are, for example, suppositories, which consist of a combination of an active ingredient with a suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or high alkanols. Gelatin rectal capsules, which contain a combination of the active ingredient with a base, can also be used; base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinhydrocarbons.

Preparations suitable for parenteral administration are, in particular, aqueous solutions of an active ingredient in a water-soluble form, for example of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or tri5 glycerides, are used, or aqueous injection suspensions which contain substances which increase the viscosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and can also contain stabilisers.

Pharmaceutical preparations for topical applica10 tion are, in particular, creams, ointments, pastes, foams, tinctures and solutions, which contain from about 0.5 to about 20% of the active ingredient.

Creams are oil-in-water emulsions which contain more than 50% of water. Substances used as the oleaginous base are, in particular, fatty alcohols, for example lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty acids, for example palmitic acid 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 emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl-sulfate, sodium cetyl-sulfate or sodium stearyl-sulfate, which are customarily used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents which reduce the extent to which the creams dry out, for example 35 polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes and the like.

Ointments are water-in-oil emulsions which contain up to 70%, but preferably from about 20% to about 50%, of water or aqueous phases. The oleaginous phase comprises, in particular, hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which preferably contain hydroxy compounds suitable for improving the water-binding capacity, 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 glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes and the like.

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

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

Foams are administered from pressurised dispensers and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons, such as chlorofluorolower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, being used as propellants.

Substances used as the oleaginous phase are, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. The emulsi5 fiers used are, inter alia, mixtures of those which have primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens) and those which have primarily lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, the conventional 10 additives, such as preservatives and the like, are used.

Tinctures and solutions in most cases have an aqueous-ethanolic base, to which the following substances are added, inter alia: polyalcohols·, for example glycerol, glycols and/or polyethylene glycol, as humec15 tants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, i.e, lipophilic substances which are soluble in the aqueous mixture, as a replacement for fatty substances which are removed from the skin with the ethanol, and, if necessary, other adjuncts and additives.

The pharmaceutical preparations for topical use are prepared in a manner known per se, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When pro25 cessing the active ingredient in the form of a solution, it is usually dissolved in one of the two phases before emulsifying, and when processing the active ingredient in the form of a suspension, it is mixed with a part of the base after emulsifying and then added to the remainder of the formulation.

The present invention also relates to the use of the compounds of the formulae I and II, and of the salts of such compounds with salt-forming properties, preferably for the treatment of inflammations, in particular of inflammatory chronic diseases of the rheumatic type, particularly chronic arthritis.

The following examples illustrate the present <7 invention without in any way restricting the scope thereof. Temperatures are in degrees Centigrade.

Example 1 0.8 g of sodium is dissolved in 200 ml of ethanol. g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole are added to the solution and the mixture is heated under reflux. After a clear solution has formed, 2.3 ml of 2-chloroethanol are added dropwise and the reaction mixture is heated under reflux for 16 hours. The solvent is evaporated off in vacuo and the residue is partitioned between water and ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated.

Crystalline 2-(2-hydroxyethylthio)-5(4)-phenyl-4(5)-(3pyridyl)-imidazole is obtained as the residue and after recrystallisation from ethyl acetate/petroleum ether this melts at 128-130°C.

The starting material can be prepared, for example, as follows. .8 g of benzyl 3-pyridyl ketone are stirred together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine for 6 hours at 100°. The reaction mixture is poured onto ice/water and the resulting mixture is stirred for a further 15 minutes. The crystals which have precipitated are filtered off with suction, washed with water and dried under a high vacuum. Benzyl 3-pyridyl ketone oxime with a melting point of 122-126° is obtained.

A solution of 7.7 g of p-toluenesulfonyl chloride in 15 ml of pyridine is added dropwise in the course of 5 minutes to a solution, which is stirred at -10°, of 8,5 g of benzyl 3-pyridyl ketone oxime in 20 ml of pyridine.

The reaction mixture is placed in a refrigerator for 24 hours and then poured onto ice/water. After some stirring and grinding, the oil which has separated out solidifies to crystals. These are filtered off with suction, washed with water and dried under a high vacuum.

