Substituted thiosemicarbazonethiones
This is a 371 of PCT/EP 94/03778, filed Nov. 15, 1994. 
     The present invention relates to novel substituted thiosemicarbazonethiones containing 6-ring members of formula I ##STR2## wherein R 1  is lower alkyl, lower alk-2-en-1-yl, lower alk-2-yn-1-yl, or aryl-lower alkyl, R 2  is hydrogen, lower alkyl, lower alk-2-en-1-yl, lower alk-2-yn-1-yl, aryl, aryl-lower alkyl, unsaturated or saturated heterocyclyl-lower alkyl, lower alkoxycarbonyl-lower alkyl or the group --C(═O)-R 3  or --C(═S)-R 3 , wherein R 3  is lower alkyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl (hetaryl), aryloxy, aryl-lower alkoxy or lower alk-2-en-1-yloxy, and the salts thereof, to a process for the preparation of said compounds, to pharmaceutical compositions containing them, and to the use thereof as medicaments. 
     In this specification, radicals and compounds qualified by the term &#34;lower&#34; will be taken to mean those containing preferably up to and including 7, preferably up to and including 4, carbon atoms. 
     Lower alk-2-en-1-yl will typically be C 3  -C 5  alk-2-en-1-yl, preferably allyl or methallyl. 
     Lower alk-2-yn-1-yl will typically be C 3  -C 5  alk-2-yn-1-yl, preferably prop-2-yn-1-yl or also but-2-yn-1-yl. 
     Lower alkyl is C 1  -C 4  alkyl, typically methyl, ethyl, propyl or butyl. 
     Lower alkoxy is typically n-propoxy, isopropoxy, n-butoxy or tert-butoxy, preferably ethoxy and, most preferably, methoxy. 
     Aryl by itself and as moiety of composite radicals such as aryl-lower alkyl is typically phenyl or naphthyl, for example 1- or 2-naphthyl, or substituted phenyl or naphthyl, typically phenyl or naphthyl which are substituted by lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, cyano and/or nitro. Aryl is preferably unsubstituted phenyl or phenyl which is substituted as indicated above, and is most preferably phenyl. 
     Aryl-lower alkyl is preferably phenyl-lower alkyl and, most preferably, benzyl. 
     Lower alkoxycarbonyl-lower alkyl will typically be methoxy- or ethoxycarbonylmethyl or also methoxy- or ethoxycarbonylethyl. 
     Lower alkanoyloxy is typically propionyloxy or pivaloyloxy, and is preferably acetoxy. 
     Hydroxy-lower alkyl will typically be 2- or 3-hydroxy-lower alkyl such as 2-hydroxypropyl, 3-hydroxypropyl or 3-hydroxy-2-methylpropyl. 
     Halogen will be taken to mean halogen having an atomic number of up to and including 35, typically chloro or fluoro, and also bromo. 
     Halo-lower alkyl will typically be 2- or 3-halo-lower alkyl such as 2-halopropyl, 3-halopropyl or 3-halo-2-methylpropyl. 
     Unsaturated heterocyclyl-lower alkyl is typically heteroaryl-lower alkyl (hetaryl-lower alkyl). 
     Hetaryl in composite radicals such as hetaryl-lower alkyl is preferably a monocyclic and also bicyclic or polycyclic heterocyclic radical having aromaticity. Bicyclic and polycyclic heteroaryl may be comprised of a plurality of heterocyclic rings or, preferably, may consist of one heterocycle and one or more than one, conveniently one or two and preferably one, fused carbocyclic ring, preferably a benzene ring. Each individual ring typically contains 3, 5, 6 or 7 ring members and, preferably, 5 or 6 ring members. Hetaryl is preferably an azacyclic, thiacyclic, oxacyclic, thiazacyclic, thiadiazacyclic, oxazacyclic, diazacyclic, triazacyclic and tetrazacyclic radical. 
     Hetaryl is most preferably monocyclic monoazacyclic, monothiacyclic or monooxacyclic radicals such as pyrryl, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl; bicyclic monoazacyclic, monooxacyclic or monothiacyclic radicals such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzofuranyl, e.g. 2- or 3-benzofuranyl, or benzothienyl, e.g. 2-or 3-benzothienyl; monocyclic diazacyclic, triazacyclic, tetrazacyclic, oxazacyclic, thiazacyclic or thiadiazacyclic radicals such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, tetrazolyl, e.g. 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl; or bicyclic diazacyclic, oxazacyclic or thiazacyclic radicals such as benzimidazolyl, e.g. benzimidazolyl, benzoxazolyl, e.g. 2-benzoxazolyl, or benzothiazolyl, e.g. 2-benzothiazolyl. 
     Hetaryl radicals are unsubstituted or they carry substituents. Suitable substituents at the ring carbon atoms are conveniently those named above in connection with the aryl radicals and, additionally, oxo (═O). Ring nitrogen atoms may be substituted by lower alkyl, aryl-lower alkyl, lower alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, lower alkanoyloxy or oxido (). 
     Hetaryl is most preferably pyridyl, thienyl, pyrryl or furyl. 
     Hetaryl-lower alkyl is most preferably pyridylmethyl, thienylmethyl, pyrrylmethyl or furylmethyl. 
     Saturated heterocyclyl-lower alkyl contains a 5- or 6-membered saturated heterocyclic ring which carries a nitrogen or oxygen atom and is preferably an azacyclic or oxacyclic radical which may be substituted or unsubstituted. 
     A saturated 6-membered heterocyclic ring may contain a nitrogen atom in addition to an oxygen atom. 
     A saturated 5- or 6-membered heterocyclic radical is conveniently pyrrolidinyl, piperidino, piperidyl, tetrahydrofuranyl or tetrahydropyranyl, wherein one or also more than one hydrogen atom may be replaced by one or more than one substituent, typically by lower alkyl. 
     A saturated 6-membered heterocyclic radical which also contains a nitrogen atom in addition to an oxygen atom is typically morpholino or also morpholinyl. 
     Saturated heterocyclyl-lower alkyl is most preferably pyrrolidinylmethyl, tetrahydrofuranylmethyl or also tetrahydropyranylmethyl. 
