US3860590A - Derivatives of 2-(4-aminophenylimino)-thiazolidine and 4h-5,6-dihydro-1,3-thiazines - Google Patents

Derivatives of 2-(4-aminophenylimino)-thiazolidine and 4h-5,6-dihydro-1,3-thiazines Download PDF

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US3860590A
US3860590A US289092A US28909272A US3860590A US 3860590 A US3860590 A US 3860590A US 289092 A US289092 A US 289092A US 28909272 A US28909272 A US 28909272A US 3860590 A US3860590 A US 3860590A
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methylthiazolidine
compound according
substituted
unsubstituted
hydrogen
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Hartmund Wollweber
Winfried Flucke
Hans Peter Schulz
Herbert Thomas
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Bayer AG
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • ABSTRACT 2-(4-Aminophenylimino) derivatives of thiazolidine and -4H-5,6-dihydro-1,3-thiazines, the corresponding amide and sulfonamide derivatives, and the salts thereof are anthelmintic agents.
  • the compounds, of which 2-(4-aminophenylimino)-N-methylthiazolidine is a typical embodiment, are prepared through cyclization of a thiourea, optionally with subsequent hydrolysis, alkylation or acetylation.
  • Z is an ethylene or trimethylene chain which is unsubstituted or substituted by lower alkyl;
  • R is lower alkyl, lower alkenyl or lower alkynyl;
  • lower alkynyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal acetylenic unsaturation as, for example, ethynyl, 2-propynyl, 4-pentynyl, and the like.
  • cycloalkyl denotes a univalent saturated monocyclic hydrocarbon of from 3 to 7 carbon atoms as, for example, cyclopropyl, cyclobutyl, cyclopentyl,
  • lower alkoxy denotes a straight or branched hydrocarbon chain bound to the remainder of the molecule through an ethereal oxygen atom as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and hexoxy.
  • R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl
  • each of R and R independent of the other is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, chloro, fluoro, bromo, nitro or trifluoromethyl.
  • alkyl denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 18 carbon atoms.
  • Representative of such alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl, tert.pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like.
  • lower alkyl denotes aunivalent saturated branched or straight hydrocarbon chain containing from 1 to 6 carbon atoms. Representative of such lower alkylgroups are thus methyl, ethyl, propyl, isopropyl,
  • lower alkenyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal ethylenic unsaturation as, for example, vinyl, allyl, isopropenyl, Z-butenyl, 3-methyl-2-butenyl, Z-pentenyl, 3-pentenyl, 2-hexenyl, 4-hexenyl, and the like.
  • salts of these basic compounds include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulphonic acid. acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.
  • organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulphonic acid.
  • Preferred compounds are those wherein R is methyl, ethyl, allyl, methallyl or crotyl, R is methyl, ethyl, propyl, isopropyl or an amide or sulfamide residue, R is hydrogen and R is hydrogen or chloro.
  • amide and sulfonamide embodiments of the present invention are those derived from any of the well-known carboxylic and sulfonic acids, respectively.
  • the structure of the residue of these acids does not appear to be critical and, as shown below, can vary widely without adversely affecting the activity of the parent amine moiety.
  • these amides can be broadly described as those of Formula I wherein R is the group R CO-with R being hydrogen, lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, cycloalkyl, phenyl, phenoxy, or a heterocyclic group.
  • R is the group R CO-with R being hydrogen, lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, cycloalkyl, phenyl, phenoxy, or a heterocyclic group.
  • R is the group R CO
  • the lower alkyl and lower alkoxy groups can be substituted by lower alkoxy, cycloalkyl, methyl substituted cycloalkyl, tetrahydrofuryl, thienyl, phenyl or phenoxy, with the phenyl or phenoxy substituents on such lower alkyl and lower alkoxy embodiments being in turn optionally substituted by chloro, fluoro, bromo, loweralkyl, lower alkoxy, trifluoromethyl or nitro.
