NO782357L - PROCEDURE FOR MAKING BICYCLIC THIA-DIAZA COMPOUNDS - Google Patents

Description

Process for the preparation of bicyclic thia-diaza compounds.

The invention relates to new bicyclic thia-diaza compounds, in particular 1,3-diaza-cyclopent-2-eno-/2,1-b/(1-thia-3-aza-cycloalkanes) with the general formula in (I):

if 1,3-diaza-cyclopent-2-ene ring can have an additional double bond, Alk means lower alkylene, which separates thia- from the aza atom by 2-4 carbon atoms, Ar^ and Ar2 independently of each other mean optionally substituted phenyl, pyridyl or thienyl, and n =

0, 1 or 2, with the precaution that at least one of the residues Ar^

and A^ is different from phenyl, when Alk means ethylene and the [1,3-diaza-cyclopent-2-ene ring is an imidazole ring, as well as their salts, as well as methods for their preparation, further pharmaceutical preparations containing these compounds and their use preferably in the form of pharmaceutical preparations.

The residues and compounds designated as "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.

The lower alkylene Alk is preferably unbranched but also branched lower alkylene with 2-4 carbon atoms in the chain between the sulfur and nitrogen atoms.

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

Substituted phenyl, pyridyl or thienyl are e.g.

once, twice or even several times substituted. Substip tuents, especially at the phenyl residue are i.a. lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro. Substituents on the pyridyl or thienyl residue are preferably lower alkyl, halogen or trifluoromethyl.

Above as in the following may general terms

have the following meaning:

lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, or tert.-butyl, further n-pentyl, n-hexyl, isohexyl or n-heptyl.

The lower alkylene is ethylene, as well as 1,3-propylene, 1,4-butylene, but can also be 1,2-propylene, 1,2- or 2,3-butylene, 1,3- or 2,4-pentylene or 1 ,4-pentylene.

Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.

Halogen is like this with atomic numbers up to and including 35 and means

fluorine or bromine, preferably chlorine.

Lower alkylsulfonyl means e.g. methylsulfonyl,

ethylsulfonyl or n-propylsulfonyl.

The compound according to the invention has valuable pharmacological properties, especially anti-inflammatory and anti-rheumatic effects, as can be shown in animal experiments, e.g. in the kaolin paw edema test (Helv.Physiol. Acta 25(1967) 156) on rats at a perorally administered dose of approx. 10 mg/kg or in the turpentine pleuritis test (Helv.Physiol.Acta 26 (1969)287) on rats given orally at a dose from 30 to 100 mg/kg they show an anti-inflammatory resp. anti"-exudative effect* Especially the unsaturated compounds also show an excellent effect in the adjuvant arthritis test (Pharmacology 2 (1969) 288) on rats at an oral dose of 10-30 mg/kg.

The new compounds are also analgesically effective,

as shown in the phenyl-p-benzoquinone test on mice (Proe. Soc.Exp.Biol. 95 (1957) 729) at doses from 30 to 100 mg/kg, given orally.

Furthermore, the inhibitory effect of the new preparations on prostaglandin synthetase in vitro (Prostaglandins, 7 (1974) 123) is worth mentioning in concentrations from 0.05 to 20 µg/ml. Moreover, they show a valuable antithrombotic effect, namely a protection against fatal pulmonary embolism in rabbits (Pharmacology 14 (1976) 522) in peroral doses of 0.03-3 mg/kg.

The tetrahydro compounds also show an enhancing effect in the pertussis edema test (Agents and Actions, vol. 6, 613, 1976) at 5-50 mg/kg/rat.

The new compounds can therefore be used as anti-phlogistics, e.g. for the treatment of rheumatic, arthritic and other diseases associated with inflammation, especially rheumatic arthritis or as analgesics, e.g. for the treatment of pain conditions.

The invention relates in particular to connections with

foicmel I, in which A and Ar 2 independently of each other mean an optionally with lower alkyl, lower alkoxy, halogen or, trifluoromethyl substituted phenyl radical, a pyridyl-, such as a 2-, 3- or 4-pyridyl- or thienyl-, especially a 2 -thienyl residue, Alk means a lower alkylene residue, which connects sulfur- .and. the nitrogen atom with each other over 2-3 carbon atoms primarily an unbranched lower alkylene residue and n in particular means 0, further also 1 or 2, as well as their salts.

