IE46829B1 - 4-hydroxythiazolidine-2-thione derivatives - Google Patents

Abstract

(19) AU (21) 36137/78 (22) 16.5.78 (23) 16.5.78 (24) 17.5.77 (31) 7715072 (32) 17.5.77 (33) FR 7812185 25.4.78 FR (43) 22.11.79 [AU3613778A]

Description

; THIS INVENTION relates to new 4-hydroxythiazolidine2-thione derivatives, a process for their preparation and pharmaceutical compositions containing them.

The 4-hydroxythiazolidine-2-thione derivatives 5 of the present invention are those compounds of general formula: wherein Rj represents a hydrogen or halogen atom ^located in the 4-, 5- or 6-position of the pyridyl radical, R2 represents a hydrogen atom, an alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 to 4 carbon atoms and is substituted by 1, 2 or 3 halogen atoms or by a·phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, aeyloxy, acyloxyalkoxy or acyloxyalkylthio radical, or R2 represents a cycloaikyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a phenyl radical' which is optionally substituted by a halogen atom or by an alkyl, alkoxy, hydroxy or nitro radical, a thien-2-yl radical or an alkoxycarbonyl radical, and R3 represents a hydrogen atom, or an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical, or R2 and R^ together represent - 2 46828 an alkylene radical which contains 3 cr 4 carbon atoms and in the chain of which two adjacent carton atoms can form part of a benzene ring (for example, R2 and R3 may together represent a tetramethylene group or together represent a phenylene group linked to a methylene or ethylene group), and R^ represents a hydrogen atom or an alkyl radical, it being understood that the alkyl radicals, and alkyl and acyl moieties of any of the aforementioned groups, have straightor branched-chains and that, unless specifically indicated, they contain from 1 to 4 carbon atoms.

The products according to the invention can be in one of the forms 1(A) or 1(B) or an equilibrium mixture of these two forms, depending on internal parameters (especially the radicals and R2) or external parameters (especially the presence of a solvent), as will be ehown hereafter.

This existence of the two forms 1(A) and 1(B) of the 4-hydroxythiazolidine-2-thiones is well-known and forms the subject of various publications, especially those by R.W. Lamon et al., J. Org. Chem., 29, 2146 (1964) and J. Het. Chem., 4, 349 (1967).

The general formula 1(A) generally corresponds to the preponderant form, in the crystalline state, of the products in which: (a) R2 represents a hydrogen atom, or an alkyl radical containing 1 to 3 carbon atoms or the n-butyl radical (these radicals being optionally substituted by 1, 2, or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, - 3 468 28 carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, acyloxy, acyloxyalkoxy or acyloxyalkylthio radical\, an alkyl radical which contains 5 to 8 carbon atoms and is straight- or branched- in a position other than the 1- or 2-position, a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a 3-nitrophenyl or 4-nitrophenyl radical or an alkoxycarbonyl radical, Rg has the meaning hereinbefore given with the proviso that it does not form·, together with Rg, an alkylene radical in the chain of which two adjacent carbon atoms form part of a benzene ring, and and have the meanings hereinbefore given: (b) Rg represents a phenyl radical (which is optionally substituted in the 2-, 3- or 4-position by a halogen 2.5 atom, in the 2- or 3-position by an alkoxy radical, in the 3- or 4-position by a hydroxy radical or in the 3-position by an alkyl radical), and either Rg represents a hydrogen atom» or an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical or forms, together with Rg, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms form part of a benzene ring, R^ has the meanings hereinbefore given and Rg represents a hydrogen atom, or Rg represents an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical or forms, together with Rg, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of - 4 46828 which two adjacent carbon atoms form part of a benzene ring, R^ represents an alkyl radical and R^ represents a halogen atom.

The general formula 1(B) generally corresponds to the preponderant form, in the crystalline state, of the products in which: (a) R2 represents an alkyl radical which contains 4 to 8 carbon atoms and is branched in the 1- or 2-position, a branched butyl radical which is substituted by 1, 2 or halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, acyloxy, acyloxyalkoxy or acyloxyalkylthio radical, or R2 represents a phenyl radical which is substituted in the 2-position by a hydroxy, alkyl or nitro radical or in the 4-position by an alkyl or alkoxy radical, or a thien-2-yl radical, has the meaning hereinbefore given with the proviso that it doe· not form, together with Rj, an alkylene radical which may or may not be involved in a benzene ring, and R^ and R^ have the meanings hereinbefore given; (b) R2 represents a phenyl radical which is optionally substituted in the 2-, 3- or 4-position by a halogen atom, in the 2- or 3-position by an alkoxy radical, in the 3- or 4-position by a hydroxy radical or in the 3-position by an alkyl radical, R3 represents a hydrogen atom, or an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical - 5 4 0 8 29 or forms, together with.R2, an alkylene radical which, contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms form part of a benzene ring, R^ represents a halogen atom and R^ represents a hydrogen atom.

According to a feature of the present invention, the compounds of general formula I are prepared by reacting a compound, which can be prepared in situ, of the general formula: R2-C0-c-x ii V wherein R2« Rg ant^ R4 are as Hereinbefore defined and X represents a halogen atom, preferably a bromine or chlorine atom, (and which can be in the form of a salt when R2 is a carboxyalkyl radical), with a dithiocarbamate of the general formula: R NH CS-^.HN (R5)3 III wherein R^ is as hereinbefore'defined and the symbols Rg (which are identical or different) each represent an alkyl radical containing 1 to 4 carbon atoms.

The reaction is generally carried out in an organic solvent (for example dimethylformamide or acetonitrile), in water or in an aqueous-organic medium 6 8 2 9 (for example in a mixture of water and dimethylformamide or water and acetonitrile), at a temperature between -10° and +50°C.

The dithiocarbamates of general formula III can 5 be obtained, in accordance with the method described by E.B. Knott, J. Chem. Soc., 1644-9 (1956), by the action of carbon disulphide, in the presence of a tertiary amine, on a 2-aminopyridine of the general formula: IV wherein R is as hereinbefore defined, or in accordance 1 with the method described by D.B. Capps in United States Patent Specification 3726880.

The compounds of the general formula II can be prepared by applying various general methods described in the literature, which are illustrated in greater detail in the following Examples.

The compounds of general formula I can optionally be purified by physical methods such as crystallisation or chromatography.

The compounds according to the invention when R^ represents a carboxyalkyl radical can optionally be converted into metal salts or into addition salts with a nitrogen-containing base. These salts can be obtained by the action of a metal base (especially an alkali metal or - 7 4 6829 alkaline earth metal base), ammonia or a nitrogencontaining base, in a suitable solvent such as an alcohol, an ether or water, or by an exchange reaction with a salt of an organic acid. The salt formed precipitates, if necessary after concentration of its solution; it is separated off by filtration or decantation.

The new compounds according to the invention, and - when appropriate - their pharmaceutically acceptable salts, are particularly active as anthelmintics which have a broad spectrum of action on nematodes.

Their activity has been demonstrated, especially in mice, against Nematospiroides dubius at doses of between 5 and 200 mg/kg animal body weight administered orally.

Furthermore, the majority of the compounds according to the invention have been found to be active against filariasis in cotton rats having Litomosoides carinii at doses of between 25 and 100 mg/kg animal body weight per day administered orally for a treatment over five consecutive days.

Certain of them have also been shown to be active in dogs at doses of between 10 and 50 mg/kg animal body weight administered orally against Ankvlostoma caninum and Oftcinaria stenOcephale, and at doses of between 5 and 50 mg/kg animal body weight administered orally against Toxocara cania or Toxascaria leonina. - 8 46828 t?.

The toxicity of the compounds according to the present invention, expressed as their 50% lethal dose (LDgQ),in the case of mice is between 200 mg/kg and more than 1000 mg/kg animal body weight administered orally.

The compounds which are of particular value for their level of activity are those of general formula I in which; (a) represents a hydrogen atom, and either R3 and R4 ]_q represent hydrogen atoms and R2 represents a hydrogen atom, alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by 1, 2 or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl or acyloxy radical, or R2 represents a cycloalkyl radical containing 3 to 6-carbon atoms, a cyclohexenyl radical, a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy or nitro radical, or a thien-2-yl radical or an alkoxycarbonyl radical, or R3 represents an alkyl radical which is optionally substituted by an acyloxy radical, or an alkoxycarbonyl radical, R^ represents a hydrogen atom or an alkyl radical and R2 represents a hydrogen atom, an alkyl radical or a phenyl radical, or R3 forms, together with R2< an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon an « β'· t atoms can form part of a benzene ring, and R^ represents a hydrogen atom, or (b) Rj. represents a halogen atom, R, represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and R3 and R^ represent hydrogen atoms, (it being understood that the alkyl radicals are straight or branched and that, unless specifically indicated, the alkyl radicals and moieties thereof of other groups contain 1 or 2 carbon atoms).

Amongst these products, those which are more especially active, in particular against Nematospiroides dubius, are the compounds of general formula I in which: (a) R^ and R^ each represent a hydrogen atom, and either R^ represents a hydrogen atom and Rj represents an alkyl IS radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by a phenyl, alkoxy, alkylthio, methoxycarbonyl or carboxy radical, or Rj represents a cycloalkyl radical containing 5 or 6 carbon atoms, a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy or nitro radical, or a thien-2-yl radical, an alkoxycarbonyl radical or a trifluoromethyl radical, or R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl or phenyl radical, or R3 forms, together with Rj, a tetramethylene radical in the chain of which the carbon atoms located in the a- and β10 46829 positions to the carbon atom carrying Rg form part of a benzene ring, or (b) Rg represents a halogen atom, Rg represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and Rg and R^ each represent a hydrogen atom, it being understood that the aforementioned alkyl radicals are straight or branched and that, unless specifically indicated, the alkyl radicals and moieties thereof of other groups contain 1 or 2 carbon atoms.

Amongst such compounds those of general formula I wherein the symbols have the meanings indicated in Table 1 below are of particular interest.

