CA1093078A - No translation available - Google Patents

Abstract

New derivatives of hydroxy-4 thiazolidinethione-2, corresponding to the general formula: (A) (B) in which R1 represents a hydrogen or halogen atom located in position -4, -5 or -6; R2 represents a hydrogen atom or an alkyl radical containing 1 to 8 carbon atoms, an alkyl radical containing 1 to 4 carbon atoms substituted (by 1 to 3 halogen atoms or by a phenyl, hydroxy, alkyloxy, alkylthio radical , carboxy, alkyloxycarbonyl, alkyloxycarbonylalkoyloxy, alkyloxycarbonylalkoylthio, acyloxy, acyloxyalkyloyl or acyloxyalkylthio), a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, an alkyl radical or an alkyl radical , hydroxy or nitro), a 2-thienyl radical or an alkyloxycarbonyl radical; R3 represents a hydrogen atom, an alkyl, acyloxyalkyl, alkyloxycarbonylalkyl or alkyloxycarbonyl radical, or forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 adjacent carbon atoms may be part of a benzene ring; and R4 represents a hydrogen atom or an alkyl radical; it being understood that the alkyl and acyl radicals and portions mentioned above are straight or branched and that, unless otherwise mentioned, they contain from 1 to 4 carbon atoms; and their pharmaceutically acceptable salts when R2 represents a carboxyalkyl radical. The derivatives according to the invention are particularly useful as anthelmintics.

Description

9; ~ (37 ~

The present invention relates to new derivatives 4-hydroxy thiazolidinethione-2, of general formula:

RR

3 ~ R ~ - ~ \\ 3 ~ R (I) (A) (B) : in which:
Rl represents a hydrogen or halogen atom located in position -4, -5 or -6, R2 represents a hydrogen atom or an alkyl radical containing 1 to 8 carbon atoms, an alkyl radical containing 1 to 4 substituted carbon atoms (with 1 to 3 halogen atoms : or by a phenyl, hydroxy, alkyloxy, alkylthio radical, carboxy, alkyloxycarbonyl, alkyloxycarbonylalkoyloxy, alkyloxycarbonylalkoylthio, acyloxy, acyl.oxyalcoyloxy or acyloxyalcoylthio), a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a radical phenyl (optionally substituted by a halogen atom . 20 or by an alkyl, alkyloxy, hydroxy or nitro radical), a r ~ dical thienyl-a or an alkyloxycarbo radical-nyle, R3 represents a hydrogen atom, an alkyl radical, acyloxy-alkyl, alkyloxycarbonylalkyl or alkyloxycarbonyl, or forms with R2 an alkylene radical containing 3 or 4 atoms of carbon in the chain of which 2 adjacent carbon atoms can be part of a benzene cycle, and R4 represents a hydrogen atom or an alkyl radical, it being understood that the alkyl and acyl radicals and portions mentioned above are straight and that, unless otherwise stated special, they contain from 1 to 4 carbon atoms. The invention : tion also targets a prepax-ation process for these new .

9; ~ 78 derivatives.
The products according to the invention can be presented in one of the forms (IA) or (IB) or as a mixture in - balance of these two forms, according to internal parameters (in particular radicals Rl and R2) or external (in particular presence solvent), as will be shown below.
This existence of the two forms (IA) and (IB) of 4-hydroxy-thiazolidinethiones-2 is well known and has done The subject of various publications, in particular by RW LAMON
et al., J. Org. Chem., 29, 2146 (1964) and J. Het. Chem., 4, 349 (1967).
Generally, the general formula (IA) corresponds in the preponderant form, in the crystallized state, of the products for which:
(a) R2 represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms or n.butyl (these radicals being optionally substituted by 1 to 3 halogen atoms or by a phenyl, hydroxy, alkyloxy, alkylthio radical, ; carboxy, alkyloxycarbonyl, alkyloxycarbonylalkoyloxy, alkyloxycarbonylalkoylthio, acyloxy, acyloxyalcoyloxy, acyloxyalcoylthio), an alkyl radical containing 5 to 8 atoms straight or branched carbon in position other than 1 or 2, a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a nitro-3 or nitro-4 radical phenyl or an alkyloxycarbonyl radical, R3 has the meanings given above except to form with R2 an alkylene radical in the chain of which

2 adjacent carbon atoms are part of a benzene ring, and R4 and R1 have the meanings given above;
(b) R2 represents a phenyl radical (optionally substituted in position 2, -3 or -4 by a halogen atom, in position 109; ~ 8 -2 or -3 by an alkyloxy radical, in posi-tion - ~ or -4 by a hydroxy radical or in position -3 by an alkyl radical) and : - either R3 represents a hydrogen atom, an alkyl radical, acyloxyalkyl, alkyloxy ~ arbonylalkyl or alkyloxycarbonyl, or forms with R2 an alkylene radical containing 3 or 4 atoms of carbon in the chain of which 2 has adjacent carbon atoms are part of a benzene cycle, R4 has the meanings given above and Rl represents a hydrogen atom, either R3 represents an alkyl or acyloxyalkyl radical, alkyloxycarbonylalkyl or alkyloxycarbonyl, or form with R2 an alkylene radical containing 3 or 4 carbon atoms in whose chain 2 adjacent carbon atoms are found part of a benzene cycle, R4 represents an alkyl radical and R1 represents a halogen atom.
Generally, the general formula tIB) corresponds in the preponderant form, in the crystallized state, of the products for which:

(a) R2 represents an alkyl radical containing 4 to 8 atoms of branched carbon in position -1 or -2, a butyl radical substituted substituted (by 1 to 3 halogen atoms or by a phenyl, hydroxy, alkyloxy, alkylthio, carboxy radical, alkyloxycarbonyl, alkyloxycarbonylalkoyloxy, alkyloxy-carbonylalcoylthio, acyloxy, acyloxyalcoyloxy, acyloxyalcoyl-thio), a substituted phenyl radical (in position -2 with a hydroxy, alkyl or nitro radical, or in position -4 with a an alkyl or alkyloxy radical) or a 2-thienyl radical, . R3 has the meanings given above except to form with R2 an alkylene radical associated or not with a henzenic cycle, and R4 and R1 have the meanings given previously;

1 (. ~ 93 ~ '78 (b) R2 is ur- phenyl radical (optionally substituted in position -2, -3 or -4 by a halogen atom, in position -2 or -3 by an alkyloxy radical, in position -3 or -4 by a hydroxy radical, or in position -3 by an alkyl radical), R3 represents a hydrogen atom, an alkyl radical, acyloxyalkyl, alkyloxycarbonylalkyl, alkyloxycarbonyl, or forms with R2 an alkylene radical containing 3 or 4 a.-tornes of carbon in the chain of which 2 has adjacent carbon atoms are part of a benzene cycle, Rl represents a halogen atom and R4 represents a hydroxogen atom.
According to the invention, the new products of formula general (I) its obtained by the action of a halogen ketone which can be prepared in situ, of general formula:

