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EP0000353A2 - Bicyclic thiadiaza compounds, process and intermediates for their preparation, and medicaments containing these compounds or the intermediates - Google Patents

Bicyclic thiadiaza compounds, process and intermediates for their preparation, and medicaments containing these compounds or the intermediates Download PDF

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Publication number
EP0000353A2
EP0000353A2 EP78100272A EP78100272A EP0000353A2 EP 0000353 A2 EP0000353 A2 EP 0000353A2 EP 78100272 A EP78100272 A EP 78100272A EP 78100272 A EP78100272 A EP 78100272A EP 0000353 A2 EP0000353 A2 EP 0000353A2
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Prior art keywords
salts
compounds
phenyl
thiazole
imidazo
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German (de)
French (fr)
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EP0000353A3 (en
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Richard Dr. Göschke
Pier Giorgio Dr. Ferrini
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Novartis AG
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Ciba Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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) of the general formula (I) whose 1,3-diaza-cyclopent-2-ene ring may have a further double bond,
  • Alk represents lower alkylene which separates the thia from the aza atom by 2-4 carbon atoms
  • Ar 1 and Ar 2 independently of one another optionally substituted phenyl, Pyridyl or thienyl and n is 0, 1 or 2, with the proviso that at least one of the radicals Ar 1 and Ar 2 is different from phenyl when alk ethylene and the 1,3-diaza-cyclopent-2-ene ring represents an imidazole ring, and their salts, and processes for their preparation, furthermore pharmaceutical preparations containing these compounds and their use, preferably in the form of pharmaceutical preparations.
  • radicals and compounds designated "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.
  • Lower alkylene alk is preferably unbranched, but also branched lower alkylene with 2-4 carbon atoms in the chain between the sulfur and the nitrogen atom.
  • Pyridyl is a 2-, 3- or 4-pyridyl and thienyl is a 3- or especially 2-thienyl.
  • Substituted phenyl, pyridyl or thienyl is e.g. single, double or multiple substituted.
  • Substituents, especially on the phenyl radical include Lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro.
  • Substituents on the pyridyl or thienyl radical are preferably lower alkyl, halogen or trifluoromethyl.
  • Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, n-hexyl, isohexyl or n-heptyl.
  • Lower alkylene is ethylene, and also 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, Be 4-pentylene.
  • Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.
  • Halogen is one with the atomic number up to and 35 and stands for fluorine or bromine, preferably for chlorine.
  • Lower alkylsulfonyl is e.g. for methylsulfonyl, ethylsulfonyl or n-propylsulfonyl.
  • the compounds according to the invention have valuable pharmacological properties, in particular 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 the rat at a dose given from around 10 mg / kg or in the turpentine pleurisy test [Helv. Physiol. Acta 26 (1969) 287) given orally to the rat at a dose of 30 to 100 mg / kg, they show an anti-inflammatory or anti-exudative effect. In particular, the unsaturated compounds also show an excellent effect in the adjuvant arthritis test [Pharmacology 2 (1969) 288] on the rat at a oral dose of 10-30 mg / kg.
  • the new compounds are also analgesic, as shown in the phenyl p-benzoquinone test on the mouse (Proc. Soc. Exp. Biol. 95 (1957) 729) at doses of 30 to 100 mg / kg, given orally leaves.
  • the tetrahydro compounds additionally show a reinforcing 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-inflammatory agents, for example for the treatment of rheumatic, arthritic and other inflammations Diseases in particular, rheumatoid arthritis or as analgesics, for example to treat painful conditions.
  • the invention relates in particular to compounds of the formula I in which Ar 1 and Ar 2 independently of one another are a phenyl radical which is optionally substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, a pyridyl such as a 2-, 3- or 4-pyridyl or thienyl , in particular represent a 2-thienyl radical, alk is a lower alkylene radical which connects the sulfur and nitrogen atoms via 2-3 carbon atoms, primarily an unbranched lower alkylene radical and n is especially 0, furthermore also 1 or 2, and their salts.
  • the invention relates primarily to compounds of the formula II in which Ar 1 and Ar 2 independently of one another represent a phenyl radical which is optionally substituted by lower alkoxy, such as methoxy or halogen, in particular chlorine, and m is primarily 1, furthermore also 2, and their salts.
  • the invention particularly relates to compounds of the formula III wherein Ar 1 and Ar 2 independently of one another, optionally by lower alkoxy, such as methoxy or halogen, ins special chlorine-substituted phenyl radical and m is primarily 1, furthermore also 2, and their salts.
  • the invention relates to the new compounds described in the examples.
  • the new compounds can be obtained by methods known per se.
  • Reactively esterified hydroxy is especially one 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 esterified hydroxy group.
  • a strong inorganic acid e.g. Hydrogen halide, especially hydrogen chloride, or sulfuric acid
  • 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,
  • the ring closure is preferably carried out under acid-releasing conditions. This is done 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 hydroxide, 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, dimethylisopropylamine, or pyridine.
  • a base e.g. an inorganic base, such as an alkali or alkaline earth hydroxide, 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. Trimethyl
  • the starting materials can be obtained if a corresponding diaza-2-mercapto compound is reacted with a dihydroxyalkylene in which at least one of the two hydroxyl groups has been reactively esterified, if appropriate the mercapto group is oxidized to the sulfinyl or sulfonyl group and then, if necessary, the second hydroxyl group reactively esterified.
  • the reactive esterified hydroxyl groups correspond to the above-mentioned conditions as well as the condensation conditions. In this reaction, in particular if both hydroxyl groups are esterified in a reactive manner, the starting materials of the formula IV can be obtained in situ, which are closed to form a ring in the same reaction.
  • the new compounds of the formula I which have a further double bond can also be obtained if compounds of the formula Va or Vb or ring-closes their tautomers and, if desired, in optionally obtained compounds in which n is 0, the thia atom is oxidized to the sulfinyl or sulfonyl group and / or, if desired, converts the free compounds obtained into their salts or salts obtained into the free ones Converting compounds and / or separating an isomer mixture obtained according to the process into the individual isomers.
  • the ring closure takes place under water-releasing conditions, such as by heating, e.g. from about 50 ° to about 150 °, preferably in the presence of a solvent such as acetonitrile or an alcohol, e.g. Methanol or ethanol.
  • a solvent such as acetonitrile or an alcohol, e.g. Methanol or ethanol.
  • the starting materials can be obtained if a compound of the formula VI with a compound of formula VII or their tautomers.
  • Reactively esterified hydroxy groups X are in particular the above.
  • this reaction is also carried out under water-releasing conditions, for example with heating in a solvent such as acetonitrile or an alcohol, the starting material of the formula Va or Vb can be obtained in situ, which closes under these reaction conditions.
  • a solvent such as acetonitrile or an alcohol
  • the oxidation of the thia 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. carry out an optionally substituted by lower alkyl, lower alkoxy, halogen or another carboxyl group, such as benzoperic acid itself or phthalmonoperacid, or an alkane percarboxylic acid such as peracetic acid or a periodate such as sodium periodate.
  • This reaction is usually carried out at low temperatures in a solvent such as glacial acetic acid or acetone.
  • the new compounds can be in the form of acid addition salts, especially pharmaceutically acceptable, 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 carbon or sulfonic acid, e.g.
  • organic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid
  • organic such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carbon or sulfonic acid, e.g.
  • Salts of this type can e.g. can be obtained by treating the free compounds, with the acids or with suitable anion exchange resins.
  • the free compounds or the salts are also to be understood as meaningful and expedient, if appropriate, the corresponding salts or free compounds.
  • the new compounds can be present as isomer mixtures, such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, such as optically active components.
  • the separation of isomer mixtures obtained into the pure isomers can be carried out by the known methods. Racemates can e.g. due to physico-chemical differences, e.g. Separate those of solubility, their diastereomeric salts, or by fractional crystallization from an optically active solvent, or by chromatography, in particular thin-layer chromatography, on an optically active carrier material, into the optically active antipodes.
  • the pharmacologically more effective or less toxic pure isomer is advantageously isolated, in particular the more effective or less toxic active antipode.
  • the process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.
  • the invention also relates to the new compounds of the general formula Va or Vb obtainable as intermediates or. or their tautomers, where Alk is lower alkylene, which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2, and their Salts.
  • Alk is lower alkylene, which separates the thia from the aza atom by 2-4 carbon atoms
  • Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2, and their Salts.
  • they are approximately as effective as the dihydro compounds of the formula I and can be used as anti-inflammatory agents, for example for the treatment of rheumatic arthritis.
  • the new compounds of the present invention can be used, for example, for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or contain organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral or parenteral administration.
  • tablets or gelatin capsules which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate. and / or polyethylene glycol; Tablets also contain binders, e.g.
  • magnesium aluminum silicate starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners.
  • disintegrants e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners.
  • the new pharmacologically active compounds can be used in the form of injectable, for example intravenously administrable, preparations or infusion solutions.
  • Such solutions are preferably isotonic aqueous solutions or suspensions, these being able to be prepared, for example, from lyophilized preparations which contain the active substance on their own or together with a carrier material, for example mannitol.
  • the pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.
  • the present pharmaceutical preparations 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, confectioning, dissolving or lyophilizing processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates up to 100% of the active ingredient.
  • the single dose for a warm-blooded animal weighing approximately 70 kg is between 0.1 and 0.75 g, the daily dose between 0.2 and 1.0 g.
  • 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 within one hour with the suspension of 4.7 g of 4,5-diphenyl-imidazolidin-2-thione in 110 ml of l, 5% sodium hydroxide solution added.
  • the reaction mixture is refluxed for 7 hours, then the isopropanol and the dibromoethane are removed on a rotary evaporator and the remaining suspension is extracted with toluene.
  • the toluene extract is washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel.
  • a suspension of 3.5 ml of 1,2-dibromoethane, 3.5 g of sodium carbonate and 30 ml of isopropanol is stirred in with the suspension of 3 g of 4,5-di-anisyl-2-mercapto-imidazole in at room temperature for one hour 50 ml of 1.5% sodium hydroxide solution are added.
  • the reaction mixture is refluxed for 6 hours, then the isopropanol and the dibromoethane are removed on a rotary evaporator and the remaining suspension is mixed with 10 ml of 20% potassium hydroxide solution and extracted with ethyl acetate. The organic phases are washed with brine, dried with sodium sulfate and evaporated.
  • the starting material can e.g. are prepared: 2.5 g of sodium are dissolved in 220 ml of ethanol. 35 g of 4,5-dianisyl-imidazolin-2-thione are added. A suspension is obtained. For this purpose, 15.7 ml of 2-chloroethanol are added dropwise at room temperature (stirring). The mixture is stirred for 1 hour at 60 ° and 4 hours at reflux. The weak suspension is then evaporated to dryness. The residue is purified from acetone / water.
  • the starting material used can e.g. received as follows:
  • the 2-mercapto-4,5-di-p-chlorophenylimidazole with 2-chloroethanol is the 2- (2-hydroxyethylthio) -4,5-di-p-chlorophenylimidazole from F. 197-199 ° and from it by cyclization with thionyl chloride the 5,6-di-p-chlorophenyl-imidazo [2,1-b] dihydro-thiazole of mp 199-204 °.
  • the 5,6-di-p-methoxyphenyl-4H-imidazo [2,1-b] dihydro-thiazole can also be prepared analogously.
  • the hydrobromide of 5,6-di- (p-methoxyphenyl) imidazo [2, l-b] dihydro-thiazole can be obtained from the mother liquor, mp. 200-210 °.
  • the L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b] thiazole N-benzenesulfonyl L (+) - glutamate is filtered off with a little Washed water, suspended in water and decomposed with dilute sodium hydroxide solution. From this, the L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b] thiazole is extracted with ethyl acetate.
  • sucrose, calcium dihydrate and the active ingredient are mixed and granulated with a 10% gelatin solution.
  • the moist granules are sieved, dried, mixed with the starch, talc and stearic acid, sieved and compressed into tablets.