  • R when R is lower alkenyl or lower alkenyloxy, it can be substituted by phenyl which in turn can bear a further substituent such as for example chloro.
  • R When R is cycloalkyl, it can be substitutedby lower alkyl. When R is phenyl or phenoxy it can similarly be substituted as for example by chloro, fluoro, bromo, lower alkyl, lower alkoxy, nitro, trifluoromethyl, lower alkenoyloxy, lower alkanoyl or carbo (lower alkoxy).
  • R is a heterocyclic group, such as furyl, thienyl, isoxazoyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl, it can also be substituted, as for example by lower alkyl.
  • Preferred amide derivatives are those wherein R is hydrogen, a lower alkyl, lower alkoxy or lower alkenyl group of up to 3 carbon atoms, lower alkynyloxy of up to 4 carbon atoms, cycloalkyl, fufuryl, S-methylisoxazolyl or phenyl.
  • the sulfonamide derivatives can be broadly described as a compound of Formula I wherein R is RSO with R being lower alkyl or phenyl, the phenyl group in turn being optionally substituted by chloro, fiuoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro.
  • Preferred sulfonamides are those wherein R is methyl or ethyl.
  • the preferred embodiments are generally those in which the lower alkyl and lower alkoxy groups present in the molecule contain 1 to 3 carbon atoms and more specifically l or 2, the lower alkenyl, lower alkenyloxy lower alkynyl and lower alkynyloxy groups contain 2 to 4 carbon atoms, and the cycloalkyl groups contain 5 or 6 carbon atoms,
  • Typical compounds of the present invention include: 2-(4-aminophenylimino)-N-methylthiazolidine; 2-(4-aminophenylimino)-N-ethylthiazolidine; 2-(4-amino-3-chlorophenylimino)-N- methylthiazolidine; 2-(4-aminophenylimino)-N-methyl-4I-I-5,6-dihydrol,3-thiazine: 2-(4-methylaminophenylimino)-N-methylthiazolidine; 2-(4-allylaminophenylimino)-N-methylthiazolidine; and 2-(4-isobutylaminophenylimino)-N- methylthiazolidine.
  • Typical of the amide derivatives of the present invention are: 2-(4-carbethoxyaminophenylimino)-N- methylthiazolidine; 2-(4-benzamidophenylimino)-N-methylthiazolidine; 2-[4-(Z-furylcarbonyl)-aminophenylimino]-N- methylthiazolidine; 2-(4acetamidophenylimino)-N-methylthiazolidine; 2-(4-carbethoxyamino-3-chlorophenylimino)-N- methylthiazolidine; 2(4-formamidophenylimino)-N-methylthiazolidine; 2-(4 carbethoxyaminophenylimino)-N-methyl-4H-5,6- dihydro-l ,3-thiazine; 2-[4-(4-chlorobenzamido)-phenylimino]-N- methylthiazolidine; 2-[4-(3
  • the compounds of the present invention are prepared utilizing a number of synthetic procedures. Formation of the thiazolidine or 4H-5,6-dihydro-l ,3- thiazine ring with simultaneous formation of the imino linkage is accomplished through cyclization of an appropriate thiourea of the formula:
  • R, R, R R Z and X are as herein defined and Y is as defined for X or amino
  • the cyclization ofthe thioureas of Formula II and the reaction of the compounds of Formulas Ill and IV can be carried out in a diluent or at melt.
  • diluents is desirable but not absolutely essential, the choice of the suitable diluent being determined by the stability and reactivity of the particular reactants.
  • Any diluent which is inert to the reaction can be employed, such as hydrocarbons, as for example benzene and ligroin, ethers such as diethyl ether and dioxan'e, halogenated hydrocarbons such as for example methylene chloride, esters such as ethyl acetate, alcohols such as methanol, ethanol and propanol, and water, as well as mixtures thereof, can be used.
  • the cyclization of the thioureas is conducted in the presence of an aqueous or anhydrous strong acids, as for example hydrochloric acid.