TABLE I R1R2 'R3r4 5-chloro t-butyl H H H phenyl H H H 3-chlorophenyl H H 5-chloro ' phenyl H H H 3-methoxyphenyl H H H cyclohexyl H H H 3-methylphenyl H Η H 4-methoxyphenyl H H H thien-2-yl H H H phenethyl H H H 2-nitrophenyl H H - 11 46829 The compounds of general formula I which have also been found to be of value for their good activity against filariaais in cotton rats having Litomosoides carinii, b'oth against macrofilariae and microfilariae, are those in which and R^ each represent a hydrogen atom,and (a) Rg represents a hydrogen atom and R2 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by a phenyl, hydroxy, alkoxy, alkylthio, alkoxycarbonyl, acetoxy or carboxy radical, or R2 represents a cyclohexyl radical, a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy or hydroxy radical, or a thien-2-yl radical, an alkoxycarbonyl radical or a trifluoromethyl radical, or (b) Rg represents a methyl or methoxycarbonyl radical and R2 represents a methyl radical,' or (c) Rg forms, together with Rg, a tetramethylene radical, the aforementioned alkyl radicals and moieties thereof of other groups containing 1 or 2 carbon atoms.

Amongst such compounds, those of general formula I wherein the symbols have the meanings indicated in Table II below are more particularly interesting. - 12 4eass TABLE II R1R2R3r4 H methyl H H H ethyl H H H n-propyl H H H isopropyl H H H n-butyl H H H t-butyl H H H n-octyl H H H trifluoromethyl H H H phenethyl H H H hydroxymethyl H H H methoxymethyl H H H ethoxymethyl H H H methylthiomethyl H H H ethylthiomethyl H H H methoxycarbonylethyl H H H ethoxycarbonylmethyl H H H acetoxymethyl H H H carboxyethyl H H H cyclohexyl H H H phenyl H H H 4-fluorophenyl H H H 3-chlorophenyl H H H 4-methylphenyl H H H 3-methoxyphenyl H H 4G32S TABLE II (continued) R1R2R3r4 H 4-methoxyphenyl H H H 2-hydroxyphenyl H H H thien-2-yl H H H, ethoxycarbonyl H H methyl methyl H H methyl methoxy- carbonyl H H tetrar -;- nethylene _ H The most preferred compounds of the invention are those of general formula I wherein R^, R^ and R^ represent hydrogen atoms and R2 represents the methyl radical, e.g. 4- hydroxy-4-methyl-3-(pyrid-2-yl)-thia2olidine-2-thione, and wherein R^ represents a chlorine atom in the - position of the pyrid-2-yl radical, R2 represents the t-butyl radical and R3 and R^ represent hydrogen atoms, e.g. 3,3-dimethyl-2-oxobutyl (5-chloropyrid-2-yl)di thiocarbamate . - 14 46828 The following non-limitative Examples illustrate the preparation of compounds'of the present invention.

EXAMPLE 1 A 50% (by weight) aqueous solution (37.7 g) of chloroacetaldehyde is added, at 10°C, to a solution of triethylammonium pyrid-2-yldithiocarbamate (65.4 g) in dimethylformamide (300 cc) - The reaction is allowed to proceed for 16 hours at 20°C. After evaporating off the solvents under reduced pressure (0.1 mm Hg) at 50eC, the residual oil is treated with chloroform (750 cc). The chloroform solution is washed twice with distilled water (200 cc in total), dried over sodium sulphate and evaporated. The oily residue (38 g) is dissolved in boiling ethanol (180 cc), and boiling diisopropyl ether (180 cc) and decolourising charcoal (1 g) are added.

After filtering the boiling solution and then cooling for 2 hours at 2°C, the resulting crystals are filtered off, washed with an ice-cooled mixture (50 cc in total) of ethanol (25 cc) and diisopropyl ether (25 cc) and dried under reduced pressure (0.1 mm Hg) at 45°C. 4-Hydroxy-3(pyrid-2-yl)-thiazolidine-2-thione (17.8 g), which melts at 110°C, is thus obtained.

Triethylammonium pyrid-2-yldithiocarbamate (m.p. 95°C) is prepared in accordance with the method described by E.B. Knott, J. Chem. Soc., 1644-49 (1956) res , EXAMPLE 2 / 2-Bromopropanal (27.4 g) is added, at about 15e-17°C, to a suspension of triethylammonium pyrid-2yldithiocarbamate (54.2 g) in distilled water (300 cc).

The reaction is allowed to proceed for 35 minutes at 20°C. The water is removed by decantation and the pasty product obtained is treated with ethanol (250 cc). After filtering and evaporating off the solvent under reduced pressure (20 mm Hg) at 40°C, the residual oil (48.3 g) is dissolved in chloroform (400 oc) and the solution is filtered on silica (0.2-0.5 mm; 350 g) contained in a column 4.5 cm in diameter. Elution is carried out with • chloroform (3.6 litres). After evaporating off the solvent under reduced pressure (20 mm Hg) at 4o°C, the product obtained (13.3 g; m.p. 107°C) is dissolved in a boiling mixture comprising methylcyclohexane (200 cc) and ethanol (55 cc). After filtering the boiling solution and then cooling to 20°C, the resulting crystals are filtered off, washed with methylcyclohexane (50 cc) and dried under reduced pressure (0.1 mm Hg) at 55°C. 4-Hydroxy-5-methyl-3(pyrid-2-yl)-thiazolidine-2-bhione ' (10--.3, g)·’; 'which melts at 1 112®C, is thus obtained. 2-Bromopropanal (b.p. 48°-62°C/100 mm Hg) is prepared in accordance with the method described by J.J.

Riebl, Comptes rendus Acad. Sci., C, 245, 1321 (1957). - 16 46829 EXAMPLE 3 2-Bromo-2-methylpropanal (39.7 g) is added, at about 5°C, to a suspension of triethylammonium pyrid-2yldithiocarbamate (71.2 g) in anhydrous acetonitrile (330 cc). The reaction is allowed to proceed for 1 hour at 20eC. The insoluble triethylamine hydrobromide is removed by filtration. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 40°C. The residual oil is treated with methylene chloride (300 cc). The organic solution is washed twice with distilled water (100 cc in total), dried over sodium sulphate and evaporated. The product obtained (60 g) is dissolved in methylene chloride (300 cc) and the solution is filtered on silica (0.2-0.5 mm; 850 g) contained in a column 5 cm I in diameter. Elution is carried out with methylene chloride (9 litres). After evaporating off the solvent under reduced pressure (20 mm Hg) at 40°C, the product obtained (50 g) is dissolved in boiling methylcyclohexane (150 cc). After cooling for 16 hours at 2°C, the resulting crystals are filtered off, washed with methylcyclohexane (50 cc) and dried under reduced pressure (0.1 mm Hg) at 40°C. 5,5-Dimethyl-4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (44.1 g), which melts at 80®C, is thus obtained. 2-Bromo-2-methylpropanal (b.p. 112°C/760 mm Hg) is prepared in accordance with the method described by - 17 4682S C.L· Stevens and B.T. Gilus, J. Amer. Chem. Soc., 79, 3448 (1957).

EXAMPLE 4 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.6 g) and chloroacetone (14.0 g) in distilled water (250 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation from ethanol (40 cc), 4-hydroxy-4-methyl-3(pyrid-2-yl)-thiazolidine-2-thione (20.0 g), which melts at 122°C, is obtained.

EXAMPLE 5 Chloroacetone (13.5 g) is added, at 2°c, to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (44.5 g) in dimethylformamide (180 cc). The reaction is allowed to proceed for 45 minutes at 2°c.

The insoluble triethylamine hydrochloride is removed by filtration and washed with dimethylformamide (20 cc). The dimethylformamide (filtrate and washings) is evaporated off under reduced pressure (0.1 mm Hg) at 45°C and the residual oil is treated with ethyl acetate (400 cc). The organic solution is washed twice with distilled water (100 cc in total), dried over sodium sulphate and evaporated. The product obtained (41 g) is dissolved in boiling ethanol (100 cc). After cooling for 4 hours at 2°C, the resulting crystals are filtered off( washed twice with ice-cooled - 18 46828 ethanol (15 cc in total) and dried under reduced pressure (0.1 mm Hg) at 45° C. 3-(5-Chloropyrid-2-yl)-4-hydroxy-4methylthiazolidine-2-thione (16.8 g), which melts at 95°C, is thus obtained.

Triethylammonium 5-chloropyrid-2-yldithiocarbamate (m.p. 130°C) is prepared in accordance with the method described by D.B. Capps in United States Patent 3726880.

EXAMPLE 6 The procedure of Example 5 is followed, but triethylammonium pyrid-2-yldithiocarbamate (66.0 g) and 3-chlorobutan-2-one (26.0 g) in dimethylformamide (300 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 20°C.

After recrystallisation of the product from ethanol (540 cc), 4,5-dimethyl~4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (48.5 g), which melts at 159eC, is obtained.

EXAMPLE 7 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (27.0 g) and 3-bromo-3-methylbutan-2-one (16.5 g) in anhydrous acetonitrile (400 cc) at 20°c are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 20’C. After recrystallisation of the product from ethanol (200 cc), 4-hydroxy-3-(pyrid-2-yl)-4,5,5trimethylthiazolidine-2-thione (15.0 g), which melts at A68SS l46°c, is obtained. 3-Bromo-3-methyl-butan-2-one (b.p. 55°-57°C/40 ran Hg) is prepared in accordance with the method described by J.R. Catch et al., J. Chem. Soc., 276 (1948).

EXAMPLE 8 The procedure of Example .3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and methyl 2-chloro-3-oxobutanoate (22.1 g) in anhydrous acetonitrile (270 cc) at a maximum of 25°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°-25°C. After recrystallisation of the product from a mixture of ethanol (30 cc) and diisopropyl ether (130 cc), methyl [4-hydroxy-4-methyl-3-(pyrid-2-yl)2-thioxothiazolidin-5-yl]-carboxylate (23.6 g), which melts at 95°C, is obtained.

EXAMPLE 9 The procedure of Example 3 is followed buttriethylammonium pyrid-2-yldithiocarbamate (50.0 g) and 3«chloro-4-oxopentyl acetate (32.9 g) in anhydrous acetonitrile (250 cc) at a maximum of 29®C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-29°C. After recrystallisation of the product from a mixture of ethanol (50 cc) and diisopropyl ether (210 cc), 2-[4-hydroxy-4-methyl-3-(pyrid-2-yl)25 2-thioxothiazolidin-5-yl]-ethyl acetate (46.0 g), which melts at 98°C, is obtained.

EXAMPLE 10 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (21.8 g) and methyl 4-bromo-5-oxohexanoate (17.9 g) in anhydrous acetonitrile (200 cc) at a maximum of 30°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-30°C. After recrystallisation of the product from a mixture of methylene chloride (10 cc) and diethyl ether (70 cc), methyl 3-[4-hydroxy-4-methyl-310 (pyrid-2-yl)-2-thioxothiazolidin-5-yl]-propionate (20.4 g), which melts at 86°C, is obtained.