Benzyl 3-pyridyl ketone oxime p-toluenesulfonate is obtained and this is employed in the next stage without further purification. 11.6 g of crude benzyl 3-pyridyl ketone oxime p-toluenesulfonate are suspended in 90 ml of absolute ethanol. A solution of 3·7 g of potassium tert.-butylate in 30 ml of absolute ethanol are then added dropwise at 0°, with stirring. The reaction mixture is stirred at 0° for 2 hours. The suspension is filtered with suction and the io filtrate, which contains the desired α-amino-benzyl 3-pyri dyl ketone, is immediately reacted further in the next stage. 3.6 g of sodium thiocyanate are dissolved in ml of ethanol and 4.5 ml of concentrated hydrochloric acid are added to the solution. The suspension is fills tered with suction and the filtrate is heated, together with the alcoholic solution of α-amino-benzyl 3-pyridyl ketone, for 18 hours under reflux. After cooling, crude 2-mercapto-4(5)-phenyl-=5(4)-(3-pyridyl)-imidazole can be filtered off, with suction, from the reaction mixture. The filtrate contains further product.

The crude product is recrystallised from dimethylformamide/water and then melts at 290-300°.

Example 2 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)25 imidazole are dissolved in 50 ml of methanol and 10 ml of 2 N sodium hydroxide solution. 2.85 g of methyl iodide are added dropwise, the mixture is stirred for 2 hours at room temperature, 50 ml of water are added, the resulting mixture is filtered with suction and the residue is washed with water. This yields crude 2-methylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole, which when recrystallised from a mixture of isopropanol and petroleum ether (8:5 parts by volume) melts at 193-194°. 8 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)imidazole are dissolved in 40 ml of methanol and 16 ml of 2 N sodium hydroxide solution· 4·55 g of methyl iodide are added dropwise to the solution. The mixture is stirred for a further 2 hours at room temperature. 40 ml of water are added, the resulting mixture is filtered with suction and the residue is washed with water. A mixture of l-methyl-2-methylthio-4-phenyl-5-(3-pyridyl)imidazole and l-methyl-2-methylthio-5-phenyl-4-(3-pyridyl)imidazole is obtained. This mixture can be separated into the components by chromatography. Thus, on a silica gel column, first one component with a melting point of 141-143° is eluted with chloroform and then the other component with a melting point of 125-127° is eluted with chloroform/ethyl acetate (8:2 parts by volume). Example 4 The following compounds can also be prepared in a manner analogous to that described in Examples 1-3: 2-(2hydroxyethylthio)-l-methyl-4-phenyl-5-(3-pyridyl)-imidazole , 2-(2-hydroxyethylthio)-l-methyl-5-phenyl-4-(3pyridyl)-imidazole, (2-(2-methoxyethylthio)-4(5)-phenyl5(4)-(3-pyridyl)-imidazole),2-(2-methoxyethylthio)-1methyl-4-phenyl-5-(3-pyridyl)-imidazole, 2-(2-methoxyethylthio)-l-methyl-5-phenyl-4-(3-pyridyl)-imidazole, 2(2-methylthi oethylthio)-4(5)-phenyl-5(4)-(3-pyridyl)imidazole, l-methyl-2-(2-methylthioethylthio)-4-phenyl-5(3-pyridyl)-imidazole, l-methyl-2-(2-methylthioethylthio)5-phenyl-4-(3-pyridyl)-imidazole, 2-ethylthio-4(5)-phenyl5(4)-(3-pyridyl)-Imidazole, 2-propylthio-4(5)-phenyl-5(4)(3-pyridyl)-imidazole, 2-isopropylthio-4 (5) -phenyl-5 (4)-(3pyridyl)-Imidazole, 2-methylthio-4,5-bis-(2-thienyl)imidazole and 2-ethylthio-4,5-bis-(2-thienyl)-imidazole. Example 5 In a manner analogous to that described in Example 2, the following compounds can be prepared using, in each case, 7.6 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)imidazole as the starting material: 2-ethylthio-4(5)phenyl-5(4)-(3-pyridyl)-imidazole, melting point 196-198° (from isopropanol/petroleum ether), 2-propylthi0-4(5)phenyl-5(4)-(3-pyridyl)-imidazole, melting point 143-144° (from isopropanol/petroleum ether) and 2-isopropylthio4(5)-phenyl-5(4)-(3-pyridyl)-imidazole, melting point 182-184° (from isopropanol/petroleum ether).