     Pharmaceutically acceptable acid addition salts of compounds of formula I are typically their pharmaceutically acceptable salts with suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, including hydrochlorides, hydrobromides, sulfates, hydrogensulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, including methanesulfonates, benzenesulfonates, p-tosylates or N-cyclohexylsulfamates (cyclamates), or salts with strong organic carboxylic acids such as lower alkanecarboxylic acids or unsaturated or hydroxylated aliphatic dicarboxylic acids, including acetates, oxalates, malonates, maleates, fumarates, tartrates or citrates. Salts of compounds of formula I are typically their pharmaceutically acceptable salts with suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, including hydrochlorides, hydrobromides, sulfates, hydrogensulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, including methanesulfonates, benzenesulfonates, p-tosylates or N-cyclohexylsulfamates (cyclamates). 
     The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. In particular, they have pronounced antiarthritic properties. These properties can be demonstrated in vivo in the adjuvans arthritis model in rats in accordance with the assay of I. Wiesenberg et at. Clin. Exp. Immunol. 78, 245 (1989) in the dosage range from about 0.1 to about 10.0 mg/kg p.o. or i.p., preferably from about 0.1 to about 3.0 mg/kg p.o. or i.p. 
     The compounds of formula I and their pharmaceutically acceptable salts can therefore be used for treating diseases of rheumatoid genesis. Such diseases include in particular rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis and other seronegative spondylarthrides, e.g. spondylarthritides in ulcerative colitis and Crohn&#39;s disease, and also reactive arthritides, collagen diseases such as lupus erythematosus, degenerative rheumatic diseases, extraarticular rheumatic and pararheumatic diseases such as gout and osteoporosis. 
     The invention relates in particular to compounds of formula I, wherein R 1  is C 1  -C 4  alkyl, C 3  -C 5  alk-2-en-1-yl, C 3  -C 5  alk-2-yn-1-yl, or phenyl-lower alkyl, R 2  is hydrogen, C 1  -C 4  alkyl, C 3  -C 5  alk-2-en-1-yl, C 3  -C 5  alk-2-yn-1-yl, phenyl, naphthyl, phenyl-lower alkyl, pyridyl-lower alkyl, thienyl-lower alkyl, pyrryl-lower alkyl or furyl-lower alkyl, pyrrolidinyl-lower alkyl, tetrahydrofuranyl-lower alkyl or tetrahydropyranyl-lower alkyl, or C 1  -C 4  alkoxycarbonyl-C 1  -C 4  alkyl or the group --C(═O)-R 3  or --C(═S)-R 3 , wherein R 3  is C 1  -C 4  alkyl, phenyl, naphthyl, pyridyl, thienyl, pyrryl, furyl, phenoxy, phenyl-C 1  -C 4  alkoxy or C 3  -C 5  alk-2-en-1-yloxy, phenyl-lower alkyl or phenyl-lower alkenyl, and the salts, preferably the pharmaceutically acceptable salts, thereof. 
     More particularly, the invention relates to compounds of formula I, wherein R 1  is C 1  -C 4  alkyl, typically methyl or ethyl, preferably propyl, C 3  -C 5  alk-2-en-1-yl such as allyl or methallyl, C 3  -C 5  alk-2-yn-1-yl such as prop-2-yn-1-yl, or phenyl-lower alkyl such as benzyl or phenylethyl, and 
     R 2  is hydrogen, C 1  -C 4  alkyl such as methyl or ethyl, C 3  -C 5  alk-2-en-1-yl, typically allyl or methallyl, C 3  -C 5  alk-2-yn-1-yl such as prop-2-yn-1-yl, phenyl, phenyl-lower alkyl such as benzyl or phenethyl, pyridyl-lower alkyl, thienyl-lower alkyl, pyrryl-lower alkyl or furyl-lower alkyl, pyrrolidinyl-lower alkyl, tetrahydrofuranyl-lower alkyl or tetrahydropyranyl-lower alkyl, for example pyridylmethyl, thienylmethyl, pyrrylmethyl, or furylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl, C 1  -C 4  alkoxycarbonyl-C 1  -C 4  alkyl such as methoxy- or ethoxycarbonylmethyl or methoxy- or ethoxycarbonylethyl or the group --C(═O)-R 3  or --C(═S)-R 3 , wherein R 3  is C 1  -C 4  alkyl such as methyl, phenyl, pyridyl, thienyl, phenoxy, benzoxy, C 3  -C 5  alk-2-en-1-yloxy such as allyl or methallyloxy or also benzyl or phenylallyl, and the salts, preferably the pharmaceutically acceptable salts, thereof. 
     The invention relates very particularly to compounds of formula I, wherein R 1  is propyl, allyl, methallyl, prop-2-yn-1-yl or benzyl, and 
     R 2  is hydrogen, methyl, allyl, prop-2-yn-1-yl, phenyl, benzyl, pyridylmethyl, thienylmethyl, pyrrylmethyl or furylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl or the group --C(═O)-R 3  or --C(═S)-R 3 , wherein R 3  is methyl phenyl, phenoxy, benzoxy, allyloxy, benzyl or phenylallyl, and the salts, preferably the pharmaceutically acceptable salts, thereof. 
     The invention relates specifically to the compounds of formula I and the salts, preferably the pharmaceutically acceptable salts, thereof, named in the Examples. 
     The compounds of formula I can be prepared in a manner known per se by reacting a compound of formula II ##STR3## wherein R 1  and R 2  are as defined above, with a sulfonating agent. Compounds of formula II, wherein R 2  is a --C(═O)-R 3  group, can be convened by reaction with a sulfonating agent simultaneously into compounds of formula I, wherein R 2  is --C(═S)-R 3 , i.e. the oxo group in the ring and also the oxo group of --C(═O)-R 3  can be replaced by sulfo. 
     Suitable sulfonating agents are conveniently Lawesson&#39;s reagent or Yokayama&#39;s reagent. 
     The reaction with the sulfonating agent is carried out in conventional manner in a protic or aprotic solvent, typically an aliphatic or cycloaliphatic ether such as tetrahydrofuran or dioxane. Other suitable solvents are aliphatic halogenated hydrocarbons such as methylene chloride. 
     The compounds of formula II and the sulfonating agent are reacted together in the temperature range from 20° to 120° C., preferably from 60° to 90° C. 
     Starting compounds of formula II are novel and can be prepared by reacting a compound of formula Ill ##STR4## wherein R 1  is as defined above, with an isothiocyanate of formula IV 
     