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Abstract

Bicyclische Thia-diaza-verbindungen, insbesondere 1,3-Diaza-cyclopent-2-eno[2,1-b]-(1-thia-3-aza-cycloal- kane) der allgemeinen Formel

Figure imga0001
deren 1,3-Diaza-cyclopent-2-en-ring eine weitere Doppelbindung aufweisen kann, Alk Niederalkylen darstellt, welches das Thia- vom Aza-atom durch 2-4 Kohlenstoffatome trennt, Ar1 und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist, mit der Massgabe, dass mindestens einer der Reste Ar1 und Ar2 von Phenyl verschieden ist. wenn Alk Äthylen und der 1,3-Diaza-cyclopent-2-en-ring einen Imidazolring darstellt, und deren Salze, sowie Verfahren zu ihrer Herstellung.Bicyclic thia-diaza compounds, in particular 1,3-diaza-cyclopent-2-eno [2,1-b] - (1-thia-3-aza-cycloalkanes) of the general formula
Figure imga0001
 whose 1,3-diaza-cyclopent-2-ene ring can have a further double bond, Alk represents lower alkylene which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another optionally substituted phenyl, Are pyridyl or thienyl and n is 0, 1 or 2, with the proviso that at least one of the radicals Ar 1 and Ar 2 is different from phenyl. when alk ethylene and the 1,3-diaza-cyclopent-2-ene ring represents an imidazole ring, and their salts, and process for their preparation.

Die neuen Verbindungen I und Zwischenverbindungen der Formel Va bzw. Vb

Figure imga0002
besitzen wertvolle pharmakologische Eigenschaften.The new compounds I and intermediate compounds of the formula Va and Vb
Figure imga0002
 have valuable pharmacological properties.

Description

Die Erfindung betrifft neue bicyclische Thia-diaza-verbindungen, insbesondere 1,3-Diaza-cyclopent-2-eno [2,1-b](1-thia-3-aza-cycloalkane) der allgemeinen Formel (I)

Figure imgb0001
deren l,3-Diaza-cyclopent-2-en-ring eine weitere Doppelbindung aufweisen kann, Alk Niederalkylen darstellt, welches das Thia- vom Aza-atom durch 2-4 Kohlenstoffatome trennt, Ar1 und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist, mit der Massgabe, dass mindestens einer der Reste Ar1 und Ar2 von Phenyl verschieden ist, wenn Alk Aethylen und der 1,3-Diaza-cyclopent-2-en-ring einen Imidazolring darstellt, und deren Salze, sowie Verfahren zu ihrer Herstellung, ferner pharmazeutische Präparate enthaltend diese Verbindungen und ihre Verwendung, vorzugsweise in Form von pharmazeutischen Präparaten.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) of the general formula (I)
Figure imgb0001
 whose 1,3-diaza-cyclopent-2-ene ring may have a further double bond, Alk represents lower alkylene which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another optionally substituted phenyl, Pyridyl or thienyl and n is 0, 1 or 2, with the proviso that at least one of the radicals Ar 1 and Ar 2 is different from phenyl when alk ethylene and the 1,3-diaza-cyclopent-2-ene ring represents an imidazole ring, and their salts, and processes for their preparation, furthermore pharmaceutical preparations containing these compounds and their use, preferably in the form of pharmaceutical preparations.

Die im Zusammenhang mit der vorliegenden Beschreibung mit "nieder" bezeichneten Reste und Verbindungen enthalten vorzugsweise bis 7 und in erster Linie bis 4 Kohlenstoffatome.The radicals and compounds designated "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.

Niederalkylen Alk ist vorzugsweise unverzweigtes, aber auch verzweigtes Niederalkylen mit 2-4 Kohlenstöffatomen in der Kette zwischen dem Schwefel- und dem Stickstoffatom.Lower alkylene alk is preferably unbranched, but also branched lower alkylene with 2-4 carbon atoms in the chain between the sulfur and the nitrogen atom.

Pyridyl ist ein 2-, 3- oder 4-Pyridyl und Thienyl ein 3- oder insbesondere 2-Thienyl.Pyridyl is a 2-, 3- or 4-pyridyl and thienyl is a 3- or especially 2-thienyl.

Substituiertes Phenyl, Pyridyl oder Thienyl ist z.B. einfach, zweifach oder auch mehrfach substituiert. Substituenten, insbesondere am Phenylrest sind u.a. Niederalkyl, Niederalkoxy, Halogen, Trifluormethyl, Niederalkylsulfonyl oder Nitro. Substituenten am Pyridyl- oder Thienyl-rest sind vorzugsweise Niederalkyl, Halogen oder Trifluormethyl.Substituted phenyl, pyridyl or thienyl is e.g. single, double or multiple substituted. Substituents, especially on the phenyl radical, include Lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro. Substituents on the pyridyl or thienyl radical are preferably lower alkyl, halogen or trifluoromethyl.

Vorstehend wie nachfolgend können die Allgemeinbegriffe folgende Bedeutung haben:Above and below, the general terms can have the following meanings:

Niederalkyl ist z.B. Methyl, Aethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec.-Butyl oder tert.-Butyl, ferner n-Pentyl, n-Hexyl, Isohexyl oder n-Heptyl.Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, n-hexyl, isohexyl or n-heptyl.

Niederalkylen ist Aethylen, sowie 1,3-Propylen, 1,4-Butylen, kann aber auch 1,2-Propylen, 1,2- oder 2,3-Butylen, 1,3- oder 2,4-Pentylen oder 1,4-Pentylen sein.Lower alkylene is ethylene, and also 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, Be 4-pentylene.

Niederalkoxy ist z.B. Methoxy, Aethoxy, n-Propyloxy, Isopropyloxy, n-Butyloxy oder tert.-Butyloxy.Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.

Halogen ist solches mit der Atomnummer bis und mit 35 und steht fUr Fluor oder Brom, vorzugsweise fUr Chlor.Halogen is one with the atomic number up to and 35 and stands for fluorine or bromine, preferably for chlorine.

Niederalkylsulfonyl steht z.B. für Methylsulfonyl, Aethylsulfonyl oder n-Propylsulfonyl.Lower alkylsulfonyl is e.g. for methylsulfonyl, ethylsulfonyl or n-propylsulfonyl.

Die erfindungsgemässen Verbindungen besitzen wertvolle pharmakologische Eigenschaften, insbesondere entzündungshemmende und antirheumatische Wirkungen, wie sich in Tierversuchen zeigen lässt. z.B. im Kaolin-Pfotenoedem-Test (Helv. Physiol. Acta 25 (1967) 156) an der Ratte bei einer peroral gegebenen Dosis ab etwa 10 mg/kg oder im Terpentin-Pleuritis-Test [Helv. Physiol. Acta 26 (1969) 287) an der Ratte peroral gegeben bei einer Dosis von 30 bis 100 mg/kg zeigen sie eine antiinflammatorische bzw. anti-exsudative Wirkung. Insbesondere die ungesättigten Verbindungen zeigen auch im AdjuvansArthritis-Test [Pharmacology 2 (1969) 288] an der Ratte bei einer peroralen Dosis von 10-30 mg/kg eine ausgezeichnete Wirkung.The compounds according to the invention have valuable pharmacological properties, in particular 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 the rat at a dose given from around 10 mg / kg or in the turpentine pleurisy test [Helv. Physiol. Acta 26 (1969) 287) given orally to the rat at a dose of 30 to 100 mg / kg, they show an anti-inflammatory or anti-exudative effect. In particular, the unsaturated compounds also show an excellent effect in the adjuvant arthritis test [Pharmacology 2 (1969) 288] on the rat at a oral dose of 10-30 mg / kg.

Die neuen Verbindungen sind auch analgetisch wirksam, wie sich im Phenyl-p-benzochinon-Test an der Maus (Proc. Soc. Exp. Biol. 95 (1957) 729) bei Dosen von 30 bis 100 mg/kg, peroral gegeben, zeigen lässt.The new compounds are also analgesic, as shown in the phenyl p-benzoquinone test on the mouse (Proc. Soc. Exp. Biol. 95 (1957) 729) at doses of 30 to 100 mg / kg, given orally leaves.

Ferner ist die Hemmwirkung der neuen Präparate auf die Prostaglandin-Synthetase in vitro [Prostaglandins, 7 (1974) 123] in Konzentrationen von 0.05-20 µg/ml zu nennen. Ausserdem zeigen sie einen wertvollen antithrombotischen Effekt, nämlich einen Schutz vor tödlicher Lungenembolie am Kaninchen [Pharmacology 14 (1976) 522] in peroralen Dosen von 0.03-3 mg/kg.Furthermore, the inhibitory effect of the new preparations on prostaglandin synthetase in vitro [Prostaglandins, 7 (1974) 123] in concentrations of 0.05-20 µg / ml should be mentioned. In addition, they show a valuable antithrombotic effect, namely protection against fatal pulmonary embolism in rabbits [Pharmacology 14 (1976) 522] in oral doses of 0.03-3 mg / kg.

Die Tetrahydro-verbindungen zeigen zusätzlich dazu im Pertussisoedem-Test (Agents and Actions, vol. 6, 613, 1976) bei 5-50 mg/kg/Ratte eine verstärkende Wirkung.The tetrahydro compounds additionally show a reinforcing effect in the pertussis edema test (Agents and Actions, vol. 6, 613, 1976) at 5-50 mg / kg / rat.

Die neuen Verbindungen können desshalb als Antiphlogistika z.B. zur Behandlung von rheumatischen, arthritischen und anderen, mit EntzUndungen verbundenen Erkrankungen insbesondere, rheumatischer Arthritis oder als Analgetika, z.B. zur Behandlung von Schmerzzuständen, verwendet werden.The new compounds can therefore be used as anti-inflammatory agents, for example for the treatment of rheumatic, arthritic and other inflammations Diseases in particular, rheumatoid arthritis or as analgesics, for example to treat painful conditions.

Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkyl, Niederalkoxy, Halogen oder Trifluormethyl substituierten Phenylrest, einen Pyridyl-, wie einen 2-, 3- oder 4-Pyridyl-,oder Thienyl-, ins besondere einen 2-Thienylrest darstellen, Alk einen Niederalkylenrest, der das Schwefel- und Stickstoffatom Uber 2-3 Kohlenstoffatome miteinander verbindet, in erster Linie einen unverzweigten Niederalkylenrest und n besonders 0, ferner auch 1 oder 2 bedeuten, und deren Salze.The invention relates in particular to compounds of the formula I in which Ar 1 and Ar 2 independently of one another are a phenyl radical which is optionally substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, a pyridyl such as a 2-, 3- or 4-pyridyl or thienyl , in particular represent a 2-thienyl radical, alk is a lower alkylene radical which connects the sulfur and nitrogen atoms via 2-3 carbon atoms, primarily an unbranched lower alkylene radical and n is especially 0, furthermore also 1 or 2, and their salts.

Die Erfindung betrifft in erster Linie Verbindungen der Formel II

Figure imgb0002
worin Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkoxy, wie Methoxy oder Halogen, insbesondere Chlor substituierten Phenylrest bedeuten und m in erster Line 1, ferner auch 2 ist, und ihre Salze.The invention relates primarily to compounds of the formula II
Figure imgb0002
 in which Ar 1 and Ar 2 independently of one another represent a phenyl radical which is optionally substituted by lower alkoxy, such as methoxy or halogen, in particular chlorine, and m is primarily 1, furthermore also 2, and their salts.

Die Erfindung betrifft aber besonders auch Verbindungen der Formel III

Figure imgb0003
worin Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkoxy, wie Methoxy oder Halogen, insbesondere Chlor substituierten Phenylrest bedeuten und m in erster Linie 1, ferner auch 2 ist, und ihre Salze.However, the invention particularly relates to compounds of the formula III
Figure imgb0003
 wherein Ar 1 and Ar 2 independently of one another, optionally by lower alkoxy, such as methoxy or halogen, ins special chlorine-substituted phenyl radical and m is primarily 1, furthermore also 2, and their salts.

