GB2039882A - Bicyclic thiadiaza compounds and their use as medicaments - Google Patents

Abstract

New bicyclic thiadiaza compounds of the general formula (I> <IMAGE> the 1,3-diazacyclopent-2-ene ring of which may have a further double bond, Alk represents lower alkylene that separates the sulphur atom from the nitrogen atom by 2 to 4 carbon atoms, Ar1 and Ar2 represent, independently of one another, an optionally substituted phenyl, pyridyl or thienyl radical and n is 0, 1 or 2, provided that at least one of the radicals Ar1 and Ar2 is not phenyl when Alk represents ethylene and the 1,3-diazacyclopent-2-ene ring represents an imidazole ring, and the salts thereof, anti-inflammatory and anti- rheumatic effects. They also an analgesic effect and have an inhibitory effect on prostaglandin synthetase in vitro. Compounds of the general formulae <IMAGE> or their tautomers, and the salts thereof are also claimed.

Description

SPECIFICATION Bicyclic thiadiaza compounds, process for their preparation and use as medicaments The invention relates to new bicyclic thiadiaza compounds, in particular 1 ,3-diazacyclopent-2-eno[2,i -bj(1 - thia-3-azacycloalkenes) of the general formula (I)

the 1,3-diazacyclopent-2-ene ring of which may have a further double bond, Alk represents lower alkylene that separates the sulphur atom from the nitrogen atom by 2 - 4 carbon atoms, Ar1 and Ar2 represent, independently of one another, an optionally substituted phenyl, pyridyl or thienyl radical, and n is 0, 1 or 2, provided that at least one of the radicals Ar, and Ar2 is not phenyl when Alk represents ethylene and the 1 ,3-diazacyclopent-2-ene ring represents an imidazole ring, and to the salts thereof, and also to a process for their production. In addition, the invention relates to pharmaceutical preparations containing these compounds and their use, preferably in the form of pharmaceutical preparations.

The radicals and compounds designated "lower" in connection with the present description and claims contain up to 7 and especially up to 4 carbon atoms.

The lower alkylene radical denoted by Alk is preferably unbranched but can also be a branched lower alkylene radical having 2 - 4 carbon atom in the chain between the sulphur atom and the nitrogen atom.

Pyridyl is a 2-, or 4-pyridyl radical and thienyl is a 3-thienyl or, especially, a 2-thienyl radical.

Substituted phenyl, pyridyl or thienyl is, for example, substituted once, twice or more times by the same or different substituents. Substituents, especially in the phenyl radical, are, among others, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulphonyl and/or nitro. Substituents in the pyridyl orthienyl radical are preferably lower alkyl, halogen and/ortrifluoromethyl.

The general terms used above and hereinafter may have the following meanings: Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, also n-pentyl, n-hexyl, isohexyl or nheptyl.

Lower alkylene is ethylene, as well as prop-1,3-ene and but-i, 4-ene, but it can also be prop-1,2-ene, but-l, 2-ene or but-2,3-ene, pent-1,3-ene or pent-2,4-ene or pent-1,4-ene.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy.

Halogen is a halogen atom having an atomic number of up to and including 35 and can be fluorine or bromine but is preferably chlorine.

Lower alkylsulphonyl stands, for example, for methylsulphonyl, ethylsul phonyl or n-propylsulphonyl.

The compounds according to the invention have valuable pharmacological properties, in particular anti-inflammatory and anti-rheumatic effects, as shown in experiments on animals. For example, in the kaolin paw-oedema test (Helv. Physiol. Acta 25(1967)156) on rats at a dose, administered perorally, of at least about 10 mg/kg, or in the turpentine pleuritis test [Helv. Physiol. Acta 26(1969) 287] on rats at a dose, administered perorally, of 30 to 100 mg/kg, they exhibit anti-inflammatory and anti-exudation effects. The unsaturated compounds in particular exhibit an excellent effect also in the adjuvant arthritis test [Pharmacology 2 (1969) 288] on rats at a peroral dose of 10 - 30 mg/kg.

The new compounds also have an analgesic effect, as shown in the phenyl-p-benzoquinone test on mice (Proc. Soc. Exp. Biol. (1957) 729) at doses, administered perorally, of 30 to 100 mg/kg.

There should also be mentioned the inhibitory effect of the new preparations on the prostaglandinsynthetase in vitro [Prostaglandins, 7 (1974) 123] at concentrations of 0.05 - 20 g/ml. In addition, they have a valuable anti-thrombotic effect, namely protection against fatal pulmonary embolism in rabbits (Pharmacology 14(1976) 522] at peroral doses of 0.03 - 3 mg/kg.

In addition, the tertrahydro compounds exhibit a strong effect in the pertussis oedema test (Agents and Actions, vol. 6,613, 1976) at 5 - 50 mg/kgirat.