         R.sub.2 -NCS                                               (IV) 
    
     wherein R 2  is as defined above. 
     The reaction of a hydrazone of general formula III with an isothiocyanate of general formula IV is preferably carried out in an inert solvent, typically in a lower alkanol such as methanol, ethanol, propanol or isopropanol, an ethereal solvent such as diethyl ether, dibutyl ether, tetrahydrofuran or dioxane, a hydrocarbon such as benzene, toluene or hexane, or a halogenated hydrocarbon such as chloroform, at room temperature or at moderately elevated temperature up to c. 100° C. or the boiling temperature of the solvent employed. Depending on the reaction temperature and the reactivity of the starting materials, the reaction time is from about half an hour to 24 hours. 
     The starting materials of general formula III are also novel and can be obtained from compounds of general formula V ##STR5## wherein R 1  is as defined above and R 4  is a lower alkyl or aryl-lower alkyl radical, preferably methyl or benzyl, by treatment with a mineral acid, preferably hydrochloric acid. 
     The reaction is carried out in an anhydrous inert solvent as already noted above in connection with the reaction of compounds of formula III with compounds of formula IV, preferably in an anhydrous lower alkanol, conveniently in an anhydrous mixture of methanol and ethanol at room temperature, to give a salt, e.g. the hydrochloride, of a compound of general formula IV, which salt can be converted into the free hydrazine by addition of a base, conveniently a solution of an alkali metal carbonate or alkaline earth metal carbonate, preferably a solution of sodium carbonate. 
     Compounds of general formula V can in turn be obtained by alkylating a compound of general formula VI ##STR6## wherein R 4  is as defined for formula V, with the corresponding halide of formula VII 
     