R2 ~ C0 - C - X (II) R ~
in which R2, R3 and R4 are defined as above and X represents a halogen atom, preferably an atom bromine or chlorine (possibly in the form of salt when R2 is a carboxyalkyl radical), on a dithio-carbamate of general formula:

NH CS-S (), ~) (R5) 3 (III) in which Rl is defined as above and the symbols R5 (which are identical or different) each represent a alkyl radical containing 1 to 4 carbon atoms.
Generally, the reaction is carried out in a solvent organic (such as dimethylformamide or acetonitrile), in water or in a hydroorganic medium (for example in a mixture of water ~ dimethylformamide or water-acetonitrile) at one lOg3 ~ 78 temperature between -10 and + 15C.
The dithiocarbamates of general formula (III) can be obtained, according to the method described by EB I ~ OTT, J. Chem.
soc ~ 1644-9 (195 ~), by the action of carbon sulfide in presence of a tertiary amine on a 2-amino pyridine of general formula:

r ~~ (IV) ~ NJ 2 in which Rl is defined as above, or according to the method described by DB, CAPPS in US Patent 3,726,880.
The ~ -haloketones of general formula (II) can be prepared by application of various general methods described in the literature, which are taken up in more detail in the examples.
The new products according to the present invention can optionally be purified by physical methods such as crystallization or chromatography.
The new products according to the invention can possibly be transformed into metallic salts or into salts addition with a nitrogenous base when R2 represents a carboxyalkyl radical. ~ These salts can be obtained by action of a metal base (in particular alkaline or alkaline-earthy), ammonia or nitrogenous base, in a solvent suitable such as alcohol, ether or water, or by reaction of ec ~ angel with a salt of an organic acid. The salt formed precipitated after possible concentration of its solution, it is separated by filtration or decantation.
The new products according to the invention, and possible-their salts are particularly active as anthelmin-broad spectrum ethics on nematodes.
Their activity could be highlighted nota ~ ment in mice on Nematospiroides dubius at doses included between 5 and 200 mg / kg orally.
In addition, the majority of the products according to the invention have been active on cotton rat filariasis in Litomosoides carinii in doses between 25 and 100 mg / kg orally per day during a treatment of 5 consecutive days.
Some have also been active in the dog at doses between 10 and S0 mg / kg per route oral on Ankylostoma caninum and Uncinaria stenocephale and at doses between 5 and 50 mg / kg orally on Toxocara canis or Toxascaris leonina.
The toxicity of the products according to the present invention expressed by their lethal dose 50% (LD50) is between 200 mg / kg orally in mice and higher at 1000 mg / kg orally.
Are of particular interest for their level ~ ", of activity, the products of general formula (I) for which:
(a) R1 represents a hydrogen atom, - R3 and R4 represent a hydrogen atom and - R2 represents a hydrogen atom, or an alkyl radical containing 1 to 8 atoms of earbone, a radieal aleoyle containing 1 or 2 atoms of substituted earbone (by 1 to 3 halogen atoms or by a phenyl, hydroxy, alkyloxy, alkylthio, carboxy, alkyloxycarbonyl or acyloxy), an eyelo- radical alkyl containing 3 to 6 carbon atoms, a cyclo radical hexenyl, Ull phenyl radical (optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy radical or nitro), a 2-thienyl radical or an alkyloxycarbon radical .,.
nyle, or - R3 represents an alkyl radical (optionally substituted by an acyloxy radical) or an alkyloxycarbonyl radical, R4 1 ~ 9; ~

represents a hydrogen atom or an alkyl radical and R2 represents a hydrogen atom, an alkyl radical or a xadical ph ~ nyle, or - R3 forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 carbon atoms adjacent can be part of a benzene ring and R4 represent a hydrogen atom, or (b) Rl represents a halogen atom, R2 represents a radical alkyl containing 1 ~. 4 carbon atoms or phenyl and R3 and R4 represent hydrogen atoms, (it being understood that the alkyl radicals are straight or branched and that, unless otherwise stated, the alkyl radicals and portions contain 1 or 2 carbon atoms).
Among these are more especially active in particular on Nematospiroides dubius the products of general formula (I) for which :
(a) Rl and R4 each represent a hydrogen atom, - R3 represents a hydrogen atom, and R2 represents a alkyl radical containing 1 to ~ 3 carbon atoms, a radical alkyl containing 1 or 2 carbon atoms substituted (by a phenyl, alkyloxy, alkylthio, methoxycarbonyl or carboxy), - a cycloalkyl radical containing 5 or 6 atoms of carbon, a phenyl radical (optionally substituted by a halogen atom or by a methyl, methoxy, hycroxy radical or nitro), a 2-thienyl radical, an alkyloxycarbonyl radical, or a trifluoromethyl radical, or - R3 represents a methyl or methoxy carbonyl radical and R2 represents a methyl or phenyl radical, or - R3 forms with R2 a tetramethylene radical in the chain of which the carbon atoms located in ~ and ~ of the atom of carbon bearing R2 belong to a benzene ring, or good 0 ~ 78 (b) R1 represents a halogen atom, R2 represents an alkyl radical containing 1 ~ 4 atoms of carbon or phenyl and R3 and R4 each represents a hydrogen atom it being understood that the alkyl radicals mentioned above are straight or branched, and that, unless otherwise noted, radicals and alkyl portions contain 1 or 2 carbon atoms.
Among these, the products in the formula of which the symbols have the following meanings are particularly 10 worthy of interest:

!
. ' ¦ Rl R2 R3 R4 C1 - (- 5 (CH3) 3c- H- j H-¦ H- ~ ~ H-H- Cl ~ Cl- ~ -5) ~ _ - ~ H-H- ~ _ - H-H- O H- H-H- ~ _ - H-H- CH3-0- ~ - H- H-1 ~ 9 ~ 7 ~ 3 r - ~ - i 1 ~ 2 R3 ¦ 4 H- ~ ~ H- H-H- ~ ~ -CH2CH2- H- H-1 ~ _ ~ H- ~~

These are also shown to be interesting for their : good activity on cotton rat filariasis at Litomosoides carinii, on macrofilaires and microEilaires the products of general formula (I) for which:
R1 and R4 each represents a hydrogen atom and (a) R3 represents a hydrogen atom, and R2 represents a straight or branched alkyl radical containing 1 to 8 atoms of carbon an alkyl radical containing 1 or 2 carbon atoms substituted (by a phenyl, hydroxy, alkyloxy, alkylthio radical, alkyloxycarbonyl, acetoxy or carboxy), a cyclohexyl radical, a phenyl radical (optionally substituted by an atom halogen, or by a methyl, methoxy or hydroxy radical), a thienyl-2 radical, an alkyloxycarbonyl radical or a radical : trifluoromethyl, or (b) R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl radical or (c) R3 forms with R2 a tetramethylene radical, the radicals and alkyl portions mentioned above comprising 1 or 2 carbon atoms. Among these products, more particular-the products of general formula (I) in which the radicals have the following meanings:

_ g _ ~ 3 ~ 7 ~ 3 T

EI- 'CH3- H- H-H- 1 3 7 ¦ H- H-H- '4 9 ~ H-H- -t. C ~ Hg- H- H-H- n. C8H17- H-H- CF3 H- I Il-II- ~ - (CH2) 2- H- H-H- HO CH2- H- 'H--H- CH3 0 CH2- H- i H-H- CH3 S CH2- EI- j H-H- CH300C (CH2) 2 H- H-H- CH3CH2ooc CH2 H- H-H- ~ IOOC (CH2) 2- H- d H-H- C ~~ H- I II-/ == ~ ^
: H- ~ ~ H- H-H- F- ~ - H- H-H- ~ _ H- H-H CH3- ~ ~ H- I H-!