Methyl 4-bromo-5-oxohexanoate (b.p. 94°C/0.2 mm Hg; 23.0 g) is obtained by the action of diazomethane (5.4 g) on 4»bromo-5-oxohexanoic acid (26.5 g) in diethyl ether (200 cc) at about 5°C. 4-Bromo-5-oxohexanoic acid (oily) is prepared in accordance with the method described by R.Y. Levina et al, Chemical Abstracts, 51, 14704 h (1957).

EXAMPLE 11 The procedure of Example 5 is followed but triethylammonium pyrid-2-yldithiocarbamate (64.0 g) and l-chlorobutan-2-one (25.6 g) in dimethylformamide (300 cc) at a maximum of 30°C are used as the starting materials.

The reaction is allowed to proceed for 30 minutes at °-30°C. After recrystallisation of the product from a mixture of ethanol (75 cc) and diisopropyl ether (75'cc), 4G828 4-ethyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (29.9 g), which melts at 113°C, is obtained. l-Chlorobutan-2-one (b.p. 119°-122°C/760 mm Hg) is prepared in accordance with the method described by P.J. Ashworth et al.. J. Chem. Soc., 4633 (1957).

EXAMPLE 12.

The procedure of Example- 5 is followed but triethylammonium pyrid-2-yldithiocarbamate (65.0 g) and l-chloropentan-2-one (29.0 g) in dimethylformamide (300 cc) at a maximum of 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°25°C. After recrystallisation of the product from a mixture of ethanol (75 cc) and diisopropyl ether (75 cc), 4-hydroxy-4-propyl-3-(pyrid-2-yl)-thiazolidine-2-thione (41.5 g), which melts at 88°C, is obtained. l-Chloropentan-2-one (b.p. 65°-67°C/30 mm Hg) is prepared in accordance with the method described by R.D. Haworth et al.. J. Chem. Soc., 3617 (1954).

EXAMPLE 13 The procedure of Example 5 is followed but triethylammonium pyrid-2-yldithiocarbamatfe (43.2 g) and l-chloro-3-methylbutan-2-one (19.8 g) in dimethylformamide (210 cc) at 20°c are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation of the product from a mixture of ethanol (35 cc) and diisopropyl ether (75 cc), 4-hydroxy22 46829 4-isopropyl-3-(pyrid-2-yl)-thiazolidine-2-thione (33.8 g), which melta at 116°C, is obtained. l-Chloro-3-methylbutan-2-one (b.p. 62°C/25 mm Hg) is prepared in accordance with the method described by R. Justoni and M. Terruzzi, Gazz. Chim. Itai., 78, 166 (1948).

EXAMPLE 14 The procedure of Example 5 is followed but triethylammonium pyrid-2-yldithiocarbamate (56.5 g) and l-chlorohexan-2-one (28.0 g) in dimethylformamide (250 cc) at a maximum of 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. The product is purified by chromatography on silica (0.2-0.5 mm; 600 g) distributed in a column 5.5 cm in diameter. Elution is carried out with chloroform (3000 cc). After evaporation of the solvent, an oily product (46.4 g) is obtained. The product is purified by recrystallisation from methylcyclohexane (250 cc). 4-Butyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2thione (37.4 g), which melts at 56°C, is thus obtained.

In the infra-red spectrum, respectively 2 to 3% (carbonyl band at 1710 cm”1) and 2 to 5% (carbonyl band at 1710 cm-1) of 2-oxohexyl pyrid-2-yldithiocarbamate are observed in the product, depending on whether it is examined between plates in Vaseline (a registered Trade Mark) or in chloroform solution. l-Chlorohexan-2-one (b.p. 80°-81°C/25 mm Hg) is prepared in accordance with the method described by 46828 Η. Erlenmeyer and J.P. Jong, Helv. Chim. Acta, 32, 35 (1949) EXAMPLE 15 l-Chloro-4-methylpentan-2-one (23.0 g) is added, at a maximum of 25ec, to a suspension of triethylammonium pyrid-2-vldithiocarbamate (46.0 g) in dimethylformamide (210 cc). The reaction is allowed to proceed for 2 hours at 20°-25°C. The insoluble triethylamine hydrochloride is removed by filtration and washed with dimethylformamide (50 cc). The dimethylformamide is evaporated off under reduced pressure (0.1 mm Hg) at 50°C and the residual oil is treated with ethyl acetate (700 cc). The organic solution is washed three times with distilled water (300 cc in total), dried over sodium sulphate, treated with decolourising charcoal (3-0 g), filtered and evaporated under reduced pressure (20 mm Hg) at 50°C. The product obtained (48 g) is dissolved in boiling ethanol (30 cc), and diisopropyl ether (60 cc) is added to the boiling solution. After cooling for 2 hours at 2°C, the resulting crystals are filtered off, washed three times with di20 isopropyl ether (75 cc) and dried under reduced pressure (0.1 mm Hg) at 4o°C. 4-Methyl-2-oxopentyl pyrid-2yldithiocarbamate (35.0 g), which melts at 92°C, is thus obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 80-90% of 4-hydroxy-4-isobutyl-3-(pyrid-2-yl)-thiazolidine-2-thiona (-0H and -NH bands combined from 2700 to 3600 cm~l, - 24 48828 reduction in intensity of the carbonyl band at 1710 cm-1) is observed. This form is not detected when the product is examined between plates in Vaseline. l-Chloro-4-methylpentan-2-one (b.p. 72°-73®C/25 mm Hg) is prepared in accordance with the method described by P. Asinger et al.. Ann. Chem., 672, 156 (1964).

EXAMPLE 16 l-Bromo-3, 3-dimethylbutan-2-one (138 g) is added, over the course of 15 minutes and at between 18° and 23°C, to a suspension of triethylammonium pyrid-2-yldithiocarbamate (210 g) in anhydrous acetonitrile (1000 cc). The reaction is allowed to proceed for 16 hours at 20°C. The resulting crystals are filtered off and washed with acetonitrile (100 cc). The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 50°C. The residual oil obtained is combined with the crystals which have been filtered off beforehand and is treated with ethyl acetate (2000 cc). The organic solution is washed with distilled water (500 cc), dried over sodium sulphate, filtered and evaporated under reduced pressure (20 mm Hg) at 50°C.

The product obtained is dissolved in boiling acetonitrile (1000 cc), decolourising charcoal (5.0 g) is added and the boiling solution is filtered. After cooling for 2 hours at 2*C, the resulting crystals are filtered off, washed twice with ice-cooled acetonitrile (100 cc) and dried under reduced pressure (0.1 mm Hg) at 50°C. 3,3-Dimethyl25 46829 2-oxobutyl pyrid-2-yldithiocarbamate (137 g), which melts at 103°C, is thus obtained. . l-Bromo-3,3-dimethylbutan-2~one (b.p. 106°C/40 rem Hg) is prepared in accordance with the method described by J. Colonge and J. Grevet, Bull. Soc. Chim. France, 1304 (1954).

EXAMPLE 17 The procedure of Example 16 is followed but triethylammonium 5-chloropyrid-2-yldithiocarbamate (230 g) and l-bromo-3,3-dimethylbutan-2-one (135 g) in anhydrous acetonitrile (2000 cc) at 20°c are used as the starting materials. The.reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation from ethanol (1700 cc), 3,3-dimethyl-2-oxobutyl (5-chloropyrid-2-yl)di15 thiocarbamate (142.1 g), which melts at 139°C, is obtained EXAMPLE 18 The procedure of Example 5 is followed but triethylammonium pyrid-2-yldithiocarbamate (27.1 g) and *1 1 ' l-chlorononan-2-one (17.6 g) in dimethylformamide (135 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C. The product is purified by chromatography on silica (0.2-0.5 mm; 1 kg) distributed in a column 6.5 cm in diameter. Elution is carried out with chloroform (5 litres) which is removed, and then with chloroform (4 litres) which is evaporated off under reduced pressure (20 mm Hg) at 50°C. The oily ( purified product is dried for 4 hours at 70°C under a pressure of 0.1 mm Hg. 4-Heptyl-4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (15.0 g) is thus obtained.

When the product is examined by infra-red spectroscopy between plates in Vaseline or in chloroform solution, 3 to 5% of 2-oxononyl pyrid-2-yldithiocarbamate (carbonyl band at 1710 cm”3-) is detected. 1-Chlorononan-2-one (b.p. 95°C/4 mm Hg) is prepared in accordance with the method described by S. Archer et al., J. Amer. Chem. Soc., 78, 6182 (1956).

NMR spectrum (60 MHz), run in an approximately 10% solution in chloroform: 0.85 ppm : triplet (3H) -CH^ 1.2 ppm: hump (10H) -(CH2)515 1.6 to 2.2 ppm: multiplet (2H) heterocyclic -CH2~ 3.55 ppm: AB (2H) -CH2S6.1 ppm: broad hump (IH) -OH 7.3 ppm: DDD (IH) J = 8, 5 and 2 Hg 7.7 ppm: doublet of multiplets (IH) J = 8 7.9 ppm: triplet of multiplets (IH) J = 8 and 2 8.5 ppm: doublet of doublets (IH) J = 5 and 2 Hg.

EXAMPLE 19 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (55.0 g) and 1-chlorodecan-2-one (38.7 g) in distilled water (280 cc) at 20’C.are used as the starting materials. The reaction / 46839 is allowed to proceed for 20 hours at 20°C. The product is purified by chromatography on silica (0.2-0.5 mm; 1.5 kg) distributed in a-column 7.5 cm in diameter. Elution is carried out with chloroform (2 litres) which is removed, and then with chloroform (1.6 litres) which is evaporated off under reduced pressure (20 mm Hg) at 50eC. The oily purified product is dried for 3 hours at 60°C under a pressure of 0.1 mm Hg. 4-Hydroxy-4-octyl3-(pyrid-2-yl)-thiazolidine-2-thione (29.0 g) is thus obtained.

When the product is examined by infra-red spectroscopy between plates in Vaseline or in chloroform solution, 5 to 10% of 2-oxodecyl pyrid-2-yldithiocarbamate (carbonyl band at 1710 cm ^) is detected. l-Chlorodecan-2-one (b.p. 88°-98°C/0-5 mm Hg) is prepared in accordance with the method described by S. Archer et al.. J. Amer. Chem. Soc., 78, 6182 (1956).