         R.sub.1 -X                                                 (VII) 
    
     wherein R 1  is as defined for general formula I, and X is a halogen atom, preferably a bromine atom. 
     The alkylation is carried out in an inert solvent, preferably dimethyl formamide (DMF), in the presence of a strong base, conveniently potassium tert-butylate, sodium hydride, sodium amide or also lithium diisopropylamide (LDA), to give a mixture of the N-alkylamide of general formula V and the O-alkylated imino ether of general formula VIII ##STR7## wherein R 1  and R 4  are as defined for formula V, in a specific ratio. The separation of the resultant compound of general formula V from the compound of general formula VIII can be effected by fractional crystallisation and/or by chromatography. 
     Compounds of general formula V can in turn be prepared by cyclising the known compounds of general formula IX ##STR8## wherein R o  is an acryloyl group (vinylcarbonyl group) or a radical that is convertible into an acryloyI group, e.g. 3-chloropropionyl, and R 4  is as defined for formula VI. 
     The cyclisation is carried out by gentle heating in an inert solvent as already noted above in connection with the reaction of a compound of formula IV with a compound of formula V, preferably in a lower alkanol such as ethanol or also in acetonitrile. 
     The isothiocyanates of formula IV can usually be prepared from the corresponding amines of formula X 
     
         R.sub.2 -NH.sub.2                                          (X) 
    