3 ~ 78 R2 ¦ i l ~ l H- ~ H3 0 H- H-E ~ CH 0 ~ H-- H--H \ 1 ~ H H- EI-o ~ _ i ~

H- CH3- C ~ 13- H-____ ..
The following examples, given without limitation, illustrate the present invention.
Example 1 -To a solution of 65.4 g of 2-pyridyl dithiocarbamate of triethyl ammonium in 300 cm3 of dimethylfo ~ mamide, we add, at 10C, 37.7 g of a 50% aqueous solution (by weight) of chloroacetaldehyde. The reaction is continued for 16 hours at 20C. After evaporation of the solvents under pressure reduced (0.1 mm of mercury) to 50C, the residual oil is treated with 750 cm3 of chloroform. The chloroform solution is washed twice with 200 cm3 in total of distilled water, dried over sodium sulfate and evaporated. The residue oily (38 g ~ is dissolved in 180 cm3 of boiling ethanol and 180 cm3 of boiling isopropyl ether and 1 g of bleaching black. After filtration of the boiling solution : 1 ~ 9 ~ 7 ~ 3 then 2 hours of cooling ~ 2c, the crystals appeared are separated by filtration, washed with 50 cm3 in total of frozen mixture of 25 cm3 of ethanol and 25 crn3 of iso- oxide propyl and dried under reduced pressure (0.1 mm of mercury) at 45C. 17.8 g of hydroxy-4 (pyridyl-2) -3 are thus obtained thiazolidinethione-2 melting at 110C.
Pyri ~ yl-2 triethylarnmonium dithiocarbamate (PF - 95C) is prepared according to the method described by EB
~ Ol'T, J. Chem. Soc. 1644-49 (1956).
Example 2 -To a suspension of 54.2 g of pyridyl-2 dithio-triethylammonium carbamate in 300 cm3 of distilled water, 27.4 g of bromo-2 propanal are added around 15-17C. The reaction is continued for 35 minutes at 20C? Water is eliminated by decantation, the pasty product obtained is treated with 250 cm3 of ethanol. After filtration and evaporation of the solvent under reduced pressure (20 mm of mercury) at 40C, the oil residual (48.3 g) is dissolved in 400 cm3 of chloroform, the solution is filtered through 350 g of silica (0.2-0.5 mm) contained in a column 4.5 cm in diameter. We elect with 3.6 liters of chloroform. After evaporation of the solvent under reduced pressure (20 mm of mercury) at 40C, the product obtained (13.3 g, PF = 107C) is dissolved in a boiling mixture formed of 200 crn3 of methylcyclohexane and 55 cm3 of ethanol.
After filtration of the boiling solution, then cooling at 20C, the crystals which appear are separated by filtration, washed with 50 cm3 of methylcyclohexane and dried under pressure reduced (0.1 mm of mercury) to 55C. This gives 10.3 g hydroxy-4 methyl-5 (pyridyl-2) -3 thiaæolidinethione-2 fondant at 112C.
Bromo-2 propanal (PEloo = 4 ~ -62C) is prepared according to the method described by JJ RIE ~ IL, Acadian Reports.

105 ~ 78 Sci., C, 245, 1321 (1 ~ 57).
Example 3 -To a suspension of 71.2 g of 2-pyridyl dithiocarba-triethylammonium mate in 330 cm3 of anhydrous acetonitrile 39.7 g of 2-methyl-2-propanal bromo are added at about 5C. The reaction is continued for 1 hour at 20C. Hydrobromide insoluble triethylamine is removed by filtration. Aceto-nitrile is evaporated under reduced pressure (20 mm of mercury) at 40C. The residual oil is treated with 300 cm3 of chloride methylene. The organic solution is washed twice with 100 cm3 in total of distilled water, dried over sulphate sodium and evaporated. The product obtained (60 g) is dissolved in 300 cm3 of methylene chloride, the solution is filtered on 850 g of silica (O, 2-0,5rl ~ n) contained in a column of 5 cm in diameter. Eluted with 9 liters of chloride methylene. After evaporation of the solvent under reduced pressure (20 mm of mercury) at 40C, the product obtained (50 g) is dissolved in 150 cm3 of boiling methylcyclohexane. After 4 p.m.
cooling to 2C, the crystals that appear are separated by filtration, washed with 50 cm3 of methylcyclohexane and dried under reduced pressure (0.1 mm of mercury ~ at 40C. We obtain thus 44.1 g of 5,5-dimethyl-4-hydroxy (2-pyridyl) -3 thiazol-idinethione-2 melting at 80C.
2-bromo-2 methyl propanal (PE760 = 112C) is prepared according to the method described by CL STEVENS, BT GILUS, J.
Am. Chem. Soc. 79, 3448 (1957).
Example 4 -The procedure is as in Example 2 but from 40.6 g 2-pyridyl triethylammonium dithiocarbamate and 14.0 g of chloroacetone in 250 cm3 of distilled water at 20C. The reaction is continued for 2 hours at 20C. After ; recrystallization from 40 cm3 of ethanol, 20.0 g are obtained ~ 09; ~ 7 ~

of hydroxy-4 ml ~ thyl-4 (pyridyl-2) -3 thiazolidinethione-2 melting at 122C.
Example 5 -To a suspension of 44.5 g of 5-chloro-pyridyl-2 triethylammonium dithiocarbamate in 180 cm3 of dimethyl-formamide 13.5 g of chloroacetone are added to 2C. The reaction is continued for 45 minutes at 2C. Chlor-insoluble triethylamine hydrate is removed by filtration and washed with 20 crn3 of dimethylformamide. Dimethylformamide 10 (filtrate and washing) is evaporated under reduced pressure (0.1 mm of mercury) at 45C, the residual oil is treated with 400 cm3 ethyl acetate. The organic solution is washed two times per 100 cm3 in total of distilled water, dried on sodium sulfate and evaporated. The product obtained (41 g) is dissolved in 100 cm3 of boiling ethanol. After 4 hours of cooling to 2C, the crystals which appear are separated by filtration, washed twice with 15 cm3 in total of frozen ethanol and dried under reduced pressure (0.1 mm of mercury) at 45C.
16.8 g of (5-chloro-pyridyl-2) -3-hydroxy-4 are thus obtained 4-methyl-thiazolidinethione-2 melting at 95C.
5-chloro-2-pyridyl-dithiocarbamate ammonium (PF = 130C) is prepared according to the method described by DB CAPPS in US Patent 3,726,880.
Example 6 -The procedure is as in Example 5 but ~ from 66.0 g 2-pyridyl-triethylammonium dithiocarbamate and 26.0 g of 3-chloro-butanone-2 in 300 cm3 of dimethylformamide . at 20C. The reaction is continued for 30 minutes at ~. 20C. After recrystallization from 540 cm3 of ethanol, obtains 48.5 g of 4,5-dimethyl-4-hydroxy (2-pyridyl) -3 thiazol-idinethione-2 melting at 159C.