The new compounds can therefore be used as anti-inflammatory agents, for example, for the treatment of rheumatic, arthritic and other diseases connected with inflammations, in particular rheumatoid arthritis, or as analgesic agents, for example, for the treatment of painful conditions.

The invention relates especially to compounds of the formula I, wherein Ar1 and Ar2 represent, independently of one another, a pyridyl radical, such as a 2-, or 4- pyridyl radical, a thienyl radical, especially a 2-thienyl radical, or a phenyl radical, optionally substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl, and wherein Alk represents a lower alkylene radical that connects the sulphur atom and nitrogen atom to one another via 2 or 3 carbon atoms, especially an unbranched lower alkylene radical, and n represents 1 or 2, but especially 0, to the salts thereof.

The invention relates especially to compounds of the formula ll.

in which Ar1 and Ar2 represent, independently of one another, a phenyl radical optionally substituted by lower alkoxy, such as methoxy, or halogen, in particular chlorine, and m is preferably 1, but can also be 2, and to the salts thereof.

The invention also relates, more especially to compounds of the formula Ill.

wherein Ar, and Ar2 represent, independently of one another, a phenyl radical optionally substituted by lower alkoxy, such as methoxy, or halogen, in particular chlorine, and m is preferably 1, but can also be 2, and to the salts thereof.

The invention also relates especially to the new compounds described in the Examples.

The new compounds can be obtained according to methods known per se.

Thus, for example, compounds of the formula IV

wherein X represents a reactive esterified hydroxy group, can be ring-closed and, if desired, in any optionally resulting compound, in which n is 0, the sulphur atom can be oxidised to form the sulphinyl group or sulphonyl group and/or, if desired, free compounds obtained can be converted into their salts or salts obtained can be converted into the free compounds and/or an isomer mixture obtained according to the process can be separated into the individual isomers.

Reactively esterified hydroxy is, in particulary, a hydroxy group esterified with a strong inorganic acid, for example, a hydrogen halide, especially hydrochloric acid, or sulphuric acid, or with a strong organic acid, such as a lower alkanesulphonic acid, for example, methanesulphonic acid or ethanesulphonic acid or a benzene-sulphonic acid optionally substituted by lower alkyl, lower alkoxy or halogen, for example, p-toluenesulphonic acid orp-bromobenzenesulphonic acid.

The ring closure is preferably carried out under conditions for splitting off acids. This operation is effected preferably in a low-boiling solvent, such as dimethylformamide or acetone, an alcohol, for example, methanol or ethanol, if desired in the presence of a base, for example, an inorganic base, such as an alkali metal or alkaline earth metal hydride, hydroxide or carbonate, especially sodium hydride, sodium hydroxide or sodium carbonate, or an organic base, preferably a nitrogen base, such as a tri-lowr alkylamine, for example, trimethylamine, triethylamine or dimethylisopropylamine or pyridine.

The starting materials can be obtained by reacting a corresponding diaza-2-mercapto compound with a dihydroxyalkylene in which at least one of the two hydroxy groups is reactively esterified, optionally oxidising the mercapto group to form the sulphinyl group or sulphonyl group and then, if necessary, reactivety esterifying the second hydroxy group. The reactively esterified hydroxy groups and the conditions of condensation correspond to those mentioned above. In the case of this reaction in particular if both hydroxyl groups are reactively esterified, the starting materials of the formula IV can be obtained in situ and closed to form the ring in the same reaction.

The new compounds of formula I, which have a further double bond, can also be obtained by ring-closing compounds of the formula Va or Vb

or their tautomers and, if desired, in optional resulting compounds in which n is 0, oxidising the sulphur atom to form the sulphinyl group or the sulphonyl group and/or, if desired, converting free compounds obtained into their salts or salts obtained into the free compounds and/or separating an isomer mixture obtained according to the process into the individual isomers.

The ring closure is effected under conditions for splitting off water, the instance by heating, for example from about 50 to about 1500, preferably in the presence of a solvent, such as acetonitrile or an alcohol, for example, methanol or ethanol.

The starting materials can be obtained if a compound of the formula Vl

is reacted in a manner known perse with a compound of the of the formula Vll

or a tautomer thereof.

Reactively esterified hydroxy groups X are in particular those mentioned above.

If this reaction is also carried out under conditions for splitting off water, for example, while heating in a solvent such as acetonitrile or in an alcohol, the starting material of the formula Va or Vb can be obtained in situ and forms a ring under these reaction conditions.