     wherein R 2  is as defined above, by treatment with thiophosgene. 
     Resultant salts can be convened in a manner known per se into other salts, acid addition salts conveniently by treatment with a suitable metal salt, typically a sodium, barium or silver salt, of another acid in a suitable solvent in which a resultant inorganic salt is insoluble and is thus eliminated from the equilibrium of reaction, and salts of bases by generating the free acid and repeated salt-formation. 
     The compounds of formula I, including their salts, may also be obtained in the form of hydrates or include the solvent used for crystallisation. 
     Because of the close relationship between the novel compounds in the free form and in the form of their salts, the references made throughout this specification to the free compounds and their salts will also apply by analogy to the corresponding salts and free compounds. 
     Racemates can also be separated by known methods into the optical antipodes, conveniently by recrystallisation from an optically active solvent, with the aid of microorganisms or by reacting the mixture of diastereoisomers or racemate with an optically active compound, e.g. depending on the acid, basic or functionally modifiable groups present in the compound of formula I, with an optically active acid, base or an optically active alcohol, into mixes of diastereoisomeric salts or functional derivatives such as esters, separating said mixtures into the diastereoisomers from which each desired enantiomer can be set free in the customary manner. Bases, acids or alcohols suitable for the purpose are typically optically active alkaloid bases such as strychine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine or similar bases which are obtainable by synthesis, optically active carboxylic or sulfonic acids such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, or optically active alcohols such as borneol or D- or L-(1-phenyl)ethanol. 
     The invention relates also to those embodiments of the process in which a compound obtainable as intermediate in any stage of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the form of a salt or, preferably, is formed under the reaction conditions. 
     The invention also relates to the novel starting materials which have been specially developed for the preparation of the novel compounds, especially those which result in the compounds of formula I described at the beginning as being especially preferred, to processes for their preparation and to the use thereof as intermediates. 
     The pharmaceutical compositions of this invention which contain the novel compound, or a pharmaceutically acceptable salt thereof, are those for enteral, e.g. oral, and also rectal and parenteral administration to warm-blooded animals, and they contain the pharmacologically active compound alone or together with a pharmaceutically acceptable carrier. The daily dose will depend on the age, sex and individual condition of the patient as well as on the mode of administration. 
     The novel pharmaceutical compositions contain from about 10 to 80%, preferably from about 20 to 60%, of the active compound. Pharmaceutical compositions for enteral or parenteral administration are typically those in dosage unit forms such as dragees, tablets, capsules or suppositories, and also ampoules. These dosage forms are prepared in a manner known per se, typically by conventional mixing, granulating, confectioning, dissolving or lyophilising methods. Pharmaceutical compositions for oral administration can typically be prepared by combining the active compound with solid carriers, granulating the mixture so obtained and, if desired or necessary, processing the mixture or granulate, after addition of suitable excipients, to tablets or dragee cores. 
     Suitable carriers are especially fillers such as sugars, conveniently lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, typically tricalcium phosphate or calcium hydrogen phosphate, and also binders such as starch pastes, conveniently using maize, corn, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinyl pyrrolidone, and/or, if desired, disintegrators such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are in particular glidants, flow control agents and lubricants, conveniently silica, talcum, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores can be provided with suitable non-enteric or enteric coatings, typically using concentrated sugar solutions which may contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, shellac solutions in suitable organic solvents or mixtures of solvents or, for the preparation of enteric coatings, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments can be added to the tablets or dragee coatings, conveniently to identify or indicate different doses of active compound. 
     Further pharmaceutical compositions for oral administration are dry-filled capsules made of gelatin and also soft-sealed capsules consisting of gelatin and a plasticiser such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, conveniently in admixture with fillers such as lactose, binders such as starches, and/or glidants such as talcum or magnesium stearate, and with or without stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid, typically a fatty oil, paraffin oil or a liquid polyethylene glycol, to which a stabiliser can also be added. 
     Suitable pharmaceutical compositions for rectal administration are typically suppositories, which consist of a combination of the active compound with a suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. It is also possible to use gelatin capsules for rectal administration that contain a combination of the active compound with a base substance. Suitable base substances are typically liquid triglycerides, polyethgylene glycol or paraffin hydrocarbons. 
     Most suitable for parenteral administration are aqueous solutions of an active compound in water-soluble form, for example of a water-soluble salt,, and also sispensions of the active compound, conveniently oily injection suspensions using suitable lipophilic solvents or vehicles such as fatty oils, typically sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or aqueous injection suspensions which may contain viscosity increasing substances, conveniently sodium carboxymethyl cellulose, sorbitol and/or dextran, and also with or without stabilisers. 
     The invention also relates to the use of the compounds of formula I, preferably in the form of pharmaceutical compositions. The dosage of the active compound will depend on the species of the warm-blooded animal, on the age and individual condition of the patient, and also on the mode of administration. The contemplated dally dosage for oral administration to a patient of approximately 75 kg body weight will normally be from about 5 mg to 1000 mg, preferably from about 10 mg to 200 mg. This dose can be administered in a single dose or in several, typically from 2 to 4, individual doses. Pharmaceutical compositions in dosage unit form thus contain from about 5 mg to 250 mg, preferably from about 10 mg to 50 mg, of active compound. 
    
