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

Abstract

2-(4-Aminophenylimino) derivatives of thiazolidine and -4H-5,6dihydro-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.

Description

United States Patent 1191 Wollweber et al.

[ Jan. 14, 1975 DERIVATIVES OF 2-(4-AMINOPHENYLIMINO)- THIAZOLIDINE AND 4H-5,6-DIHYDRO-1,3-THIAZINES inventors: Hartmund Wollweber,

Wuppertal-Elberfeld, Germany; Winiried Flucke, Beenleigh, Queensland, Australia; Hans Peter Schulz; Herbert Thomas, both of Wuppertal-Elberfeld, Germany Bayer Aktiengesellschaft, Leverkusen, Germany Filed: Sept. 14, 1972 Appl. No.: 289,092

Assignee:

Foreign Application Priority Data Sept. 14, 1971 Germany 2145807 US. Cl 260/243 R, 260/243 AE, 260/2565 R, 260/287 R, 260/3067 T,

Primary Examiner-Richard J. Gallagher [57] 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.

24 Claims, N0 Drawings DERIVATIVES F 2-(4-AMINOPHENYLIMINO)-THIAZOLIDINE AND 4H-5,6-DIHYDRO-1 ,3-THIAZINES thiacycloalkanes are known to possess pharmacodynamic activity such as for example anaesthetic, blood pressure depressing and central nervous system action (see, eg H. Najcr et al., Bull. 1961 960; and South African Patent 63/2420). The known pharmacological activity of such compounds appears to be specifically connected with the o-substitution in the phenyl nucleous and none of the compounds having such an arrangement possesses anthelmintic action.

The compounds of the present invention are characterized by the formula:

in which Z is an ethylene or trimethylene chain which is unsubstituted or substituted by lower alkyl; R is lower alkyl, lower alkenyl or lower alkynyl;

The term 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.

The term cycloalkyl denotes a univalent saturated monocyclic hydrocarbon of from 3 to 7 carbon atoms as, for example, cyclopropyl, cyclobutyl, cyclopentyl,

cyclohexyl, and cycloheptyl.

The term 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.

As indicated, the present invention also pertains to the physiologically acceptable non-toxic acid addition R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; and

each of R and R independent of the other, is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, chloro, fluoro, bromo, nitro or trifluoromethyl.

Also included within the scope of the present invention are the salts of the foregoing amines formed from pharmaceutically acceptable organic and inorganic acids and the amide and sulfonamide derivatives of those amines in which R is hydrogen.

The term 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. i

The term 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,

butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl,

neopentyl, tert.pentyl, hexyl, and the like.

The term lower alkenyl denotesa 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. Such salts 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.

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.

The 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. Thus 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. The groups thus embraced by R, other than hydrogen, can in turn be further substituted. For example, 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. Similarly, 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. 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). When 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.

In most instances, 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-chlorobenzamido)-phenylimino]-N- methylthiazolidine; 2-[4-(2-chlorobenzamido)-phenylimino]-N- methylthiazolidine; 2-[4-(4-methylbenzamido)-phenylimino]-N- methylthiazolidine; 2-[4-(3-methylbenzamido)-phenylimino]-N- methylthiazolidine; 2-[4-(Z-methylbenzamidol-phenyliminol-N- methylthiazolidine; and 2-[4-(2.6-dichlorobenzamido)-phenylimino]-N- methylthiazolidine.

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:

4 in which R, R, R R and Z are as herein defined and X is chloro, bromo, hydroxy or sulfonyloxy. The same result can be obtained, possibly by in situ formation of a thiourea of Formula II, through use of a thiourea of the formula:

and a compound of the formula: IV

wherein 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. The use of 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. hydrobromic acid, phosphoric acid, polyphosphoric acid, sulphuric acid, benzenesulphonic acid, methanesulphonic acid and the like. 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.