The sulphur atom can be oxidised to form the sulphinyl group or the sulphonyl group in a manner known per se, for example, with perioxides, such as hydrogen peroxide, or per acids, for example, a perbenzoic acid optionally substituted by lower alkyl, lower alkoxy, halogen or a further carboxyl group, such as perbenzoic acid itself or monoperphthalic acid, or an alkanepercarboxylic acid, such as peracetic acid or a periodate such as sodium periodate. This reaction is carried out chiefly at low temperatures in a solvent, such as glacial acetic acid or acetone.

The new compounds may be in the form of acid addition salts, in particular non-toxic salts that are pharmaceutically acceptable, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphaticcarboxylic or sus phonic acids, for example, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, 4-amino-benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, embonic acid or nicotinic acid, as well as methanesulphonic acid, ethane-sulphonic acid, 2-hydroxyethanesulphonic acid, ethylene-sulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, naphthalenesulphonic acid, sulphanilic acid or cyclohexy Isulphamic acid. Salts of this type can be obtained, for example, by treating the free compounds with the acids or with suitable anion exchange resins.

As a result of the close relationship between the new compounds in the free form an in the form of their salts, the free compounds and their salts are to be understood above and hereinafter, both with regard to meaning and use, as indicating optionally also the corresponding salts and free compounds respectively.

The new compounds may be in the form of isomer mixtures, such as racemates or diastereoisomer mixtures, or in the form of the individual isomers, such as optionally active components. The separation of isomer mixtures obtained into the individual isomers can be effected according to known methods.

Racemates can be separated into the optically active antipodes, for example, as a result of physico-chemical differences, such as, for example, those of solubility, of their diastereoisomeric salts, or by fractionaly crystallisation from an optically active solvent, or by chromatography, in particular thin layer chromatography, using an optically active carrier material. In the course of this operation the pharmacologically more effective or less toxic individual isomer, in particular the more effective or less toxic active antipode, is advantageously isolated.

The above reactions are carried out in the normal manner in the presence or absence of diluents, condensation agents and/or catalysts, if necessary at a lower or raised temperature, in a closed vessel and/or in an inert gas atmosphere.

The process also includes those embodiments according to which compounds occurring as intermediates are used as starting materials and the remaining process steps are carried out using these, or the process is interrupted at some stage; in addition, starting materials may be used in the form of derivatives or may be formed during the reaction.

Preferably, such starting materials are used and the reaction conditions are selected in such a manner that the compounds specified initially as being particularly preferred are obtained.

The invention also relates to the new compounds of the general formula Va and Vb,

ortheirtautomers obtainable as intermediates, in which Alk represents lower alkylene that separates the sulphur atom from the nitrogen atom by 2 - 4 carbon atoms, Ar1 and Ar2 represent, independently of one another, optionally subsituted phenyl, pyridyl, orthienyl and n is 1 or 2, and to the salts thereof. In the above-mentioned biological test procedures they have approximately the same effects as the dihydro compounds of the formula I and may be used as anti-flammatory agents, for example, for the treatment of rheumatoid arthristis.

The new compounds of the present invention may be used, for example, forthe production of pharmaceutical preparations that contain an effective quantity of the active substance together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for enteral or parenteral administration.Tablets or gelatine capsules are therefore used which contain the active substance together with diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose andlor glycerine, and lubricants, for example, silica, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; tablets also contain binders, for example, magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium, carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrating agents, for example, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescing mixtures, or adsorption agents, dyestuffs, flavourings and sweeteners.Furthermore, the new pharmacologically effective compounds may be used in the form of injectable, for example, intravenously administrable, preparation or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible to produce the latter before use, for example, from lyophilised preparations containing the active substant alone or together with a carrier material, for example, mannitol. The pharmaceutical preparations may be sterilised and/or may contain adjuvants, for example, preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.The pharmaceutical preparations of the present invention, which, if desired, may contain other pharmacologically valuable substances, are produced in a manner known per se, for example, by means of conventional mixing, granulating, coating, dissolving or lyophilising processes and contain from about 0.1% to 100%, especially from about 1% to about 50%, in the case of lyophilisates up to 100%, of the active substance. The single dose for a warm-blooded animal weighing about 70 kg is preferably from 0.1 to 0.75 g, and the daily dose is preferably from 0.2 to 1.0 g.

The following Examples illustrate the invention; temperatures are given in degrees Centigrade. Unless otherwise stated, percentages are by weight and ratios by volume.

Example 1 A mixture of 5 g of a-bromodesoxyanisoin, 3 g of 2-aminothiazoline and 30 ml of ethanol is stirred for 4 hours at 60 , then for 2 hours at reflux and afterwards for a further 12 hours at room temperature. The crystals formed during this operation are suction-filtered and then washed with ethanol and diethyl ether.

Crude 5,6-di-(p-methoxphenyl)-imidazo[2,1 -b]dihydrothiazole is thus obtained. Melting point after recrystallising from toluene/petroleum ether 152 - 154".