NMR spectrum (60 MHz), run in an approximately % solution in carbon tetrachloride: 0.9 ppm: triplet (3H) -CHg 1.2 ppm: hump (14h) -(CHg)?1.8 ppm: hump (2H) heterocyclic -CHg3.38 to 3.55 ppm: AB (2H) -CH,,S5.85 ppm: hump (1H)-OH 7.3 ppm: DDD (IH) J=8, 5 and 2 Hg 7.76 ppm: doublet of doublets (IH) J = 8 and 2 Hg 468 28 τ t' 7.8 ppm: doublet of triplets (1H) J = 8 and 2 8.45 ppm: doublet of doublets (1H) J = 5 and 2 Hg.

EXAMPLE 20 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (51.5 g) and 2-chloro-l-cyclopropylethan-l-one (22.5 g) in anhydrous acetonitrile (500 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from a mixture comprising acetonitrile (230 cc) and diisopropyl ether (1200 cc), 4-cyclopropyl-4-hydroxy-3(pyrid-2-yl)-thiazolidine-2-thione (30.8 g), which melts at 95°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 30% of 2-cyclopropyl-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1695 cm-1') is observed. This form is not detected when the product is examined between plates in Vaseline. 2-Chloro-l-cyclopropylethan-l-one (b.p. 67°C/ mm Hg) is prepared in accordance with the method described by E.M. Kosower et al., J. Org. Chem., 28, 630 (1963).

EXAMPLE 21 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (47.4 g) and 2-chloro-l-cyclobutylethan-l-one (23.2 g) in anhydrous acetonitrile (450 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile (100 cc), 4-cyclobutyl-4-hydroxy-3-(pyrid2-yl)-thiazolidine-2-thione (33.1 g), which melts at 123°C, is obtained.

Wh<=n the product is examined by infra-red spectroscopy in chloroform solution, a broad band is observed at about 1700 cm’1, which may correspond to 2 to 3% of 2-cyclobutyl-2-oxaethyl pyrid-2-yldit)iiocarbamate. This band is_ not observed when the product is examined between plates in Vaseline. 2-Chloro-l-cyclobutylethan-l-one (b.p. 94°-95°C/ mm Hg) is prepared in accordance with the method described by D. Sorg, German Patent Application DE 2404050.

EXAMPLE 22 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (47.4 g) and 2-chloro-l-cyclopentylethan-l-one (25.7 g) in anhydrous acetonitrile (450 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile (90 cc), 4-cyclopentyl-4-hydroxy-3-(pyrid25' 2-yl)-thiazolidine-2-thione (31.3 g), which melts at 118°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, a broad band is observed at about 1700 cm-1, which may correspond to 5% of 2-cyclopentyl-2-oxo-ethyl pyrid-2-yldithiocarbamate.

This band is not observed when the product is examined between plates in Vaseline. 2-Chloro-l-cyclopentylethan-l-one (b.p. 106°C/ mm Hg) is prepared in accordance with the method described by M. Mousseron et al., Compt. Rend. Acad. Sci., C, 232, 1562 (1951).

EXAMPLE 23 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (38.0 g) and 2-chloro-l-cyclohexylethan-l-one (22.5 g) in distilled water (175 cc) at a maximum of 25°c are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. After recrystallisation of the product from ethanol (250 cc), 4-cyclohexyl-4-hydroxy-3(pyrid-2-yl)thiazolidine-2-thione (27.0 g), which melts at 112°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, 2 to 3% of 2-cyclohexyl-2oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1710 oifl) is observed. This form is not detected when the product is examined between plates in Vaseline. 2-Chloro-l-cyclohexylethan-l-one (b.p. 96°C/8 mm Hg) is prepared in accordance with the method described by M. Mousseron et al., Compt, Rend. Acad, Sci., C, 232, 1562 (1951).

EXAMPLE 24 A 5.5N aqueous solution of sodium hydroxide (36 cc) is added, over the course of 5 minutes and at 22°-23°C, to a suspension of 3-chloro-2-oxopropyl acetate (29.9 g) in distilled water (500 cc). The hydrolysis reaction is allowed to proceed for 15 minutes at 22°C and triethylammonium pyrid-2-yldithiocarbamate (53.6 g) is then added over the course of 5 minutes at a maximum temperature of 23°C. The reaction is allowed to.proceed for 2 hours at 20°-23°C. The resulting crystals are filtered off, washed with distilled water (50 cc) and then IS with diethyl ether (50 cc) and dried under reduced pressure (0.1 mm Hg) at 45°C. 4-Hydroxy-4-hydroxymethyl-3-(pyrid2-yl)-thia2o!idine-2-thione (12.0 g), which melts at 134°-135°C, is thus obtained. 3-Chloro-2-oxopropyl acetate (b.p. 129°-131°C/ mm Hg) is prepared in accordance with the method described by E.R. Curk and J.B.G. Howes, J. Chem. Soc., 1152 (1956).

EXAMPLE 25 A solution of l,3-dichloropropan~2-one (15.2 g) in acetonitrile (32 cc) is added, over the course of 45 minutes and at a maximum temperature of 4°C, to a 46828 suspension of triethylammonium pyrid-2-yl-dithiocarbamate (32.4 g) in a mixture of acetonitrile (100 cc) and distilled water (32 cc). The reaction is allowed to proceed for 1 hour at 2°C. The resulting crystals are filtered off, washed twice with a mixture of acetonitrile (15 cc) and distilled water (15 cc) and then with diethyl ether (15 cc) and dried under reduced pressure (20 mm Hg) at 20°C. The product obtained (18.2 g; m.p. 118°-120°C) is purified by recrystallisation from methanol (250 cc). 4-Chloromethyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2thione (8.6 g), which melts at 120°C, is thus obtained.

EXAMPLE 26 The procedure of Example 25 is followed but triethylammonium pyrid-2-yldithiocarbamate (46.0 g) and 3-bromo-l,l-dichloropropan-2-one (35.1 g) in a mixture of acetonitrile (450 cc) and distilled water (46 cc) at a maximum temperature of 4°C are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 2°C. After recrystallisation of the product from a mixture of diisopropyl ether (200 cc) and ethanol (50 cc), 4-dichloromethyl-4-hydroxy-3-(pyrid-2-yl)~ thiazolidine-2-thione (13.5 g), which melts at 130°C, is obtained. 3-Bromo-l,l-dichloropropan-2-one (b.p. 65°-67°C/ 1.5 mm Hg) is prepared in accordance with the method described by W. Polacskowa and Z. Bankowska, Roczniki. 6 8 2 9 ., ., Chem-,'30, 119 (1956).

EXAMPLE 27 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (29.5 g) and 3-chloro-2-oxopropyl acetate (16.4 g) in distilled water (125 cc) at 25°C are used as the starting materials. The reaction is allowed to proceed for 20 hours at 20°-25°C. After recrystallisation from ethanol (210 cc), 4-acetoxymethyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine~2-thione (16.7 g), which melts at 121°C, is obtained. 3-Chloro-2-oxopropyl acetate is prepared as indicated in Example 24.

EXAMPLE 28 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (36.5 g) and l-chloro-3-methoxypropan-2-one (16.5 g) in distilled water (-2p0 cc) at a maximum temperature of 25°C are used as the starting materials. The reaction is allowed to proceed for 2¾ hours at 20°-25°C. After recrystallisation of the product from ethanol (180 cc), 4-hydroxy-4-methoxymethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (22.8 g), which melts at 114°C, is obtained. l-Chloro-3-methoxypropan-2-one (b.p. 84°-85°C/25 mm Hg) is prepared ih accordance with the method described by B.G. Christensen and R.W. Ratcliffe, German Patent Application DE 2318829. - 34 4 6 8 2s f EXAMPLE 29 The procedure of Example 2 is fallowed but triethylammonium pyrid-2-yldithiocafbamate (36.6 g) and l-chloro-3~ethoxypropan-2-one (18.5 g) in distilled water (180 cc) at a maximum temperature of 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. After rectyetallisation from diisopropyl ether (270 cc), 4-ethoxymethyl-4-hydroxy3-(pyrid-2-yl)-ttjiazolidine-2-thione (22.5 g), which melts at 75°C, is obtained. l-Chloro-3-ethoxypropan-2-one (b.p. 94°C/30 mm Hg) is prepared in accordance with the method described by A. Grtin and W. Stoll, United States Patent 2374283.

EXAMPLE 30 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (43.5 g) and l-chloro-3-methylthiopropan-2-one (22.2 g) in distilled water (200 cc) at a maximum temperature of 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. After recrystallisation of the product from ethanol (100 cc) 4-hydroxy-4-methylthio methyl-3-(pyrid-2-yl)-thiazolidine-2-thione (27.0 g), which melts at 104°C, is obtained. l-Chloro-3-methylthiopropan-2-one (b.p. 98°-100°C/ 28 ran Hg) (22.5 g) is obtained by reacting diazomethane (22.4 g) at between ~10°C and 0°C, followed by an aqueous 4 68 2 9 . solution of hydrochloric acid (d = 1.19; 35 cc) at between 0° and 5°C, with methylthioacetyl chloride (40.1 g) in diethyl ether (300 cc).

Methylthioacetyl chloride (b.p. 66°C/30 mm Hg) is prepared in accordance with the method described by A. Mooradian et al., J. Amer. Chem. Soc., 71, 3372 (1949).

EXAMPLE 31 The procedure of Example 2 is followed but triethyl ammonium pyrid-2-yldithiocarbamate (27.1 g) and l-chloro-310 ethylthiopropan-2-one (15.3 g) in distilled water (130 cc) at a maximum temperature of 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. The product is purified by chromatography on silica (0.2-0.5 mm; 650 g) distributed in a column 5.5 cm in diameter. Elution is carried out with cyclohexane (1.5 litres), followed by cyclohexane (1 litre) containing 10% by volume of ethyl acetate and then by cyclohexane (1 litre) containing 15% by volume of ethyl acetate.. These various eluates are removed. Elution is continued with cyclohexane (1.5 litres) containing 25% by volume of ethyl acetate which is evaporated off under reduced pressure (20 mm Hg) at 50°C. The product obtained (21.0 g) is recrystallised from a mixture of diethyl ether (100 cc) and diisopropyl ether (46 cc). 4-Ethylthiomethyl-4-hydroxy-3-(pyrid-2-yl)25 thiazolidine-2-thione (14.4 g), which melts at 50°C, is thus obtained. - 36 Pi l-Chloro-3-ethylthiopropan-2-one (b.p. 94°C/30 mm Hg) is prepared in accordance with the method described by B.G, Christensen et al., French Patent Application 2034480.