Example 7 _ The procedure is as in Example 3 but from 27.0 g 2-pyridyl triethylammonium dithiocarbamate and 16.5 g of 3-bromo-3-methyl-2-butanone in 400 cm3 of anhydrous acetonitrile at 20C. The reaction is continued for 30 minutes at 20C.
After recrystallization from 200 cm3 of ethanol, one obtains 15.0 g of hydroxy-4 (pyridyl-2) -3-trimethyl-4,5,5 thiazolidine-thione-2 fondant ~ 146C.
3-bromo-3-methyl-butanone-2 (PE40 = 55-57C) is prepared according to the method described by JR CATCH et al., J.
Chem. Soc. 276 (1948).
Example 8 The procedure is as in Example 3 but from 40.0 g 2,1-pyridyl dithiocarbamate triethylammonium and 22.1 g methyl chloro-2 oxo-3 butanoate in 270 cm3 of acetoni-anhydrous trile at 25C maximum. The reaction is continued for 3 hours at 20-25C. After recrystallization from a mixture of 30 cm3 of ethanol and 130 cm3 of isopropyl ether, we obtain 23.6 g of / 4-hydroxy-methyl-4 (pyridyl-2 ~ 3 thioxo-2 thiazolidinyl-~ Methyl carboxylate melting at 95C.
Example 9 -The procedure is as in Example 3, starting from 50.0 g 2-pyridyl triethylammonium dithiocarbamate and 32.9 g 3-chloro-oxo-4 pentyl acetate in 250 cm3 of acetonitrile anhydrous at 29C maximum. The reaction is continued for 2 hours at 20-29C. After recrystallization from a mixture of 50 cm3 of ethanol and 210 cm3 of isopropyl ether, we obtain 46.0 g of ~ 4-hydroxy-methyl-4 (pyridyl-2) -3 thioxo-2 acetate thiazolidiny] - ~ J-2 ethyl melting at 98C.
Example 10 -We operate as in Example 3 but from 21, ~ g 2-pyridyl-triethylarnmonium dithiocarbamate and 17.9 g lQ9; ~ 78 methyl bromo-4 oxo-5 hexanoate in 200 cm3 of aceto-anhydrous nitrile at 30C maximum. The reaction is continued for 2 hours at 20-30C. After recrystallization in a mixture of 10 cm3 of methylene chloride and 70 cm3 of ether ethyl, we obtain 20.4 g of / hydroxy ~ 4 methyl-4 (pyridyl-2) -3 thioxo-2 thiazolidinyl- ~ J-3 methyl propionate fondant at 86C.
23.0 g of bromo-4 oxo-5 hexanoate are obtained.
methyl (PEo 2 = 94C) per action of 5.4 g of diazomethane on 26.5 g of bromo-4 oxo-5 hexanoic acid in 200 cm3 of ethyl ether towards 5C.
Bromo-4 oxo-5 hexanoic acid (oily) is prepared according to the method described by RY LEVINA et al., CA 51 14704 h (1957).
Example 11 -The procedure is as in Example 5 but from 64.0 g 2-pyridyl triethylammonium dithiocarbamate and 25.6 g of chloro-l butanone-2 in 300 cm3 of dimethylformamide at 30C
maximum. I, the reaction is continued for 30 minutes at 25-30C.
After recrystallization from a mixture of 75 cm3 of ethanol and 75 cm3 of isopropyl ether, 29.9 g of 4-hydroxyethyl-

4 (pyridyl-2) -3 thiazolidinethione-2 melting at 113C.
Chloro-l butanone-2 (P.E760 = 119-122C) is prepared rée according to the method described by PJ AS ~ ORTH et al., J. Chem.
Soc. 4633 (1957).
Example 12 -The procedure is as in Example 5 but from 65.0 g 2-pyridyl-triethylammonium dithiocarbamate and 29.0 g of chloro-l pentanone-2 in 300 cm3 of dimethylformamide to 25C maximum. The reaction is continued for 2 hours at ; 20-25C. After recrystallization in a mixture of 75 cm3 ethanol and 75 cm3 of isopropyl ether, 41.5 g are obtained lQ ~ 7 ~

4-hydroxy-propyl-4 (pyridyl-2) -3 thiazolidinethione-2 fondant at 88C.
Chloro-l pentanone-2 ~ PE30 = 65-67C) is ?, pr, ~ par / ~ e according to the method described by RD ~ WORTI-I et al., ; J. Chem. Soc., 3617 (1954).
; Exe ~ 13 -The procedure is as in Example 5 but ~ from 43.2 g ? of pyridyl-2 dithiocarbamate of tricthylammonium and of 19.8 g of chloro-l ms ~ thyl-3 butanone-2 in 210 cm3 of dimethylformami-from to 20C. The reaction is continued for 2 hours at 20C.
After recrystallization from a mixture of 35 cm3 of ethanol and 75 cm3 of isopropyl ether, 33.8 g of hydroxy-4 are obtained isopropyl-4 (pyridyl-2) -3 thiazolidinethione-2 melting at 116C.
Chloro-1 methyl-3-butanone-2 tP.E.25 = 62C) is prepared according to the method described by R. JUSTONI, M. TERRUZZI, Gazz. Chirn. Ital. 78, 166 (194i3).
pl ~ 14 -The procedure is as in Example 5 but from 56.5 g 2-pyridyl-triethylammonium dithiocarbamate and 28.0 g of chloro-l hexanone-2 in 250 cm3 of dimethylformamide to 25C maximum. The reaction is continued for 2 hours at 20-25C. After chromatography on 600 g of silica (0.2-0.5 mm) distributed in a column 5.5 cm in diameter, eluting with 3,000 cm3 of chloroform, then evaporation of the solvent, 46.4 g of oily product are obtained. The product is purified by recrystallization from 250 cm3 of methyl-cyclohexane. We thus obtains 37.4 g of 4-butyl-4-hydroxy (2-pyridyl) -3 thiazo-lidinethione-2 melting at 56C.
We observe in IR, respectively 2 to 3% (band carbonyl at 1710 cm l) and 2 to 5% (carbonyl band at 1710 cm 1) 2-pyridyl-oxo-2 dithiocarbamate hexyl in the product depending on whether it is examined between lamellae in vaseline or in chloroform solution.