Example 2 A suspension of 7 ml of 1,2-dibromoethane, 7 g of sodium carbonate and 55 ml of isopropanol is stirred at room temperature and a suspension of 4.7 g of 4,5-diphenyl-imidazolidine-2-thione in 110 ml of 1.5% sodium hydroxide solution is added in the course of one hour. The reaction mixture is boiled for 7 hours at reflux, then the isopropanol and the dibromoethane are removed using a rotary evaporator and the remaining suspension is extracted with toluene. The toluene extract is washed with brine, dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel. After separating off non-polar impurities with ethyl acetate cis-5,6-diphenyl-2,3,5,6-tetrahydroimidazo[2,i-b)thiazole is eluted in the form of a colourless oil with a mixture of ethyl acetate: methanol = 99 1. It crystallises spontaneously to form white crystals having a melting point of 110 - 113 (sintering point 103").

Example 3 In the course of one hour a suspension of 3 g of 4,5-dianisyl-2-mercaptoimidazol in 50 ml of 1.5% sodium hydroxide solution is added, while stirring at room temperature, to a suspension of 3.5 ml of 1,2-dibromoethane, 3.5 g of sodium carbonate and 30 ml of isopropanol. The reaction mixture is boiled for 6 hours at reflux, then the isopropanol and the dibromoethane are removed using a rotary evaporator and 10 ml of 20% potassium hydroxide solution are added to the remaining suspension and extraction is effected with ethyl acetate. The organic phases are washed with brine, dried with sodium sulphate and concentrated by evaporation. After recrystallising from toluene/petroleum ether 5,6-di-(p-methoxyphenyl)-imidazo[2,1b]dihydrothiazole with a melting point of 152 - 154" is obtained from the residue.

Example 4 14.8 g of 4,5-di-(p-methoxyphenyl)-2-ss-hydroxyethyl-mercaptoimidazole are dissolved in 50 ml of absolute pyridine and added dropwise while stirring at about -5" internal temperature, to a solution of 15.8 g of benzene sulphochloride in 6-0 ml of absolute pyridine. Thorough stirring is then carried out for 60 hours at 0 .

The reaction mixture is poured on to ice water and extracted with dichloromethane. The dichloromethane extracts, washed three times with water and combined, are dried over sodium sulphate and concentrated to dryness by evaporation. The viscous oil so obtained is crystallised from toluene/petroleum ether. The 5,6-di-(p-methoxyphenyl)-imidazo[2,1-b]dihydrothiazole thus obtained has a melting point of 152 - 154 .

The starting material may be obtained, for example, as follows: 2.5 g of sodium are dissolved in 220 ml of ethanol. 35 g of 4,5-dianisylumidazoline-2-thione are added. A suspension is obtained. 15.7 ml of 2-chloroethanol are added dropwise at room temperature while stirring in the course of 2 minutes. Stirring is continued for 1 hour at 60" and for 4 hours at reflux. The weak suspension is then concentrated to dryness by evaporation. The residue is purified using acetone/water.

Example 5 A mixture of 60 g of N-ethyldiisopropylamine, 70 g of 2-aminodihydrothiazole, 150 g of a bromodesoxyanisoin and 800 ml of acetonitrile is stirred for 48 hours at room temperature. The 5,6-di-(p-methoxyphenyl)-imidazo[2,1 -b]dihydrothiazoline formed is suction-filtered and then washed with acetonitrile. By concentrating the filtrate by evaporation and distributing between ethyl acetate and water the residue thus free from the solvent a further 50 g of crude product are obtained. By recrystallising the crude product from toluene 5,6-di-(p-methoxyphenyl)-imidazo[2,1 -b]dihydrothiazole having a melting point of 152 - 154" is obtained.

Example 6 A solution of 20 g of 2-(2-hydroxyethythio)-4(5)-3'-pyridyl-5(4)-phenylimidazole is added at 0", while stirring, to a solution of 23 g of p-toluene sulphochioride in 80 ml of pyridine. The reaction mixture is stirred for 16 hours at 0", poured on to ice water and extracted with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated; the residue obtained, after chromatographing on silica gel with toluene and ethyl acetate and after recrystallising the appropriate fractions from ethyl acetate, yields the isomer mixture 5(6)-(3-pyridyl)-6(5)-phenylimidazo-[2,1 -b]dihydrothiazole in the form of white crystals having a melting point of 150 - 151".

The starting material may be obtained as follows: 10.8 g of benzyl pyrid-3-yl ketone are stirred for 6 hours at 1000 together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine. The reaction mixture is poured on to ice water and stirred for a further 15 minutes. The resulting crystals are suction-filtered, washed with water and dried under high vacuum. Benzyl pyrid-3-yl ketone oxime having a melting point of 122 - 126" is obtained.