Thus for example, 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. In

the former case, it is often advantageous to utilize an.

a l V R in which R, R R and Z are as herein defined. This compound,.upon reduction, yields the corresponding 4-amino compound, i.e., a compound of Formula I wherein R is hydrogen.

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.

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-. Upon completion of the cyclization, 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.

1n the case of 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. One to two moles of the alkylating agent are employed, preferably in an inert organic solvent such as diethyl ether, tetrahydrofuran or acetonitrile. Preferably 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. Here the reaction can be carried outat temperatures of 20 to 80C.

The intermediate Schiff base can also be employed in a further alkylation. Thus 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. Preferably the lower alkyl groups of these agents contain 1 to 4 carbon atoms.

It is also possible to perform the above described cyclizations of thioureas in which 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.

Utilization of the foregoing procedures, which are typified hereafter, thus permits formation of the compounds of the present invention. Although the individual species of these compounds can be generically depicted in a variety of formal groupings, and while each species is considered an equal embodiment of the iiivention, whether taken alone or in any combination with one or more species of the invention, the compounds can in their broadest aspect be formally depicted by the structural formula:

R1-HN wherein Z is ethylene or trimethylene which is:

(A) unsubstituted or (E.) substituted by lower alkyl; R is (A.) lower alkyl, (8.) lower alkenyl, or (C.) lower alkynyl; R is:

(A.) hydrogen, (8.) lower alkyl, (C.) lower alkenyl, (D.) lower alkynyl, (E.) the group RCO- in which R is (l) hydrogen (ll) lower alkyl or lower alkoxy which is:

(a.) unsubstituted or (b.) substituted by (1) lower alkoxy, (2) cycloalkyl which is (i) unsubstituted or (ii) substituted by methyl (3) tetrahydrofuryl, (4) thienyl. (5) phenyl or phenoxy which is (i) unsubstituted or (ii) substituted by [a] chloro. [b] fluoro,

[c] bromo, [d] lower alltyl, [e] lower alkoxy, [f] trifluoromethyl o [g] nitro;

(lll) lower alkenyl or lower alkenyloxy which is:

(a) unsubstituted or (b.) substituted by phenyl which is:

(l) unsubstituted or (Z) substituted by chloro; (lV) lower alkynyl or lower alkynyloxy;

(V) cycloalkyl which is:

('a.) unsubstituted or (b.) substituted by lower alkyl;

(Vl) phenyl or phenoxy which is:

(a.) unsubstituted or (b.) substituted by (l) ehloro, (2) fluoro, (3) bromo, (4) lower alkyl, (5) lower alkoxy, (6) nitro, (7) trifluoromethyl, (8) lower alkanoyloxy, (9) lower alkanoyl, or (10) carbo(lower alkoxy); or

(Vll) furyl, thienyl, isoxazolyl, pyrimidinyl.

imidazolyl. pyrazolyl, indolyl, thianaphthyl. quinolyl, phenothiazinyl thiadiazolyl or thiazolyl which is:

(21,) unsubstituted or (b.) substituted by lower ulkyl; or

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.

In particular, 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.

This action can be conveniently observed in animal models through oral and parenteral administration to test animals, severely infected with parasites, as seen from the following:

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.

Compound Bephenium Parasite Table l-Continued Effective minimum dose (Red. 907.)

Anczlostoma caninum Uncinaria stenocephala in (mg/kg Thiabendazole Piperazine Ancxlostoma c ani num Uncinaria stenocephala Anczlostoma Only partial action Only partial action Only partial caninum action Lh'nmler, G. and E. Saupe (1969) Z. Trop. Parasitol. 2 0 346 Nematospiroides dubius Mice experimentally infected with Nematospiroides 35 dubius were treated after the end of the pre-patency period of the parasites. The amount of active compound was administered orally as an aqueous suspension.