The invention primarily relates to compounds of formula II

in which Ar-^ and Ar2, independently of each other, mean a phenyl radical optionally substituted with lower alkoxy, such as methoxy or halogen, especially chlorine, and m means primarily 1, further also 2, as with their salts. However, the invention also particularly relates to compounds of formula III

^wherein Ar^ and Ar 2 independently of each other mean an optionally lower alkoxy, such as methoxy or halogen, especially chlorine substituted phenyl residue and m means primarily 1, further also 2, as well as their salts.

In particular, the invention relates to the new compounds

discussed, in the examples.

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

Thus, one can e.g. ring-closed compounds of formula IV

in which X means a reactive esterified hydroxy group, and if desired in any compounds formed, in which n =0, the thia atom oxidizes to the sulfinyl or sulfonyl group, and/or if desired transfers formed free compounds into their salts, or converts formed salts into the free compounds and/or separates a procedurally formed isomer mixture into the individual isomers.

Reactive esterified hydroxy is particularly j

a hydroxyl group esterified with a strong inorganic acid, e.g. hydrogen halide, especially hydrogen chloride or sulfuric acid, or with a strong organic acid, such as with a lower alkanesulfonic acid, e.g. methane or ethanesulfonic acid or a benzenesulfonic acid optionally substituted by lower alkyl, lower alkoxy or halogen, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid.

The cyclization is preferably carried out under acid-cleaving conditions. Thereby, one works primarily in a low-boiling solvent, such as dimethylformamide or acetone, an alcohol, e.g. methanol or ethanol, if desired, in the presence of a base, e.g. an inorganic base such as an alkali or alkaline earth hydride hydroxide or carbonate, primarily sodium hydride, sodium hydroxide or sodium carbonate, or an organic base, preferably a nitrogen base, such as tri-lower alkylamine, e.g. trimethylamine, triethylamine, dimethyl-isopropylamine or pyridine.

The starting materials can be obtained when one reacts a corresponding diaza-2-mercapto compound with a dihydroxyalkylene, with each other, in which at least the two hydroxy groups are reactively esterified, possibly oxidizing the mercapto group to the sulfinyl or sulfonyl group, and then, if necessary, reactively esterifying the second hydroxy group. The reactive esterified hydroxy groups correspond to the above as well as the conditions for condensation. In this reaction, especially when both hydroxyl groups are reactively esterified, starting substances of formula IV can be obtained in situ which in the same reaction are joined to form a ring.

The new compounds of formula I, which contain an additional double bond, can also be obtained when ring-closing compounds of formula Va or Vb:

ell are their tautomers, and if desired in possibly formed compounds, in which *~n"~= oxidizes the thia atom. to the sulfinyl or sulfonyl group and/or if desired transfers formed free compounds into their salts or formed salts into the free compounds and / el^r divides a formed i^ome^r^la^djLng into the individual isomers.

The ring closure takes place under water-splitting conditions such as during heating, e.g. from approx. 50°C to approx. 150°C, preferably in the presence of a solvent such as acetonitrile or an alcohol, e.g. methanol or ethanol.

The starting materials can be obtained when, in a manner known per se, reacting a compound with- -formula VI,

with a compound of formula VII

or their tautomers.

Reactively esterified hydroxy groups X are especially those mentioned above.,

If this transaction is also carried out under yannavsavvning conditions, e.g. by heating in a solvent such as acetonitrile or an alcohol, the starting materials of formula Va or Vb is obtained in situ, which forms a ring under these reaction conditions.

The oxidation of the t-i-a atom to the sulfinyl or sulfonyl group can be carried out in a manner known per se, e.g. with peroxides, such as hydrogen peroxide, or peracids, e.g. a: optionally with lower alkyl, lower alkoxy, halogen or a further carboxyl group substituted benzperic acid, such as benzoperic acid itself or phthalmonoperic acid, or an alkane percarboxylic acid, such as peracetic acid or a periodate, such as sodium periodate. This reaction is mostly carried out at lower temperatures in a solvent such as glacial acetic acid or acetone.