Insbesondere betrifft uie Erfindung die neuen in den Beispielen beschriebenen Verbindungen.In particular, the invention relates to the new compounds described in the examples.

Die neuen Verbindungen lassen sich nach an sich bekannten Methoden gewinnen.The new compounds can be obtained by methods known per se.

So kann man z.B. Verbindungen der Formel IV

Figure imgb0004
worin X eine reaktionsfähige veresterte Hydroxygruppe darstellt, ringschliessen, und, wenn erwünscht, in gegebenenfalls erhaltenen Verbindungen, worin n 0 ist, das Thia - atom zur Sulfinyl- oder Sulfonylgruppe oxidieren, und/ oder, wenn erwünscht, erhaltene freie Verbindungen in ihre Salze überführen oder erhaltene Salze in die freien Verbindungen umwandeln und/oder ein verfahrensmässig erhaltenes Isomerengemisch in die einzelnen Isomeren trennen.For example, compounds of the formula IV
Figure imgb0004
 wherein X represents a reactive esterified hydroxy group, ring, and, if desired, in optionally obtained compounds, wherein n is 0, oxidize the thia atom to the sulfinyl or sulfonyl group and / or, if desired, convert the free compounds obtained into their salts or convert the salts obtained into the free compounds and / or separate a mixture of isomers obtained by the process into the individual isomers.

Reaktionsfähig verestertes Hydroxy ist insbesondere eine mit einer starken anorganischen Säure, z.B. Halogenwasserstoff, insbesondere Chlorwasserstoff, oder Schwefelsäure, oder mit einer starken organischen Säure, wie mit einer Niederalkansulfonsäure, z.B. Methan- oder Aethansulfonsäure oder einer gegebenenfalls durch Niederalkyl, Niederalkoxy oder Halogen substituierten Benzolsulfonsäure, z.B. p-Toluolsulfonsäure oder p-Brombenzolsulfonsäure veresterte Hydroxygruppe.Reactively esterified hydroxy is especially one 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 esterified hydroxy group.

Der Ringsschluss wird vorzugsweise unter Säureabspaltenden Bedingungen durchgeführt. Dabei arbeitet man in erster Linie in einem niedersiedenden Lösungsmittel, wie Dimethylformamid oder Aceton, einem Alkohol, z.B. Methanol oder Aethanol, wenn erwünscht, in Gegenwart einer Base, z.B. einer anorganischen Base, wie einem Alkali-oder Erdalkalihydrid, -hydroxyd oder -carbonat, in erster Linie Natriumhydrid, Natriumhydroxyd oder Natriumcarbonat, oder einer organischen Base, vorzugsweise einer Stickstoffbase, wie Triniederalkylamin, z.B. Trimethylamin, Triäthylamin, Dimethyl-isopropylamin, oder Pyridin.The ring closure is preferably carried out under acid-releasing conditions. This is done 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 hydroxide, 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, dimethylisopropylamine, or pyridine.

Die Ausgangsstoffe lassen sich erhalten, wenn man eine ensprechende Diaza-2-mercapto-verbindung mit einem Dihydroxyalkylen, worin mindestens eine der beiden Hydroxygruppen reaktionsfähig verestert ist, miteinander umsetzt, gegebenenfalls die Mercaptogruppe zur Sulfinyl-oder Sulfonylgruppe oxidiert und anschliessend, falls notwendig, die zweite Hydroxygruppe reaktionsfähig verestert. Die reaktionsfähig veresterten Hydroxygruppen entsprechen den obgenannten wie auch die Bedingungen der Kondensation. Bei dieser Reaktion können, insbesondere wenn beide Hydroxylgruppen reaktionsfähig verestert sind, die Ausgangsstoffe der Formel IV in situ erhalten werden, welche in der gleichen Reaktion zum Ring geschlossen werden.The starting materials can be obtained if a corresponding diaza-2-mercapto compound is reacted with a dihydroxyalkylene in which at least one of the two hydroxyl groups has been reactively esterified, if appropriate the mercapto group is oxidized to the sulfinyl or sulfonyl group and then, if necessary, the second hydroxyl group reactively esterified. The reactive esterified hydroxyl groups correspond to the above-mentioned conditions as well as the condensation conditions. In this reaction, in particular if both hydroxyl groups are esterified in a reactive manner, the starting materials of the formula IV can be obtained in situ, which are closed to form a ring in the same reaction.

Die neuen Verbindungen der Formel I, die eine weitere Doppelbindung aufweisen, können auch erhalten werden, wenn man Verbindungen der Formel Va bzw. Vb

Figure imgb0005
oder ihre Tautomeren ringschliesst, und wenn erwünscht, in gegebenenfalls erhaltenen Verbindungen, worin n 0 ist, das Thia-atom zur Sulfinyl- oder Sulfonylgruppe oxidiert, und/oder, wenn erwünscht, erhaltene freie Verbindungen in ihre Salze uberführt oder erhaltene Salze in die freien Verbindungen umwandelt und/oder ein verfahrensgemäss erhaltenes Isomerengemisch in die einzelnen Isomeren auftrennt.The new compounds of the formula I which have a further double bond can also be obtained if compounds of the formula Va or Vb
Figure imgb0005
 or ring-closes their tautomers and, if desired, in optionally obtained compounds in which n is 0, the thia atom is oxidized to the sulfinyl or sulfonyl group and / or, if desired, converts the free compounds obtained into their salts or salts obtained into the free ones Converting compounds and / or separating an isomer mixture obtained according to the process into the individual isomers.

Der Ringschluss erfolgt unter wasserabspaltenden Bedingungen, wie durch Erwärmen, z.B. von etwa 50° bis etwa 150°, vorzugsweise in Gegenwart eines Lösungsmittels, wie Acetonitril oder einem Alkohol, z.B. Methanol oder Aethanol.The ring closure takes place under water-releasing conditions, such as by heating, e.g. from about 50 ° to about 150 °, preferably in the presence of a solvent such as acetonitrile or an alcohol, e.g. Methanol or ethanol.

Die Ausgangsstoffe lassen sich erhalten, wenn man in an sich bekannter Weise eine Verbindung der Formel VI

Figure imgb0006
mit einer Verbindung der Formel VII
Figure imgb0007
oder ihren Tautomeren umsetzt.The starting materials can be obtained if a compound of the formula VI
Figure imgb0006
 with a compound of formula VII
Figure imgb0007
 or their tautomers.

Reaktionsfähig veresterte Hydroxygruppen X sind insbesondere die obgenannten.Reactively esterified hydroxy groups X are in particular the above.

Wird diese Umsetzung auch unter wasserabspaltenden Bedingungen vorgenommen, z.B. unter Erwärmen in einem Lösungsmittel wie Acetonitril oder einem Alkohol, kann der Ausgangsstoff der Formel Va bzw. Vb in situ erhalten werden, der sich unter diesen Reaktionsbedingungen ringschliesst.If this reaction is also carried out under water-releasing conditions, for example with heating in a solvent such as acetonitrile or an alcohol, the starting material of the formula Va or Vb can be obtained in situ, which closes under these reaction conditions.

Die Oxydation des Thia-atoms zur Sulfinyl- oder Sulfonylgruppe lässt sich in an sich bekannter Weise z.B. mit Peroxyden, wie Wasserstoffperoxyd, oder Persäuren, z.B. einer gegebenenfalls durch Niederalkyl, Niederalkoxy, Halogen oder einer weiteren Carboxylgruppe substituierten Benzoepersäure, wie Benzoepersäure selbst oder Phthalmono- persäure,oder einer Alkanpercarbonsäure, wie Peressigsäure oder einem Perjodat, wie Natriumperjodat durchführen. Diese Reaktion wird meist bei tiefen Temperaturen in einem Lösungsmittel, wie Eisessig oder Aceton vorgenommen.The oxidation of the thia 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. carry out an optionally substituted by lower alkyl, lower alkoxy, halogen or another carboxyl group, such as benzoperic acid itself or phthalmonoperacid, or an alkane percarboxylic acid such as peracetic acid or a periodate such as sodium periodate. This reaction is usually carried out at low temperatures in a solvent such as glacial acetic acid or acetone.

Die neuen Verbindungen können in Form von Säureadditionssalzen, insbesondere pharmazeutisch verwendbaren, nicht-toxischen Salzen, z.B. mit organischen Säuren, wie Chlorwasserstoff-, Bromwasserstoff-, Schwefel- oder Phosphorsäure, oder mit organischen, wie aliphatischen, cycloaliphatischen, cycloaliphatisch-aliphatischen, aromatischen, araliphatischen, heterocyclischen oder heterocyclisch-aliphatischen Carbon- oder Sulfonsäure, z.B. Essig-, Propion-, Bernstein-, Glykol-, Milch-, Aepfel-, 'Wein-, Zitronen-, Ascorbin-, Malein-, Phenylessig-, Benzoe-, 4-Aminobenzoe-, Anthranil-, 4-Hydroxybenzoe-, Salicyl-, Aminosalicyl-, Embon- oder Nicotin-, sowie Methansulfon-, Aethansulfon-, 2-Hydroxyäthansulfon-, Aethylensulfon-, Benzolsulfon-, p-Toluolsulfon-, Naphthalinsulfon-, Sulfanil- oder Cyclohexylsulfaminsäure, vorliegen. Salze dieser Art können z.B. durch Behandeln der freien Verbindungen, mit den Säuren oder mit geeigneten Anionenaustauscherharzen erhalten werden.The new compounds can be in the form of acid addition salts, especially pharmaceutically acceptable, 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 carbon or sulfonic acid, e.g. Vinegar, propion, amber, glycol, milk, apple, 'wine, lemon, ascorbic, maleic, phenylacetic, benzoic, 4-aminobenzoic, anthranil, 4-hydroxybenzoic, Salicylic, aminosalicylic, embon or nicotinic, as well as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid are present. Salts of this type can e.g. can be obtained by treating the free compounds, with the acids or with suitable anion exchange resins.

Infolge der engen Beziehungen zwischen den neuen Verbindungen in freier Form und in Form ihrer Salze sind im Vorausgegangenen und nachfolgend unter den freien Verbindungen oder den Salzen sinn- und zweckmässig gegebenenfalls auch die entsprechenden Salze bzw. freien Verbindungen zu verstehen.As a result of the close relationships between the new compounds in free form and in the form of their salts, in the preceding and the following, the free compounds or the salts are also to be understood as meaningful and expedient, if appropriate, the corresponding salts or free compounds.

Die neuen Verbindungen können als Isomerengemische, wie Racemate oder Diastereoisomerengemische, oder in Form der reinen Isomeren, wie optisch aktiven Komponenten, vorliegen. Die Auftrennung von erhaltenen Isomerengemischen in die reinen Isomeren kann nach den bekannten Methoden geschehen. Racemate lassen sich z.B. auf Grund physikalisch-chemischer Unterschide, wie z.B. solchen der Löslichkeit, ihrer diastereomeren Salze, oder durch fraktioniertes Kristallisieren aus einem optisch aktiven Lösungsmittel, oder durch Chromatographie, insbesondere DUnnschichtchromatographle, an einem optisch aktiven Trägermaterial, in die optisch aktiven Antipoden auftrennen. Dabei isoliert man vorteilhafterweise das pharmakologisch wirksamere oder weniger toxische reine Isomere, insbesondere den wirksameren oder weniger toxischen aktiven Antipoden.The new compounds can be present as isomer mixtures, such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, such as optically active components. The separation of isomer mixtures obtained into the pure isomers can be carried out by the known methods. Racemates can e.g. due to physico-chemical differences, e.g. Separate those of solubility, their diastereomeric salts, or by fractional crystallization from an optically active solvent, or by chromatography, in particular thin-layer chromatography, on an optically active carrier material, into the optically active antipodes. The pharmacologically more effective or less toxic pure isomer is advantageously isolated, in particular the more effective or less toxic active antipode.