A solution of 7.7 ofp-toluene sulphochloride in 15 ml of pyridine is added dropwise in the course of 5 minutes to a solution, stirred at -10 , of 8.5 g of benzyl pyride-3-yl ketone oxime in 20 ml of pyridine. The reaction mixture is stored for 24 hours in a refrigerator and then poured on to ice water. After stirring for a relatively long period and trituration, the precipitated oil solidifies to form crystals. These are suctionfiltered, washed with water and dried under high vacuum. 11.6 g of a crude product having a melting point of 87 - 92" are obtained which, however, after thin layer chromatography, still contain educt. It is used directly in the next stage.

11.6 g of crude product (benzyl pyride-3-yl ketone oximep-toluene sulphoester) are suspended in 90 ml of absolute ethanol and a solution of 3.7 g of potassium tert.- butylate in 30 ml of absolute ethanol is added dropwise at 0" while stirring. The reaction mixture is stirred for 2 hours at 0". The suspension is suction-filtered and the filtrate is used immediately in the next stage.

3.6 g of sodium thiocyanate are dissolved in 60 ml of ethanol and 4.5 ml of concentrated hydrochloride acid are added. The suspension is suction-filtered and the filtrate is maintained at reflux for 18 hours together with the alcoholic solution of the a-aminobenzyl pyrid-3-yl ketone obtained. After cooling, 2.8 g of crude 4-phenyl-5-pyrid-3-yl-mercapto-imidazole can be suction-filtered from the reaction mixture. The filtrate contains further quantities of the product. After recrystallising from dimethylformamide is melts at 290 - 300".

0.8 g of sodium is dissolved in 200 ml of ethanol. 8 g of 1-phenyl-5-pyrid-3-yl-2-mercapto-imidazole are added to the solution and the whole is heated to reflux. After a clear solution has formed 2.3 ml of 2-chloroethanol are added dropwise and the reaction mixture is boiled for 16 hours at reflux.

The solvent is evaporated in vacuo and the residue is distributed between water and ethyl acetate. The organic phases are washed with water and brine, dried with sodium sulphate and concentrated by evaporation. Crystalline 2-(2-hydroxyethylthio)-4(5)-3'-pyridyl-5(4)-phenylimidazole is obtained as the residue. After recrystallising from ethyl acetate/ethanol it has a melting point of 157 - 159".

Using the corresponding starting substances, the following compounds can be produced in a similar manner: 5,6-di-(p-methyl phenyl)-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole, 5,6-di-(p-chlorophenyl )-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole, 5,6-di-(m-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole, 5,6-di-(p-methoxyphenyl)-3-methyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole or 6,7-di-(p-methoxyphenyl)-2,3,4,5,6,7-hexahydroimidazo[2,1 -b)thiazine.

Example 7 14.3 g of 2-[N-( 1 ,2-bis-p-methoxyphenyl-2-hydroxy-ethyl )-amino-]thiazole are dissolved in 24.3 ml of concentrated sulphuric acid and stirred for one hour at room temperature. The reaction mixture is poured on to ice, adjusted to an alkaline pH with 2N sodium carbonate solution and extracted with ethyle acetate. The organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. By recrystallising from toluene/petroleum ether, 5,6-trans-di-(p-methoxyphenyl )-2,3,5,6-tetrahydro-4H- imidazole[2,1-b]thiazole having a melting point of 125 - 126" is obtained from the residue.

The starting material used may be produced for example, as follows: 45 g of bromodesoxyamisoine are suspended in 170 ml of acetonitrile. 23 ml of N-ethyldiisopropylamine and 15.4 g of 2-aminothiazole are added to the suspension and the whole is stirred for 2 hour at room temperature, suction-filtered and the residue is then washed with a little ethyl acetate.2-[N-(1,2-bis-p- methoxyphenyl-2-oxoethyl)-amino]thiazoline or 2-imino-3-(1 ,2-bis-p-methoxyphenyl-2-oxoethyl)-thiazoline having a melting point of 95 - 98" is thus obtained.

There are obtained in a similar manner 2-[N-( 1 ,2-bis-p-methoxyphenyl-2-oxoethyl )-am ino]-5-methylthiazole or 2-imino-5-methyl-3-(1 ,2-bis-pmethoxyphenyl-2-oxoethyl)-thiazoline or the tautomers thereof, 2-[N-(1 ,2-bis-p-methoxyphenol-2-oxoethyl)-amino or mino]-4-methyylthiazoline on 2-imino-4-methyl-3-(1,2-bis-p- methoxyphenyl-2-oxoethyl)-thiazol ine or the tautomers thereof.