The new compounds can be obtained in the form of acid addition salts, especially pharmaceutically usable non-toxic salts, e.g. with organic acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic, such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic or sulphonic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, embonic acid or nicofcic acid, as well as methanesulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid-ethylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid. Salts of this type can e.g. obtained by treating the free compounds with the acids or with suitable anion exchange resins.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds or salts are also possibly understood as corresponding salts or free connections.

The new compounds can exist as isomeric mixtures such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, as optically active components. The separation of the isomer mixtures formed into the pure isomers can be carried out according to known methods. Racemate can e.g. divide due to physico-chemical differences such as e.g. such.in solubility, in their diastereomeric salts or by fractional crystallization from an optically active solvent or by chromatography, especially thin layer chromatography on an optically active. carrier material in the optically active antipodes. Thereby, the pharmacologically most effective and least toxic isomer is preferably isolated, especially the most effective and least toxic active antipode.

The above-mentioned reactions are carried out in the usual way in the presence or absence of dilution, condensation and/or

catalytic agents, if necessary at reduced or elevated temperature, in a closed vessel and/or in an inert atmosphere,

j

The method also includes the embodiments according to which compounds formed as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at one or another step, starting materials can also be used in the form of derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen so that the compounds listed at the outset as particularly preferred are reached.

The invention also relates to the new compounds obtainable as intermediates with the general formulas Va or Vb

4

or their tautomers, in which Alk means the lower alkylene, which separates thia- from the aza-atom, with 2-4 carbon atoms, Ar1 and Ar2 means independently, optionally substituted by hweraridre phenyl, pyridyl or thienyl, and n means 0, 1 or 2, and their salts. In the above-mentioned biological test devices, they are approximately as effective as the dihydro compounds of formula I and can be used as anti-inflammatories, e.g. for the treatment of rheumatoid arthritis.

The new compounds according to the invention can e.g. is used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutical usable carriers, which are suitable for enteral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sbrbitol, cellulose and/or'glycerol, and. lubricants e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium

or calcium stearate and/or polyethylene glycolj... tablets also contain a binder, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice, or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or fizzy mixes or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of injectables, e.g. intravenously administrable preparations or of infusion solutions. Such solutions are preferably isotonically aqueous solutions or suspensions, as these e.g. can be prepared from lyophilized preparations before use, which preparations contain the active substance alone or together with a carrier material, e.g. mantf

The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g. by means of ordinary mixing, fine-filing, coating, dissolving or lyophilizing methods and contains from. about. 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance. The single dose' for a warm-blooded animal of approx. 70 kg is between 0.1 and 0.75 g, the daily dose is between 0.2 and 1.0 g.

The invention will be explained in more detail with the help of some examples.

Example 1

A mixture of 5 g of α-bromo-desoxyanisoin, 3 g of 2-aminotiazoline and 30 ml of ethanol is stirred for 4 hours at 60° C., then for two hours under reflux and then also for 12 hours at room temperature. The thereby precipitated crystals are suctioned off and washed with ethanol and diethyl ether. One thus obtains crude 5,6-di-(p-methoxyphenyl)-imidazo/2/1-1/dihydro-thiazole. Temp. after recrystallization from toluene-petroleum ether 152-154°C.

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 mixed during one hour with the suspension of 4.7 g of 4,5-diphenyl-imidazolidin-2-thione in 110 ml of 1, 5% caustic soda. The reaction mixture is boiled for 7 hours under reflux, then isopropanol and dibromoethane are removed in a rotary evaporator and the remaining suspension is extracted with toluene. The toluene extract is washed with the sun,

dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel. After separation of non-polar impurities with ethyl acetate, cis-5,6-diphenyl-2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole is eluted with a mixture of ethyl acetate:methanol = 99:1 as a colorless oil. It crystallizes spontaneously into white crystals at m.p. 110-113 C (sinter temp. 103 o Cf.

Example 3

A suspension of 3.5 ml of 1,2-dibromoethane, 3.5 g of sodium carbonate and 30 ml of isopropanol is mixed with stirring at room temperature during 1 hour with the suspension of 3 g of 4,5-di-anisyl-2-mercapto-imidazole in 50 ml 1.5% caustic soda. The reaction mixture is boiled for 6 hours under reflux, then isopropanol and dibromoethane are removed on a rotary evaporator and the remaining suspension is diluted with 10 ml of 20% potassium hydroxide and extracted with ethyl acetate.