Die obigen Reaktionen werden in üblicher Weise in An- oder Abwesenheit von VerdUnnungs-, Kondensations-und/oder katalytischen Mitteln, falls notwendig, bei erniedrigter oder erhöhter Temperatur, im geschlossenen Gefäss und/oder in einer Inertgasatmosphäre durchgeführt.The above reactions are carried out in the customary manner in the presence or absence of diluent, condensation and / or catalytic agents, if necessary at reduced or elevated temperature, in a closed vessel and / or in an inert gas atmosphere.

Das Verfahren umfasst auch diejenigen AusfUhrungsformen, wonach als Zwischenprodukte anfallende Verbindungen als Ausgangsstoffe verwendet und die restlichen Verfahrensschritte mit diesen durchgeführt werden, oder das Verfahren auf irgendeiner Stufe abgebrochen wird; ferner können Ausgangsstoffe in Form von Derivaten verwendet oder während der Reaktion gebildet werden.The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.

Vorzugsweise werden solche Ausgangsstoffe verwendet und die Reaktionsbedingungen so gewählt, dass man zu den eingangs als besonders bevorzugt aufgeführten Verbindungen gelangt.Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed at the outset as particularly preferred are obtained.

Die Erfindung betrifft auch die als Zwischenprodukte erhältlichen neuen Verbindungen der allgemeinen Formel Va bzw. Vb

Figure imgb0008
bzw.
Figure imgb0009
oder ihre Tautomeren, worin Alk Niederalkylen darstellt, welches das Thia- vom Aza-atom durch 2-4 Kohlenstoffatome trennt, Ar1 und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist, und deren Salze. In den oben erwähnten biologischen Testanordnungen sind sie ungefähr gleich wirksam wie die Dihydroverbindungen der Formel I und können als Antiinflammatorika, z.B. zur Behandlung von rheumatischer Arthritis, verwendet werden.The invention also relates to the new compounds of the general formula Va or Vb obtainable as intermediates
Figure imgb0008
 or.
Figure imgb0009
 or their tautomers, where Alk is lower alkylene, which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2, and their Salts. In the biological test arrangements mentioned above, they are approximately as effective as the dihydro compounds of the formula I and can be used as anti-inflammatory agents, for example for the treatment of rheumatic arthritis.

Die neuen Verbindungen der vorliegenden Erfindung können z.B. zur Herstellung von pharmazeutischen Präparaten verwendet werden, welche eine wirksame Menge der Aktivsubstanz zusammen oder im Gemisch mit anorganischen oder organischen, festen oder flüssigen, pharmazeutisch verwendbaren Trägerstoffen enthalten, die sich zur enteralen oder parenteralen Verabreichung eignen. So verwendet man Tabletten oder Gelatinekapseln, welche den Wirkstoff zusammen mit Verdünnungsmitteln, z.B. Laktose, Dextrose, Sukrose, Mannitol, Sorbitol, Cellulose und/oder Glycerin, und Schmiermitteln, z.B. Kieselerde, Talk, Stearinsäure oder Salze davon, wie Magnesium- oder Calciumstearat, und/oder Polyäthylenglykol, aufweisen; Tabletten enthalten ebenfalls Bindemittel, z.B. Magnesiumaluminiumsilikat, Stärken, wie Mais-, Weizen-, Reis- oder Pfeilwurzstärke, Gelatine, Traganth, Methylcellulose, Natriumcarboxymethylcellulose und/oder Polyvinylpyrrolidon, und, wenn erwUnscht, Sprengmittel, z.B. Stärken, Agar, Alginsäure oder ein Salz davon, wie Natriumalginat, und/oder Brausemischungen, oder Adsorptionsmittel, Farbstoffe, Geschmackstoffe und SUssmittel. Ferner kann man die neuen pharmakologisch wirksamen Verbindungen in Form von injizierbaren, z.B. intravenös verabreichbaren Präparaten oder von Infusionslösungen verwenden. Solche Lösungen sind vorzugsweise isotonische wässrige Lösungen oder Suspensionen, wobei diese z.B. aus lyophilisierten Präparaten, welche die Wirksubstanz allein oder zusammen mit einem Trägermaterial, z.B. Mannit, enthalten, vor Gebrauch hergestellt werden können. Die pharmazeutischen Präparate können sterilisiert sein und/oder Hilfsstoffe, z.B. Konservier-, Stabilisier-, Netz- und/oder Emulgiermittel, Löslichkeitsvermittler, Salze zur Regulierung des osmotischen Druckes und/oder Puffer enthalten. Die vorliegenden pharmazeutischen Präparate, die, wenn erwUnscht, weitere pharmakologisch wertvolle Stoffe enthalten können, werden in an sich bekannter Weise, z.B. mittels konventioneller Misch-, Granulier-, Dragier-, Lösungs- oder Lyophilisierungsverfahrcn, hergestellt und enthalten von etwa 0,1% bis 100%, insbesondere von etwa 1% bis etwa 50%, Lyophilisate bis zu 100% des Aktivstoffes. Die Einzeldosis fUr einen Warmblüter von etwa 70 kg Gewicht beträgt zwischen 0,1 und 0,75 g, die Tagesdosis zwischen 0,2 und 1,0 g.The new compounds of the present invention can be used, for example, for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or contain organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate. and / or polyethylene glycol; Tablets also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of injectable, for example intravenously administrable, preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being able to be prepared, for example, from lyophilized preparations which contain the active substance on their own or together with a carrier material, for example mannitol. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, 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, confectioning, dissolving or lyophilizing processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates up to 100% of the active ingredient. The single dose for a warm-blooded animal weighing approximately 70 kg is between 0.1 and 0.75 g, the daily dose between 0.2 and 1.0 g.

Die folgenden Beispiele dienen zur Illustration der Erfindung; Temperaturen werden in Celsiusgraden angegeben.The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.

Beispiel 1example 1

Eine Mischung aus 5 g a-Brom-desoxyanisoin, 3 g 2-Aminothiazolin und 30 ml Aethanol wird 4 Stunden bei 60°, danach 2 Stunden am RUckfluss und anschliessend noch 12 Stunden bei Raumtemperatur gerührt. Die dabei ausgefallenen Kristalle werden abgenutscht und mit Aethanol und Diäthyläther nachgewaschen. Man erhält so rohes 5,6-Di-(p-methoxy-phenyl)-imidazo[2,1-b]dihydro-thiazol. F. nach dem Umkristallisieren aus Toluol-Petroläther 152-1540 A mixture of 5 g of a-bromo-deoxyanisoin, 3 g of 2-aminothiazoline and 30 ml of ethanol is stirred for 4 hours at 60 °, then for 2 hours at reflux and then for a further 12 hours at room temperature. The crystals which have precipitated are filtered off with suction and washed with ethanol and diethyl ether. This gives crude 5,6-di- (p-methoxyphenyl) imidazo [2,1-b] dihydro-thiazole. F. after recrystallization from toluene-petroleum ether 152-154 0

Beispiel 2Example 2

Eine Suspension von 7 ml 1,2-Dibromäthan, 7 g Natriumcarbonat und 55 ml Isopropanol wird bei Raumtemperatur gerührt und innert einer Stunde mit der Suspension von 4,7 g 4,5-Diphenyl-imidazolidin-2-thion in 110 ml l,5%-iger Natronlauge versetzt. Das Reaktionsgemisch wird 7 Stunden am RUckfluss gekocht, dann werden das Isopropanol und das Dibromäthan am Rotationsverdampfer entfernt und die verbleibende Suspension wird mit Toluol extrahiert. Der Toluolextrakt wird mit Sole gewaschen, über Natriumsulfat getrocknet und eingedampft. Der Rückstand wird auf Silicagel chromatographiert. Nach dem Abtrennen unpolarer Verunreinigungen mit Aethylacetat wird das cis-5,6-Dipheny1-2,3,5,6-tetrahydro-imidazo[2,1-b]thiazol mit einem Gemisch aus Aethylacetat:Methanol = 99:1 als farbloses Oel eluiert. Es kristallisiert spontan zu weissen Kristallen vom Smp. 110-113° (Sinterpunkt 103°)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 within one hour with the suspension of 4.7 g of 4,5-diphenyl-imidazolidin-2-thione in 110 ml of l, 5% sodium hydroxide solution added. The reaction mixture is refluxed for 7 hours, then the isopropanol and the dibromoethane are removed on a rotary evaporator and the remaining suspension is extracted with toluene. The toluene extract is washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel. After separating non-polar impurities with ethyl acetate, the cis-5,6-dipheny1-2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole is mixed with a mixture of ethyl acetate: methanol = 99: 1 as a colorless oil eluted. It spontaneously crystallizes to white crystals of mp 110-113 ° (sintering point 103 °)

Beispiel 3Example 3

Eine Suspension von 3,5 ml 1,2-Dibromäthan, 3,5 g Natriumcarbonat und 30 ml Isopropanol wird unter Rühren bei Raumtemperatur während einer Stunde mit der Suspension von 3 g 4,5-Di-anisyl-2-mercapto-imidazol in 50 ml 1,5%-iger Natronlauge versetzt. Das Reaktionsgemisch wird 6 Stunden am RUckfluss gekocht, dann werden das Isopropanol und das Dibromäthan am Rotationsverdampfer entfernt und die verbleibende Suspension wird mit 10 ml 20%-iger Kalilauge versetzt und mit Aethylacetat extrahiert. Die organischen Phasen werden mit Sole gewaschen, mit Natriumsulfat getrocknet und eingedampft. Aus dem Rückstand erhält man nach dem Umkristallisieren aus Toluol-Petroläther das 5,6-Di-(p-methoxy-phenyl)-imidazo[2,1-b]dihydro-thiazol vom F. 152-154°.A suspension of 3.5 ml of 1,2-dibromoethane, 3.5 g of sodium carbonate and 30 ml of isopropanol is stirred in with the suspension of 3 g of 4,5-di-anisyl-2-mercapto-imidazole in at room temperature for one hour 50 ml of 1.5% sodium hydroxide solution are added. The reaction mixture is refluxed for 6 hours, then the isopropanol and the dibromoethane are removed on a rotary evaporator and the remaining suspension is mixed with 10 ml of 20% potassium hydroxide solution and extracted with ethyl acetate. The organic phases are washed with brine, dried with sodium sulfate and evaporated. After recrystallization from toluene-petroleum ether, the 5,6-di- (p-methoxy-phenyl) -imidazo [2,1-b] dihydro-thiazole of mp 152-154 ° is obtained from the residue.

Beispiel 4Example 4

14,8 g 4,5-Di-(p-Methoxy-phenyl)-2-ß-hydroxy- äthylmercapto-imidazol werden in 50 ml absolutem Pyridin gelöst und unter Rühren bei ca -5° Innentemperatur zu einer Lösung von 15,8 g Benzolsulfochlorid in 60 ml absolutem Pyridin getropft. Anschliessend rührt man 60 Stunden bei 0° aus. Das Reaktionsgemisch wird auf Eiswasser gegossen und mit Dichlormethan extrahiert. Die mit Wasser 3-mal gewaschenen und vereinigten Dichlormethanextrakte werden über Natriumsulfat getrocknet und zur Trockne eingedampft. Das viskose Oel wird aus Toluol-Petroläther kristallisiert. Das so erhaltene 5,6-Di-(p-methoxyphenyl)-imidazo(2,1-b]dihydro-thiazol vom F. 152-154°.14.8 g of 4,5-di- (p-methoxy-phenyl) -2-ß-hydroxy-ethylmercapto-imidazole are dissolved in 50 ml of absolute pyridine and with stirring at about -5 ° internal temperature to a solution of 15.8 g of benzenesulfonyl chloride dropwise in 60 ml of absolute pyridine. The mixture is then stirred at 0 ° for 60 hours. The reaction mixture is poured onto ice water and extracted with dichloromethane. The dichloromethane extracts washed and combined 3 times with water are dried over sodium sulfate and evaporated to dryness. The viscous oil is crystallized from toluene-petroleum ether. The 5,6-di- (p-methoxyphenyl) imidazo (2,1-b] dihydro-thiazole of mp 152-154 ° thus obtained.