  • reaction temperatures can be varied over a wide range. In general the reaction is carried out at between 0 and C, conveniently at the boiling point of the diluent (although it is frequently advantageous to cool the reactants at the beginning of the reaction).
  • the thioureas employed as starting materials are known or can be readily obtained by known methods.
  • a phenylisothiocyanate and an amine are allowed to react at a temperature of from about 10 to about 50C, in an inert solvent such as ether or tetrahydrofuran.
  • the amine component which is allowed to react with the thioisocyanate can be of the structure RHN-Z-X, yielding the thioureas of Formula II, or RH N, yielding the thioureas of Formula III.
  • This reduction can be carried out catalytically, as for example with hydrogen in the presence of a noble metal catalyst, optionally in the presence of a diluent, such as an alcohol such as methanol or ethanol, ethanolic hydrochloric acid, or an ether such as tetrahydrofuran at temperatures of from 0 to 100C, preferably of 20 to 80C, optionally under pressure, for example at 1 to 100, preferably 60 to 80, atmospheres gauge.
  • a noble metal catalyst optionally in the presence of a diluent, such as an alcohol such as methanol or ethanol, ethanolic hydrochloric acid, or an ether such as tetrahydrofuran at temperatures of from 0 to 100C, preferably of 20 to 80C, optionally under pressure, for example at 1 to 100, preferably 60 to 80, atmospheres gauge.
  • the reduction can also be carried out chemically as with zinc/hydrochloric acid and tin-(ll) chloride, preferably in an aqueous medium, with sodium sulphide in an alcohol or ether at a temperature of 20 to 100C, preferably at the boiling point of the diluent, or with a complex metal hydride such as sodium borohydrate at temperatures of from 20 to 80C.
  • a preferred embodiment of the cyclization reactions for the compounds of Formulas I1 and 111 are those in which RHN- is an amide function, e.g. R COHN-.
  • RHN- is an amide function
  • the amide group can be hydrolyzed, again leading to the compounds of Formula 1 where R is hydrogen.
  • This hydrolysis can be effected through the use of a strong acid, such as hydrochloric or sulfuric acid, in the presence of water or mixture of water and alcohol. This is generally performed at the boiling point of the aqueous acid mixture.
  • Compounds of Formula I wherein R is hydrogen which are thus obtained by the above methods can in turn be alkylated (including alkenylation and alkynylation) or acylated to yield amides or sulfonated to yield sulfonamides.
  • alkylation one can employ for example an alkyl, alkenyl or alkynyl halide, such as the chloride, bromide or iodide, or the corresponding arylsulfonyloxy or alkylsulfonyloxy derivatives such as a benzenesulfonyloxy or methanesulfonyloxy compound.
  • an alkylating agent such as an inert organic solvent such as diethyl ether, tetrahydrofuran or acetonitrile.
  • an acid binding agent such as an alkali metal or alkaline earth metal carbonate or biscarbonate, or a tertiary amine, is present.
  • the alkylation can be conducted at temperatures of from 20 to 80C.
  • Alkylation can also be accomplished through formation of a Schiff base, by the reaction of a compound of Formula I where R is hydrogen and an appropriate aldehyde or -ketone, followed by reduction of the Schiff tetrahydrofuran, or aromatic hydrocarbons such as benzene and toluene.
  • the Schiff bases thus obtained are hydrogenated, with or without prior isolation, either catalytically as with a noble metal catalyst or chemically.
  • the catalytic reduction is preferably carried out at about 20C and optionally under pressure of from 1 to atmoshperes gauge, preferably 60 atmospheres gauge with the same solvents described above.
  • Chemical reduction can be carried out with complex metal hydrides such as for example sodium borohydride, in which case approximately the stoichiometric amount of'metal hydride is employed.
  • the reaction can be carried outat temperatures of 20 to 80C.
  • the intermediate Schiff base can also be employed in a further alkylation.