The organic phases are washed with sunlight, dried with sodium sulphate and evaporated. From the residue, after recrystallization from toluene-petroleum ether, 5,6-di-(p-methoxy-phenyl)-imidazo/2,1-b/dihydro-thiazole is obtained at m.p. 152-154°C.

Example 4

14.8 g of 4,5-di-(p-methoxy-phenyl)-2-g-hydroxy-ethyl-mercapto-imidazole are dissolved in 50 ml of absolute pyridyl and added dropwise while stirring at approx. -5°C internal temperature to a solution of 15.8 g of benzene sulfochloride in 60 ml of absolute pyridine. The mixture is then stirred for 60 hours at 0°C. The reaction mixture is poured onto ice water and extracted with dichloromethane. The combined dichloromethane extracts, washed 3 times with water, are darkened over sodium sulphate and evaporated to dryness. The viscous oil is crystallized from toluene-petroleum ether. 5,6-di-(p-methoxyphenyl)-imidazo/2,1-b/dihydro-thiazole with m.p. 152-154°C is obtained.

The starting material can e.g. is prepared as follows: dissolve 2.5 g of sodium in 220 ml of ethanol. 35 g of 4,5-dianisyl-imidazolin-2-thione are added to this. You get a suspension. Over the course of 2 minutes, 15.7 ml of 2-chloroethanol are added dropwise at room temperature while stirring. The mixture is stirred for 1 hour at 60°C and four hours under reflux. The weak suspension is then evaporated to dryness. The residue is cleaned from acetone/water.

Example 5

A mixture of 60 g of N-ethylrdiisopropylamine, 70 g of 2-aminodihydrothiazole, 150 g of α-bromo-deoxyanisoin' and 800 ml of acetb-nitrile is stirred for 48 hours at room temperature. The thereby formed 5,6-di-(p-methoxy-phenyl)-imidazo/2,1-b/dihydro-thiazoline is filtered off

and washed with acetonitrile. By evaporating the filtrate and distributing the residue thus freed from solvent between ethyl acetate and water, a further 50 g of crude product is obtained. By recrystallization of the crude product from toluene, 5,6-di-(p-methoxy-phenyl)-imidazo[2,1-b]dihydro-thiazole is obtained at m.p. 152-154°C.

Example 6

To a solution of 23 g of p-toluenesulfochloride in 80 ml of pyridine is added at 0°C with stirring the solution of 20' g of 2-(2-hydroxy-ethyl-thio)-4(5)-3'-pyridyl-5( 4)-phenyl-imidazole. The reaction mixture is stirred for 16 hours at 0°C, poured onto ice and extracted with ether. From the ether extracts, after washing with water and drying over sodium sulfate, an evaporation residue is obtained which, after chromatography on silica gel with toluene and ethyl acetate and after recrystallization of the corresponding fractions from ethyl acetate, gives the isomer mixture 5(6)-(3-pyridyl)-6(5 )-phenyl-imidazo/2,1-b/dihydro-thiazole as white crystals with mp 150-151°C.

The starting material can be produced as follows:

10.8 g of benzylpyridyl(3)-ketone are stirred together with

40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride i

15 ml of pyridine for 6 hours at 100°C. The reaction mixture is poured onto ice/water and further stirred for 15 minutes. The precipitated crystals are suctioned off, washed with water and dried in high vacuum. Benzyl pyridyl (3) ketone is obtained oxime with mp 122-126°C.

To a stirred solution of 8.5 g of benzyl-pyridyl (3)-ketone oxime in 20 ml of pyridine at -10°C, the solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine is added dropwise over 5 minutes. The reaction mixture is stored for 24 hours in a refrigerator and then poured onto ice/water. After longer stirring and straining, the precipitate hardens. oil to crystals.' These are sucked off, washed with water and dried in a high vacuum. You get 11.6 g of a crude product with m.p. 87-92°C, which according to thin-layer chromatography, however, contains educt.

It is used directly in the next step.

11.6 g of crude product (benzyl-pyridyl(3^-ketone-oxime-p-toluenesulfoester)•are suspended in 90 ml of absolute ethanol and at 0°C the solution of 3.7 g of potassium tert.-butylate in 30 ml of absolute ethanol. The reaction mixture is stirred for 2 hours at 0° C. The suspension is suctioned off and the filtrate is used at once in four steps.