Example 6 A solution of 6.3 g of 85% m-chloroperbenzoic acid in 70 ml of chloroform is added dropwise to a suspension of 8 g of 2-methylthio-4(5)-pheny1-5(4)-(3-pyridyl)imidazole in 400 ml of chloroform, with stirring. The resulting solution is left to stand overnight and is then washed successively with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness. The residue is twice recrystallised from isopropanol/ petroleum ether. 2-Methanesulfinyl-4(5)-phenyl-5(4)(3-pyridyl)-imidazole with a melting point of 166-169° is obtained.

Using 2-ethylthio=4(5)-phenyl=5(4)-(3-pyridyl)imidazole as the starting material, 2-ethanesulfinyl4(5)-phenyl-5(4)-(3-pyridyl)-imidazole with a melting point of 162=164° is obtained in an analogous manner. ml of acetic acid and 0.38 ml of 30% hydrogen peroxide are added to 1.0 g of 2-ethanesulfinyl-4(5)~ phenyl-5(4)-(3-pyridyl)-imidazole and the mixture is stirred overnight at 70°. It is allowed to cool, neutralised with sodium hydroxide solution and filtered with suction. This yields 2-ethanesulfonyl-4(5)phenyl-5(4)-[3-(l-oxidopyridinio)]-imidazole, which meets at 208-210°. 2.86 g of α-bromobenzyl 3-pyridyl ketone hydrobromide and 1 g of S-methylisothiuronium bromide are suspended in 30 ml of acetonitrile, 3.1 g of N,N-diisopropylethylamine are added and the mixture is stirred overnight. The reddish orange suspension is filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in chloroform, the chloroform solution is dried over sodium sulfate and evaporated and the residue is recrystallised from chloroform/petroleum ether. 2-Methylthio-4(5)-phenyl-5(4)-(3-pyridyl)imidazole with a melting point of 193-194° is obtained.

The starting material can be prepared, for example, as follows: A solution of 17 g of bromine in 150 ml of acetic acid is added dropwise to 20 g of benzyl 3-pyridyl ketone in 200 ml of acetic acid and the mixture is stirred overnight. The α-bromobenzyl 3-pyridyl ketone hydrobromide which has precipitated is filtered off and can be used without further purification.

Example 9 The following compounds can also be prepared in a manner analogous to that described in Examples 1 to 8: 2-ethylthi0-4(5)-(p-fluorophenyl)-5(4)-(2-thienyl)-imidazole , 2-methylthio-4(5)-(p-fluorophenyl)-5(4)-(2thienyl)-imidazole and 2-propylthio-4(5)-(p-£luorophenyl)5(4)-(2-thienyl)-imidazole.

Example 10 Tablets containing 25 mg of active ingredient, for example 2-methylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole, can be prepared as follows: Constituents (for 1,000 tablets): Active ingredient 25.0 g Lactose 100.7 g Wheat starch 7.5 g Polyethylene glycol 6000 5.0 g Talc 5.0 g Magnesium stearate 1.8 g Demineralised water q.s.

Preparation: All the solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient, the lactose, the talc, the magnesium stearate and half the starch are then mixed. The other half of the starch is suspended in 4o ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting starch paste is added to the hulk of the constituents and the mixture is granulated, with the addition of water if necessary. The granules are dried overnight at 35°, forced through a sieve of 1.2 mm mesh width and compressed to tablets which are concave on both sides and about 6 mm in diameter.

Tablets containing, in each case, 25 mg of one of the other compounds of the formula I named in Examples 1 to 4 can also be prepared in an analogous manner.

Example 11 Tablets, for chewing, containing 30 mg of active ingredient, for example 2-methylthio-4(5)-phenyl-5(4-)-(3pyridyl)-imidazoline, can be prepared, for example, as follows: Composition (for 1,000 tablets): Active ingredient 30.0 g Mannitol 267.0 g Lactose 179.5 g Talc 20.0 g Glycine 12.5 g Stearic acid 10,0 g Saccharine 1.0 g % gelatin solution q.s.

Preparation: All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose are mixed and granulated with the addition of gelatin solution and the granules are 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 mixed carefully, the mannitol, the lactose granules, the stearic acid and the talc are now added and the whole is mixed thoroughly and compressed to tablets which are concave on both sides, have a diameter of about 10 mm and have a breaking notch on the top.

Tablets for chewing containing, in each case, mg of one of the other compounds of the formula I named in Examples 1 to 4 can also be prepared in an analogous manner.