  • treatment of a compound of Formula 1 wherein R is hydrogen with an aliphatic or aromatic aldehyde quaternization of the resulting Schiff base with an alkyl, alkenyl or alkynyl halide, such as the chloride, bromide or iodide, or the corresponding arylsulfonyloxy or alkylsulfonyloxy derivative, and hydrolytic cleavage of the aldehyde residue yields the compounds of Formula I wherein R is alkyl, alkenyl or alkynyl.
  • the Schiff base is formed in the same manner as described above.
  • the quaternization is performed at temperatures of from about 20 to about C, especially 60 to 80C, with or without isolation of the Schiff base.
  • the hydrolysis is preferably executed, without isolation of the salt, by heating the salt in aqueous alcohol at temperatures of from 20 to 100C, preferably 40 to 90C.
  • the amides andsulfonamides of the present invention are obtained from compounds of Formula 1 where R is hydrogen utilizing conventional and well-known acylation and sulfonylation reagents, optionally with the concurrent use of a solvent and/or acid binding agents.
  • the reaction is conducted at temperatures of from 0 to C, generally 20 to 90C.
  • Solvents which can be employed are all organic solvents which are inert in the reaction, as for example aromatic hydrocarbons such as benzene or toluene, petroleum ether, chlorinated hydrocarbons such as chloroform or methylene chloride, tetramethylenesulphone, and the like.
  • the acylation or sulphonylation agents include lower alkyl pyrocarbonic acid esters, chloroformic acid lower alkyl esters, lower alkylcarboxylic acid chlorides and bromides, formic acid alkyl esters, methanesulphonic acid chloride, aromatic and heterocyclic carboxylic acid chlorides and carboxylic acid anhydrides.
  • the lower alkyl groups of these agents contain 1 to 4 carbon atoms.
  • R is hydrogen and to then alkylate the resulting N-unsubstituted thiazolidine or 4H-5,6-dihydro-l,3-thiazine.
  • the alkylation is performed at from about 0 to 120C, preferably 20 to 80C, using about stoichiometric amounts of a compound of the structure R-B where R is as defined above and B is chloro, bromo, iodo, arylsulfonyloxy such as benzenesulfonyloxy, or lower alkylsulfonyloxy such as methanesulfonyloxy.
  • An inert organic solvent such as an ether or liquid lower alkyl nitrile is generally employed, e.g. diethyl ether, tetrahydrofuran, acetonitrile.
  • R1-HN wherein Z is ethylene or trimethylene which is:
  • R is (A.) lower alkyl, (8.) lower alkenyl, or (C.) lower alkynyl; R is:
  • imidazolyl pyrazolyl, indolyl, thianaphthyl. quinolyl, phenothiazinyl thiadiazolyl or thiazolyl which is:
  • the compounds of this invention show very good activity against nematodes, a substantially better effect than is demonstrated by other known anthelmintics, such as for example, bephenium hydroxynaphthoate, phenylene-l,4-diisothiocyanate, thiabendazole and piperazine.
  • the compounds show surprisingly good and broad action against such nematodes as hookworms as for example, Ancylostoma caninum, Uncinaria stenocephala; Trichlostrongylids as for example, Haemonchus contortus, Trichostrongylus colubriformis, Nippostrongylus muris, and Nematospiroides dubius; Strongylids as for example, Oesophagostomum Columbianum; threadworms as for example Srrongyloides ram; asearids as for example, Toxocara canis, Toxascaris leonina and Ascaris suum; pinworms such as Aspiculuris telraptera; Heterakids as for example, Helerakis spumosa; and Filariae such as Litomosoides carinii and Dipetalonema witei.
  • hookworms as for example, Ancylostoma caninum, Uncinaria
  • Hookworm Dogs experimentally infected with Ancylostoma caninum or Uncinaria stenocephala were treated at the end of the prepatency of the parasites.
  • the indicated amount of active compound was administered orally as the pure active compound in gelatin capsules.