3.6 g of sodium thiocyanate are dissolved in 60 ml of ethanol and mixed with 4.5 ml of concentrated hydrochloric acid.

The suspension is suctioned off and the filtrate is kept together with the alcoholic solution of the formed α-amino-benzyl-pyridyl(3)-ketone for 18 hours under reflux. After cooling, 2.8 g of crude 4-phenyl-5-pyridyl(3)-2-mercapto-imidazole can be suctioned off from the reaction mixture. The filtrate contains additional amounts of the product. After recrystallization from dimethylformamide-water it melts at 290-300°C.

0.8 g of sodium is dissolved in 200 ml of ethanol. The solution is mixed with 8 g of 1-phenyl-5-pyridyl(3)-2-mercaptoimidazole and heated to reflux. After a clear solution has formed, 2.3 ml of 2-chloroethanol is added dropwise and the reaction mixture is boiled for 16 hours under reflux. The solvent is evaporated under vacuum and the residue is distributed between water and vinegar. The organic phases are washed

with water and sun, dried with sodium sulphate and evaporated. As a residue, crystalline 2-(2-hydroxy-ethyl-thio)-4(5)-3'-pyridyl-5(4)-phenyl-imidazole is obtained. It melts after recrystallization from ethyl acetate/ethanol at 157-159°C.

In an analogous way, the following compounds are obtained, in that

it is assumed from corresponding starting substances: 5,6-di-(p-methyl-phenyl)-2,3,5,6-tetrahydroimidaao/2,1-bJ thiazole 5,6-di-(p-chloro-phenyl) -2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole 5,6-di-(m-chloro-phenyl)-2,3,5,6-tetrahydro-imidazo/2,1-b/ thiazole 5 , 6-di-(p-methoxyphenyl) )-3-methyl-2 ,3,5, ε-tetrahydro-imidazo/^ , 1-b_7-thiazole or

6.7-di-(p-methoxy-phenyl)-2,3,4,5,6,7-hexa-hydro-imidazo/2,1-b/- thiazine.

Example 7.

14.3 g of 2-/N-(1,2-bis-p-methoxy-phenyl-2-hydroxyethyl7-amino-thiazoline) are dissolved in 24.3 ml of concentrated sulfuric acid and stirred for one hour at room temperature. The reaction mixture is poured onto ice, made alkaline with 2-n soda solution and extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated. From the residue, recrystallization from toluene-petroleum ether gives 5,6-trans-di-(p-methoxyphenyl)- 2,3,5,6-tetrahydro-|4H-imidazole/2,1-bJ?-thiazole with melting point 125-126°C. The starting material used can, for example, be prepared as follows: 45 g of bromo-deoxy-anisoin are suspended in 17.0 ml of acetonitrile. The suspension is mixed with 23 ml of N-ethyl-diisopropylamine and 15.4 g of 2-aminotiazoline, stirred for 2 hours at room temperature, aspirated off and the filter material washed with a little acetic ester. One thus obtains 2-[fo-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-thiazoline or 2-imino-3-(1,2-bis-p-methoxy- phenyl-2-6xo-ethyl)-thiazoline with mp 95-98°C.

In an analogous way, one obtains: 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-5-methyl-thiazoline resp. 2-imino-5-methyl-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-thiazoline or their tautomers,

2-/N-(1,2-bis-pemethoxyphenyl-2-oxo-ethyl)-amino-4-methyl-

thiazoline or 2-amino-4-methyl-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-thiazoline or their tautomers,

2-[N-(1,2-bis-phenyl-2-oxo-ethyl)-amino-thiazoline

respectively 2-imino-3-(1,2-bis-phenyl-2-oxo-ethyl)-thiazoline or their tautomers with m.p. 121-123°C or

2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-5,6-dihydro-4H-thiazine resp. 2-imino-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-5,6-dihydro-4H-thiazine or their tautomers.

31.5 g of 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-aminothiazoline or its isomers are dissolved in 350 ml of methanol and mixed in portions with 4.26 g of sodium borohydride. The suspension is stirred for 2 hours at room temperature, then suctioned off and washed with methanol. Thus, 2-[alpha]-(1,2-bis-p-methoxy-phenyl-2-hydroxy-ethyl)-amino-thiazoline with m.p. 185-187°C.