Das Ausgangsmaterial kann z,B. hergestellt werden: 2,5 g Natrium werden in 220 ml Aethanol gelöst. Dazu gibt man 35 g 4,5-Dianisyl-imidazolin-2-thion. Man erhält eine Suspension. Innerhalb 2 Minuten werden dazu bei Raumtemperatur (RUhren) 15,7 ml 2-Chloräthanol getropft. Man rührt 1 Stunde bei 60° und 4 Stunden am RUckfluss weiter. Anschliessend wird die schwache Suspension zur Trockne eingedampft. Der Rückstand wird aus Aceton/ Wasser gereinigt.The starting material can e.g. are prepared: 2.5 g of sodium are dissolved in 220 ml of ethanol. 35 g of 4,5-dianisyl-imidazolin-2-thione are added. A suspension is obtained. For this purpose, 15.7 ml of 2-chloroethanol are added dropwise at room temperature (stirring). The mixture is stirred for 1 hour at 60 ° and 4 hours at reflux. The weak suspension is then evaporated to dryness. The residue is purified from acetone / water.

Beispiel 5Example 5

Ein Gemisch aus 60 g N-Aethyl-diisopropylamin, 70 g 2-Aminodihydrothiazol, 150 g a-Brom-desoxyanisoin und 800 ml Acetonitril wird 48 Stunden bei Raumtemperatur gerUhrt. Das dabei entstandene 5,6-Di-(p-methoxyphenyl)-imidazo[2,1-b)dihydro-thiazolin wird abgenutscht und mit Acetonitril nachgewaschen. Durch Eindampfen des Filtrates und Verteilen des so vom Lösungsmittel befreiten Rückstandes zwischen Aethylacetat und Wasser erhält man weitere 50 g Rohprodukt. Durch Umkristallisieren des Rohproduktes aus Toluol erhält man 5,6-Di-(p-methoxyphenyl)-imidazo[2.1-b]dihydro-thiazol vom F. 152-154°.A mixture of 60 g of N-ethyl-diisopropylamine, 70 g of 2-aminodihydrothiazole, 150 g of a-bromo-deoxyanisoin and 800 ml of acetonitrile is stirred for 48 hours at room temperature. The resulting 5,6-di- (p-methoxyphenyl) imidazo [2,1-b) dihydro-thiazoline is filtered off and washed with acetonitrile. Evaporation of the filtrate and distribution of the residue thus freed from solvent between ethyl acetate and water gives a further 50 g of crude product. By recrystallizing the crude product from toluene, 5,6-di- (p-methoxyphenyl) imidazo [2.1-b] dihydro-thiazole of mp 152-154 ° is obtained.

Beispiel 6Example 6

Zu einer Lösung von 23 g p-Toluolsulfochlorid in 80 ml Pyridin wird bei 0° unter Rühren die Lösung von 20 g 2-(2-Hydroxy-äthyl-thio)-4(5)-3'-pyridyl-5(4)-phenyl-imidazol zugegeben. Das Reaktionsgemisch wird 16 Stunden bei 0° gerührt, auf Eis-Wasser gegossen und mit Aether extrahiert. Aus den Aetherextrakten erhält man nach dem Waschen mit Wasser und Trocknen über Natriumsulfat einen Eindampfrückstand der nach dem Chromatographieren auf Silicagel mit Toluol und Essigester und nach dem Umkristallisieren der entsprechenden Fraktionen aus Essigester das Isomerengemisch 5(6)-(3-Pyridyl)-6(5)-phenyl-imidazo-[2,1-b]-dihydro-thiazol als weisse Kristalle vom F. 150-151° ergibt.The solution of 20 g of 2- (2-hydroxyethylthio) -4 (5) -3'-pyridyl-5 (4) is added to a solution of 23 g of p-toluenesulfochloride in 80 ml of pyridine at 0 ° with stirring. -phenyl imidazole added. The reaction mixture is stirred at 0 ° for 16 hours, poured onto ice-water and extracted with ether. After washing with water and drying over sodium sulfate, an ether residue is obtained from the ether extracts, which after chromatography on silica gel with toluene and ethyl acetate and after recrystallization install the appropriate fractions from ethyl acetate, the isomer mixture 5 (6) - (3-pyridyl) -6 (5) -phenyl-imidazo- [2,1-b] -dihydro-thiazole as white crystals of mp 150-151 ° .

Das Ausgangsmaterial lässt sich wie folgt erhalten:

  • 10,8 g Benzyl-pyridyl(3)-keton werden zusammen

mit 40 ml Pyridin und einer Lösung von 8 g Hydroxylaminhydorchlorid in 15 ml Pyridin während 6 Stunden bei 100° gerührt. Das Reaktionsgemisch wird auf Eis/Wasser gegossen und 15 Minuten weitergerührt. Die ausgefallenen Kristalle werden abgenutscht, mit Wasser gewaschen und am Hochvakuum getrocknet. Man erhält das Benzyl-pyridyl(3)-keton-oxim vom F. 122-126°.The starting material can be obtained as follows:
  • 10.8 g of benzyl pyridyl (3) ketone are combined

stirred with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine at 100 ° for 6 hours. The reaction mixture is poured onto ice / water and stirred for a further 15 minutes. The precipitated crystals are filtered off, washed with water and dried in a high vacuum. The benzyl-pyridyl (3) -ketone-oxime of mp 122-126 ° is obtained.

Zu einer bei -10° gerührten Lösung von 8,5 g Benzyl-pyridyl(3)-keton-oxim in 20 ml Pyridin wird innert 5 Minuten die Lösung von 7,7 g p-Toluolsulfochlorid in 15 ml Pyridin zugetropft. Das Reaktionsgemisch wird 24 Stunden im Eisschrank aufbewahrt und dann auf Eis/Wasser gegossen. Nach längerem Rühren und Verreiben erstarrt das ausgefallene Oel zu Kristallen. Diese werden abgenutscht, mit Wasser gewaschen und am Hochvakuum getrocknet. Man erhält 11,6 g eines Rohproduktes vom F. 87-92°, welches nach Dünnschichtchromatographie jedoch noch Edukt enthält. Es wird direkt in der nächsten Stufe eingesetzt.The solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine is added dropwise to a solution of 8.5 g of benzylpyridyl (3) ketone oxime in 20 ml of pyridine which is stirred at -10 ° within 5 minutes. The reaction mixture is kept in the refrigerator for 24 hours and then poured onto ice / water. After stirring and rubbing for a long time, the precipitated oil solidifies to crystals. These are filtered off, washed with water and dried in a high vacuum. 11.6 g of a crude product having a melting point of 87-92 ° are obtained, which however still contains starting material after thin layer chromatography. It is used directly in the next stage.

11,6 g Rohprodukt (Benzyl-pyridyl(3)-keton-oxim- p-toluolsulfoester) werden in 90 ml absolutem Aethanol suspendiert und bei 0° unter Rühren die Lösung von 3,7 g Kalium-tert.-butylat in 30 ml absolutem Aethanol zugetropft. Das Reaktionsgemisch wird 2 Stunden bei 0° gerührt. Die Suspension wird abgenutscht und das Filtrat sofort in der nächsten Stufe eingesetzt.11.6 g of crude product (benzyl-pyridyl (3) -ketone-oxime-p-toluenesulfoester) are suspended in 90 ml of absolute ethanol and at 0 ° with stirring the solution of 3.7 g of potassium tert-butoxide in 30 ml dropped in absolute ethanol. The reaction mixture is stirred at 0 ° for 2 hours. The suspension is filtered off and the filtrate is immediately used in the next stage.

3,6 g Natriumthiocyanat werden in 60 ml Aethanol gelöst und mit 4,5 ml konzentrierter Salzsäure versetzt. Die Suspension wird abgenutscht und das Filtrat wird zusammen mit der alkoholischen Lösung des erhaltenen a-Amino- benzyl-pyridyl(3)-keton während 18 Stunden am RUckfluss gehalten. Nach dem Abkühlen lässt sich aus dem Reaktionsgemisch 2,8 g rohes 4-Phenyl-5-pyridyl(3)-2-mercapto- imidazol abnutschen. Das Filtrat enthält weitere Mengen des Produktes. Nach dem Umkristallisieren aus Dimethylformamid-Wasser schmilzt es bei 290-300°.3.6 g of sodium thiocyanate are dissolved in 60 ml of ethanol and 4.5 ml of concentrated hydrochloric acid are added. The suspension is filtered off with suction and the filtrate, together with the alcoholic solution of the a-aminobenzyl-pyridyl (3) ketone obtained, is refluxed for 18 hours. After cooling, 2.8 g of crude 4-phenyl-5-pyridyl (3) -2-mercapto-imidazole can be sucked off from the reaction mixture. The filtrate contains further amounts of the product. After recrystallization from dimethylformamide water, it melts at 290-300 °.

0,8 g Natrium werden in 200 ml Aethanol gelöst. Die Lösung wird mit 8 g l-Phenyl-5-pyridyl(3)-2-mercapto- imidazol versetzt und zum Rückfluss erhitzt. Nachdem eine klare Lösung entstanden ist, werden 2,3 ml 2-Chloräthanol zugetropft und das Reaktionsgemisch wird 16 Stunden am RUckfluss gekocht. Das Lösungsmittel wird am Vakuum abgedampft und der Rückstand zwischen Wasser und Essigester verteilt. Die organischen Phasen werden mit Wasser und Sole gewaschen, mit Natriumsulfat getrocknet und eingedampft. Als Rückstand erhält man kristallines 2-(2-Hydroxy-äthyl-thio)-4(5)-3'-pyridyl-5(4)-phenyl-imidazol. Es schmilzt nach dem Umkristallisieren aus Essigester/Aethanol bei 157-159°C.0.8 g of sodium are dissolved in 200 ml of ethanol. The solution is mixed with 8 g of l-phenyl-5-pyridyl (3) -2-mercapto-imidazole and heated to reflux. After a clear solution has formed, 2.3 ml of 2-chloroethanol are added dropwise and the reaction mixture is boiled 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 brine, dried with sodium sulfate and evaporated. The residue obtained is crystalline 2- (2-hydroxyethylthio) -4 (5) -3'-pyridyl-5 (4) -phenyl-imidazole. It melts after recrystallization from ethyl acetate / ethanol at 157-159 ° C.

In analoger Weise, ausgehend von den entsprechenden Ausgangsstoffe lassen sich die folgenden Verbindungen herstellen:

  • das 5,6-Di-(p-methyl-phenyl)-2,3,5,6-tetrahydro- imidazo[2,1-b]thiazol,
  • das 5,6-Di-(p-chlor-phenyl)-2,3,5,6-tetrahydro- imidazo[2,1-b]thiazol,
  • das 5,6-Di-(m-chlor-phenyl)-2,3,5,6-tetrahydro- imidazo[2,1-b]thiazol,
  • das 5,6-Di-(p-methoxy-phenyl)-3-methyl-2,3,5,6-tetrahydro-imidazo(2,1-b]thiazol oder
  • das 6,7-Di-(p-methoxy-phenyl)-2,3,4,5,6,7-hexa- hydro-imidazo(2,1-b]thiazin.
The following compounds can be prepared analogously, starting from the corresponding starting materials:
  • 5,6-di- (p-methylphenyl) -2,3,5,6-tetrahydroimidazo [2,1-b] thiazole,
  • the 5,6-di- (p-chlorophenyl) -2,3,5,6-tetrahydroimidazo [2,1-b] thiazole,
  • the 5,6-di- (m-chlorophenyl) -2,3,5,6-tetrahydroimidazo [2,1-b] thiazole,
  • the 5,6-di- (p-methoxy-phenyl) -3-methyl-2,3,5,6-tetrahydro-imidazo (2,1-b] thiazole or
  • the 6,7-di- (p-methoxy-phenyl) -2,3,4,5,6,7-hexa- hydroimidazo (2,1-b] thiazine.