, 7 ~

Chloro-l hexanorle-2 (PE25 - 80-alC) is prepared according to the method described by ~ -I.ERLENMEYER, JP JONG, Helv. Chim. Acta, 32, 35 (1949).
Example 15 -To a suspension of 46.0 g of 2-pyridyl dithiocarbama-te de tri ~ thylammonium in 210 cm3 of dimethylformamide 23.0 g of chloro-1 methyl-4 are added at 25 ° C. maximum pentanone-2. The reaction is continued for 2 hours at 20-25C. Insoluble triethylamine hydrochloride is removed by filtration and washed with 50 cm3 of dimethylformamide.
Dimethylformamide is evaporated under reduced pressure (0.1 mm of mercury) at 50C, the residual oil is treated with 700 cm3 ethyl acetate. The organic solution is washed in 3 times per 300 cm3 in total of distilled water, dried over sulfate of sodium, treated with 3.0 g of bleaching black, filters and evaporated under reduced pressure (20 ~ n of mercury) at 50C. The product obtained (48 g) is dissolved in 30 cm3 of ethanol boiling and 60 cm3 of oxide are added to the boiling solution isopropyl. After 2 hours of cooling at 2C the appeared crystals are separated by filtration, washed in 3 times with 75 cm3 of isopropyl ether and drying under reduced pressure (0.1 mm of mercury). At 40C. 35.0 g of pyridyl ~ 2 4-methyl-2 oxo-pentyl dithiocarbamate fondant at 92C.
When the product is examined in IR solution chloroformic about 80-90% of 4-hydroxy-isobutyl-4 is observed (2-pyridyl) -3 thiazolidinethione-2 (-OH and -NH bands linked from 2700 to 3600 cm, decrease in tape intensity carbonyl at 1710 cm). This form is not detected when the product is examined between strips in petroleum jelly.
Chloro-1 methyl-4 pentanone-2 (PE25 = 72-73C) is prepared according to the method described by F. ASINGE ~ et al., ~ 05 ~ 078 Ann. Chem., 672, 156 (1964).
Example 16 -To a suspension of 210 g of 2-pyridyl dithiocarbamate tri- ~ thylammonium in 1000 cm3 of anhydrous acetonitrile add, in 15 minutes, centers 18 and 23C, 138 g of bromo-l dimethyl-3,3 butanone-2. The reaction is continued for 4 p.m. to 8C. The crystals that appear are separated by filtration and washed with 100 cm3 of acetoni-trile. Acetonitrile is evaporated under reduced pressure (20 mm of mercury) at 50C.
the residual oil obtained is combined with the crystals beforehand separated by filtration and treated with 2000 cm3 of acetate ethyl. The organic solution is washed with 500 cm3 of water distilled, dried over sodium sulfate, filtered and evaporated under reduced pressure (20 mm of mercury) at 50C. The product obtained is dissolved in 1000 cm3 of boiling acetonitrile, add 5.0 g of bleaching black and filter the boiling solution.
After 2 hours of cooling at 2C the crystals appeared are separated by filtration, washed in 2 times per 100 cm3 glazed acetonitrile and dried under reduced pressure (t 1 mm of mercury) at 50C. 137 g of pyridyl-2 are thus obtained 3,3-dimethyl-2-oxo-butyl dithiocarbamate melting at 103C.
Bromo-l dimethyl-3,3 butanone-2 (PE40 = 106C ~
is prepared according to the method described by J. COLCNGE, J. GREVET, Bull. Soc. Chim. France, 1304 (1954).
F, xe ~ 17 -; The procedure is as in Example 16 but from 230 g of 5-chloro-2-pyridyl-dithiocarbamate of triethylammonium and 135 g of bromo-l dimethyl-3,3 butanone-2 in 2000 cm3 anhydrous acetonitrile at 20C. The reaction is continued for 2 hours at 20C. After recrystallization in 1700 cm3 ethanol, 142.1 g of 5-chloro-pyridyl-2 dithio- are obtained 3,3-dimethyl-2-oxo-butyl carbamate melting at 139C.

1 ~ 93 ~

Example 18 -The procedure is as in Example 5 but from 27.1 g 2-pyridyl triethylammonium dithiocarbamate and 17.6 g of chloro-1 nonanone-2 in 135 cm3 of dimethylformamide at 20C.
The reaction is continued for 2 hours at 20C. The product is purified by chromatography on 1 kg of silica (0.2 - 0.5 mm) distributed in a column of 6.5 cm in diameter Eluted with 5 liters of chloroform which is eliminated, then with 4 liters of chloroform which is evaporated under reduced pressure (20 mm of mercury) at 50C. The purified, oily product is dried for 4 hours at 70C SOU5 0.1 mm of mercury. We thus obtain 15.0 g of heptyl-4 hydroxy-4 (pyridyl-2) -3 thiazolidinethione-2.
When the product is examined in IR between lamellae in petroleum jelly or in chloroform solution we dec ~ the 3 to

5% 2-pyridyl-oxo-2 dithiocarbamate nonyl (carbonyl band at 1710 cm 1) Chloro-1 nonanone-2 (PE4 = 95C) is prepared - according to the method described by S. ARCI- ~ R et al., J. Am. Chem.
Soc., 78, 6] 82 (1956).
NMR spectrum (60 M ~ Iz) taken in solution at approximately 10% in chloroform:
0.85 ppm: triplet (3H) -CH3 1.2 ppm: solid (lOH) - (CH2) s-1.6 to 2.2 ppm: multiplet (2H) -CH2- heterocycle 3.55 ppm: AB (2H) -CH2S-

6.1 ppm: spreading mass (1H) -OH

7.3 ppm: DDD (1H) J = 8, ~ 5 and 2 H5 7.7 ppm: doublet of multiplets (1H) J = 8 H3 7.9 ppm: triplet of multiplets (1H) J = 8 and 2 H4

8.5 ppm: doublet of doublets (1H / D = 5 and 2 H6 Example 19 ~
The procedure is as in Example 2 but from 55.0 g V ~