Starting from corresponding thiazoline compounds, the following compounds can be prepared in an analogous way:•

5-phenyl-6-p-chlorophenyl-2,3,5,6-tetrahydroimidazo/2,1-b/-thiazole 6-phenyl-5-p-chlorophenyl-2,3,5,6-tetrahydroimidazo/2,l- b7~thiazole 5,6-di-(p-methoxyphenyl)-2-methyl-2,3,5,e-tetrahydroimidazo^ , 1-bJ7-thiazole or

5,6-Di-(p-Methoxyphenyl-3-methyl-2,3,5,6-tetrahydro-imidazo[2,1-b]-thiazole.

Example 8

2 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo-Cl,1-b/thiazole are suspended in 33 ml of ethanol and mixed during 5 minutes with 7.91 ml of 30% hydrogen peroxide . The reaction mixture is refluxed for 90 minutes, cooled, poured into 200 ml of ice water and extracted with vinegar. From the evaporation residue of the organic phases washed with water and dried over sodium sulfate, 5,6-di-p-methoxy is obtained by recrystallization phenyl-imidazo/2,1-b/2,3-dihydro-thiazole sulfoxide with m.p. 176-177°C.

Example 9

0.69 g of sodium is dissolved in 60 ml of ethanol and mixed with 9.36 g of 2-mercapto-4,5-di-p-methoxyphenyl-imidazole. The reaction mixture is stirred for 30 minutes, mixed with 3.1 g of 3-chloro-1-propanol, held under reflux for 2 hours, cooled, filtered clear and in-

evaporate to dryness. The residue, the crude 2-(3-hydroxy-propyl-thio)-4,5-di-p-methoxyphenyl-imidazole is refluxed for 30 min.

in 50 ml of thionyl chloride. Excess thionyl chloride is evaporated, driven off by distilling off 100 ml of additionally added chloroform,

and the residue is kept together with 100 ml of ethanol and 50 ml of 40% potassium hydroxide for 4 hours under reflux. The reaction mixture is then evaporated on a rotary evaporator, mixed with ice water and extracted with vinegar. The organic_phases are washed with water, dried and evaporated. The residue is chromatographed with toluene:acetic ester 1:1

on silica gel. Recrystallization of the corresponding fractions from acetone yields 6,7-di-p-methoxyphenyl-2,3,4,5-tetrahydro-imidazo/2,1-b_7(1,3)-thiazine with m.p. 189-191°C.

Example" 10. _j

Analogously to Example 9, 2-(2-hydroxy-ethyl-thio)-4,5-di-p-chlorophenyl-imidazole is prepared from 2-mercapto-4,5-di-p-chlorophenyl-imidazole with 2-chloroethanol with m.p. 197-199°C and from this by cyclization with thionyl chloride 5 , 6-di-'p-chlorophenyl-imidazo/2 , 1-b7 dihydro-thiazole with m.p. 199-204°C.

Analogously, 5,6-di-p-methoxyphenyl-4H-imidazo/!>, 1-b_7dihydro-thiazo can also be prepared.

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 mixed with 0.9 ml of 30% hydrogen peroxide. The reaction mixture is stirred for 7 hours at 60°C, then poured onto ice-water and extracted with vinegar.

The organic phases are washed with l-n caustic soda until the extracts remain basic, then neutral washed with water and sun, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate and recrystallized from ethyl acetate-petroleum ether. One thus obtains 5,6-di-p-methoxyphenyl-imidazb/5,1-b_7-dihydro-thiazole-sulfone with m.p. 186-187°C.

Example 12

35 g of 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-aminotiazoline (cf. Example 7) are kept together with 250 ml of isopropanol and 1 ml of hydrogen bromide (48%-ig) in 2 hours during reflux. By cooling in an ice bath and suctioning off the product, 5,6-di-(p-methoxy-

phenyl)-imidazole/*2,1-b/dihydro-thiazole with m.p. 155-156°C.

From the mother liquor it is possible to recover the hydrobromide of 5,6-di-(p-methoxyphenyl)-imidazo/2,1-b/dihydro-thiazole, m.p. 200-210°C.