Example 12 Tablets containing 100 mg of active ingredient, for example 2-methylthio-4(5)-phenyl-5(4)-(3-pyridyl)imidazole, can be prepared as follows: Composition (for 1,000 tablets): Active ingredient 100.0 g Lactose 248.5 g Maize starch 17.5 g Polyethylene glycol 6000 5.0 g Talc 15.0 g Magnesium stearate 4.0 g Demineralised water q.s.

Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient, the lactose, the talc, the magnesium stearate and half the starch are then 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. The resulting paste is added to the pulverulent substances and the whole is mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35°, forced through a sieve of 1.2 mm mesh width and compressed to tablets which are concave on both sides, are about 10 mm in diameter and have a breaking notch on the top.

Tablets containing 100 mg of another compound of the formula I according to Example 1 can also be prepared in an analogous manner.

Example 13 Tablets containing, in each case, 25 or 100 mg of a compound according to one of Examples 5 to 8, and tablets for chewing containing 30 mg of a compound accor48738 ding to one of Examples 5 to 8, can also be prepared in a manner analogous to that described in Examples 10 to 12. Example 14 In an analogous manner as described in Examples 5 1 to 8 also 2-ethanesulphinyl-4(5)-(4-fluorophenyl)-5(4)(2-thienyl)-imidazole; 2-ethanesulphonyl-4(5)-(4-fluorophenyl)-5(4)-(2-thienyl,-imidazole and 2-ethan sulphonyl4(5)-phenyl-5(4)-(3-pyridyl)imidazole can be manufactured.

Claims (34)

1. A compound of the formula R. R. '2 N R. '3 (I) wherein at least one of the radicals R. and R„ is a mono1 2 cyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thia-alkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is N-substituted by lower alkyl, lower alkoxy-lcwer alkyl or hydroxy-lower alkyl or is an N-oxide thereof, and a radical R^ or R^ different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, R 3 is hydrogen or lower alkyl, n is 0, 1 or 2, and R 4 is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino. « 48738 di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the a-posi5 tion by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 10 ring members, or by nitro and/or trifluoromethyl with the proviso that heteroaryl radicals R and/or R_ are different from 5-membered heteroaryl radicals containing one sulfur atom and from 6-membered heteroaryl radicals containing one nitrogen atom, or radicals R 3 are different from hydrogen, 15 if R^ is lower alkyl substituted in the 2-, 3- or 4-position by a hydroxyl group, and with the further proviso that, in a compound of the formula 1, in which n is 1 or 2, heteroaryl radicals and/or Rg differ from 5-membered heteroaryl radicals containing one sulfur atom or one oxygen atom, 20 and from 6-membered heteroaryl radicals containing one nitrogen atom, if is lower alkyl substituted by one or two hydroxyl groups,by a lower alkoxy group or by phenyl which is unsubstituted or substituted as indicated above, or is an unsubstituted lower alkynyl, the radicals qualified 25 by lower containing up to and including 7 carbon atoms, or an acid addition salt thereof.

2. A compound according to claim 1, wherein at least one of the radicals Rg and Rg is a monocyclic 5-menibered heteroaryl group containing one oxygen atom or one sulfur atom, 30 one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6-membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or Csubstituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is N-substituted by lower alkyl, lower alkoxy-lower alkyl, hydroxylower alkyl, and a radical R^ or R,, different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, R 3 is hydrogen or lower alkyl, n is 0, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the exposition by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring nenibers, or by nitro and/or tri fluoromethyl, with the proviso that heteroaryl radicals R^ and/or R^ are different from 5-membered heteroaryl radicals containing one sulfur atom and from 6-membered heteroaryl radicals containing one nitrogen atom, or radicals R 3 are different from hydrogen, if R^ is lower alkyl substituted in the 2-, 3- or 4-position 4-8 by a hydroxyl group, or an acid addition salt thereof.

3. A compound according to claim 1, wherein at least one of the radicals R^ and R 2 is furyl, thienyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl 5 or triazinyl, and the ring carbon atoms of said radicals Rl and R 2 may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa- or 3-thiaalkyleneamino, each contain10 ing 5 or 6 ring members, and the ring nitrogen atoms of pyrimidinyl, triazinyl or pyridyl radicals may also bear' an oxygen atom, and a radical R^ or R 2 -different therefrom is phenyl which may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and 15 including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, R^ is hydrogen or lower alkyl, n is 0, 1 or 2, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which 20 is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or is a lower 25 alkyl radical which is substituted in a position higher than the α-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, 30 trifluoromethyl, nitro, amino, lower alkyleneamino and/or alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or an acid addition salt thereof.