  • the degree of action was determined by counting the worms expelled after the treatment, and the worms remaining in the test animal after dissection, and calculating the percentage of worms expelled.
  • the table which follows lists the active compounds, the type of parasite and the minimum dosage which reduces the worm infection of the test animals by more than percent (Red 90%), in comparison to commercially available preparations.
  • the dosage is quoted in mg of active substance per kg of body weight.
  • the degree of action of the preparation is determined after dissection, in comparison to untreated control animals, and from this calculating the percentage action.
  • the degree of action of the preparation is determined by counting the worms remaining in the test animal after dissection, in comparison to untreated control animals, and calculating the percentage action therefrom. 7
  • mice experimentally infected with Heterakis spumosa The degree of action-of the preparation is detc rmined were treated at the end of the pre-patency period of the 65 by counting the worms remaining in .the test animal parasites. after dissection in comparison to untreated control ani- The amount of active compound was administered mals and calculating the percentage action therefrom.
  • Table Minimum effective dose Compound (Red. 901) in trig/kg H N c 2 H61 I CH /S on -CO-NH-N- :1 100 Thiabendazole 500 Bitosc'anate Inactive
  • the compounds of the present invention are administered parenterally or orally in any of the usual pharmaceutical forms. These include solid and liquid oral unit dosage forms such as tablets, capsules, powders, suspensions, solutions, syrups and the like, including sustained release preparations, and fluid injectable forms such as sterile solutions and suspensions.
  • unit dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage to animals, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch.
  • Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation;
  • a glidant such as colloidal silica may be added to improve flow properties;
  • a disintegrating or solubilizing agent may be added to improve the availability of the medicament when the capsule is ingested Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base such as starch, sucrose, kaolin, dicalcium phosphate and the like.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps.
  • a protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a given quantity, e.g., a teaspoonful, contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a nontoxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle in which it is insoluble.
  • Fluid unit dosage forms for parenteral administration can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively a measured amount of the compound is placed in-a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration.
  • the compounds of the present invention are administered in doses of from about 1 mg/kg to about 100 mg/kg of body weight of the animal in need of treatment, i.e., to an infected animal for therapeutic purprogress of the infection. In some cases it will suffice to use less than 1 mg/kg while in other cases more than 100 mg/kg must be administered. Where larger amounts are administered, it can be advisable to divide these into several individual administrations over the course of the day. In all cases attention should be paid to the recognized and usual precautions of medical and veterinary practice. i
  • EXAMPLE 1 A mixture of 11.2 g of N-(4- carbethoxyaminophenyl)-N-methyl-N'-(B-hydroxyethyl)-thiourea and 35 ml of concentrated hydrochloric acid is heated at C for 30 minutes. The mixture is cooled and rendered alkaline with sodium hydroxide solution, and the oil which separates is taken up in chloroform. After evaporation, 9.8 g of 2-(4- carbethoxyaminophenylimino)-N-methylthiazolidine, melting point l27l28C, are obtained; the hydrochloride salt demonstrates a melting point of 203205C. Yield: 94 percent of theory.
  • This compound can also be produced as follows: 29.7 g of N-(4-carbethoxyaminophenyl)-N-methyl-N"-(B- hydroxyethyl)-thiourea are dissolved .in ml of methylene chloride. Twelve grams of thionyl chloride are added dropwise and the mixture is then heated under reflux for 1 hour. The mixture is evaporated in vacuo and crystalline N-(4-carbethoxyaminophenyl)- N'-methyl-N-(B-chloroethyl)-thiourea is obtained as the residue which is then heated with ml of water under reflux for 90 minute s.
  • the starting material'can be prepared according to the following procedure:
  • 7.5 g of N- methylethanolamine are added to 18 g of 4- nitrophenylisoeyanatc dissolved in 200 ml of tetrahydrofuran at 20 25C, with stirring.
  • N-(4-Nitrophenyl)N-methyl-N'- (B-hydroxyethyl)thiourea is obtained, which is immediately processed further.