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 table which follows lists the active compounds and the minimum dosage which reduces the infection of the test animals by worms by more than 90 percent by counting the worms remaining in the test animal 40 in comparison to commercial Preparations- Compound Effective minimum dose (Red 907.) in mg/kg r1 21 0. N-C 1 Table 2 Continued Minimum effective dose (Red. 907.)

Compound in trig/kg CH -C-NH- N o-ca -co-m n act" Thiabendazole 500 Bephenium S00 the parasites. The amount of active compound was ad Effective minimum ministered orally as an aqueous suspension. Compound 'dose ff g The degree of action of the preparation was determined by counting the worms remaining in the test aniigitoscarlate 2?) mal after dissection, in comparison to untreated con- WA [Mum trol animals, and thereafter calculating the percentage action.

The table which follows lists the active compounds Strongyloides ratti and the minimum dosage which reduces the infection Rats experimentally infected with Strongyloides ratti by worms of the test animals by more than 90 percent,

were treated after the end of the pre-patency period of 40 in comparison to commercial preparations.

Table 3 Minimum effective dose Compound (Red )90"/,) in rug/kg I S fQ J 2nc1 TABLE 3 (Iontinued C ompound Effective minimum dose (Red. 907) Parasite in rag/kg Y S l -Q n=c :l RC].

Thiabendazole Bephenium L000 Bitoscanate 2S0 Piperazine Inactive Ascarid test tive compound was administered orally as an aqueous suspension.

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

The table which follows lists the active compounds and the minimum dosage which reduces the infection of the test animals by worms by more than percent, in comparison to commercial preparations.

Table 4 Minimum effective dose (Red. )907.) Compound Parasite in mgzkg Ascaris suum (larvae) Ascaris suum 250 (larvae) Toxocara 25 CH canis Table 4v-Continued llinirium effective dose (Red. 901) Cozzaound Parasite in nit/kg Ascaris suum 2 .5

(larvae) CH3 CH3 (larvae) Thiabendazole Ascaris suum I 500 (larvae) Tocascaris 5 x 50* leonina Ascaris suum Inactive Bitoscanate (larvae) Toxascaris 12 x 6** leonina Ascaris suum Inactive (larvae) Piperazine Toxocara 200*** canis Toxascaris 200*** leonina l'lucke, w. (-1963) Die Kleintierpraxis 176 Limler, G. and E. Slupe (1960) Z. Trap. Paruitol. Q, 346

*** Xutzer, E. (1965) Wien. Tierirztl. Msehr. 5 2 242 Heterakis spumosa orally as an aqueous'suspension. r

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. The term 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.

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. As an alternative to granulating, 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. I

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

The following examples will serve to further typify the nature of the invention.

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 mixture is cooled, rendered alkaline with sodium hydroxide solution and extracted with ether/chloroform. After evaporation of-the solvent and recrystallization from ethyl acetate, 22.5 g of 2-(4-carbethoxyaminophenylimino)-N- methylthiazolidine are obtained. Yield: 81 percent of theory.

The starting material'can be prepared according to the following procedure:

7.5 g of N-methylethanolamine-are added to a solution of 22.2 g of 4-carboethoxyaminophenylisothiocyanate in 200 ml of tetrahydrofuran at 20 2 5C, with stirring. After concentration in a rotary evaporator and recrystallization, N-(4-carboethoxyaminophenyl)-N- methyl-N-(,B-hydroxyethyl)-thiourea of melting point 131C is obtained. Alternatively, 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. After mixing in a rotary evaporator, 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. This is heated with l25 ml of water for 90 minutes under reflux. The mixture is cooled, rendered alkaline with sodium hydroxide solution and extracted with ether/chloroform. After evaporation and recrystallization from ethyl acetate, 2-(4-nitrophenylimino)-N- methylthiazolidine is obtained. 7

The following compounds areprepared analogously from the appropriate thioureas:

2-(4-carbethoxyaminophenylimino)-N- ethylthiazolidine hydrochloride 205206C with dec.; 2-(4-carbethoxyaminophenylimino)-N-npropylthiazolidine; 2-(4-carbethoxyaminophenylimino)-N- isopropylthiazolidine hydrochloride 229231C with dec.; 2-(4-carbethoxyaminophenylimino)-N- n.butylthiazolidine hydrochloride 205206C with dec.; 2-(4-carbethoxyaminophenylimino)-N- allylthiazolidine hydrochloride of mp. 350C with dec.; 2-(4-carbethoxyaminophenylimino)-N- methallylthiazolidine; 2-(4-carbethoxyaminophenylimino)-N-'ychloroallyl-thiazolidine; 2-(4-carbethoxyaminophenylimino)-N-B- chloroallyl-thiazolidine; 2-(4-carbethoxyaminophenylimino)-N-B-(ychloroally)-thiazlidine; 2-(4-carbethoxyaminophenylimino)-N- crotylthiazolidine; and 2-(4-carbethoxyaminophenylimino)-N- propargylthiazolidine.

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.

of m.p.

of m.p.

of m.p.

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. After recrystallization from ethanol/ethyl acetate, 24.6 g of 2-(4- carbethoxyaminophenyl)-N-methylthiazolidine hydrochloride are obtained; melting point of fr ee bas TfF" 2-[4-carbo-( 2-methoxyethoxy)-aminophenylimino]- N-methylthiazolidine; 2-(4-carbocyclopropoxyaminophenylimino)-N- methylthiazolidine; 2-(4-carbocyclobutoxyaminophenylimino )-N- methylthiazolidine; 2-(4-carbocyclopentyloxyaminophenylimino )-N- methylthiazolidine; '2-(4-carbocyclohexyloxyaminophenylimino)-N- methylthiazolidine; 2-(4-carbocyclohexylmethoxyaminophenylimino)- N-methylthiazolidine; 2-(4-carbobenzoxyaminophenylimino)-N- methylthiazolidine; 2-[4-carbo-(2-phenethoxy)-aminophenylimino]-N- methylthiazolidine; 2-(4-carbotetrahydrofuryloxyaminophenylimino )-N- methylthiazolidine; 2-(4-carbofurfuryloxyaminophenylimino)-N- methylthiazolidine; 2-(4-carbothienyl-( 2 )-methoxy-aminophenylimino]- N-methylthiazolidine; 2-(4-carbophenoxyaminophenylimino )-N- methylthiazolidine; and 2-[4-carbo-(4-ch1orophenoxy)-aminophenylimino]- N-methylthiazolidine.

EXAMPLE 4 Using the method described in Example 3, 20.7 g of 2-(4-aminophenylimino)-N-methylthiazolidine, dissolved in ml of ethanol, and 16.9 g of benzoyl chloride yield 28.5 g of 2-(4-benzoylaminophenylimino-N- methylthiazolidine hydrochloride, metling point 279C (with decomposition). The free base is obtained by adding sodium hydroxide solution, crude melting point 172C, naphthalenedisulphonate melting point 296C(with decomposition), (82 percent of theory). Using the appropriate acid chlorides, the following are obtained by proceeding analogously:

2-[4-(4-chlorobenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 300C; 2-[4-(3-chlorobenzoylamino)-phcnylimino]-N- methylthiazolidine hydrochloride of melting point 279 281C (with dec.); 2-[4-(2-chlorobenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 279 281C (with dec.); 2-[4-(4-methylbenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 281 283C (with dec.); 2-[4-(3-methylbenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 267C (with dec.); 2-[4-(2-methylbenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 279 281C (with dec.); 2-[4-(2,6-dichloroben2oylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 300C; 2-[4-(4-nitrobenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 310C (with dec.); 2-[4-( 3-nitrobenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride of melting point 301 302C (with dec.);

27 methylthiazolidine hydrochloride (85 percent of theory) of melting point 146 150C (with dec.). The free base is obtained therefrom on addition of sodium hydroxide solution.