2-pyridyl-triethylammonium dithiocarbamate and 38.7 g of chloro-1 decanone-2 in 280 cm3 of distilled water at 20C.
The reaction is continued for 20 hours at 20C. The product is purified by chromatography on 1.5 kg of silica (0.2 -0.5 mm) distributed in a column 7.5 cm in diameter. We eluted with 2 liters of chloroform which is eliminated, then with 1.6 liters of chloroform which is evaporated under pressure reduced (20 mm of mercury) to 50C ~ The purified product, oily, is dried for 3 hours at 60C under 0.1 mm mercury. This gives 29.0 g of 4-hydroxy-4-octyl (pyridyl-2) -3 thiazolidinethione-2.
When the product is examined in IR between lamellae in petroleum jelly or in chloroform solution we die 5 to 10% 2-pyridyl-2-oxo-decyl dithiocarbamate (band carbonyl at 1710 cm 1).
Chloro-1 decanone-2 (PEo 5 ~ 88-98C) is prepared according to the method described by S. ARCHER et al., J.
Am. Chem. Soc., 78, 6182 (1956).
NMR spectrum (60 MHz) taken in solution at approximately 20 ~ 10% in carbon tetrachloride:
0.9 ppm: triplet (3H) -CH3 - 1.2 ppm: massive (14 H) - (CH2) 7-1.8 ppm: solid (2H) -CH2- heterocycle 3.38 to 3.55 ppm: AB (2H) -CH2S-5.85 ppm: solid (1H) -OH
7.3 ppm: DDD (1H) J = 8, 5 and 2 H5 7.76 ppm: doublet of doublets (1H) J = 8 and 2 H3 7.8 ppm: doublet of triplets (1H) J = 8 and 2 H4 8.45 ppm: doublet of doublets (1H) J = 5 and 2 H6 Example 20 -The procedure is as in Example 3 but from 51.5 g 2-pyridyl-dithiocarbamate triethylammonium and 22.5 g of 2-chloro-cyclopropyl-1-ethanone in 500 cm3 of acetonitrile anhydrous at 20C. The reaction is continued for 3 hours at 20C. ~ close recrystallization in the mixture formed of 230 cm3 of acetonitrile and 1200 cm3 of isopropyl ether, 30.8 g of 4-cyclopropyl-4-hydroxy (2-pyridyl) -3 are obtained thiazolidinethione-2 melting at 95C.
When the product is examined in IR solution chloroformic we observe about 30% of pyridyl-2 dithio-2-cyclopropyl-oxo-2 ethyl carbamate (carbonyl band with 1695 cm 1), This shape is not detected when the product is examined between lamellae in petroleum jelly.
Ia chloro 2 cyclopropyl-l ethanone-l (PE20 = 67C) is prepared according to the method described by EM KOSO ~ R et al., J. Org. Chem. 28, 630 (1963).
Example 21 -The procedure is as in Example 3 but from 47.4 g 2-pyridyl-triethylammonium dithiocarbamate and 23.2 y 2-chloro-cyclobutyl-1 ethanone-1 in 450 cm3 of acetonitrile anhydrous at 20C. The reaction is continued for 1 hour at 20C. After recrystallization from 100 cm3 of acetonitrile, we obtains 33.1 g of 4-cyclobutyl-hydroxy-4 (pyridyl-2) -3 thiazoli-dinethione-2 melting at 123C.
When the product is examined in IR solution chloroform there is a wide band around 1700 cm 1 which can correspond to 2 to 3% of pyridyl-2 dithiocarbamate of 2-cyclo-2-oxo-ethyl. We do not observe this band when the product is examined between tears in petroleum jelly.
2-chloro-cyclobutyl-1 ethanone-1 (PE20 = 94-95C) is prepared according to the method described by D. SORG, request for German patent DE 2,404,050.
Example 22 . , The procedure is as in Example 3 but from 47.4 g 2-pyridyl-dithiocarbamate triethylammoniurn and 25.7 g 2-chloro-cyclopen-tyl-1 ethanone-1 in 450 cm3 of acetonitrile anhydrous at 20C. The reaction is continued for 1 hour at 20C. After recrystallization from 90 cm3 of acetonitrile, 31.3 g of cyclopen-tyl-4 hydroxy-4 (pyridyl-2) -3 are obtained thiazolidinethione-2 melting at 118C.
When the product is examined in IR solution chloroform there is a wide band around 1700 cm 1 which may correspond to 5% of 2-pyridyl dithiocarbamate 2-cyclopentyl-2-oxo ethyl. We do not observe this band when the product is examined between strips in petroleum jelly.
2-chloro cyclopentyl-1 ethanone-1 (PE20 = 106C) is prepared according to the method described by M. MOUSSERON et al.
Compt. Give back. Acad. Sci., C, 232, 1562 (1951).
Example 23 -The procedure is as in Example 2 but starting with 38.0 g of 2-pyridyl-dithiocarbamate of triethylammonium and 22.5 g 2-chloro-cyclohexyl-1 ethanone-1 in 175 cm3 of distilled water at 25C maximum. The reaction is continued for 2 hours at 20-25C. After recrystallization in 250 cm3 ethanol, 27.0 g of 4-cyclohexyl-4-hydroxy (2-pyridyl) -3 thiazolidinethione-2 melting at 112C.
; When the product is examined in IR solution chloroform 2 to 3% of 2-pyridyl dithiocarbamate - 2-cyclohexyl-2-oxo-ethyl (carbonyl band at 1710 cm 1).
This form is not detected when the product is examined between lamellae in petroleum jelly.
2-chloro cyclohexyl-l ethanone-1 (PE8 = 96C) is prepared according to the method described by M. MOUSSERON et al., Compt. Give back. Acad. Sci., C, 232, 1562 (1951) Example 24 -To a suspension of 29.9 g of 3-chloro-oxo-2 acetate propyl in 500 cm3 of distilled water, in 5 minutes, . .

1 ~ 93 ~ 78 at 22-23C, 36 crn3 of an aqueous sodium hydroxide solution 5.5 N. The hydrolysis reaction is continued for 15 minutes at 22C.
then we add in 5 minutes, at 23C maximum, 53.6 g of pyridyl-2 dithiocarb ~ triethylammonium mate. The reaction is continued for 2 hours at 20-23C. Appeared crystals are separated by filtration, washed with 50 cm3 of distilled water and then with 50 cm3 of ethyl ether and dried under reduced pressure (0.1 mm of mercury) at 45C. 12.0 y of hydroxy-4 are thus obtained hydroxymethyl-4 (pyridyl-2) -3 thiazolidine-thione-2 melting at 134-134C.
3-chloro-oxo-2-propyl acetate (PE25 = 129-131C) is prepared according to the method described by EF CURK, JBGHOWES, J. Chem. Soc., 1152 (1956).
Example 25 -To a suspension of 32.4 g of 2-pyridyl dithio-triethylammonium carbamate in a 100 cm3 mixture acetonitrile and 32 cm3 of distilled water, 45 minutes, ~ 4C maximum a solution of 15.2 g of dichloro--1.3 propanone-2 in 32 cm3 of acetonitrile. The reaction is continued for 1 hour at 2C. The crystals that appeared separated by filtration, washed twice with the mixture 15 cm3 of acetonitrile and 15 cm3 of distilled water, then by 15 cm3 of ethyl ether and dried under reduced pressure (20 mm of mercury) at 20C. The product obtained (18.2 g; PF = 118-120C) is purified by recrystallization from 250 cm3 of methanol. 8.6 g of 4-chloromethyl-4-hydroxy are thus obtained.
(pyridyl-2) -3 thiazolidinethione-2 melting at 120C.
Example 26 -The procedure is as in Example 25 but from 46.0 g 2-pyridyl triethylammonium dithiocarbamate and 35.1 g of bromo-3 dichloro-l, propanone-2 in a mixture of 450 cm3 acetonitrile and 46 cm3 of distilled water, at 4C maximum.