Beispiel 7Example 7

14,3 g 2-[N-(1,2-Bis-p-methoxy-pheny1-2-hydroxyäthyl]-amino-thiazolin werden in 24,3 ml konzentrierter Schwefelsäure gelöst und eine Stunde bei Raumtemperatur gerührt. Das Reaktionsgemisch wird auf Eis gegossen, mit 2-n Sodalösung alkalisch gestellt und mit Essigester extrahiert Die organischen Phasen werden mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Aus dem Rückstand erhält man durch Umkristallisieren aus Toluol-Petroläther das 5,6-trans-Di-(p-methoxyphenyl)-2,3,5,6-tetrahydro-4H-imidazol[2,1-b]thiazol vom F. 125-126°.14.3 g of 2- [N- (1,2-bis-p-methoxy-pheny1-2-hydroxyethyl] amino thiazoline are dissolved in 24.3 ml of concentrated sulfuric acid and stirred for one hour at room temperature. The reaction mixture is stirred up Poured ice, made alkaline with 2N sodium carbonate solution and extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated. The residue obtained by recrystallization from toluene-petroleum ether gives 5,6-trans-di- (p -methoxyphenyl) -2,3,5,6-tetrahydro-4H-imidazole [2,1-b] thiazole, mp 125-126 °.

Das verwendete Ausgangsmaterial lässt sich z.B. wie folgt erhalten:The starting material used can e.g. received as follows:

45 g Brom-desoxy-anisoin werden in 170 ml Acetonitril suspendiert. Die Suspension wird mit 23 ml N-Aethyl-diisopropylamin und mit 15,4 g 2-Aminothiazolin versetzt, 2 Stunden bei Raumtemperatur gerührt, abgenutscht und das Nutschgut mit wenig Essigester nachgewaschen. Kan erhält so das 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-aminothiazolin bzw. das 2-Imino-3-(l,2-bis-p-methoxy-phenyl-2-oxo-äthyl)-thiazolin vom F. = 95-98°.45 g of bromo-deoxy-anisoin are suspended in 170 ml of acetonitrile. The suspension is mixed with 23 ml of N-ethyl-diisopropylamine and with 15.4 g of 2-aminothiazoline, stirred for 2 hours at room temperature, suction filtered and the filter cake washed with a little ethyl acetate. Kan thus receives the 2- [N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) aminothiazoline or the 2-imino-3- (1,2-bis-p-methoxy-phenyl- 2-oxo-ethyl) -thiazoline with mp = 95-98 °.

In analoger Weise erhält man

  • das 2-(N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-amino-5-methyl-thiazolin bzw. 2-Imino-5-methyl-3-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-thiazolin oder deren Tautomeren,
  • das 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-amino-4-methyl-thiazolin bzw: 2-Imino-4-methyl-3-(1,2-bis- p-methoxyphenyl-2-oxo-äthyl)-thiazolin oder deren Tautomeren,
  • das 2-[N-(1,2-Bis-phenyl-2-oxo-äthyl)-aminothiazolin bzw. 2-Imino-3-(1,2-bis-phenyl-2-oxo-äthyl)-thiazolin oder deren Tautomeren vom F. 121-123°, oder
  • das 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-amino-5,6-dihydro-4H-thiazin bzw. 2-Imino-3-(1,2-bis-p-methoxyphenyl-2-oxo-äthyl)-5,6-dihydro-4H-thiazin oder deren Tautomeren.
One obtains in an analogous manner
  • the 2- (N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) amino-5-methylthiazoline or 2-imino-5-methyl-3- (1,2-bis- p-methoxyphenyl-2-oxo-ethyl) thiazoline or its tautomers,
  • the 2- [N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) amino-4-methylthiazoline or: 2-imino-4-methyl-3- (1,2-bis- p-methoxyphenyl-2-oxo-ethyl) thiazoline or its tautomers,
  • the 2- [N- (1,2-bis-phenyl-2-oxo-ethyl) aminothiazoline or 2-imino-3- (1,2-bis-phenyl-2-oxo-ethyl) thiazoline or their Tautomers of F. 121-123 °, or
  • the 2- [N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) amino-5,6-dihydro-4H-thiazine or 2-imino-3- (1,2-bis- p-methoxyphenyl-2-oxo-ethyl) -5,6-dihydro-4H-thiazine or its tautomers.

31,5 g 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo- äthyl)-amino-thiazolin oder dessen Isomeren werden in 350 ml Methanol gelöst und portionsweise mit 4,26 g Natriumborhydrid versetzt. Die Suspension wird 2 Stunden bei Raumtemperatur gerührt, dann abgenutscht und mit Methanol nachgewaschen. Man erhält so das 2-[N-(l,2-Bis-p-methoxyphenyl-2-hydroxy-äthyl)-amino-thiazolin vom F. 185-187°.31.5 g of 2- [N- (1,2-bis-p-methoxyphenyl-2-oxoethyl) amino thiazoline or its isomers 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 washed with methanol. This gives the 2- [N- (1,2-bis-p-methoxyphenyl-2-hydroxy-ethyl) amino thiazoline of mp 185-187 °.

Ausgehend von den entsprechenden Thiazolinverbindungen lassen sich in analoger Weise die folgenden Verbindungen erhalten:

  • das 5-Phenyl-6-p-chlorphenyl-2,3,5,6-tetrahydro- imidazo[2,1-b]thiazol,
  • das 6-Phenyl-5-p-chlorphenyl-2,3,5,6-tetrahydro- imidazo[2,1-b]thiazol,
  • das 5,6-Di-(p-methoxyphenyl)-2-methyl-2,3,5,6-tetrahydro-imidazo[2,1-b]thiazol oder
  • das 5,6-Di-(p-methoxyphenyl-3-methyl-2,3,5,6-tetrahydro-imidazo(2,1-b]thiazol.
Starting from the corresponding thiazoline compounds, the following compounds can be obtained in an analogous manner:
  • 5-phenyl-6-p-chlorophenyl-2,3,5,6-tetrahydroimidazo [2,1-b] thiazole,
  • 6-phenyl-5-p-chlorophenyl-2,3,5,6-tetrahydroimidazo [2,1-b] thiazole,
  • the 5,6-di- (p-methoxyphenyl) -2-methyl-2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole or
  • the 5,6-di- (p-methoxyphenyl-3-methyl-2,3,5,6-tetrahydro-imidazo (2,1-b) thiazole.

Beispiel 8Example 8

2 g 5,6-Di-p-methoxyphenyl-2,3-dihydro-4H-imida- zo[2,1-b] thiazol werden in 33 ml Aethanol suspendiert und innert 5 Minuten mit 7,91 ml 30%-igem Wasserstoffperoxyd versetzt. Das Reaktionsgemisch wird 90 Minuten am RUckfluss gehalten, abgekühlt, auf 200 ml Eiswasser gegossen und mit Essigester extrahiert. Aus dem EindampfrUckstand der mit Wasser gewaschenen und über Natriumsulfat getrockneten organischen Phasen erhält man durch Umkristallisieren das 5,6-Di-p-methoxyphenyl-imidazo[2,1-b]2,3-dihydro-thiazol-sulfoxid vom F. 176-177°.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 within 5 minutes with 7.91 ml of 30% strength Hydrogen peroxide added. The reaction mixture is refluxed for 90 minutes, cooled, poured onto 200 ml of ice water and extracted with ethyl acetate. From the evaporation residue the organic phases, washed with water and dried over sodium sulfate, are obtained by recrystallization from the 5,6-di-p-methoxyphenyl-imidazo [2,1-b] 2,3-dihydro-thiazole sulfoxide of mp 176-177 °.

Beispiel 9Example 9

0,69 g Natrium werden in 60 ml Aethanol gelöst und mit 9,36 g 2-Mercapto-4,5-di-p-methoxyphenyl-imidazol versetzt. Das Reaktionsgemisch wird 30 Minuten gerührt, mit 3,1 g 3-Chlor-l-propanol versetzt, 2 Stunden am Rückfluss gehalten, abgekühlt, klar-filtriert und zur Trockne eingedampft. Der Rückstand, das rohe 2-(3-Hydroxy-propyl- thio)-4,5-di-p-methoxyphenyl-imidazol wird in 50 m1 Thionylchlorid 30 Minuten am RUckfluss gehalten. Das Uberschüssige Thionylchlorid wird abgedampft, durch Abdestillieren von 100 ml noch zugesetztem Chloroform abgetrieben und der Rückstand zusammen mit 100 ml Aethanol und 50 ml 40%-iger Kalilauge 4 Stunden am RUckfluss gehalten. Danach wird das Reaktionsgemisch am Rotationsverdampfer eingedampft, mit Eiswasser versetzt und mit Essigester extrahiert. Die organischen Phasen werden mit Wasser gewaschen, getrocknet und eingedampft. Der Rückstand wird mit Toluol:Essigester 1:1 auf Silicagel chromatrographiert. Durch Umkristallisieren der entsprechenden Fraktionen aus Aceton erhält man das 6,7-Di-p-methoxyphenyl-2,3,4,5-tetrahydro-imidazo[2,1-b] (1,3)-thiazin vom 189-191°.0.69 g of sodium are dissolved in 60 ml of ethanol and 9.36 g of 2-mercapto-4,5-di-p-methoxyphenyl-imidazole are added. The reaction mixture is stirred for 30 minutes, 3.1 g of 3-chloro-l-propanol are added, the mixture is kept under reflux for 2 hours, cooled, filtered clear and evaporated to dryness. The residue, the crude 2- (3-hydroxy-propyl-thio) -4,5-di-p-methoxyphenyl-imidazole, is refluxed in 50 ml of thionyl chloride for 30 minutes. The excess thionyl chloride is evaporated, stripped off by distilling off 100 ml of chloroform still added, and the residue is refluxed for 4 hours together with 100 ml of ethanol and 50 ml of 40% potassium hydroxide solution. The reaction mixture is then evaporated on a rotary evaporator, mixed with ice water and extracted with ethyl acetate. The organic phases are washed with water, dried and evaporated. The residue is chromatographed on silica gel with toluene: ethyl acetate 1: 1. By recrystallizing the corresponding fractions from acetone, the 6,7-di-p-methoxyphenyl-2,3,4,5-tetrahydro-imidazo [2,1-b] (1,3) -thiazine at 189-191 ° is obtained .

Beispiel 10Example 10

Analog Beispiel 9 wird aus dem 2-Mercapto-4,5-di-p-chlorphenyl-imidazol mit 2-Chloräthanol das 2-(2-Hydroxy-äthyl-thio)-4,5-di-p-chlorphenyl-imidazol vom F. 197-199° hergestellt und daraus durch Cyclisation mit Thionylchlorid das 5,6-Di-p-chlorphenyl-imidazo[2,1-b]dihydro-thiazol vom F. 199-204°.Analogously to Example 9, the 2-mercapto-4,5-di-p-chlorophenylimidazole with 2-chloroethanol is the 2- (2-hydroxyethylthio) -4,5-di-p-chlorophenylimidazole from F. 197-199 ° and from it by cyclization with thionyl chloride the 5,6-di-p-chlorophenyl-imidazo [2,1-b] dihydro-thiazole of mp 199-204 °.

Analog kann auch das 5,6-di-p-Methoxyphenyl-4H-imidazo[2,1-b]dihydro-thiazol hergestellt werden.The 5,6-di-p-methoxyphenyl-4H-imidazo [2,1-b] dihydro-thiazole can also be prepared analogously.