  • 25.5 g of N-(4-nitrophenyl)- N'-methyl-N-(B-hydroxyethyl)thiourea are dissolved in 100 ml of methylene chloride and 12 g of thionyl -chloride are then added dropwise and the mixture is heated for 1 hour under reflux and then evaporated in vacuo. Crystalline N-(4-nitrophenyl)-N-methyl-N'- (B-chloroethyD-thiourea is obtained as the residue.
  • EXAMPLE 2 A mixture of 2-(4-carbethoxyaminophenylimino)-N- methylthiazolidine and 150 ml of concentrated hydrochloric acid is heated under reflux for 16 hours. After evaporation of the solvent and recrystallization of the residue from ethanol/water, 18.8 g of 2-(4- aminophenylimino)-N-methylthiazolidine hydrochloride, melting point 270C, are obtained, from which the free base is obtained on adding sodium hydroxide solution, melting point 130 131C (recrystallized from ethyl acetate). Yield: 77.5 percent of theory.
  • EXAMPLE 3 Twelve grams of chloroformic acid ethyl ester are added dropwise at 20C to a solution of 20.7 g of 2-(4- aminophenylimino)-N-methylthiazolidine in 150 ml of ethanol. The mixture is heated at 60C for 1 hour and evaporated in vacuo.
  • EXAMPLE 9 7.8 g of formic acid-acetic anhydride are added dropwise at 20C to 10.3 g of 2(4-aminophenylimino)-N- methylthiazolidine and the mixture is heated at 50 to 60C for 1 hour. Eighty milliliters of ice water are added and the mixture is evaporated in vacuo. The residue is rendered alkaline with sodium hydroxide solution and extracted with chloroform. After evaporation and distillation (boiling point 178 182C/O.2 mm), 7.9 g of 2-(4-formylaminophenylimino)-N- methylthiazolidine (67 percent of theory), are obtained.
  • EXAMPLE 10 Following the procedure described in Example 1, 31.1 g of N-(4-carboethoxyaminophenyl)-N-methyl- N'-('y-hydroxypropyl)-thiourea, melting point 142 143C, and 100 ml of concentrated hydrochloric acid are allowed to react to yield 16.6 g of 2-(4- carbethoxyphenylimino)-N-methyl-4H-5,6-dihydro- 1,3-thiazine, melting point 178 180C in a yield of 57 percent of theory.
  • N-methylethanolamine N-methylethanolamine.
  • the product, N-(4- nitrophenyl)-N-methy1-N-(2-hydroxyethyl)-thiourea is obtained on a rotary evaporator and used immediately in the following procedure.
  • To a solution of 25.5 g of this thiourea in ml of methylene chloride are added dropwise 12 g of thionyl chloride. The mixture is heated at reflux for 1 hour. Evaporation in vacuo yields N-(4-nitrophenyl )-N'-methyl'N'-(2-chloroethyl) thiourea. This is heated under reflux with ml of water for 90 minutes.
  • EXAMPLE l3 1 Twenty grams of the 2-(4- isobutylideneaminophenylimino)-N-methylthiazolidine obtained according to Example 12, dissolved in 250 ml of tetrahydrofuran, are hydrogenated with palladiumon-carbon catalyst at 20C. After filtering off the catalyst Y and distilling, 13.5 g of -2-(4- isobutylaminophenylimino)-N-methylthiazolidine,
  • Methyl iodine (15.8 g) is added dropwise to a solution of 26.5 g of 2-(4-carbethoxyaminophenylimino)- thiazolidine (m.p. 146 147C), in 250 ml of tetrahydrofuran, at 20C.
  • the mixture is heated for 4 hours under reflux and then evaporated in vacuo.
  • the residue is taken up in a mixture of chloroform/ether and this solution is extracted repeatedly with water.
  • the organic phase is evaporated and after recrystallization from ethyl acetate, 8.5 g of 2-(4- carbethoxyaminophenylimino)-N-methylthiazolidinc, m.p. l27 128C, are obtained in a yield of 30 percent of theory.