Example 13

17 ml of 1-n hydrochloric acid and 5 g of N -benzenesulfonyl-L(+)-glutamic acid. The mixture is dissolved by heating, and brought to crystallization by cooling. L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo/2,1-b/-thiazole N-benzenesulfonyl L(+)-glutamate is suctioned off, washed with a little water, suspend in water and decompose with dilute caustic soda.

From this L-5,6-di-p-anisyl-2,3,5>6-tetrahydro-4H-imidazo/2,1-b_7thiazole is extracted with ethyl acetate.

Example 14

Pharmaceutical preparations containing:

The ingredients are sieved, mixed well and the mixture is filled into hard gelatin capsules.

Example 15

Tablets containing:

The sucrose, calcium dihydrate and the active substance are mixed and granulated with a 10% gelatin solution.

The moist granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and pressed into tablets.

Claims (13)

1. Process for the preparation of 1,3-diaza-cyclo-pent-2-eno/2,1-b7(1-thia-3-aza-cycloalkanes) with the general formula I if 1,3-diaza-cyclopent-2-ene ring can have an additional double bond, Alk means lower alkylene, which separates thia- from the aza atom by 2-4 carbon atoms, Ar^ and Ar2 independently mean optionally substituted phenyl, pyridyl or thienyl, and n means 0, 1 or 2, with the proviso that at least one/of the residues A^ and Ar2 is different from phenyl, when Alk means ethylene and the 1,3-diaza-cyclopent-2-ene ring means an imidazole ring, as well as their salts, characterized in that compounds with formula IV in which X means a reactive esterified hydroxy group, is ring-closed, or that compounds with the formulas Va resp. Vb is ring-closed, and if desired, in any compounds formed in which n means 0, the thia atom is oxidized to sulfinyl or sulfonyl groups and/or if desired, free compounds formed are transferred into their salts, or salts formed are converted into the free compounds and/ or an isomer mixture formed. are divided into the individual isomers. 2. Process according to claim 1, characterized in that compounds of formula 1 are prepared, in which Ar ■ and Ar2 independently of each other means an optionally with lower alkyl, lower alkoxy, halogen or trifluoromethyl substituted phenyl residue, a pyridyl or thienyl residue, Alk means a lower alkylene residue, as compounds the sulfur and nitrogen atom over 2-3 carbon atoms and n means 0, 1 or 2 as well as their salts. 3. Procedure! according to claim 1, characterized in that compounds of formula II are prepared in which Ar 1 and Ar 2 independently of each other mean a optionally substituted phenyl radical, such as methoxy or halogen, especially chlorine, and m means primarily 1, further also 2, as well as their salts. 4. Process according to claim 1, characterized in that 5,6-diphenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole and its salts are produced. 5. Process according to claim 1, characterized in that 5,6-di-(p-methyl-phenyl)-2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole and its salts are produced. 6. Process according to claim 1, characterized in that 5,6-di-(p-chloro-phenyl)-2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole and its salts are produced. 7. Process according to claim 1, characterized in that 5,6-di-(m-chloro-phenyl)-2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole and its salts are produced. 8. Process according to claim 1, characterized in that 5,6-di-(p-methoxy-phenyl)-2- or 3-methyl-2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole is prepared and its salts. 9. Process according to claim 1, characterized in that 5,6-di-(p-methoxy-phenyl)-3-methyl-2,3,5,6-tetrahydro-imidazo/2,1-b7thiazole and its salts are produced. 10. Process according to claim 1, characterized in that 5,6-di-(p-methoxy-phenyl)-2,3,4,5,6,7-hexahydro-imidazole is prepared and its salts. 11. Method according to claim 1, characterized in that compounds of formula III are prepared in which Ar^ and Ar^ independently of each other mean a phenyl radical optionally substituted with lower alkoxy, such as methoxy or halogen, especially chlorine, and m means in the first row 1, further also 2, as well as its salts. 12. Process according to claim 1, characterized in that 5,6-di-(p-methoxy-phenyl)-imidazo/2,1-b/dihydro-thiazole and its salts are primarily obtained. 13. Method according to claim 1, characterized in that 5 (6) - (3-pyridyl)-6-(5)-phenyl-imidazole/2,1-b7 dihydrop-thiazole and its salts are produced.