Beispiel 11Example 11

0,5 g 5,6-Di-p-Methoxyphenyl-2,3-dihydro-4H-imidazo[2,1-b]thiazol werden in 1,5 ml Eisessig suspendiert und mit 0,9 ml 30%-igem Wasserstoffperoxid versetzt. Das Reaktionsgemisch wird 7 Stunden bei 50° gerührt, dann auf Eis-Wasser gegossen und mit Essigester extrahiert. Die organischen Phasen werden mit 1-n Natronlauge gewaschen bis die Extrakte basisch bleiben, dann mit Wasser und Sole neutralgewaschen, über Natriumsulfat getrocknet und eingedampft. Der RUckstand wird aus Essigester kristallisiert, und aus Essigester-Petroläther umkristallisiert. Man erhält so das 5,6-di-p-Methoxyphenyl-imidazo[2,1-b]dihydro-thiazol-sulfon vom F. 186-187°.0.5 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo [2,1-b] thiazole are suspended in 1.5 ml of glacial acetic acid and with 0.9 ml of 30% hydrogen peroxide transferred. The reaction mixture is stirred at 50 ° for 7 hours, then poured onto ice-water and extracted with ethyl acetate. The organic phases are washed with 1N sodium hydroxide solution until the extracts remain basic, then washed neutral with water and brine, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate and recrystallized from ethyl acetate-petroleum ether. This gives the 5,6-di-p-methoxyphenylimidazo [2,1-b] dihydro-thiazole sulfone of mp 186-187 °.

Beispiel 12Example 12

35 g 2-[N-(1,2-Bis-p-methoxypheny 1-2-oxo-äthyl)-aminothiazolin (vgl. Beispiel 7) werden zusammen mit 250 ml Isopropanol und 1 ml Bromwasserstoff (48%-ig) 2 Stunden am Rückfluss gehalten. Durch Abkühlen im Eisbad und Abnutschen des Produktes erhält man das 5,6-Di-(p-methoxyphenyl)-imidazol [2,1-b]dihydro-thiazol vom F. 155-156°.35 g of 2- [N- (1,2-bis-p-methoxypheny 1-2-oxo-ethyl) aminothiazoline (see Example 7) together with 250 ml of isopropanol and 1 ml of hydrogen bromide (48%) 2 Held at reflux for hours. Cooling in an ice bath and filtering off the product gives the 5,6-di- (p-methoxyphenyl) imidazole [2,1-b] dihydro-thiazole of mp 155-156 °.

Aus der Mutterlauge lässt sich das Hydrobromid des 5,6-Di-(p-methoxyphenyl)-imidazo[2,l-b]dihydro-thia- zols gewinnen, Smp. 200-210°.The hydrobromide of 5,6-di- (p-methoxyphenyl) imidazo [2, l-b] dihydro-thiazole can be obtained from the mother liquor, mp. 200-210 °.

Beispiel 13Example 13

Zu einer Suspension von 11,8 g 5,6-di-p-Anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b]-thiazol in 30 ml Wasser werden 17 ml 1-n Salzsäure und 5 g N-Benzolsulfo- nyl-L(+)-glutaminsäure zugegeben. Das Gemischwird durch Erwärmen gelöst und durch Abkühlen zur Kristallisation gebracht. Das L-5,6-di-p-Anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b]thiazol N-benzol-sulfonyl L(+)-glutamat wird abgenutscht, mit wenig Wasser gewaschen, in Wasser suspendiert und mit verdünnter Natronlauge zerlegt. Daraus wird das L-5,6-di-p-Anisyl-2,3,5,6-tetrahydro-4H-imidazo[2,1-b]thiazol mit Aethylacetat extrahiert.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, 17 ml of 1-n Hydrochloric acid and 5 g N-benzenesulfo- nyl-L (+) - glutamic acid added. The mixture is dissolved by heating and crystallized by cooling. The L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b] thiazole N-benzenesulfonyl L (+) - glutamate is filtered off with a little Washed water, suspended in water and decomposed with dilute sodium hydroxide solution. From this, the L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo [2,1-b] thiazole is extracted with ethyl acetate.

Beispiel 14Example 14

Figure imgb0010
Figure imgb0010

Diese Bestandteile werden gesiebt, gut gemischt und die Mischung in Hargelatinekapseln gefüllt.These ingredients are sieved, mixed well and the mixture is filled into Hargelatine capsules.

Beispiel 15Example 15

Figure imgb0011
Figure imgb0011

Die Saccharose, das Calzium-dihydrat und der Wirkstoff werden gemischt und mit einer 10%-ige Gelatinelösung granuliert. Das feuchte Granulat wird gesiebt, getrocknet, mit der Stärke, dem Talkum und der Stearinsäure vermischt, gesiebt und zu Tabletten verpresst.The sucrose, calcium dihydrate and the active ingredient are mixed and granulated with a 10% gelatin solution. The moist granules are sieved, dried, mixed with the starch, talc and stearic acid, sieved and compressed into tablets.

Claims (15)

1. 1,3-Diaza-cyclopent-2-eno(2,1-b](1-thia-3-aza- cycloalkane) der allgemeinen Formel I
Figure imgb0012
deren 1,3-Diaza-cyclopent-2-en-ring eine weitere Doppelbindung aufweisen kann. Alk Niederalkylen darstellt, welches das Thia- vom Aza-atom durch 2-4 Kohlenstoffatome trennt, Arl und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist, mit der Massgabe, dass mindestens einer der Reste Ar1 und Ar2 von Phenyl verschieden ist, wenn Alk Aethylen und der 1,3-Diaza-cyclopent-2-en-ring einen Imidazolring darstellt, und deren Salze.1. 1,3-diaza-cyclopent-2-eno (2,1-b] (1-thia-3-aza-cycloalkanes) of the general formula I
Figure imgb0012
 whose 1,3-diaza-cyclopent-2-ene ring can have a further double bond. Alk represents lower alkylene, which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2, with the proviso that at least one the radicals Ar 1 and Ar 2 are different from phenyl when alk ethylene and the 1,3-diaza-cyclopent-2-ene ring represent an imidazole ring, and their salts. 2. Verbindungen der-Formel I, worin Ar1 und Ar2 unabhängig voneinander einen gegebenfalls durch Niederalkyl, Niederalkoxy, Halogen oder Trifluormethyl substituierter.Phenylrest, einen Pyridyl oder Thienylrest darstellen, Alk ein Niederalkylenrest, der das Schwefel- und Stickstoffatom über 2-3 Kohlenstoffatome miteinander verbindet und n 0, 1 oder 2 bedeutet und ihre Salze.2. Compounds of the formula I, in which Ar 1 and Ar 2 independently of one another represent a phenyl radical optionally substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, a pyridyl or thienyl radical represent, Alk is a lower alkylene radical which connects the sulfur and nitrogen atom via 2-3 carbon atoms and n is 0, 1 or 2 and their salts. 3. Verbindungen der Formel II
Figure imgb0013
worin Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkoxy, wie Methoxy oder Halogen, insbesondere Chlor, substituierten Phenylrest bedeuten und m in erster Linie 1, ferner auch 2 ist, und ihre Salze.3. Compounds of formula II
Figure imgb0013
 in which Ar 1 and Ar 2 independently of one another represent a phenyl radical which is optionally substituted by lower alkoxy, such as methoxy or halogen, in particular chlorine, and m is primarily 1, and also 2, and their salts. 4. 5,6-Diphenyl-2,3,5,6-tetrahydroimidazo[2,1-b] thiazol und dessen Salze. 5,6-Di-(p-methyl-phenyl)-2,3,5,6-tetrahydro-imi- dazo [2,1-b]thiazol und dessen Salze. 5,6-Di-(p-chlor-phenyl)-2,3,5,6-tetrahydro-imi- dazo [2,1-b]thiazol und dessen Salze. 5,6-Di-(m-chlor-phenyl)-2,3,5,6-tetrahydro-imi- dazo [2,1-b]thiazol und dessen Salze. 5,6-Di-(p-methoxy-phenyl)-2- oder 3-methyl-2,3, 5,6-tetrahydro-imidazo[2,1-b]thiazol und dessen Salze. 5,6-Di-(p-methoxy-phenyl)-3-methyl-2,3,5,6-tetrahydro-imidazo [2,1-b]thiazol und dessen Salze. 4. 5,6-diphenyl-2,3,5,6-tetrahydroimidazo [2,1-b] thiazole and its salts. 5,6-Di- (p-methyl-phenyl) -2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole and its salts. 5,6-Di- (p-chlorophenyl) -2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole and its salts. 5,6-Di- (m-chlorophenyl) -2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole and its salts. 5,6-Di- (p-methoxy-phenyl) -2- or 3-methyl-2,3, 5,6-tetrahydro-imidazo [2,1-b] thiazole and its salts. 5,6-Di- (p-methoxy-phenyl) -3-methyl-2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole and its salts. 5. 5,6-Di-(p-methoxy-phenyl)-2,3.4,5,6,7-hexahydro- imidazol [2,1-b]thiazin und dessen Salze.5. 5,6-Di- (p-methoxy-phenyl) -2,3,4,5,6,7-hexahydroimidazole [2,1-b] thiazine and its salts. 6. Verbindungen der Formel III
Figure imgb0014
worin Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkoxy, wie Methoxy oder Halogen, insbesondere Chlor, substituierten Phenylrest bedeuten und m in erster Linie 1, ferner auch 2 ist, und ihre Salze.6. Compounds of formula III
Figure imgb0014
 in which Ar 1 and Ar 2 independently of one another represent a phenyl radical which is optionally substituted by lower alkoxy, such as methoxy or halogen, in particular chlorine, and m is primarily 1, and also 2, and their salts. 7. 5,6-Di-(p-methoxy-phenyl)-imidazo [2,1-b] dihydro-thiazol und dessen Salze.7. 5,6-Di- (p-methoxyphenyl) imidazo [2,1-b] dihydro-thiazole and its salts. 8. 5(6)-(3-Pyridyl)-6(5)-phenyl-imidazol [2,1-b] dihydro-thiazol und dessen Salze.8. 5 (6) - (3-pyridyl) -6 (5) -phenyl-imidazole [2,1-b] dihydro-thiazole and its salts. 9. Verfahren zur Herstellung von 1,3-Diaza-cyclo- pent-2-eno [2,1-b] (1-thia-3-aza-cycloalkane) der allgemeinen Formel I
Figure imgb0015
 deren 1,3-Diaza-cyclopent-2-en-ring eine weitere Doppelbindung aufweisen kann. Alk Niederalkylen darstellt, welches das Thia- vom Aza-atom durch 2-4 Kohlenstoffatome trennt, Ar1 und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist, mit der Massgabe, dass mindestens einer der Reste Ar1 und Ar2 von Phenyl verschieden ist, wenn Alk Aethylen und der 1,3-Diaza-cyclopent-2-en-ring einen Imidazolring darstellt, und deren Salze. dadurch gekennzeichnet, dass man Verbindungen der Formel IV
Figure imgb0016
 worin X eine reaktionsfähige veresterte Hydroxygruppe darstellt, ringschliesst, oder dass man Verbindungen der Formel Va bzw. Vb
Figure imgb0017
bzw.
Figure imgb0018
 ringschliesst, und, wenn erwünscht, in gegebenenfalls erhaltenen Verbindungen, worin n 0 ist, das Thiaatom zur Sulfinyl- oder Sulfonylgruppe oxidiert, und/oder, wenn erwünscht, erhaltene freie Verbindungen in ihre Salze überführt oder erhaltene Salze in die freien Verbindungen umwandelt und/oder ein verfahrensgemäss erhaltenes Isomerengemisch in die einzelnen Isomeren auftrennt. 9. Process for the preparation of 1,3-diaza-cyclopent-2-eno [2,1-b] (1-thia-3-aza-cycloalkanes) of the general formula I
Figure imgb0015
 whose 1,3-diaza-cyclopent-2-ene ring can have a further double bond. A lk represents lower alkylene, which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2, with the proviso that at least one of the residues Ar 1 and Ar 2 different from phenyl that is when Alk Aethylen and the 1,3-diaza-cyclopent-2-en-ring represents an imidazole ring, and their salts. characterized in that compounds of the formula IV
Figure imgb0016
 wherein X represents a reactive esterified hydroxy group, ring-closing, or that compounds of the formula Va or Vb
Figure imgb0017
 or.
Figure imgb0018
 ring closes and, if desired, in optionally obtained compounds in which n is 0, the thia atom is oxidized to the sulfinyl or sulfonyl group, and / or, if desired, the free compounds obtained are converted into their salts or the salts obtained are converted into the free compounds and / or separates an isomer mixture obtained according to the process into the individual isomers. 10. Verbindungen der Formel Va bzw. Vb
Figure imgb0019
bzw.
Figure imgb0020
oder ihre Tautomeren, worin Alk Niederalkylen darstellt, welches das Thia- vom Azaatom durch 2-4 Kohlenstoffatome trennt, Ar1 und Ar2 unabhängig voneinander gegebenenfalls substituiertes Phenyl, Pyridyl oder Thienyl bedeuten und n 0, 1 oder 2 ist und deren Salze.10. Compounds of the formula Va or Vb
Figure imgb0019
 or.
Figure imgb0020
 or their tautomers, in which alk is lower alkylene which separates the thia from the aza atom by 2-4 carbon atoms, Ar 1 and Ar 2 independently of one another are optionally substituted phenyl, pyridyl or thienyl and n is 0, 1 or 2 and their salts. 11. Verbindungen der in Anspruch 10 gezeigten Formel Va bzw. Vb oder ihre Tautsmeren, worin Alk ein Niederalkylenrest ist, der das Schwefel- und Stickstoffatom über 2-3 Kohlenstoffatome miteinander verbindet, Ar1 und Ar2 unabhängig voneinander einen gegebenenfalls durch Niederalkoxy oder Halogen substituierten Phenylrest und n 0, 1 oder 2 bedeutet, und deren Salze.11. Compounds of formula Va or Vb or their tautsers shown in claim 10, wherein Alk is a lower alkylene radical which connects the sulfur and nitrogen atom via 2-3 carbon atoms, Ar 1 and Ar 2 independently of one another, optionally by lower alkoxy or halogen substituted phenyl radical and n is 0, 1 or 2, and their salts. 12. 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-ami- no-thiazolin bzw. 2-Imino-3-(1,2-bis-p-methoxy-phenyl-2-oxo-äthyl)-thiazolin oder deren Tautomere. 2-[N-(1,2-Bis-phenyl-2-oxo-äthyl)-amino-thiazo-1in bzw. 2-Imino-3-(l,2-bis-phenyl-2-oxo-äthyl)-thiazolin oderen deren Tautomere. 2-[N-(1,2-Bis-p-methoxyphenyl-2-oxo-äthyl)-amino-5,6-dihydro-4H-thiazin bzw. 2-Imino-3-(l,2-bis-p-mcthoxy- phenyl-2-oxo-äthyl)-5,6-dihydro-4H-thiazin oder deren Tautomere. 12. 2- [N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) -amino-thiazoline or 2-imino-3- (1,2-bis-p-methoxy-phenyl -2-oxo-ethyl) thiazoline or its tautomers. 2- [N- (1,2-bis-phenyl-2-oxo-ethyl) -amino-thiazo-1in or 2-imino-3- (1,2-bis-phenyl-2-oxo-ethyl) - thiazoline or their tautomers. 2- [N- (1,2-bis-p-methoxyphenyl-2-oxo-ethyl) amino-5,6-dihydro-4H-thiazine or 2-imino-3- (1,2-bis-p -mcthoxy-phenyl-2-oxo-ethyl) -5,6-dihydro-4H-thiazine or its tautomers. 13. Pharmazeutische Präparate enthaltend eine der in den Ansprüchen 1-8 und 10-12 genannten Verbindungen.13. Pharmaceutical preparations containing one of the compounds mentioned in claims 1-8 and 10-12. 14. Verwendung einer der in den Ansprüchen 1-8 und 10-12 beanspruchten Verbindungen oder eines ihrer therapeutisch verwendbaren Salze zur Herstellung eines Arzneimittels auf nicht-chemischem Wege.14. Use of one of the compounds claimed in claims 1-8 and 10-12 or one of their therapeutically usable salts for the production of a medicament in a non-chemical way. 15. Eine der in den Ansprüche 1-8 und 10-12 beanspruchten Verbindungen oder eines ihrer therapeutisch verwendbaren Salze als Arzneimittel.15. One of the compounds claimed in claims 1-8 and 10-12 or one of their therapeutically usable salts as medicaments.
EP78100272A 1977-07-07 1978-06-29 Bicyclic thiadiaza compounds, process and intermediates for their preparation, and medicaments containing these compounds or the intermediates Withdrawn EP0000353A3 (en)