4. A compound according to claim 2, wherein at least one of the radicals R^ and R^ is furyl, thienyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or triazinyl, and the ring carbon atoms of said radicals R^ and R 2 may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and a radical or R 2 different therefrom is phenyl which may be substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, R^ is hydrogen or lower alkyl, n is 0, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, nitro, amino, lower alkylamino and/or alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or is a lower alkyl radical which is substituted in a position higher than the α-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen having an atomic number of up to and including 35, trifluororaethyl, nitro, amino, lower alkyleneamino and/or alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or an acid addition 4 8 7 38 salt thereof.

5. A compound according to claim 2, in which one of the radicals and R 2 is pyridyl and the other is phenyl, and these radicals independently of each other may be substitu5 ted by lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms, halogen having an atomic number of up to and including 35 and/or Ν,Ν-di-lower alkylamino containing 1 to 4 carbon atoms in each alkyl moiety, R^ is hydrogen or lower alkyl having 1 to 4 C atoms, n is 0 and is lower 10 alkyl of 1 to 4 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, phenyl-lower alkyl which contains 1 to 4 carbon atoms in the alkyl moiety and is unsubstituted or substituted by lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms and/or halogen having an atomic number of up 15 to and including 35, mono- or dihydroxy-lower alkyl which contains 2 to 4 carbon atoms and carries the hydroxyl group or groups in a position higher than the α-position, or lower alkoxy- or lower alkylthio-lower alkyl, which contains 1 to 4 carbon atoms in the alkoxy or alkylthio moiety and 20 2 to 4 carbon atoms in the alkyl moiety, and carries the alkoxy or alkylthio group in a position higher than the aposition, or an acid addition salt thereof.

6. A compound according to claim 1, wherein one of the radicals R^ and R 2 is unsubstituted pyridyl or thienyl and 25 the other is phenyl which is unsubstituted or substituted by lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms and/or halogen having an atomic number of up to and including 35, R 3 is hydrogen or lower alkyl of 1 to 4 carbon atoms, n is 0, 1 or 2, and R^ is lower alkyl of 1 30 to 4 carbon atoms, or an acid addition salt thereof.

7. A compound according to claim 2, wherein one of the radicals R^ and R^ is unsubstituted pyridyl and the other is phenyl which is unsubstituted or substituted by lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms or halogen, is hydrogen or lower alkyl of 1 to 4 carbon atoms, n is 0, and R 4 is lower alkyl of 1 to 4 carbon atoms or hydroxy-lower alkyl of 2 to 4 carbon atoms which carries the hydroxyl group in a position higher than the aposition, or an acid addition salt thereof.

8. A compound according to claim 1, wherein one of the radicals R^ and R 2 is pyridyl and the other is phenyl, R 3 is hydrogen, n is 0 or 1, and R 4 is lower alkyl of 1 to 4 carbon atoms, or an acid addition salt thereof.

9. A compound according to any one of claims 1 to 8 as antiinflammatory or antinociceptive agent.

10. 2-Ethylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof.

11. 2-Ethanesulfinyl-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof.

12. 2-Ethylthio-4 (5)- (p-fluoropheny 1)-5(4) - (2-thienyl)imidazole or an acid addition salt thereof.

13. 2-(2-Hydroxyethylthio)-4(5)-phenyl-5 (4)-(3-pyridyl)imidazole or an acid addition salt thereof.

14. 2-Methylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof.

15. 2-(2-Methylthioethylthio)-4(5)-phenyl-5 (4)-(3-pyridyl)imidazole or an acid addition salt thereof.

16. 2-(2-Methoxyethylthio)-4(5)-phenyl-5(4)-(3-pyridyl)imidazole or an acid addition salt thereof. 4-8 7 38

17. 2-Propylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof.

18. 2-lsopropylthio-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof. 5

19. 2-Ethanesulfonyl-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole or an acid addition salt thereof.

20. 2-Ethanesulfinyl-4(5)-(p-fluorophenyl)-(2-thienyl)imidazole or an acid addition salt thereof.