EXAMPLE 32 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (7.1 g) and 3-bromo-l,1,1trifluoropropan-2-one (5.0 g) in anhydrous acetonitrile (70 cc) at between 2° and 5°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 2°C. The product is purified by chromatography on silica (0.2-0.5 mm; 140 g) distributed in a column 3 cm in diameter. Elution is carried out with chloroform (240 cc) which is removed, and then with chloroform (360 cc) which is evaporated off under reduced pressure (20 mm Hg) at 40°C.

The product obtained (6.1 g) is purified by recrystallisation from a mixture of ethanol (13 cc) and distilled water (13 co). 4-Hydroxy-3-(pyrid-2-yl)-4-trifluoromethylthiazolidine-2-thione (4.3 g), which melts at 60°C, is thus obtained. 3-Bromo-l,l,l-trifluoropropan-2-one (b.p. 80°85°C/760 mm Hg) is prepared according to E. Cherbuliez et al., Helv. Chim. Acta, 48, 1423 (1965).

EXAMPLE 33 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (27.0 g) and 46 8 29 4-chloro-3-oxobutyl acetate (16.4 g) in anhydrous acetonitrile (150 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation of the product from a mixture of methylene chloride (40 cc) and diisopropyl ether (100 cc), 2-[4-hydroxy-3-(pyrid-2-yl)2- thioxothiazolidin-4-yl]-ethyl acetate (19.0 g), which melts at 96°C, is obtained. 4-Chloro-3-oxobutyl acetate (b.p. 103°-104°C/ 0.1 mm Hg) is prepared in accordance with the method described by Y.A. Arbuzov et al., Doklady, Akad. Nauk. S.S.S.R., 112, 261 (1957).

EXAMPLE 34 The procedure of Example 3 is followed but 15 triethylammonium pyrid-2-yldithiocarbamate (81.0 g) and ethyl bromopyruvate (58.5 g) in anhydrous acetonitrile (550 cc) at a maximum temperature of 30°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°-30°C. After recrystallisation of the product from diisopropyl ether (250 cc), ethyl [4-hydroxy3- (pyrid-2-yl)-2-thioxothiazolidin-4-yl]-carboxylate (71.0 g)., which melts at 64°C, is obtained.

EXAMPLE 35 The procedure of Example 5 is followed but 25 triethylammonium pyrid-2-yldithiocarbamate (56.5 g) and ethyl 4-chloro-3-oxobutyrate (34.2 g) in dimethylformamide - 38 46829 (250 cc) at 20’C are used as the starting materials.

The reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation of the product from a mixture of ethanol (100 cc) and diisopropyl ether (100 cc), ethyl [4-hydroxy-3-(pyrid-2-yl)-2-thioxothiazolidin-4-yl]~ acetate (22.0 g), which melts at 104°C, is obtained.

EXAMPLE 36 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (54.0 g) and methyl 5-bromo-4-oxopentanoate (42.0 g) in distilled water (250 cc) at a maximum temperature of 25°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°-25°C. After recrystallisation of the product from a mixture of ethanol (60 cc) and diisopropyl ether (120 cc), methyl 3-[4-hydroxy-3-(pyrid-2-yl)~2thioxothiazolidin-4-yl]-propionate (42.0 g), which melts at 75°C, is obtained.

Methyl 5-bromo-4-oxopentanoate (b.p. 84°-85°C/ 0.1 mmHg) is prepared in accordance with the method described by H. Dannenberg and S. Laiifer, Chem. Ber., 89, 2242 (1956).

EXAMPLE 37 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (19.0 g) and methyl 7-chloro-6-oxoheptanoate (13.5 g) in anhydrous acetonitrile (200 cc) at a maximum temperature of 30°C 8 29 »4j,r are used, as the starting materials. The reaction is allowed to proceed for 16 hours at 20°C. After recrystallisation of the product from a mixture of ethanol {25 cc) and diisopropyl ether (50 cc), methyl 5-[4-hydroxy5 3-{pyrid-2-yl)-2-thioxothiazolidin-4-yl]-pentanoate (18.0 g), which melts at 72°C, is obtained.

Methyl 7-chloro-6-oxoheptanoate (b.p. 121°-122°C/ 0.05 mm Hg) (45.0 g) is obtained by the action of diazomethane (16.8 g) at between -10°C and 0°C, and then of an aqueous solution of hydrochloric acid (d = 1.18; 30 cc) at between 0° and 5°C, on methyl 5-chlorocarbonylvalerate (44-5 g) in diethyl ether (400 cc).

EXAMPLE 38 A solution of 5-bromo-4-oxopentanoic acid (14.6 g) in a mixture of distilled water (30 cc) and an N aqueous solution of sodium hydroxide (75 cc) is prepared just before use, working at a maximum temperature of 5°C. This solution is added, at a maximum temperature of 20°C, to a suspension of triethylammonium pyrid-2-yldithiocarbamate (21.6 g) in distilled water (150 cc). After stirring for 4 hours at 20°C, decolourising charcoal (2.0 g) Is added and the mixture is filtered. Without exceeding 20°C, an N aqueous solution of hydrochloric acid (75 cc) is added to the filtrate. After cooling for 1 hour at 2°C, the resulting crystals are filtered off, washed four times with distilled water (60 cc) and dried in air. The product (14.2 g; m.p. 148°C) is purified by recrystallisation from - 40 .46828 acetonitrile (250 co). 3-[4-Hydroxy-3-(pyrid-2-yl)-2thioxothiazolidin-4-yl]-propionic acid (10.8 g), which melts at 154°C, is thus obtained.

-Bromo-4-oxopentanoic acid (m.p. 72°C) is prepared in accordance with the method described by S. Vartillot and C. Baron, Bull. Soc. Chim. France, 3798 (1966).

EXAMPLE 39 The procedure of Example 5 is followed but triethylammonium pyrid-2-yldithiocarbamate (30.4 g) and l-chloro-3-phenylpropan-2-one(18.9 g) in dimethylformamide (140 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C.

After recrystallisation of the product from a mixture of acetonitrile (50 cc) and ethanol (100 cc), 4-benzyl-4hydroxy-3~(pyrid-2-yl)-thiazolidine-2~thione (21.5 g), which melts at 135°C, is obtained. l-Chloro-3-phenylpropan-2-one (b.p. 98°-100°c/ 0.2 nm Hg) is prepared in accordance with the method described by D.A. Clibbens and M. Nierenstein, J. Chem. Soc., 1491 (1915).

EXAMPLE 40 The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (23.6 g) and l-chloro-4-phenylbutan-2-one (16.2 g) in distilled water (150 cc) at 20°C are used as the starting materials. The - 41 reaction is allowed to proceed for 2 hours at 2Cfc.

After recrystallisation of the product from ethanol (110 cc), 4-hydroxy-4-phenylethyl-3-(pyrid-2-yl)thiasolidine-2-thione (21.5 g), which melts at 118°C, is obtained. l-Chloro-4-phenylbutan-2-one (b.p. 115°C/0.5 mm Hg) is prepared in accordance with the method described by D.A. Clibbens and M. Nierenstein, J.

Chem. Soc., 1491 (1915).

EXAMPLE 41 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (43.4 g) and l-chloro-2-(cyclohex-3-enyl)-ethan-2-one (25.4 g) in anhydrous acetonitrile (500 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from a mixture of acetonitrile (185 cc) and diisopropyl ether (1250 cc), 4-(cyclohex-3-enyl)-4hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (28.8 g), which melts at 111°C, is obtained. l-Chloro-2-(cyclohex-3-enyl)-ethan-2-one (b.p. 106°-107°C/13 mm Hg) is prepared in accordance with the method described by G.P. Kugatova et al., Zh. Organ. Khim, 2, 844 (1966).

EXAMPLE 42 The procedure of Example 3 is followed but - 42 46829 triethylammonium pyrid-2-yldithiocarbamate (201.5 g) and phenacyl bromide (148 g) in anhydrous acetonitrile (1600 cc) at between 18° and 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-25°C. After recrystallisation of the product from ethanol (2000 co), 4-hydroxy-4-phenyl-3(pyrid-2-yl)-thiazolidine~2-thione (168.1 g), which melts at 135°C, is obtained.

When the product is examined by infra-red spectroscopy in bromoform solution, about 10% of phenacyl pyrid-2-yldithiocarbamate (carbonyl band at 1685 cm”3·) is observed. This band is not observed when the product is examined between plates in Vaseline.

EXAMPLE 43 The procedure of Example 16 is followed but triethylammonium 5-chloropyrid-2-yldithiooarbamate (38.3 g) and phenacyl bromide (24.9 g) in anhydrous acetonitrile (250 cc) at between 20° and 25°C are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 20°C. After recrystallisation of the product from acetonitrile (200 cc), phenacyl 5-chloropyrid-2yldithiocarbamate (33.9 g), which melts at 145°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 95% of 3-(5chloropyrid-2-yl)-4-hydroxy-4-phenylthiazolidine-2-thione - 43 46829 (reduction in the carbonyl band at 1690 cm ^) is observed. This form· is not detectable when the product is examined between plates in Vaseline.

EXAMPLE 44 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (54.2 g) and 2-brorao-l-phenylpropan-l-one (42.6 g) in anhydrous acetonitrile(320 cc) at between 20° and 25°C are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 20°C. After recrystallisation of the product from acetonitrile (180 cc), 4-hydroxy-5methyl-4-phenyl-3-(pyrid-2-yl)-thiazolidine-2-thione (46.5 g), which melts at 150°G, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, 1 to 3% of 2-methyl1- oxo-l-phenylprop-2-yl pyrid-2-yldithiocarbamate (carbonyl band at 1680 cm·^) is observed. This band is not observed when the product is examined between plates in Vaseline.

EXAMPLE 45 The procedure of Example 3 is followed but triethylammoniuro pyrid-2-yldithiocarbamate (33.9 g) and 2- bromo-2-methyl-l-phenylpropan-l-one (28.4 g) in anhydrous acetonitrile (175 cc) at between 20° and 25°C are used as the starting materials. The reaction is allowed to proceed for 30 minutes at 20°C. After reerystallisation of the product from acetonitrile (120 cc), 5,5-dimethyl- 44 46828 4-hydroxy-4-phenyl-3-(pyrid-2-yl)-thiazolidine-2-thione (30.1 g) , which melts at 171°C, is obtained.