    
     The invention is illustrated by the following Examples. Pressures are given in mbar. 
     Example 1 
     With stirring, 0.3 g of 1-(3-allyl-4-oxo-[1,3]thiazinan-2-ylidene)-4-methylthiosemicarbazone and 0.4 g of Lawesson&#39;s reagent are refluxed in 20 ml of tetrahydrofuran as solvent for 5 hours. After cooling to room temperature, the solvent is stripped off on a rotary evaporator and the residue is chromatographed on silica gel with methylene chloride. The product is crystallised from methylene chloride/ether, collected by filtration, washed with petroleum ether and dried under vacuum, giving the solid 1-(3-allyl-4-thio[1,3]thiazinan-2-ylidene)-4-methylthiosemicarbazone; m.p. 89°-90° C. 1H-NMR: 3.15 (m, 2H), 3.2 (d, 3H), 3.45 (m, 2H), 5.15-5.3 (m, 4H), 5.85-6.0 (m, 1H), 7.0 (br. s, 1H), 8.1 (br. s, 1H). 
     Example 2 
     With stirring, 0.4 g of 1-(3-allyl-4-oxo-[1,3]thiazinan-2-ylidene)-4-benzoyl-thiosemicarbazone and 0.5 g of Lawesson&#39;s reagent are refluxed in 30 ml of tetrahydrofuran as solvent for 2 hours. After cooling to room temperature, the solvent is stripped off on a rotary evaporator and the residue is crystallised from methylene chloride, collected by filtration, washed with petroleum ether and dried under vacuum, giving the solid 1-(3-allyl-4-thio[1,3]thiazinan-2-ylidene)-4-thiabenzoylthiosemicarbazone; m.p. 190° C. 
     1H-NMR: 3.05 (m, 2H), 3.65 (m, 2H), 4.3 (m, 2H), 5.15-5.3 (m, 2H), 5.8-5.95 (m, 1H), 7.45-7.6 (m, 3H), 8.1 (d, 2H), 8.65 (br. s, 1H), 12,3 (br. s, 1H). 
     Example 3 
     Tablets each containing 10 mg of active ingredient may be prepared as follows: 
     Composition (10,000 tablets) 
     
         ______________________________________                                    
active ingredient  100.0 g                                                
lactose            450.0 g                                                
potato starch      350.0 g                                                
gelatin             10.0 g                                                
talcum              60.0 g                                                
magnesium stearate  10.0 g                                                
silica (highly dispersed)                                                 
                    20.0 g                                                
ethanol            q.s.                                                   
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     The active ingredient is mixed with the lactose and 292 g of potato starch. The mixture is moistened with an ethanolic solution of gelatin and granulated through a sieve. The granulate is dried and the remainder of the potato starch, the talcum, the magnesium stearate and the silica are added and the mixture is compressed to 100.0 mg tablets each containing 10.0 mg of active ingredient. If desired, the tablets can be provided with a breaking notch for finer adjustment of the dose. 
     Example 4 
     Hard gelatin capsules containing 20 mg of active ingredient may be prepared as follows: 
     Composition (for 1000 capsules) 
     
         ______________________________________                                    
active ingredient       20.0   g                                          
lactose                 240.0  g                                          
microcrystalline cellulose                                                
                        30.0   g                                          
sodium lauryl sulfate   2.0    g                                          
magnesium stearate      8.0    g                                          
______________________________________                                    
 