21. 2-Ethanesulfonyl-4(5)-(p-fluorophenyl)-(2-thienyl)10 imidazole or an acid addition salt thereof.

22. 2-Ethylthio-4(5)-bis-(2-thienyl)-imidazole or an acid addition salt thereof.

23. A pharmaceutical preparation containing, as the active ingredient, canpound of the formula wherein at least one of the radicals and R 2 is a monocyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or c-substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and/or by trifluoro25 487 38 methyl, and/or is N-substituted by lower alkyl, lower alkoxy-lower alkyl, hydroxy-lcwer alkyl or is an N-oxide thereof, and a radical or R^ different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, is hydrogen or lower alkyl, n is 0, 1 or 2, and is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza, 3-oxa- or 3thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the a-position by hydroxy, lower alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, with the proviso that, in a compound of the formula 1, in which n is 1 or 2, heteroaryl radicals R^ and/or R 2 differ from 5-menibered heteroaryl radicals containing one sulfur atom or one oxygen atom, and from 6-membered heteroaryl radicals containing one nitrogen atom, if R is lower alkyl 4 substituted by one or two hydroxyl groups, by a lower alkoxy group or by phenyl which is unsubstituted or substituted as indicated above, or is an unsubstituted lower alkynyl radical, the radicals qualified by lower contain48738 ing up to and including 7 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable excipient therefor.

24. A compound according to any one of claims 2, 4, 5, 5 7, 10, 13—18 and 22, for the treatment of inflammatoryconditions.

25. A compound according to any one of claims 1, 3, 6, 8, 9 and 19—21, for the treatment of inflammatory conditions. 10

26. A pharmaceutical preparation containing a compound according to any one of claims 2, 4, 5, 7, 10, 13—18, 22 and 24, together with conventional pharmaceutical excipients

27. A pharmaceutical preparation containing a compound according to any one of claims 1, 3, 6, 8, 9, 19—21, 15 23 and 25, together with conventional pharmaceutical excipients.

28. A process for the production of a compound of the formula IO IO R, N N S(0) -R. n 4 (I) '2 wherein at least one of the radicals Rg and Rg is a monocyclic 5-membered heteroaryl group containing one oxygen atom or one sulfur atom, one sulfur atom and one nitrogen atom, or at least two nitrogen atoms, or a monocyclic 6-membered heteroaryl group containing at least one nitrogen atom, which group is linked through a carbon atom and is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, and/or by trifluoromethyl, and/or is N-substituted by lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl and a radical Rg or Rg different therefrom is a phenyl group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, R^ is hydrogen or lower alkyl, n is 0, and R^ is a lower alkyl, lower alkenyl or lower alkynyl radical which is unsubstituted or substituted by phenyl which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkyleneamino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, or is a lower alkyl radical which is substituted in a position higher than the α-position by hydroxy, lower C 48738 alkoxy, lower alkylthio, or by a phenoxy or phenylthio group which is itself unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 3-aza-, 3-oxa- or 3-thiaalkylene5 amino, each containing 5 or 6 ring members, or by nitro and/or trifluoromethyl, the radicals qualified by lower containing up to and including 7 carbon atoms, or an acid addition salt thereof, which process comprises a) reacting compounds of the formulae (II) and Y—R^ (III), wherein one of the radicals X and Y is mercapto which may be in salt form and the other is a radical which is replaceable by etherified mercapto, with the proviso that, in compounds of the formula (II) , in which X Is mercapto which may be in salt form, heteroaryl radicals R^ and/or differ from 5-membered heteroaryl radicals containing a sulfur atom and from 6-membered heteroaryl radicals containing a nitrogen atom, or radicals R 3 differ from hydrogen, if in compounds of the formula (III) Y is reactive esterified hydroxy and R^ is lower alkyl monosubstituted in the 2-, 3- or 4-position by hydroxy, with one another, or b) reacting compounds of the formulae (II) and (III ), wherein one of the radicals X and ¥ is a group of the formula —S(0) —Y,, wherein Y, is a reactive esterified η 1 1 hydroxyl group or, if n is 0, an etherified mercapto group, or if n is 1 or 2, an etherified hydroxyl group, and the other is a metal radical Y 2 , with one another, or c) reacting a compound of the formula wherein X is the mercapto group, with a lower alkene which is unsubstituted or substituted as indicated for lower alkyl R 4 < or d) reacting a compound of the formula X (II) wherein X is a sulfinic or sulfonic acid group in salt form, with a compound of the formula Y—R 4 (III) wherein Y is a reactive esteri fied hydroxyl group, or 5 e) reacting a compound of the formula κ t °\Z (VI) wherein one of the radicals R is a group R. and the other ο 1 is a group R 2 and X,_ is a reactive esterified hydroxyl group. or an acid addition salt thereof, with a Nthiourea, or -R 4 ISO - f) rearranging a compound of the formula (VII) wherein X is lower alkylthio which is unsubstituted or sub6 stituted by phenyl which may itself be substituted as for R^ and R 2< or an acid addition salt thereof, and, if desired, in a compound of the formula I obtained by one of process variants a) to f) and in which n is 0, and R^, R 2< R^ and R 4 are as defined above, with the proviso that, in compounds of the formula I obtained by process variant a) by reacting compounds of the formulae (II) and (ill),in which X is mercapto which may be in salt form and Y is reactive esterified hydroxy, heteroaryl radicals and/or R^ differ from 5membered heteroaryl radicals containing a sulfur atom or an oxygen atom, or from 6-membered heteroaryl radicals containing a nitrogen atom, if R^ is a lower alkyl radical which is substituted by one or two hydroxyl groups, a lower alkoxy group or by phenyl which is unsubstituted or substituted as indicated, or is an unsubstituted lower alkynyl radical, oxidising the thio group to the sulfinyl or sulfonyl group,and/or in a compound obtained by one of process variants a) to f), wherein R^ and/or R 2 contain at least one ?N, N-oxidising said nitrogen atom, or in a compound obtained by one of process variants b) or f), in which n is 1 or 2, reducing the sulfinyl or sulfonyl group to the thio group, and/or in a compound obtained by one of process variants a) to £), in which and R 2 contain a Noxidised nitrogen atom, reducing said nitrogen atom to a group >N, N-lower alkylating a compound of the formula 1, in which R^ is hydrogen, or in a compound of the formula I optionally introducing additional C-substituents into radicals R^, R 2 and/or into phenyl, phenoxy or phenylthio groups as constituents of R^, and/or converting a free compound into an acid addition salt or an acid addition salt into the free compound or into another salt.