EXAMPLE 46 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (36.0 g) and 2-chloro-l-(3-chlorophenyl)-ethan-l-one (31.0 g) in anhydrous acetonitrile (300 cc) at between 10° and 15°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 15°-20°C. After recrystallisation of the product from a mixture of ethanol (25 cc) and diisopropyl ether (300 cc), 4-(3-chlorophenyl)~ 4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (30.0 g), which melts at 100°C, is obtained.

When the product is examined by infra-red spectroscopy in a chloroform solution, 2 to 5% of 2-(3chlorophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1685 cm^) is observed. This band is not observed when the product is examined between plates in Vaseline. 2-Chloro-tl-(3-chlorophenyl)-ethan-l-one (b.p. 110°-115°C/0.4 mm Hg) is prepared in accordance with the method described by R.E. Lutz et al., J. Org. Chem., 12, 617 (1947).

EXAMPLE 47 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and - 45 46 8 2 9 2-bromo-l-(4-chlorophenyl)-ethan-l-one (34.6 g) in anhydrous acetonitrile (500 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After three recrystallisations of the product, successively from ethanol (300 cc) (m.p. 125°C), followed by ethyl acetate (150 cc) (m.p. 130°C) and then by ethyl acetate (240 cc), 4-(4-chlorophenyl)-4-hydroxy-3-(pyrid-2-yl)-thiazolidine2-thione (17.3 g), melting at 147°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 10% of 2-(4chlorophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1680 cm-'1') is observed. This band is not observed when the product is examined between plates in Vaseline.

EXAMPLE 48 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-chloro-l-(3-fluorophenyl)-ethan-l-one (31.8 g) in anhydrous acetonitrile (300 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation from ethanol (400 cc), 4-(3-fluorophenyl)-4-hydroxy—3(pyrid-2-yl)-thiazolidine-2-thione (31.0 g), which melts at 130°C, is obtained.

When the product is examined by infra-red - 46 46829 spectroscopy in chloroform solution, 5 to 8% of 2-(3fluorophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1690 cm is observed. This band is not observed when the product is examined between plates in Vaseline. 2-Chloro-l-(3-fluorophenyl)-ethan-l-one (m.p. 31°C) is prepared in accordance with the method described by L.G. Levkovskaya et al., Khim. Geterotsikl. Soedin., 6, 798 (1974).

EXAMPLE 49 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-chloro-l-(4-fluorophenyl)-ethan-l-one (31.8 g) in anhydrous acetonitrile (325 cc) at between 10° and 15°C are used as the starting materials. The reaction is allowed to proceed for 4 hours at 15°-20°c. After recrystallisation of the product from ethanol (250 cc), 4-(4-fluorophenyl)-4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (30.0 g), which melts at 118°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 10% of 2-(4fluorophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1680 cm-1) is observed. This band is not observed when the product is examined between plates in Vaseline. - 47 46829 2-Chloro-i-(4-fluorophenyl)-ethan-l-one (m.p. 50°C) is prepared in accordance with the method described by R.M. Hann and J.P. Wetherill,'J. Wash. Acad- Sci., 24< 526 (1934).

.... EXAMPLE 50 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-l-(2-methylphenyl)-ethan-l-one (31.5 g) in anhydrous acetonitrile (400 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from ethanol (600 cc), 2-(2-methylphenyl)-2oxoethyl pyrid-2-yldithiocarbamate (29.9 g), which melts at 130°C, is obtained. 2-Bromo-l-(2-methylphenyl)-ethan-l-one (b.p. 116°C/0.5 mm Hg) is prepared in accordance with the method described by D. Mercer et al.. J. Chem. Soc., 997 (1935).

EXAMPLE 51 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-l-(3-methylphenyl)-ethan-l-one (31.5 g) in anhydrous acetonitrile (400 cc) at 15°-20°C are used as the starting materials. The reaction is allowed to proceed for three hours at 20°C. After recrystallisation of the product from ethanol (200 cc), 4-hydroxy-4-(3- 48 4683S methylphenyl)-3-(pyrid-2-yl)-thiazolidine-2-thione (34.0 g), which melts at 106°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 10% of 2-(3methylphenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1685 cm-1) is observed. This band is not observed when the product is examined between plates in Vaseline. 2-Bromo-1-(3-methylphenyl)-ethan-l-one (b.p. 105°C/94 mm Hg), is prepared in accordance with the method described by R.M. Laird and R.E. Parker, J. Amer. Chem.

Soc., 83, 4277 (1961).

EXAMPLE 52 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-1-(4-methylphenyl)-ethan-l-one (31.5 g) in anhydrous acetonitrile (400 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from ethanol (300 cc), 2-(4-methylphenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (31.0 g), which melts : at 133°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 85 to 90% of 4-hydroxy-4-(4-methylphenyl)-3-(pyrid-2-yl)-thiazolidine2-thione (-OH and -NH bands combined from 3100 to 3500 cm'’1, reduction in intensity of the carbonyl band at - 49 46829 1680 cm ^) is observed. This form is not detected when the product is examined between plates in Vaseline.

EXAMPLE 53 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (41.5 g) and 2-bromo-l-(2-hydroxyphenyl)-ethan-l-one (33.0 g) in anhydrous acetonitrile (400 cc) at 15°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 15°-20°C. After recrystallisation of the product from ethanol (200 cc), 2-(2-hydroxyphenyl)-2oxoethyl pyrid-2-yldithiocarbamate (34.0 g), which melts at I28°C, is obtained. 2-Bromo-l-(2-hydroxyphenyl)-ethan-l-one (b.p. 117°-119°C/0.4 mm Hg) is prepared in accordance with the method described by L.C. King and G.K. Ostrum, J. Org. Chem., 29, 3459 (1964).

EXAMPLE 54 The procedure of Example 3 is followed but /triethylammonium pyrid-2-yldithiocarbamate (45.0 g) and 2-bromo-l-(2-methoxyphenyl)-ethan-l-one (38.0 g) in anhydrous acetonitrile (400 cc) at 15°C are used as the starting materials. The reaction is allowed to proceed for three hours at 15° to 20°C. After recrystallisation from ethyl acetate (350 cc), 4-hydroxy-4-(2-methoxyphenyl) 3-(pyrid-2-yl)-thiazolidine-2-thione (28.0 g), which melts at l48°C, is obtained. . - 50 46829 When the product is examined by infra-red spectroscopy in chloroform solution, about 2% of 2-(2methoxyphenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1680 cm is observed. This band is not detected when the product is examined between plates in Vaseline. 2-Bromo-l-(2-methoxyphenyl)-ethan-l-one (m.p. 45°C) is prepared in accordance with the method described by S.J. Buckman et al., German Patent Application 1174017.

EXAMPLE 55 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-l-(3-methoxyphenyl)-ethan-l-one (34.0 g) in anhydrous acetonitrile (400 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°C. After recrystallisation of the product from ethanol (300 cc), 4-hydroxy-4-(3-methoxyphenyl)~3- When the product is examined by infra-red spectroscopy in chloroform solution, about 10% of 2-(3methoxyphenyj)-2-oxoethyl pyrid-2-yldithiocarbamate (carbonyl band at 1680 cm-1) is observed. This band is not observed when the product is examined between plates in Vaseline.

EXAMPLE 56 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-l-(4-methoxyphenyl)ethan-l-one (34.0 g) in anhydrous acetonitrile (450 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from ethyl acetate (300 cc), 2-(4-methoxyphenyl)-2-oxoethyl pyrid-2-yldithiocarbamate (20-0 g), which melts at 135°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 80% of 4-hydroxy4-(4-methoxyphenyl)-3-(pyrid-2-yl)-thiazolidine-2-thione (-0H and -NH bands combined from 2700 to 3500 cm-3·, reduction in intensity of the carbonyl band at 1680 cm-3·) is Observed. This form is not detected when the product is examined between plates in Vaseline.

EXAMPLE 57 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (42.0 g1) and 2-bromo-l-(2-nitrophenyl)-ethan-l-one (38.0 g) in anhydrous acetonitrile (450 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from ethanol (600 cc), 2-(2-nitrophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate - 52 46829 (29.0 g), which melts at 126°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 50% of 4-hydroxy4-(2-nitrophenyl)-3-(pyrid-2-yl)-thiazolidine-2-thione (-0H and -NH bands combined from 2500 to 3500 cm-·1·, reduction in intensity of the carbonyl band at 1705 cm-''·) is observed. This form is not detected when the product is examined between plates in Vaseline. 2-Bromo-l-(2-nitrophenyl)-ethan-l-one (m.p. 54°C) is prepared in accordance with the method described by H. Gevekoht, Ann. Chen., 221, 323 (1883).

EXAMPLE 58 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (42.0 g) and 2-bromo-l-(3-nitrophenyl)-ethan-l-one (38.0 g) in anhydrous acetonitrile (450 cc) at between 15° and 20°C are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation of the product from ethyl acetate (500 cc), 4-hydroxy-4-(3-nitrophenyl)-3-(pyrid-2-yl)thiazolidine-2-thione (34.7 g), which melts at 155°C, is obtained. 2-Bromo-l-(3-nitrophenyl)-ethan-l-one (m.p. 90eC) is prepared in accordance with the method described by H. Korten and R. Scholl, Chem. Ber., 34, 1901 (1901).

‘ EXAMPLE 59 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (42.0 g) and 2-bromo-l-(4-nitrophenyl)-ethan-l-one (38.0 g) in anhydrous acetonitrile (450 cc) at between 15° and 20°C I . are used as the starting materials. The reaction is allowed to proceed for 3 hours at 20°C. After recrystallisation,of the product from ethyl acetate (500 cc), 4-hydroxy-4-(4-nitrophenyl)-3-(pyrid-2-yl)10 thiazolidine-2-thione (32.8 g), which melts at 160°C, is obtained.

EXAMPLE 60 The procedure of Example 16 is followed but triethylammonium pyrid-2-yldithiocarbamate (46.5 g) and 2-bromo-l-(thien-2-yl)-ethan-l-one (35.2 g) in anhydrous acetonitrile (320 cc) at between 20°t and 25°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile (180 cc), 2-oxo-2-(thien-220 yl)-ethyl pyrid-2-yldithiocarbamate (32.2 g), which melts at 131°C, is obtained. 2-Bromo-l-(thien-2-yl)ethan-l-one (b.p. 112°114°C/O.O5 mm Hg) is prepared in accordance with the method described by N.P. Buu-Hoi and Nguyen-Hoan, Rec.