  • R-NH 2 or a pharmaceutically.acceptable salt thereof, wherein Z is ethylene or trimethylene unsubstituted or substituted by lower alkyl;
  • R is lower alkyl, lower alkenyl or lower alkynyl
  • R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, R CO or RSO wherein R is (a) hydrogen, (b) lower alkyl or lower alkoxy which is unsubstituted or substituted by l lower alkoxy; (2) cycloalkyl of 3to 7 carbon atoms which is unsubstituted or substituted by methyl; (3) tetrahydrofuryl; (4) thienyl or (5) phenyl or phenoxy which is unsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro; (c) lower alkenyl or lower alkenyloxy which is unsubstituted or substituted by chloro; (d) lower alkynyl or lower alkynyloxy; (e) cycloalkyl of 3to 7 carbon atoms which is unsubstituted or substituted by lower alkyl; (f) phen
  • each of R and R independent of the other is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, chloro, nitro, or trifluoromethyl.
  • R is R CO wherein R is (a) hydrogen, (b) lower alkyl or lower alkoxy which is unsubstituted or substituted by (1) loweralkoxy; (2) cycloalkyl of 3 to 7 carbon atoms which is unsubstituted orsubstituted by methyl; (3) tetrahydrofuryl; (4) thienyl or (5) phenyl or phenoxy which isunsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro; (c) lower alkenyl or lower alkenyloxy which is unsubsti tuted or substituted by chloro; (d) lower alkynyl or lower alkynyloxy; (e) cycloalkyl of 3 to 7 carbon atoms which is unsubstituted or substituted by lower alkyl; (f) phenyl or phenoxy which is unsubstitute
  • R is methyl, ethyl, allyl, methallyl or crotyl
  • R is hydrogen
  • R is hydrogen or chloro
  • R is hydrogen, lower alkyl of up to 3 carbon atoms
  • R is R 50 wherein R is (a) lower alkyl which is unsubstituted or s ub st it ut ed by (l) cycloalkyl of 3 to 7 carbon atoms which is unsubstituted or' substituted by methyl, or (2) phenyl which is unsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro, or (b) lower alkenyl.
  • R is methyl, ethyl, allyl, methallyl or crotyl
  • R is hydrogen
  • R is hydrogen or chloro
  • R is lower alkyl
  • R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.
  • R is methyl, ethyl, allyl, methallyl, or crotyl
  • R is methyl, ethyl, propyl, isopropyl or allyl
  • R is hydrogen
  • R is hydrogen or chloro.

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  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US289092A 1971-09-14 1972-09-14 Derivatives of 2-(4-aminophenylimino)-thiazolidine and 4h-5,6-dihydro-1,3-thiazines Expired - Lifetime US3860590A (en)

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CA (1) CA1007638A (en))
CH (2) CH569724A5 (en))
DD (2) DD105990A5 (en))
DE (1) DE2145807A1 (en))
EG (1) EG11037A (en))
ES (4) ES406622A1 (en))
FR (1) FR2154512B1 (en))
GB (1) GB1377265A (en))
HU (1) HU167410B (en))
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IL (1) IL40338A (en))
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4140784A (en) * 1976-09-17 1979-02-20 Ciba-Geigy Corporation Novel thiazolidines
EP0002723A1 (de) 1977-12-24 1979-07-11 Bayer Ag Phosphonylureidobenzol-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln
US4163791A (en) * 1976-09-17 1979-08-07 Ciba-Geigy Corporation 2-Phenyliminothiazoline compounds