29. A process according to claim 28 for the production of a compound of the formula (I), in which R , R 2 , R 3 and R 4 are as defined in claim 28, but heteroaryl radicals R^ and/or R 2 are not N-oxldes thereof, and n is 0, or an acid addition salt thereof, which process comprises a) reacting compounds of the formulae 487 38 όΰ wherein one of the radicals X and Y is mercapto which may be in salt form and the other is a radical which is replaceable by etherified mercapto, with the proviso that, in compounds of the formula (II), in which X is mercapto which may be in salt form, heteroaryl radicaLs and/or differ from 5membered heteroaryl radicals containing a sulfur atom, and from 6-membered heteroaryl radicals containing a nitrogen atom, or radicals R 3 are different from hydrogen, if in compounds of the formula (III) Y is reactive esterified hydroxy and R^ is lower alkyl mono-substituted in the 2-, 3- or 4position by hydroxy, with one another, or c) reacting a compound of the formula wherein X is the mercapto group, with a lower alkene which is unsubstituted or substituted as indicated for lower alkyl e) reacting a compound of the formula 4-8 7 38 \z (VI) wherein the radical R q α-oriented to the oxo group is a radical R, and the other radical R is a radical R_ and X„ 1 0 2 5 is a reactive esterified hydroxyl group, with a N—R—S—R 5 isothiuronium salt and, if desired, N-lower alkylating a compound of the formula I in which R^ is hydrogen, in compounds of the formula I optionally introducing additional C-substituents into radicals R^, R 2 and/or into phenyl, phenoxy or phenylthio groups as constituents of R^, and/or 10 converting a free compound into an acid addition salt or an acid addition salt into the free compound.

30. A canpound of formula I as defined in claim 28 when obtained by the process as claimed in either of claims 28 or 29.

31. A compound as claimed in any one of claims 1 to 25 as 15 antiinflammatory agent.

32. A method of preparing a pharmaceutical composition which comprises associating a compound claimed in any of claims 1-25 with at least one pharmaceutical diluent or carrier. 20

33. A process as claimed in claim 28, substantially as herein described.

34. A compound as claimed in dlaim 1, whenever prepared by a process claimed in a preceding claim.