Trav. Chim., 68, 441 (1949). - 54 46829 EXAMPLE 61 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (40.0 g) and 2-bromocyclohexanone (26.3 g) in anhydrous acetonitrile (300 cc) at between 18° and 25°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20° to 25°C. After recrystallisation of the product from ethanol (250 cc), 3a-hydroxy-3-(pyrid-2-yl)perhydrobenzothiazole-2-thione (23.4 g), which melts at 155°C, is obtained. 2-Bromocyclohexanone (b.p. 110o-120oC/25 mm Hg) is prepared in accordance with the method described by H.C. Brown et al., J. Amer. Chem. Soc., 90, 6218 (1968).

EXAMPLE 62 The procedure of Example 3 is followed but triethylammonium pyrid-2-yldithiocarbamate (54.2 g) and 2-bromoindan-l-one (38.9 g) in anhydrous acetonitrile (350 cc) at 20°C are used as the starting materials.

The reaction is allowed to proceed for 45 minutes at 20°C. After recrystallisation of the product from acetonitrile (1250 ee), 3a-hydroxy-3-(pyrid-2-yl)-3,3a,8,8a-tetrahydro2H-indeno[l,2-d]thiazole-2-thione (38.9 g), which melts at 160°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 10 to 15% of l-oxoindan-2-yl pyrid-2-yldithiocarbamate (carbonyl band 8 29 at 1710 cm-1) is observed. This band is not detected when the product is examined between plates in Vaseline. 2-Bromoindan-l-one (m.p. 40°C) is prepared in accordance with the method described by W.S. Johnson and W.E. Shelberg, J. Amer. Chem. Soc., 67, 1745 (1945).

EXAMPLE 63 The procedure of Example 3 is followed but triethyl ammonium pyrid-2-yldithiocarbamate (79.8 g) and 2-bromotetral-l-one (66.2 g) in anhydrous acetonitrile (750 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile (1 litre), 9b-hydroxy-l-(pyrid-2-yl)-3a,4,5,9b-tetrahydro-lHnaphtho[l,2-d]thiazole-2-thione (64.5 g), which melts at 125°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 20% of 1-oxoI, 2,3,4-tetrahydronaphth-2-yl pyrid-2-yldithiocarbamate (carbonyl band at 1685 cm~^) is observed. This band is not detected when the product is examined between plates in Vaseline. 2-Bromotetral-l-one (m.p. 4o°C) is prepared in accordance with the method described by A.L. Wilos and J. A. Johnson, J. Amer. Chem. Soc., 68, 86 (1946).

EXAMPLE 64 The procedure of Example 3 is followed but - 56 46829 triethylammonium 5-chloropyrid-2-yldithiocarbamate (21.5 g) and.l-chloropentan-2-one (8.5 g) in anhydrous acetonitrile (175 cc) at a maximum of 30°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20°-30°C. The product is purified by chromatography on silica (0.06-0.20 mm; 150 g) distributed in a column 2.8 cm in diameter. Elution is carried out with a mixture comprising cyclohexane (480 cc) and ethyl acetate (120 cc) which is removed, and then with a mixture comprising cyclohexane (1040 cc) and ethyl acetate (360 cc) which is evaporated off under reduced pressure (20 mm Hg) at 50°C. After recrystallisation of the purified product (16.5 g) from a mixture comprising acetonitrile (30 cc) and diisopropyl ether (60 cc), 3-(5chloropyrid-2-yl)-4-hydroxy-4-propylthiazolidine-2thione (10.6 g), which melts at 93°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 2 to 3% of 2-oxcpenfcyl 5-chloropyrid-2-yldithiocarbamate (carbonyl band at 1710 cm-3) is observed. This form is not detected when the product is examined between plates in Vaseline.

EXAMPLE 65 The procedure of Example 3 is followed but triethylammonium 5-chloropyrid-2-yldithiocarbamate (14.4 g.) and l-chlorohexan-2-one (6.35 g) in anhydrous acetonitrile I (120 cc) at a maximum of 30°C are used as the starting - 57 46829 ί ι materials. The reaction is allowed to proceed for 2 hours at 20° to 30°C. The product is purified by chromatography on silica (0.06-0;20 mm; 150 g) distributed in a column 2.8 cm in diameter. Elution is carried out with a mixture comprising cyclohexane (320 cc) and ethyl acetate (80 cc) which is removed, and then with a mixture comprising cyclohexane (1480 cc) and ethyl acetate (520 cc) which is evaporated off under reduced pressure (20 mm Hg) at 50°C.

After recrystallisation of the purified product (12.5 g) from a mixture comprising acetonitrile (10 cc) and diisopropyl ether (100 cc), 4-butyl-3-(5-chloropyrid-2-yl)-4hydroxythiazolidine-2-thione (9.2 g), which melts at 85°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 2 to 3% of ( 2-oxohexyl 5-chloropyrid-2-yldithiocarbamate (carbonyl band at 1710 cm-1) is observed. This form is not detected when the product is examined between plates in Vaseline.

' EXAMPLE 66 The procedure of Example 3 is followed but triethylammonium 5-chloropyrid-2-yldithiocarbamate • (22.9 g) and 2-chloro-l-cyclopentylethan-2-one (11.0 g) in anhydrous acetonitrile (180 cc) at a maximum of 30°C are used as the starting materials. The reaction is allowed to proceed for 2 hours at 20° to 30°C. After recrystallisation of the product from acetonitrile (240 cc), 40829 3-(5-chloropyrid-2-yl)-4-cyclopentyl-4-hydroxythiazolidine2-thione (21.4 g), which melts at 147°C, is obtained.

When the product is examined by infra-red spectroscopy in chloroform solution, about 5 to 8% of 2-eyelopentyl-2-oxoethyl 5-chloropyrid-2-yldithiocarbamate (carbonyl band at 1710 cm-·1·) is observed. This band is not observed when the product is examined between plates in Vaseline.

EXAMPLE 67 The procedure of Example 16 is followed but triethylammonium 5-ehloropyrid-2-yldithiocarbamate (61.1 g) and 2-chloro-l-(4-fluorophenyl)ethan-l-one (34.5 g) in anhydrous acetonitrile (600 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile (300 cc), 2-(4-fluorophenyl)-2oxoethyl 5-chloropyrid-2-yldithiocarbamate (30.4 g), which melts at 146°C, is obtained.

Wien the product is examined by infra-red spectroscopy in chloroform solution, about 80% of 3-(5chloropyrid-2-yl)-4-(4-fluorophenyl)-4-hydroxythiazolidine2-thione (reduction in intensity of the carbonyl band at 1685 cm”1) is observed. This form is not detected when the product is examined between plates in Vaseline.

EXAMPLE 68 The procedure of Example 16 is followed but triethylammonium5-chloropyrid-2-yldithiocarbamate (38.2 g) and 2-bromo-l-(4-methoxyphenyl)-ethan-l-one (28.6 g) in anhydrous acetonitrile (500 cc) at 20°C are used as the starting materials. The reaction is allowed to proceed for 1 hour at 20°C. After recrystallisation of the product from acetonitrile' (1000 cc), 2-(4-methoxyphenyl)-2oxoethyl 5-chloropyrid-2-yldithiocarbamate (38.1 g), which melts at 159°C, is obtained. - 60 46828 The present invention includes within its scope therapeutic compositions (for use in human or animal medicine) which comprise, as active ingredient, at least one of the compounds of general formula I or - when appropriate - a non-toxic salt thereof, in association with one or more compatible and pharmaceutically acceptable carriers, and optionally with other compatible and physiologically active products. The invention includes especially such preparations made up for oral, parenteral or rectal administration.

Solid compositions for oral administration include tablets, pills, powders and granules. Xn such solid compositions the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water or liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting, emulsifying and suspending agents, and sweetening, flavouring and aromatizing agents. The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active substance with or without the addition of diluents I , or excipients.

Compositions according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.

Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilizing agents, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Compositions for rectal administration are suppositories which contain, in addition to the active substance, excipients such as cacao butter or a suitable wax base. - 62 4 6 6 28 The compositions according to the invention are useful as anthelmintic compositions.

In veterinary medicine, the compounds according to the invention can be used in the treatment of helminthiases caused by nematodes in cattle, sheep, horses and goats, at doses, administered orally, of between 5 and 50 mg/kg animal body weight, for treatments of 1 to 3 days, or at doses of between 2.5 and 25 mg/kg animal body weight for treatments over more prolonged periods, as well as for the removal of gastro-intestinal strongyles in sheep and intestinal nematodes in dogs.

In human medicine, the compounds according to the invention can be used for eliminating anguillulae, aecarides and ankylostomes, at doses of between 5 and 50 mg/kg body weight, administered orally, for treatments lasting from 1 to 3 days.

The compositions according to the invention can also be particularly useful in therapy in the treatment and prevention of human filariases, namely cutaneo-dermic filariases (onchocercosis, loiasis and dracunculosis) and lymphatic filariases (wuchereriasis and brugiasis).

In human therapy, the doses depend on the desired effect and the duration of the treatment; for an adult, they are generally between 10 and 50 mg/kg body weight per day, administered orally, and between 5 and mg/kg body weight per day, administered intramuscularly, for treatments lasting from 1 to 30 days.

In general the physician or the veterinary surgeon will determine the posology considered appropriate, taking into account the age and weight and all other factors intrinsic to the subject being treated.

The following Examples illustrate therapeutic compositions according to the invention.

EXAMPLE 69 Tablets containing 25 mg of active compound and having the following composition are prepared in accordance with the usual technique: 3,3-dimethyl-2-oxobutyl 5-chloropyrid2-yl-dithiocarbamate 25 mg com starch 125 mg colloidal silica 45 mg magnesium stearate 5 mg.