2-[N-(1 ,2-bis-phenyl-2-oxoethyl)-aminojthiazoline or 2-imino-3-(1 ,2-bis-phenyl-2-oxoethyl )-th iazoline or the tautomers thereof having a melting point of 121 - 123", or 2-[N-(1,2-bis-p-methoxyphenyl-2-oxoethyl )-aminoj-5,6-dihyd ro-4H-thiazi ne or 2-im ino-3-(1,2-bis-p methoxyphenyl-2-oxoethyl )-5,6-dihydro-4H-thiazi ne or the tautomers thereof.

31.5 g of 2-[N-(1,2-bis-p-methoxyphenyl-2-oxoethyl)-amino]thiazoline or the isomers thereof are dissolved in 350 ml of methanol and 4.26 g of sodium borohydride are added in portions. The suspension is stirred for 2 hours at room temperature, then suction-filtered and subsequently washed with methanol. 2-[N-(1,2-bis-p- methoxyphenl-2-hydroxyethyl)-amino]thiazoline having a melting point of 185 - 187" is thus obtained.

Starting from the corresponding thiazoline compounds the following compounds may be obtained in a similar manner: 5-phenyl-6-p-chlorophenyl-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazoie, 6-phenyl-5-p-chlorophenyl-2,3,5,6-tetrahydroimidazo [2,1 -b]thiazole, 5,6-di-(p-methoxyphenyl)-2-methyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole or 5,6-di-(p-methoxyphenyl)-3-methyl-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole.

Example 8 2 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo[2,1-b]thiazole are suspended in 33 ml of ethanol and 7.91 ml of 30% by vol. hydrogen peroxide are added in the course of 5 minutes. The reaction mixture is maintained at reflux for 90 minutes, cooled, poured on to 200 ml of ice water and extracted with ethyl acetate. By recrystallising from the residue, obtained by evaporation, of the organic phases washed with water and dried over sodim sulphate 5,6-di-p-methoxyphenyl imidazo[2,1 -b]-2,3-dihydrothiazole sulphoxide having a melting point of 176 - 177" is obtained.

Example 9 0.69 g of sodium is dissolved in 60 ml of ethanol and 9.36 g of 2-mercapto-4,5-di-p methoxyphenylimidazole are added. The reaction mixture is stirred for 30 minutes, 3.1 g of 3-chloro-1 - propanol are added, the whole is maintained at reflux for 2 hours, cooled, filtered so that it is clear and concentrated to dryness by evaporation. The residue, the crude 2-(3-hydroxpropylthio)-4,5-di-p methoxyphenylimidazole, is maintained at reflux for 30 minutes in 50 ml of thionyl chloride. Most of the excess thionyl chloride is evaporated off; the remaining thionyl chloride is removed by adding chloroform and distilling off the chloroform/thionyl chloride mixture. The residue is maintained at reflux for 4 hours together with 100 ml of ethanol and 50 ml of 40% potassium hydroxide solution. The reaction mixture is then concentrated by evaporation using a rotary evaporator, ice water is added and extraction is effected with ethyl acetate. The organic phases are washed with water, dried and concentrated by evaporation. The residue is chromatographed on silica gel with toluene: ethyl acetate 1:1. By recrystallising the appropriate fractions from acetone 6,7-di-p-methoxyphenyl-2,3,4,5-tetrahydroimidazo[2,1 -b] i azi (1,3)-thiazine having a melting point of 189 - 191" is obtained.

Example 10 In a manner similar to that in Example 9 there is obtained from 2-mercapto-4,5-di-p-chlorophenylimidazole with 2-chloroethanol,2-(2-hydroxyethylthio)-4,5-di-p-chlorophenylimidazole having a meiting point of 197199" and from this there is obtained by cyclisation with thionyl chloride 5,6-dip-chlorophenylimidazo[2,1- b]dihydrothiazole having a melting point of 199 - 204".

5,6-di-p-methoxyphenyl-4H-imidazo[2,1 -bidihydrothiazole can also be produced in a similar manner.

Example 11 0.5 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo[2,1 -b]thiazole is suspended in 1.5 ml of glacial acetic acid and 0.9 ml of 30% by vol. hydrogen peroxide is added. The reaction mixture is stirred for 7 hours at 60", then poured on to ice water and extracted with ethyl acetate. The organic phases are washed with 1N sodium hydroxide solution until the extracts remain basic, they are the washed until neutral with water and brine, dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from ethyl acetate and recrystallised from ethyl acetate/petroleum ether. 5,6-di-p-methoxyphenyl-imidazo[2,1- b]dihydrothiazolesulphone having a melting point of 186 - 187" is thus obtained.

Example 12 35 g of 2-[N-(1 ,2-bis-p-methoxyphenyl-2-oxoethyl)-amino]thiazoline (cf. Example 7) are maintained at reflux for 2 hours together with 250 ml of isopropanol and 1 ml of 48% hydrogen bromide. After cooling in an ice bath and suction-filtering the product 5,6-di-(p-methoxyphenyl)-imidazole[2,1 -b)dihydrothiazole having a melting point of 155 - 156" is obtained.