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EP0011111A1 (en) * 1978-09-27 1980-05-28 Smithkline Beckman Corporation 5-(4-Pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo-(2,1-b)-thiazole, process for its preparation and medical composition
EP0013561A1 (en) * 1979-01-05 1980-07-23 Ciba-Geigy Ag Levorotatory thia-diaza bicyclic derivative, process for its preparation and pharmaceutical compositions containing it
EP0004648B1 (en) * 1978-04-11 1982-08-25 Ciba-Geigy Ag Mercapto-imidazole derivatives, their preparation, mercapto-imidazole derivatives for the treatment of inflammatory diseases and their pharmaceutical compositions
EP0005545B1 (en) * 1978-05-24 1985-09-18 Schering Aktiengesellschaft Imidazole derivatives, process for their preparation and pharmaceutical compositions containing them
EP0164765A1 (en) * 1981-02-19 1985-12-18 Yamanouchi Pharmaceutical Co. Ltd. 3,5-Di-Tert-Butyl-4-hydroxyphenyl-substituted heterocyclic compounds
EP0203787A3 (en) * 1985-05-23 1988-05-25 Smithkline Beckman Corporation Process for preparing pyridyl-substituted imidazoû2,1-b¨thiazoles and thiazines
US4803279A (en) * 1985-05-23 1989-02-07 Smithkline Beckman Corporation 1.4-dihydro-4-pyridyl-substituted imidazo (2,1-b) thiazoles and the corresponding thiazines.
EP0231622A3 (en) * 1985-12-12 1989-05-24 Smithkline Beckman Corporation Inhibition of the 5-lipoxygenase pathway
EP0411754A3 (en) * 1989-06-13 1991-03-13 Smithkline Beecham Corporation Medicament for the inhibition of interleukin-1 or tumor necrosis factor production by monocytes and/or macrophages
US5008390A (en) * 1985-05-23 1991-04-16 Smithkline Beckman Corporation Compounds for preparing 6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoles and corresponding thiazines
WO1991013876A1 (en) * 1990-03-16 1991-09-19 Rhone-Poulenc Rorer Limited Imidazoles
US5552422A (en) * 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents

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US4719218A (en) * 1985-12-12 1988-01-12 Smithkline Beckman Corporation Pyrrolo[1,2-a]imidazole and pyrrolo[1,2-a]pyridine derivatives and their use as 5-lipoxygenase pathway inhibitor
GB9019838D0 (en) * 1990-09-11 1990-10-24 Smith Kline French Lab Compounds
CA2063865A1 (en) * 1992-03-24 1993-09-25 Karoly Lempert 2-(substituted imino)-thiazolidines and process for the preparation thereof
RU2405788C1 (en) * 2009-07-14 2010-12-10 Государственное образовательное учреждение высшего профессионального образования "БАШКИРСКИЙ ГОСУДАРСТВЕННЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ ФЕДЕРАЛЬНОГО АГЕНТСТВА ПО ЗДРАВООХРАНЕНИЮ И СОЦИАЛЬНОМУ РАЗВИТИЮ" 3-CYCLOHEXYLAMINOMETHYLTHIAZOLE[3,2-a]BENZIMIDAZOLE DIHYDROCHLORIDE HAVING IMMUNOTROPIC AND ANTI-AGGREGATION ACTIVITY

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004648B1 (en) * 1978-04-11 1982-08-25 Ciba-Geigy Ag Mercapto-imidazole derivatives, their preparation, mercapto-imidazole derivatives for the treatment of inflammatory diseases and their pharmaceutical compositions
EP0005545B1 (en) * 1978-05-24 1985-09-18 Schering Aktiengesellschaft Imidazole derivatives, process for their preparation and pharmaceutical compositions containing them
EP0011111A1 (en) * 1978-09-27 1980-05-28 Smithkline Beckman Corporation 5-(4-Pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo-(2,1-b)-thiazole, process for its preparation and medical composition
EP0013561A1 (en) * 1979-01-05 1980-07-23 Ciba-Geigy Ag Levorotatory thia-diaza bicyclic derivative, process for its preparation and pharmaceutical compositions containing it
EP0013560A1 (en) * 1979-01-05 1980-07-23 Ciba-Geigy Ag Bicyclic dextrorotatory thiadiaza compound, process for its preparation, pharmaceutical compositions containing it and its use
EP0059090B1 (en) * 1981-02-19 1986-01-29 Yamanouchi Pharmaceutical Co., Ltd. 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds
EP0164765A1 (en) * 1981-02-19 1985-12-18 Yamanouchi Pharmaceutical Co. Ltd. 3,5-Di-Tert-Butyl-4-hydroxyphenyl-substituted heterocyclic compounds
EP0203787A3 (en) * 1985-05-23 1988-05-25 Smithkline Beckman Corporation Process for preparing pyridyl-substituted imidazoû2,1-b¨thiazoles and thiazines
US4803279A (en) * 1985-05-23 1989-02-07 Smithkline Beckman Corporation 1.4-dihydro-4-pyridyl-substituted imidazo (2,1-b) thiazoles and the corresponding thiazines.
US5008390A (en) * 1985-05-23 1991-04-16 Smithkline Beckman Corporation Compounds for preparing 6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoles and corresponding thiazines
EP0231622A3 (en) * 1985-12-12 1989-05-24 Smithkline Beckman Corporation Inhibition of the 5-lipoxygenase pathway
EP0411754A3 (en) * 1989-06-13 1991-03-13 Smithkline Beecham Corporation Medicament for the inhibition of interleukin-1 or tumor necrosis factor production by monocytes and/or macrophages
WO1991013876A1 (en) * 1990-03-16 1991-09-19 Rhone-Poulenc Rorer Limited Imidazoles
US5552422A (en) * 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents

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ZA783898B (en) 1979-07-25
ES471458A1 (en) 1979-10-01
NZ187789A (en) 1981-03-16
EP0000353A3 (en) 1979-06-13
PL116596B1 (en) 1981-06-30
PT68246A (en) 1978-08-01
SU850007A3 (en) 1981-07-23
ES478296A1 (en) 1979-05-16
SU873886A3 (en) 1981-10-15
NO782357L (en) 1979-01-09
DD138212A5 (en) 1979-10-17
IL55086A0 (en) 1978-09-29
DK305578A (en) 1979-01-08
FI782132A7 (en) 1979-01-08
EP0019688A1 (en) 1980-12-10
EP0020858A1 (en) 1981-01-07
ES484327A1 (en) 1980-05-16
JPS5416470A (en) 1979-02-07
AU3778878A (en) 1980-01-10
ES484033A1 (en) 1980-04-16
LU77703A1 (en) 1979-03-26
SU873887A3 (en) 1981-10-15
PL208253A1 (en) 1979-06-04
DD145538A5 (en) 1980-12-17
SU893134A3 (en) 1981-12-23
AR222309A1 (en) 1981-05-15
AR224381A1 (en) 1981-11-30
GR64978B (en) 1980-06-11
IT8149647A0 (en) 1981-11-06

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