EXAMPLE 70 Tablets containing 25 mg of active compound 20 and having the following composition are prepared in accordance with the usual technique: 4-hydroxy-4-methyl-3-(pyrid-2-yl)thiazolidine-2-thione 25 mg - 64 46829 corn starch 125 mg colloidal silica 45 mg magnesium stearate 5 mg

Claims (22)

1. CLAIMS wherein represents a hydrogen or halogen atom located in the 4-, 5- or 6-position of the pyridyl radical, Rg represents a hydrogen atom, an alkyl radical containing J 1 to 8 carbon atoms, an alkyl radical which contains 1 to 4 carbon atoms and is substituted by 1, 2 or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, acyloxy, acyloxyalkoxy or acyloxyalkylthio radical, or Rg represents a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a phenyl radical which is optionally substituted by a halogen atom or by an alkyl, alkoxy, hydroxy or nitro radical, or a thien-2-yl radical or an alkoxycarbonyl radical, Rg represents a hydrogen atom, or an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical, or Rg and Rg together represent an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms can form part of a benzene ring, and represents a hydrogen atom or an alkyl radical, it being understood that the alkyl radicals, - 66 46829 and alkyl and acyl moieties of any of the aforementioned groups, have straight or branched chains and that, unless specifically indicated, they contain from 1 to 4 carbon atoms, and salts thereof when R 2 represents a carboxyalkyl radical.

2. Compounds according to claim 1 which, in predominant form in the crystalline state, correspond to general formula 1(A) wherein (a) R 2 represents a hydrogen atom, or an alkyl radical containing 1 to 3 carbon atoms or the n-butyl radical (these radicals being optionally substituted by 1, 2 or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, acyloxy, acyloxyalkoxy or acyloxyalkylthio radical), an alkyl radical which contains 5 to 8 carbon atoms and is straight or branched in a position other than the 1- or 2-position, a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a 3-nitrophenyl or 4-nitrophenyl radical or an alkoxycarbonyl radical, Rg is defined as in claim 1 with the proviso that it does not,form, together with R 2 , an alkylene radical in the chain of which two adjacent carbon atoms form part of a benzene ring, and R^ and R x are as defined in claim 1; or (b) R 2 represents a phenyl radical (which is optionally substituted in the 2-, 3- or 4-position by a halogen atom, in the 2- or 3-position by an alkoxy radical, in the 3- 67 ( or 4-position by a hydroxy radical or in the 3-position by an alkyl radical), and either R 3 represents a hydrogen arom, or an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical or forms, together with Rj, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms form part of a benzene ring, R^ is as defined in claim 1 and R^ represents a hydrogen atom, or R 3 represents an alkyl, acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical or forms, together with R^, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms form part of a benzene ring, R^ represents an alkyl radical and R^ represents a halogen atom, and - when appropriate - salts thereof.

3. Compounds according to claim 1 which, in predominant form in the crystalline state, correspond to general formula 1(B) wherein ' V (a) R 2 re presents an alkyl radical which contains 4 to 8 carbon atoms and is branched in the 1- or 2-position, a branched butyl radical which is substituted by 1, 2 or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, acyloxy, acyloxyalkoxy or acyloxyalkylthio radical, or R 2 represents a phenyl radical which is substituted in the 2-position by a hydroxy, alkyl or nitro radical or in the 4-position by an alkyl or '•1 alkoxy radical, or a thien-2-yl radical, Rg is as defined in claim 1 with the proviso that it does not form, together with Rg, an alkylene radical which may or may not be involved in a benzene ring, and and Rg are as defined in claim 1?.or (b) Rg represents a phenyl radical which is optionally substituted in the 2-, 3- or 4-position by a halogen atom, in the 2- or 3-position by an alkoxy radical, in the 3- or 4-position by a hydroxy radical or in the 3-position by an alkyl radical, Rg represents a hydrogen atom, or an alkyl» acyloxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl radical or forms, together with Rg, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms form part of a benzene ring, Rg represents a halogen atom and R^ represents a hydrogen atom, and - when appropriate - salts thereof.

4. Compounds according to claim 1 in which (a) Rg represents a hydrogen atom, and either Rg and R^ represent hydrogen atoms and Rg represents a hydrogen atom» an alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by 1, 2 or 3 halogen atoms or by a phenyl, hydroxy, alkoxy, alkylthio, carboxy, alkoxycarbonyl or acyloxy radical, or Rg represents a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, 468 29 ,/ ι ι ' a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy or nitro radical, or a thien-2-yl radical or an alkoxycarbonyl radical, or Rg represents an alkyl radical which is optionally substituted by an acyloxy radical, or an alkoxycarbonyl radical, R^ represents a hydrogen atom or an alkyl radical and Rg represents a hydrogen atom, an alkyl radical or a phenyl radical, or Rg forms, together with Rg, an alkylene radical which contains 3 or 4 carbon atoms and in the chain of which two adjacent carbon atoms can form part of a benzene ring, and represents a hydrogen atom, or (b) R^ represents a halogen atom, Rg represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and Rg and R^ represent hydrogen atoms, it being understood that the alkyl radicals are straight or branched and that, unless specifically indicated, the alkyl radicals and moieties thereof of other groups contain f 5 1 or 2 carbon atoms, and - when appropriate - salts thereof.

5. Compounds according to claim 1 in which (a) and R^ each represent a hydrogen atom, and either Rg represents a hydrogen atom and Rg represents an alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by a phenyl, alkoxy, alkylthio, methoxycarbonyl or carboxy 46628 radical, or R 2 represents a cycloalkyl radical containing 5 or 6 carbon atoms, a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy or nitro radical, or a thien-2-yl radical, an alkoxycarbonyl radical or a trifluoromethyl radical, or Rg represents a methyl or methoxycarbonyl radical and R 2 represents a methyl or phenyl radical, or R^ forms, together with R 2 , a tetramethylene radical in the chain of which the carbon atoms located in the a- and β-positions to the carbon atom carrying R 2 form part of a benzene ring, or (b) R^ represents a halogen atom, R 2 represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and Rg and R^ each represent a hydrogen atom, it being understood that the aforementioned alkyl radicals are straight or branched and that, unless specifically indicated, the alkyl radicals and moieties thereof of other groups contain 1 or 2 carbon atoms, and - when appropriate - salts thereof.

6. Catipounds according to claim 1 in which Κ χ and R^ each repri a hydrogen atan, (a) « 3 represents a hydrogen atan and R represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkyl radical which contains 1 or 2 carbon atoms and is substituted by a phenyl, hydroxy, alkoxy, alkylthio, alkoxycarbonyl, acetoxy or carboxy radical, or R 2 represents a cyclohexyl radical, a phenyl radical which is optionally substituted by a halogen atom or by a methyl, methoxy or '\ hydroxy radical, or a thien-2-yl radical, an alkoxycarbonyl radical or a trifluoromethyl radical, or (b) represents a methyl or methoxycarbonyl radical and R^ represents a methyl radical, or (e) R 3 forms, together with R 2 , a tetramethylene radical, the aforementioned alkyl radicals and moieties thereof of other groups containing 1 or 2 carbon atoms, and - when appropriate - salts thereof.

7. Compounds according to claim 1 in which is as defined in claim 1, R 2 represents a hydrogen atom, an alkyl radical which contains 1 to 4 carbon atoms, or the benzyl or phenyl radical, and R^ and R^ are identical and each represents a hydrogen atom or an alkyl radical which contains 1 to 4 carbon atoms.

8. Compounds according to claim 1 wherein R^, R^ and R^ represent hydrogen atoms and R 2 represents the methyl radical.

9. The compound according to claim 8 which is 4-hydroxy-4-methyl-3-(pyrid-2-yl)-thiazolidine-2-thione.

10. Compounds according to claim 1 wherein represents a chlorine atom in the 5-position of the pyrid-2-yl radical, R 2 represents the t-butyl radical and Rj and R 4 represent hydrogen atoms.

11. The compound according to claim 10 which is 3,3-dimethyl-2-oxobutyl (5-chloropyrid-2-yl)dith'iocarbamate. - 72 46829

12. The compounds according to claim 1, which are 4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione and 4-ethyl-4hydroxy-3~(pyrid-2-yl)-thiazolidine-2-thione.

13. Compounds according to claim 1 wherein R^, Rg and R 4 represent hydrogen atoms and Rg represents the phenyl, 3- chlorophenyl, 3-methoxyphenyl, cyclohexyl, 3-methylphenyl, 4- methoxyphenyl, thien-2-yl, phenethyl or 2-nitrophenyl radical, or R^ represents a chlorine atom in the 5-position of the pyridyl radical, Rg represents the phenyl radical and Rg and represent hydrogen atoms.

14. Compounds according to claim 1 wherein Rg , Rg and R 4 represent hydrogen atoms and Rg represents the ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-octyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, acetoxymethyl, carboxyethyl, 4-fluorophenyl, 4-methylphenyl, 2-hydroxyphenyl or ethoxycarbonyl radical; or Rg and R 4 represent hydrogen atoms and (i) Rg and Rg represent methyl radicals, or (ii) Rg represents the methyl radical and Rg represents the methoxycarbonyl radical, or (iii) Rg and Rg together represent the tetramethylene radical.

15. Compounds according lo claim 1 identified by name in any of the foregoing Examples and not claimed in any one of claims 8 to 14.

16. A process for the preparation of a compound of general formula I defined in claim 1, or a salt thereof when R 2 represents a carboxyalkyl radical, which comprises reacting a compound of the general formula: i 3 R 2 -CO-C-X XI R 4 wherein R 2 , R-j and R 4 are as defined in claim 1 and X represents a halogen atom (and which can be in the form of a salt when R 2 is a carboxyalkyl radical), with a dithiocarbamate of the general formula: 1 q © III NH CS-S .HN (R 5 ) 3 (wherein is as defined in claim 1 and the symbols R^, which are identical or different, each represent an alkyl radical containing 1 to 4 carbon atoms) and optionally, when R 2 in the compound thus obtained of general formula I represents a carboxyalkyl radical, converting the compound into a metal salt or an addition salt with a nitrogencontaining base. 74 46829

17. A process according to claim 16 wherein X represents a bromine or chlorine atom.

18. A process according to claim 16 or 17 in which the reaction is carried out in an organic solvent, in water or in an aqueous-organic medium, at a temperature between -10° and +50°C.

19. A process for the preparation of a compound of general formula I defined . in claim 1 substantially as hereinbefore described with especial reference to any one of Examples 1 to 68.

20. Compounds of general formula I defined in claim 1 when prepared by the process claimed in any one of claims 16 to 19.

21. Therapeutic compositions which comprise, as active ingredient, at least one compound claimed in any one of claims 1 to 15, or - when appropriate - a non-toxic salt thereof, in association with one or more compatible and oha-rmaceutically-acceptable carriers, and optionally with oth-'r compatible and physiologically active products.

22. Therapeutic compositions according to claim 21 substantially as hereinbefore described with especial reference to Example 69 or 70.