The following are obtained by proceeding analogously:

2-[4-(5-methylisoxazolyl-3-carbonylamino)- phenylamino]-N-methylthiazolidine; 2-[4-(Z-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(3-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(4-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(Z-furfurylcarbonylamino)-phenylamino]-N- methyl-thiazolindine; 2-[4-(Z-indolylcarbonylamino)-phenylimino]-N- methyl-thiazolidine; 2-[4-(Z-thianaphthylcarbonylamino)-phenylimino]- N-methylthiazolidine; 2-[4-( 3-indolylacetylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(3-quinolylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-( 2-phenothiazinylcarbonylamino)- phenylimino]-N-methylthiazolidine; thienylacetylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(3-pyrazo1ylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(4-methyl-3-pyrazoly1carbonylamino)- phenylimino]-N-methylthiazo1idine; 2-{4(Z-imidazolylcarbonylamino)-phenylimino]-N- methylthiazolidine; 2-[4-(2-pyrazinylcarbonylamino)-phenylimino]-N- methyl-thiazolidine; 2-[4-(4-pyrimidinylcarbonylamino)-phenylimino]- N-methylthiazolidine; 2-[4-(S-thiazolylcarbonylamino)-phenylimino]-N- methylthiazolidine; and 2-[4-(Z-thienylcarbonylamino)-phenylimino]-N- methylthiazolidine.

EXAMPLE 6 Following the procedure described in Example 3, 103 g of 2-(4-aminophenylimino)-N- methylthiazolidine and 9 g of acetyl chloride yield 13.3

of 2-(4-acetylaminophenylimino)-N- methylthiazolidine hydrochloride, free base melting point 170 173C. Yield: 94 percent of theory.

The following are similarly obtained:

2-(4-propionylaminophenylimino)-N- methylthiazolidine; 2-(4-butyrylaminophenylimino)-N- methylthiazolidine; 2-(4-isobutyrylaminophenylimino)-N- methylthiazolidine; 2-(4-pivaloylaminophenylimino)-N- methylthiazolidine; 2-(4-valeroylaminophenylimino)-N- methylthiazolidine; 2-(4-acryloy1aminophenylimino)-N- methylthiazolidine; 2-(4-crotonoylaminophenylimino)-N- methylthiazolidine; 2-(4-methacryloylaminophenylimino)-N- methylthiazolidine;

28 propinylcarbonylaminophenylimino)-N- methylthiazolidine;

2-(4-methoxyacetylaminophenylimino)-N- methylthiazolidine, mp 197 198C; 2-(4-cyclopropylcarbonylaminophenylimino)-N- methylthiazolidine; 2-(4-cyclobutylcarbonylaminophenylimino)-N- methylthiazolidine; 2-(4-cyclopentylcarbonylaminophenylimino)-N- methylthiazolidine; 2-(4- cyclohexylcarbonylaminophenylimino)-N- methylthiazoline; 2-(4-cycloheptylcarbonylaminophenylimino)-N- methylthiazolidine; 2-[4-(3-methylcyclopentylcarbonylamino)- phenylimino]-N-methylthiazolidine; 2-[4-(4-methylcyclohexylcarbonylamino)- phenylimino]-N-methylthiazolidine; 2-(4-cyclopent-2-enylcarbonylamino)-phenylimino)- N-methylthiazolidine; and 2-(4-cyclohex-1-enylcarbon ylaminophenylimino)-N- methylthiazolidine.

Analogously, the use of alkanesulphonic acid chlorides instead of acetyl chloride according to Example 6 yields:

2-(4-methylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride of melting point 260 262C (with dec.); 2(4-ethylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-butylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-isobutylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-hexylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-allylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-methallylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-crotonylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-cyclopropylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-cyc1opentylsuIphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2(4-cyclohexylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-cycloheptylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-dodecylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(4-propylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride; and 2-(4-isopropylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride.