US4771062A (en) * 1986-03-08 1988-09-13 Bayer Aktiengesellschaft Diaryl sulphide derivatives
US6353006B1 (en) 1999-01-14 2002-03-05 Bayer Corporation Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
US20110201550A1 (en) * 2008-06-28 2011-08-18 Bayer Animal Health Gmbh Combination of amidine derivatives with cyclic depsipeptides

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU167761B (en)) * 1973-07-12 1975-12-25
ATE393150T1 (de) 1999-09-14 2008-05-15 Shionogi & Co 2-imino-1,3-thiazin-derivate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2877232A (en) * 1957-12-31 1959-03-10 Ciba Pharm Prod Inc 2-(4-isopentyloxyphenyl)-imino, 3 (4-isopentyloxyphenyl)-thiazolidine and therapeutically useful salts
US3297708A (en) * 1965-10-06 1967-01-10 American Cyanamid Co Method of preparing thiazolidines
US3505348A (en) * 1966-12-20 1970-04-07 Aquitaine Petrole Process for the preparation of imino-thiazolidines

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US327708A (en) * 1885-10-06 Wet-ore concentrator

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2877232A (en) * 1957-12-31 1959-03-10 Ciba Pharm Prod Inc 2-(4-isopentyloxyphenyl)-imino, 3 (4-isopentyloxyphenyl)-thiazolidine and therapeutically useful salts
US3297708A (en) * 1965-10-06 1967-01-10 American Cyanamid Co Method of preparing thiazolidines
US3505348A (en) * 1966-12-20 1970-04-07 Aquitaine Petrole Process for the preparation of imino-thiazolidines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4140784A (en) * 1976-09-17 1979-02-20 Ciba-Geigy Corporation Novel thiazolidines
US4163791A (en) * 1976-09-17 1979-08-07 Ciba-Geigy Corporation 2-Phenyliminothiazoline compounds
EP0002723A1 (de) 1977-12-24 1979-07-11 Bayer Ag Phosphonylureidobenzol-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln
US4771062A (en) * 1986-03-08 1988-09-13 Bayer Aktiengesellschaft Diaryl sulphide derivatives
US6353006B1 (en) 1999-01-14 2002-03-05 Bayer Corporation Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
US20110201550A1 (en) * 2008-06-28 2011-08-18 Bayer Animal Health Gmbh Combination of amidine derivatives with cyclic depsipeptides

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FR2154512B1 (en)) 1976-04-23
DE2145807A1 (de) 1973-03-22
RO84247A (ro) 1984-05-23
RO68389A (ro) 1981-09-24
ES436200A1 (es) 1977-01-16
SU556728A3 (ru) 1977-04-30
RO84248B (ro) 1984-07-30
NL7212419A (en)) 1973-03-16
DD103898A5 (en)) 1974-02-12
AU4660472A (en) 1974-03-21
JPS4836169A (en)) 1973-05-28
BE788743A (fr) 1973-03-13
HU167410B (en) 1976-04-28
FR2154512A1 (en)) 1973-05-11
CH569724A5 (en)) 1975-11-28
DD105990A5 (en)) 1974-05-20
ZA726271B (en) 1973-06-27
SU505363A3 (ru) 1976-02-28
IL40338A (en) 1976-01-30
RO84247B (ro) 1984-07-30
EG11037A (en) 1977-12-31
SU455544A3 (ru) 1974-12-30
ES436201A1 (es) 1977-01-16
AU464649B2 (en) 1975-09-04
CA1007638A (en) 1977-03-29
JPS4836168A (en)) 1973-05-28
PL93669B1 (en)) 1977-06-30
RO84248A (ro) 1984-05-23
GB1377265A (en) 1974-12-11
IL40338A0 (en) 1972-11-28
ES436202A1 (es) 1977-02-16
SE412756B (sv) 1980-03-17
IE36698L (en) 1973-03-14
AT322548B (de) 1975-05-26
CH587258A5 (en)) 1977-04-29
ES406622A1 (es) 1976-01-16
PL93690B1 (en)) 1977-06-30
RO68372A (ro) 1981-06-26
SU439988A3 (ru) 1974-08-15
IE36698B1 (en) 1977-02-02
PL93588B1 (en)) 1977-06-30
PL89701B1 (en)) 1976-12-31

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