The hydrobromide, melting point 200 - 210", of 5,6-di-(p-methoxyphenyl)-imidazo[2,1 -bidihydrothiazole can be obtained from the mother liquor.

Example 13 17 ml of 1 N hydrochloric acid and 5 g of N-benzenesulphonyl-L(+)-glutamic acid are added to a suspension of 11.8 g of 5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo[2,1 -b]thiazole in 30 ml of water. The mixture is dissolved by heating and crystallised by cooling. L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4Himidazo[2,1 -b]thiazole N-benzenesulphonyl-L(+)-glutamate is suction-filtered, washed with a little water, suspended in water and cleaved with dilute sodium hydroxide solution. L-5,6-di-p-anisyl-2,3,5,6-tetrahydro4H-amidazo[2,1-b]thiazole is extracted from this with ethyl acetate.

Example 14 Pharmaceutical preparations are made up containing 5,6-di-(p-methoxyphenyl)-imidazo[2,1 -b)di- hydrothizole 50 mg magnesium stearate 5 mg lactose 100 mg These constituents are sieved, mixed well and the mixture is placed in hard gelatine capsules.

Example 15 Tablets are made up containing 5,6-di-(p-methoxyphenyl)-imidazo[2,1 - b]dihydrothiazole 100 mg calcium hydroxide 150 mg saccharose 20 mg starch 10 mg talcum 5 mg stearic acid 3 mg The saccharose, the calcium hydroxide and the active substance are mixed and granulated with a 10% gelatine solution. The moist granulate is sieved, dried, mixed with the starch, the talcum and the stearic acid, sieved and compressed to form tablets.

Claims (43)

1. A 1 ,3-diazacyclopent-2-eno[2,1 -b](1 -thia-3-azacycloalkene) of the general formula

the 1 ,3-diazacyclopent-2-ene ring of which may have a further double bond in the position indicated, Alk represents a lower alkylene radical that separates the sulphur atom from the nitrogen atom by 2 to 4 carbon atoms, each of Ar, and Ar2 represents, independently of the other, an unsubsituted or substituted phenyl, pyridyl or thientyl radical and n represents 0, 1 or 2, provided that at least one of the radicals Ar1 and Ar2 does not represent an unsubstituted phenyl radical in the case when Alk represents ethylene and the 1,3-diazacyclopent-2-ene ring represents an imidazole ring.

2. A compound as claimed in claim 1, wherein each of Ar, and Ar2 represents, independently of the other, an unsubstituted pyridyl, thienyl or phenyl radical or a pyridyl, thienyl or phenyl radical which is substituted by one or more of the same or different substituents selected from lower alkyl and lower alkoxy radicals, halogen atoms and trifluoromethyl groups, and Alk represents a lower alkylene radical that connects the sulphur atom and the nitrogen atom to one another via 2 or 3 carbon atoms.

3. A compound as claimed in claim 1, in which each of Arr and Ar2 represents, independently of the other, an unsubstituted pyridyl orthienyl radical our a phenyl radical which is unsubstituted orsubstitued by one or more lower alkyl or lower alkoxy radicals, halogen atoms ortri-fluoromethyl groups, and Alk represents a lower alkylene radical that connects the sulphur atom and the nitrogen atom to one another via 2 or 3 carbon atoms.

4. A compound of the general formula

in which each of Ar1 and Ar2 represents, independently of the other, a phenyl radical which is unsubstituted or substituted by one or more lower alkoxy radicals or by one or more halogen atoms, and m represents 1 or 2.

5. A compound as claimed in claim 4, wherein each of Ar, and Ar2 represents, independently of the other, a phenyl radical which is unsubstituted or substituted by one or more methoxy groups or chlorine atom.

6. A compound as claimed in claim 4 or claim 5, wherein m represents 1.

7. 5,6-diphenyl-2,3,5,6-tetrahydroimidazo[2,1 -b] thiazole.

8. 5,6-di-(p-methyl phenyl )-2,3,5,6-tetrahydroim idazo [2,1 -b]thiazole.

9. 5,6-di-(p-chlorophenyl )-2,3,5,6-tetrahydroim idazo[2,1 -b]thiazole.

10. 5,6-di-(m-chlorophenyl )-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole.

11. 5,6-di-(p-methoxyphenyl)-2- or 3-methyl-2,3,5,6-tetrahydroimidazo[2,1 -bjthiazole.

12. 5,6-di-(p-methoxyphenyl)-3-methyl-2,3,5,6-tetrahydroimidazo[2,1 -b]thiazole.