EXAMPLE 7 By substituting the appropriate amount of N-(3- chloro-4-carbethoxyaminophenyl )-N '-methyl-N '-(B- hydroxyethyl)-thiourea in the procedure of Example 1, there is obtained 2-( 3-chloro-4- carbethoxyaminophenylimino)-N-methylthiazolidine hydrochloride, mp. 194C (dec.). This compound, when subjected to the procedure of Example 2, yields 2-(3-chloro-4aminophenylimino)-N- methylthiazolidine, mp 104. C.

Similarly obtained are:

2-(2,5-dichloro-4 carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2-(3-methyl-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(2-methyl-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride; 2(2,6-dimethyl-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride; 2-(3-allyl-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2-( 3-fluoro-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2 (2-chloro-4-acetylaminophenylimino)-N- methylthiazolidine hydrochloride;

2-(3-chloro-4-benzoylaminophenylimino)-N- methylthiazolidine hydrochloride;

2-(3-trifluoromethyl-4- methacryloylaminophenylimino)-N- methylthiazolidine hydrochloride; 7

2-( 3 -bromo-4-4-carbisopropoxyaminophenylimino N-methylthiazolidine hydrochloride;

2(3methoxy-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2 (3-cyano-4-carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2-(2-trifluoromethyl-4- carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride;

2-( 3-trifluoromethyl-4- carbethoxyaminophenylimino)-N- methylthiazolidine hydrochloride; and

2-( 3 -bromo-4-carbethoxyaminophenylimino )-N- methylthiazolidine hydrochloride. 7

EXAMPLE 8 By sequentially following the procedure of Examples 1 and 2, there is ultimately obtained from the corresponding N'-allylthiourea, the compound 2-(4- aminophenylimino)-N-allylthiazolidine which, as the dihydrochloride, melts at 245C.

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.

EXAMPLE 11 To 18 g of 4-nitrophenylisocyanate in 200 ml of tetrahydrofuran are added with stirring at 20 to C, 7.5

g of 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. After cooling, the solution is rendered alkaline with sodium hydroxide and extracted with ether/chloroform. Evaporation and recrystallization of the residue from ethyl acetate yields 2-(4- nitrophenylimino)-N-methylthiazolidine, m.p. 95 96C.

A solution of 23.7 g of 2-(4-nitrophenylimino)-N- methylthiazolidine in 400 ml of acetic acid is hydrogenated in the presence of platinum oxide at 20C until 0.3 mole of hydrogen is taken up. The catalyst is removed by filtration and the solution is evaporated in vacuo. The residue is taken up in water, sodium hydroxide solution is added and the base which separates out is extracted with a solution of ether and chloroform. After evaporation of the organic layer, 16.5 g of pure 2-(4-aminophenylimino)-N-methylthiazolidine, melting point 127 128C, are obtained in a yield of 80 percent of theory.

EXAMPLE 12 Ten grams of isobutyraldehyde are added dropwise to 20.7 g of 2-(4-aminophenylimino)-N- methylthiazolidine, dissolved in 300 ml of benzene, at 20C, the mixture is heated for 2 hours under a water separator and 2-(4-isobutylideneaminophenylimino)- N-methylthiazolidine is distilled in vacuo, boiling point 175 178C/0.3 mm. Nine grams of dimethyl sulphate are then added to a solution of 14 g of this compound in ml of benzene. The mixture is heated for 1 hour under reflux and the benzene is decanted. The residue is taken up in 30 ml of 50 percent strength ethanol and this solution is heated for 1 hour under reflux. After evaporation in vacuo and adding sodium hydroxide solution to the residue, the free base is extracted with ether and distilled, boiling point 162 l65C/0.2 mm. The following compounds are obtained analogously: 2(4-ethylaminophenylimino)-N-methylthiazolidine; 2-(4-propylaminophenylimino)-N- methylthiazolidine; 2-(4-butylaminophenylimino)-N-methylthiazolidine; 2-(4-isobutylaminophenylimino)-N- methylthiazolidine; 2-(4-allylaminophenylimino)-N-methylthiazolidine; 2-(4-propargylaminophenylimino)-N- methylthiazolidine; 2-(4- crotylaminophenylimino)-N-methylthiazolidine;

and 2-(4-isopropylaminophenylimino)-N- methylthiazolidine.