109; ~ 71 ~

The reaction is continued ~ for 30 minutes at 2C. After recrystallization from a mixture of 200 cm3 of iso- oxide ; propyl and 50 cm3 of ethanol, 13.5 g of dichloro-4-methyl-4-hydroxy (2-pyridyl) -3 thiazolidinethione-2 fondant at 130C.
Bromo-3 dichloro-1, propanone-2 (PEl 5 =
65-67C) is prepared according to the method described by W.
POLACSI ~ OWA and Z.BANI ~ OWSI ~ A, Roczniki, Chem. 30,119 (1956) _example 27 -The procedure is as in Example 2 but from 29.5 g triethylammonium 2-pyridyl-dithiocarbamate and 16.4 g 3-chloro-oxo-propyl acetate in 125 cm3 of distilled water at 25C. The reaction is continued for 20 hours at 20-25C.
After recrystallization from 210 cm3 of ethanol, we obtain 16.7 g of 4-acetoxymethyl-4-hydroxy (2-pyridyl) -3 thiazolidine-thione-2 melting at 121C.
3-chloro-oxo-2-propyl acetate is prepared as shown in Example 24.
Example 28 -The procedure is as in Example 2 but from 36.5 g 2-pyridyl triethylammonium dithiocarbamate and 16.5 g of chloro-l methoxy-3 propanone-2 in 200 cm3 of distilled water at 25C maximum. The reaction is continued for 2 hours and a half at 20-25C. After recrystallization in 180 cm3 ethanol, 22.8 g of 4-hydroxy-4-methoxymethyl are obtained (pyridyl-2) -3 thiazolidinethione-2 melting at 114C.
Chloro-1-methoxy-3-propanone-2 (PE25 = 84-85C) is prepared according to the method described by BG CIIRISTENSEN and RW RATCLIFFE, German patent application DE 2 318 829.
Example 29 -The procedure is as in Example 2 but from 36.6 g 2-pyridyl triethylammonium dithiocarbamate and 18.5 g D7 ~

of chloro-l ethoxy-3 propanone-2 in 180 cm3 of distilled water at 25C maximum. The reaction is continued for 2 hours ~ 20-25C. After recrystallization in 270 cm3 of oxide isopropyl, 22.5 g of 4-ethoxymethyl-4 hydroxy are obtained (2-pyridyl) -3 thiazolidinethione-2 melting at 75C.
Chloro-3-ethoxy-propanone-2 (PE3C = 94C) is prepared according to the method described by A.GRUN and W. STOLL., U.S. Patent 2,374,283.
Example 30 -The procedure is as in Example 2 but from 43.5 g 2-pyridyl-triethyla dithiocarbamate ~ unonium and 22.2 g of chloro-l methylthio-3 propanone-2 in 200 cm3 of water distilled at 25C maximum. The reaction is continued for 2 hours at 20-25C. After recrystallization in 100 cm3 ethanol, 27.0 g of 4-hydroxy-methylthiomethyl-4 is obtained (pyridyl-2) -3 thiazolidinethione-2 melting at 104C.
22.5 g of chloro-1-methylthio-propanone are obtained.
2 (PE28 = 98-100C) by reaction of 22.4 g of diazomethane between -10C and 0C, then 35 cm3 of an aqueous solution hydrochloric acid (d = 1.19) between 0 and 5C, on 40.1 g methylthioacetyl chloride in 300 cm3 of ethyl ether.
Methylthioacetyl chloride (PE30 = 66C) is prepared according to the method described by A.MOORADIAN et al., J. Am. Chem. Soc. 71, 3372 (1949).
Example 31 -The procedure is as in Example 2 but from 27.1 g 2-pyridyl triethylammonium dithiocarbamate and 15.3 g of chloro-3-ethylthio-propanone-2 in 130 cm3 of water distilled at 25C maximum. The reaction is continued for 2 hours at 20-25C. The product is purified by chromatography on 650 g of silica (0.2-0.5 mm) distributed in a column of 5.5 cm in diameter. Or- elected with 1.5 liters of cyclohexane, 09 ~) 78 then with 1 liter of cyclohexane containing 10% by volume ethyl acetate, then with 1 liter of cyclohexane containing 15% by volume of ethyl acetate. These different eluates are eliminated. Elution is continued with 1.5 liters of cyclo hexane containing 25% by volume of ethyl acetate which is evaporates under reduced pressure (20 mm of mercury) at 50C. The product obtained (21.0 g) is recrystallized from a mixture of 100 cm3 of ethyl ether and 46 cm3 of isopropyl ether.
14.4 g of ethylthiom ~ 4-thyl-4-hydroxy-4 (pyridyl-2) -3 thiazolidinethione-2 melting at 50C.
Chloro-3-ethylthio-propanone-2 (PE30 = 94C) is prepared according to the method described by BGCHRISTENSEN and coll., patent application FR 2 034 480.
Example 32 -The procedure is as in Example 3, but starting with 7.1 g of 2-pyridyl-dithiocarbamate of triethylammonium and 5.0 g of 3-bromo-1,1,1-trifluoro-2-propanone in 70 cm3 of aceto-anhydrous nitrile between 2 and 5C. The reaction is continued for 1 hour at 2C. The product is purified by chromatography written on 140 g of silica (0.2-0.5 mm) distributed in a column 3cm in diameter. Eluted with 240 cm3 of chloro-form which is eliminated, then with 360 cm3 of chloroform that it is evaporated under reduced pressure (20 mm of mercury) at 40C.
The product obtained (6.1 g) is purified by recrystallization in a mixture of 13 cm3 of ethanol and 13 cm3 of water distilled. 4.3 g of hydroxy-4 (pyridyl-2) -3 are thus obtained.
, 4-trifluoromethyl-thiazolidinethione-2 melting at 60C.
Bromo-3 trifluoro-l, l, l propanone-2 (PE760 =
80-85C) is prepared according to E. CHERBULIEZ et al., Helv. Chim.

Acta, 48, 1423 (1965).
Example 33 -~ - We operate as in Example 3 but from 27.0 g .

..:.