13. 5,6,-di-(p-methoxyphenyl)-2,3,5,6,7-hexahydroimidazole[2,1 -b]thiazine.

14. A compound of the general formula

in which Ar1, Ar2 and m have the meanings given in claim 4.

15. A compound as claimed in claim 14, wherein Ar, and Ar2 have the meanings given in claim 5.

16. A compound as claimed in claim 14 or claim 15, wherein m represents 1.

17. 5,6-di-(p-methoxyphenyl)-imidazo[2,1 -b]dihydrothiazole.

18. 5(6)-(3-pyridyl)-6(5)-phenylimidazo[2,1 -b]di-hydrothiazole.

19. A compound as claimed in claim 1, which is specified in any one of Examples 7 to 11 herein.

20. A salt of a compound claimed in any one of claims 1 to 19.

21. A physiologically tolerable salt of a compound claimed in any one of claims 1 to 19.

22. A salt as claimed in claim 20, which is specified in Example 12 or Example 13 herein.

23. A process for the production of a compound claimed in claim 1 or a salt thereof, which comprises (A) ring-closing a compound of the general formula

in which X represents a reactive esterified hydroxy group, and Ar1, Ar2, Alk and n have the meanings given in claim 1, or a salt thereof, or (B) ring-closing a component of the general formula

in which Ar1, Ar2, Alk and n have the meanings given in claim 1, or a salt thereof, and, if desired, in any compound in which n represents 0 possibly resulting from (A) or (B), oxidising the sulphur atom to form the sulphinyl group or sulphonyl group, and/or, if desired, converting a free compound into a salt or a salt into the free compound and/or separating an isomer mixture into the individual isomers.

24. A process as claimed in claim 23, carried out substantially as described in any one of the Examples 1 to 13 herein.

25. A compound as claimed in claim 1, whenever prepared by a process as claimed in claim 23 or claim 24.

26. A salt of a compound claimed in claim 1, whenever prepared by a process as claimed in claim 23 or claim 24.

27. A physiologically tolerable salt of a compound claimed in claim 1, whenever prepared by a process as claimed in claim 23 or claim 24.

28. A compound of the general formula

or a tautomer thereof, in which Alk, Ar1, Ar2 and n have the meanings given in claim 1.

29. A compound as claimed in claim 28, wherein Alk represents a lower alkylene radical that connects the sulphur atom and the nitrogen atom to one another via 2 or 3 carbon atoms, and each of Ar, and Ar2 represents, independently of the other, a phenyl radical which is unsubstituted or substituted by one or more lower alkoxy radicals or halogen atoms.

30. 2-[N-(1 ,2-bis-p-methoxyphenyl-2-oxoethyl)-aminojthiazoline or 2-imino-3-(1 ,2-bis-p-methoxyphenyl2-oxoethyl)-thiazoline or a tautomer thereof.

31. 2[N-( 1 ,2-bis-phenyl-2-oxoethyl)-amino]thiazoline or 2-imino-3-(1,2-bis-phenyl-2-oxoethyl)-thiazoline or a tautomer thereof.

32. 2-[N-(1 ,2-bis-p-methoxyphenyl-2-oxoethyl)-amino]-5,6-dihydro-4H-thiazine or 2-imino-3-(1 ,2-bis-p methoxy-phenyl-2-oxoethyl )-5,6-dihydro-4H-thiazine or a tautomer thereof.

33. A compound as claimed in claim 28, other than one claimed in claims 30 to 32, which is specified in Example 7 herein.

34. A salt of a compound claimed in any one of claims 28 to 33.

35. A physiologically tolerable salt of a compound claimed in any one of claims 28 to 33.

36. A pharmaceutical preparation which comprises a compound claimed in any one of claims 1 to 19,21, 25, 27 to 33 and 35, in admixture or conjunction with a pharmaceutically suitable carrier.

37. A pharmaceutical preparation which comprises a compound claimed in any one of claims 1 to 19,21, 25 and 27, in admixture or conjunction with a pharmaceutically suitable carrier.

38. A pharmaceutical preparation as claimed in claim 36 or claim 37, which is in dosage unit form.

39. A pharmaceutical preparation as claimed in claim 38, which contains from 0.1 to 0.75 g of active ingredient per dosage unit.

40. A pharmaceutical preparation as claimed in claim 37, having a composition substantially as described in Example 14 or Example 15 herein.

41. Use of a compound claimed in any one of claims 1 to 19,21,25,27 to 33 and 35 for the production of a medicament by a non-chemical method.

42. Use of a compound claimed in any one of claimed 1 to 19,21,25,27 to 33 and 35 as a medicament.

43. Use of a compound claimed in any one of claims 1 to 19,21,25,27 to 33 and 35 as an agent for the treatment of rheumatoid arthritis.