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,

boiling point 170 l73C/O.22 mm are obtained in a yield of 67 percent of theory.

EXAMPLE 14 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.

EXAMPLE l Fifteen grams of N-(4-carbethoxyaminophenyl)-N- methyl-thiourea are heated with 100 ml of 1,2- dibromoethane for hours under reflux. After cooling, the crystals are removed by filtration and dissolved in water. The solution is rendered alkaline and 2-(4- carboethoxyaminophenylimino)-N-methylthiazolidine is isolated in the fashion described in Example 1, mp. 127 128C.

What is claimed is:

1. A compound of the formula:

1 s\ 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) phenyl or phenoxy which is unsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, nitro, trifluoromethyl, lower alkanoyloxy, lower alkanoyl or carbo(lower alkoxy); or (g) unsubstituted or lower alkyl substituted furyl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl and R is (a) lower alkyl which is unsubstituted or substituted 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; and

each of R and R independent of the other, is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, chloro, nitro, or trifluoromethyl.

2. A compound according to claim 1, wherein 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 unsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, nitro, trifluoromethyl, lower alkanoyloxy, lower alkanoyl or carbo(lower alkoxy); or (g) unsubstituted or lower alkyl substituted furyl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl.

3. A compound according to claim 2 wherein Z is ethylene or trimethylene;

R is methyl, ethyl, allyl, methallyl or crotyl;

R is hydrogen;

R is hydrogen or chloro; and

R is hydrogen, lower alkyl of up to 3 carbon atoms,

lower alkenyl of 3 carbon atoms, lower alkoxy of up to 3 carbon atoms, lower alkynyloxy of up to 4 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, phenyl, furyl or S-methylisoxazolyl.

4. A compound according to claim 1, wherein 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.

5. A compound according to claim 4 wherein Z is ethylene or trimethylene,

R is methyl, ethyl, allyl, methallyl or crotyl;

R is hydrogen;

R is hydrogen or chloro; and

R is lower alkyl.

6. A compound according to claim 1 wherein R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

7. A compound according to claim 6 wherein Z is ethylene or trimethylene;

R is methyl, ethyl, allyl, methallyl, or crotyl;

R is methyl, ethyl, propyl, isopropyl or allyl;

R is hydrogen; and

R is hydrogen or chloro.

8. The compound according to claim 1 which is 2-(4- carbethoxyaminophenylimino)-N-methylthiazolidine.

9. The compound according to claim 1 which is 2-(4- aminophenylimino)-N-methylthiazolidone.

10. The compound according to claim 1 which is 2- (4-benzamidophenylimino)-N-methylthiazolidine.

H. The compound according to claim I which is 2- [4-(2-l'urylcarbonyl)-nminopheuyliminol-N- mcthylthiazolidinc.

[4-(3-chlorobenzamido)-phenylimino]-N- methylthiazolidine 20. The compound according to claim 1 which is 2- [4-(2-chlorobenzamido)-phenylimino]-N- methylthiazolidine.