    
     The sodium lauryl sulfate is sieved through a sieve having a mesh size of 0.2 mm and added to the lyophilised active ingredient and both components are thoroughly mixed. First the lactose is passed through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose is passed through a sieve having a mesh size of 0.9 mm. The ingredients are then thoroughly mixed again for 10 minutes. Finally, the magnesium stearate is passed through a sieve having a mesh size of 0.8 mm. After mixing for 3 minutes, size 0 hard gelatin capsules are each filled with 300 mg of the formulation so obtained. 
     Example 5 
     Hard gelatin capsules containing 100 mg of active ingredient may be prepared as follows: 
     Composition (for 1000 capsules) 
     
         ______________________________________                                    
active ingredient       100.0  g                                          
lactose                 250.0  g                                          
microcrystalline cellulose                                                
                        30.0   g                                          
sodium lauryl sulfate   2.0    g                                          
magnesium stearate      8.0    g                                          
______________________________________                                    
 
    
     The sodium lauryl sulfate is sieved through a sieve having a mesh size of 0.2 mm and added to the lyophilised active ingredient and both components are thoroughly mixed. First the lactose is passed through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose is passed through a sieve having a mesh size of 0.9 mm. The ingredients are then thoroughly mixed again for 10 minutes. Finally, the magnesium stearate is passed through a sieve having a mesh size of 0.8 mm. After mixing for 3 minutes, size 0 hard gelatin capsules are each filled with 390 mg of the formulation so obtained. 
     Example 6 
     Film-coated tablets each containing 50 mg of active ingredient may be prepared as follows: 
     Composition (for 1000 film-coated tablets) 
     
         ______________________________________                                    
active ingredient        50.0   g                                         
lactose                  100.0  g                                         
corn starch              70.0   g                                         
talcum                   10.0   g                                         
calcium stearate         2.0    g                                         
hydroxypropyl methyl cellulose                                            
                         2.36   g                                         
shellac                  0.64   g                                         
water                 q.s.                                                
methylene chloride    q.s.                                                
______________________________________                                    
 
    
     The active ingredient, the lactose and 40 g of corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating), and the mixture is granulated. The granulate is dried, the remainder of the corn starch, the talcum and the calcium stearate are added and mixed with the granulate. The mixture is compressed to 240 mg tablets which are coated with a solution of hydroxypropyl methyl cellulose and shellac in methylene chloride. Final weight of the tablets: 283 mg. 
     Example 7 
     A 0.2% injection or infusion solution of the active ingredient may be prepared as follows: 
     Composition (for 1000 ampoules) 
     
         ______________________________________                                    
active ingredient     5.0      g                                          
sodium chloride       22.5     g                                          
phosphate buffer pH = 7.4                                                 
                      300.0    g                                          
demineralised water   ad 2500.0                                           
                               ml                                         
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     The active ingredient and the sodium chloride are dissolved in 1000 ml of water and the solution is filtered through a micro filter. The buffer solution is added, followed by the addition of water to make up 2500 ml. To prepare dosage unit forms, 1.0 or 2.5 ml of the solution are filled into glass ampoules each containing 2.0 or 5.0 mg of active ingredient. 
     Example 8 
     1% ointment (O/W emulsion), containing an active ingredient, of the following composition: 
     
         ______________________________________                                    
active ingredient     1.0     g                                           
cetyl alcohol         3.0     g                                           
glycerol              6.0     g                                           
methyl parabene       0.18    g                                           
propyl parabene       0.05    g                                           
Arlacel 60            0.6     g                                           
Tween 60              4.4     g                                           
stearic acid          9.0     g                                           
isopropyl palmitate   2.0     g                                           
paraffin oil, viscous 10.0    g                                           
demin. water q.s. ad  100.0   g                                           
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     Example 9 
     1% gel, containing an active ingredient, of the following composition: 
     
         ______________________________________                                    
active ingredient      1.0    g                                           
Carbopol 934 P         1.0    g                                           
glycerol               3.0    g                                           
isopropanol            25.0   g                                           
Softigen ® 767     0.2    g                                           
demin. water q.s. ad   100.0  g.                                          
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