21. The compound according to claim 1 which is 2- [4-(4-methylbenzamido)-phenylimino]-N- methylthiazolidine.

22. The compound according to claim 1 which is 2- [4-(3-methylbenzamido)-phenylimino]-N- methylthiazolidine.

23. The compound according to claim 1 which is 2- [4-( 2-methylbenzamido )-phenylimino]-N- methylthiazolidine.

24. The compound according to claim 1 which is 2- [4-(2,6-dichlorobenzamido)-phenylimino]-N- methylthiazolidine.

Claims (23)

1. 2. A compound according to claim 1, wherein R1 is R6CO wherein R6 is (a) hydrogen, (b) lower alkyl or lower alkoxy which is unsubstituted or substituted by (1) lower alkoxy; (2) cycloalkyl of 3 to 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 3 to 7 carbon atoms which is unsubstituted or substituted by lower alkyl; (f) phenyl or phenoxy which is unsubstituted or substituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, nitro, trifluoromethyl, lower alkanoyloxy, lower alkanoyl or carbo(lower alkoxy); or (g) unsubstituted or lower alkyl substituted furyl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl.
2. 3. A compound according to claim 2 wherein Z is ethylene or trimethylene; R is methyl, ethyl, allyl, methallyl or crotyl; R2 is hydrogen; R3 is hydrogen or chloro; and R6 is hydrogen, lower alkyl of up to 3 carbon atoms, lower alkenyl of 3 carbon atoms, lower alkoxy of up to 3 carbon atoms, lower alkynyloxy of up to 4 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, phenyl, furyl or 5-methylisoxazolyl.
3. 4. A compound according to claim 1, wherein R1 is R7SO2 wherein R7 is (a) lower alkyl which is unsubstituted or substituted by (1) cycloalkyl of 3to 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.
4. 5. A compound according to claim 4 wherein Z is ethylene or trimethylene, R is methyl, ethyl, allyl, methallyl or crotyl; R2 is hydrogen; R3 is hydrogen or chloro; and R7 is lower alkyl.
5. 6. A compound according to claim 1 wherein R1 is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.
6. 7. A compound according to claim 6 wherein Z is ethylene or trimethylene; R is methyl, ethyl, allyl, methallyl, or crotyl; R1 is meThyl, ethyl, propyl, isopropyl or allyl; R2 is hydrogen; and R3 is hydrogen or chloro.
7. 8. The compound according to claim 1 which is 2-(4-carbethoxyaminophenylimino)-N-methylthiazolidine.
8. 9. The compound according to claim 1 which is 2-(4-aminophenylimino)-N-methylthiazolidone.
9. 10. The compound according to claim 1 which is 2-(4-benzamidophenylimino)-N-methylthiazolidine.
10. 11. The compound according to claim 1 which is 2-(4-(2-furylcarbonyl)-aminophenylimino)-N-methylthiazolidine.
11. 12. The compound according to claim 1 which is 2-(4-acetamidophenylimino)-N-methylthiazolidine.
12. 13. The compound according to claim 1 which is 2-(4-carbethoxyamino-3-chlorophenylimino)-N-methylthiazolidine.
13. 14. The compound according to claim 1 which is 2-(4-amino-3-chlorophenylimino)-N-methylthiazolidine.
14. 15. The compound according to claim 1 which is 2-(4-formamidophenylimino)-N-methylthiazolidine.
15. 16. The compound according to claim 1 which is 2-(4-carbethoxyaminophenylimino)-N-methyl-4H-5,6-dihydro-1,3-thiazine.
16. 17. The compound according to claim 1 which is 2-(4-isobutylaminophenylimino)-N-methylthiazolidine.
17. 18. The compound according to claim 1 which is 2-(4-(4-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
18. 19. The compound according to claim 1 which is 2-(4-(3-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
19. 20. The compound according to claim 1 which is 2-(4-(2-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
20. 21. The compound according to claim 1 which is 2-(4-(4-methylbenzamido)-phenylimino)-N-methylthiazolidine.
21. 22. The compound according to claim 1 which is 2-(4-(3-methylbenzamido)-phenylimino)-N-methylthiazolidine.
22. 23. The compound according to claim 1 which is 2-(4-(2-methylbenzamido)-phenylimino)-N-methylthiazolidine.
23. 24. The compound according to claim 1 which is 2-(4-(2,6-dichlorobenzamido)-phenylimino)-N-methylthiazolidine.