1093C ~ 78 triethylammonium 2-pyridyl-dithiocarbamate and 16.4 g 4-chloro-3-oxo-butyl acetate in 150 cm3 of acetonitrile anhydrous at 20C. The reaction is continued for 2 hours ~ 20C. After recrystallization in a mixture of 40 cm3 methylene chloride and 100 cm3 of isopropyl ether, 19.0 g of acetate of / hydroxy-4 (pyridyl-2) -3 thioxo-2 are obtained thiazolidinyl- ~ J-2 ethyl melting at 96C.
4-chloro-oxo-3 bu-tyle acetate (PEo 1 = 103-104C) is prepared according to the method described by YAARBUZOV and coll., Doklady, Akad. ~ ank. SSSR, 112, 26i (1957).
Example 34 -The procedure is as in Example 3 but from 81.0 g 2-pyridyl-triethylammonium dithiocarbamate and 58.5g ethyl brornopyruvate in 550 cm3 of anhydrous acetonitrile at 30C maximum. The reaction is continued for 3 hours at 20-30C. After recrystallization from 250 cm3 of iso- oxide propyl, 71.0 g of / hydroxy-4 (pyridyl-2) -3 thioxo-2 are obtained thiazolidinyl- ~ / ethyl carboxylate melting at 64C.
Example 35 -The operation is carried out in Example 5 but from 56.5 g 2-pyridyl-triethylammonium dithiocarbamate and 34.2 g of 4-chloro-3-oxo-butyrate in 250 cm3 of dimethyl-formamide at 20C. The reaction is continued for 2 hours at 20C. After recrystallization from a mixture of 100 cm3 ethanol and 100 cm3 of isopropyl ether, we get 22.0 g of ~ hydroxy-4 (pyridyl-2) -3 thioxo-2 thiazolidinyl- ~ /
ethyl acetate melting at 104C.
Example 36 -The procedure is as in Example 2 but from 54.0 g 2-pyridyl-triethylammonium dithiocarbamate and 42.0 g methyl bromo-5 oxo-4 pentanoate in 250 cm3 of water distilled at 25C maximum ~ The reaction is continued for ~ `- 10 ~; ~ 078 1 hour at 20-25C. After recrystallization in a mixture 60 cm3 of ethanol and 120 cm3 of isopropyl ether, we obtains 42.0 g of / hydroxy-4 (pyridyl-2) -3 thioxo-2 thiazo-lidinyl- ~ J-3 methyl propionate melting at 75C.
Methyl bromo-5 oxo-4 pentanoate ~ P ~ E ~ o 1 =
; ~ 85-85C) is prepared according to the method described by H. DANNENBERG
and S. LAUFER, Chem. Ber., 89, 2242 (1956).
Example 3? -The procedure is as in Example 3 but ~ from 19.0 g 2-pyridyl triethylammonium dithiocarbamate and 13.5 g methyl chloro-7 oxo-6 heptanoate in 200 cm3 of aceto-anhydrous nitrile at 30C maximum. The reaction is continued for 16 hours at 20C. After recrystallization in a mixture of 25 cm3 of ethanol and 50 cm3 of isopropyl ether, . i, 18.0 g of / hydroxy-4 (pyridyl-2) -3 thioxo-2 are obtained thiazolidinyl- ~ J-5 methyl pentanoate melting at 72C.
45.0 g of chloro-7 oxo-6 heptanoate are obtained.
methyl (PEo 05 = 121-122C) per action of 16.8 g of diazomethane between -10C and 0C, then 30 cm3 of a solution aqueous hydrochloric acid (d = 1.18) between O and 5C, on 44.5 g of 5-chlorocarbonyl methyl valerate in 400 cm3 ethyl ether.
Example 38 -We prepare, just before its use and by operating , ~. . .
~ at 5C maximum, a solution of 14.6 g of bromo-5 oxo-4 acid ; `pentanoic in a mixture of 30 cm3 of distilled water and ::,. . .
75 cm3 of an aqueous sodium hydroxide solution N. The solution is quickly added, at 20C maximum, to a suspension of 21.6 g l ~ 2-pyridyl triethylammonium dithiocarbamate in 150 cm3 - 30 distilled water. After 4 hours of stirring at 20C, add ; ~ 2.0 g of bleaching black and filter. The filtrate is added, without exceeding 20C, 75 cm3 of an aqueous acid solution ~. .

- 10 ~ 3078 hydrochloric N. After 1 hour of cooling to 2C, the appeared crystals are separated by filtration, washed in 4 times per 60 cm3 of distilled and air-dried water. The product obtained (14.2 g, PF = 148C) is purified by recrystallization in 250 cm3 of acetonitrile. 10.8 g of acid are thus obtained / hydroxy-4 (pyridyl-2) -3 thioxo-2 thiazolidinyl- ~ J-3 propionic melting at 154C.
5-bromo-4 oxo-pentanoic acid (PF = 72C) is prepared according to the method described by S. VARTILLOT and C.BARON, Bull. Soc. Chim. France, 3798 (1966).
Example 39 -The procedure is as in Example 5 but from 30.4 g of 2-pyridyl triethylammonium dithiocarbamate and 18.9 g of chloro-l ph ~ nyl-3 propanone-2in 140 cm3 of dimethylforma-mide at 20C. The reaction is continued for 2 hours at 20C. After recrystallization from a 50 cm3 mixture of acetonitrile and 100 cm 3 of ethanol, 21.5 g of 4-benzyl-4-hydroxy (2-pyridyl) -3 thiazolidinethione-2 fondant at 135C.

Chloro-3-phenyl-propanone-2 (PEo 2 = 98-100C) is prepared according to the method described by DACLIBBENS and M.
NIERENSTEIN, J. Chem. Soc., 1491 (1915).
Example 40 -The procedure is as in Example 2 but from 23.6 g 2-pyridyl triethylammonium dithiocarbamate and 16.2 g of chloro-l phenyl-4 butanone-2 in 150 cm3 of distilled water at 20C. The reaction is continued for 2 hours at 20C.
After recrystallization from 110 cm3 of ethanol, we obtain 21.5 g of 4-hydroxyphenethyl-4 (2-pyridyl) -3 thiazolidinethione-2 fondant ~ 118C.
Chloro-l phenyl-4 butanone-2 (PEo 5 = 115C) is prepared according to the method described by DACLIBBENS and M.

., lOg; ~ 8 NIERENSTEIN, J. Chem. Soc., 1491 (1915).
Example 41 -The procedure is as in Example 3, but starting with 43.4 g of 2-pyridyl-dithiocarbamate of triethylammonium and 25.4 g of chloro-1 (cyclohexene-3 yl) -2 ethanone-2 in 500 cm3 anhydrous acetonitrile at 20C. The reaction is continued - for 3 hours at 20C. After recrystallization in a mixture of 185 cm3 of acetonitrile and 1250 cm3 of oxide of isopropyl, 28.8 g of (cyclohexene-3yl) -4 hydroxy-4 are obtained (2-pyridyl) -3 thiazolidinethione-2 melting at 111C.
Chloro-1 (cyclohexene-3yl) -2 ethanone-2 (PE13 =
106-107C) is prepared according to the method described by GP
KUGATOVA et al., Zh. Organ. I ~ him., 2, 844 (1966).
Example 42 -The procedure is as in Example 3 but from 201.5 g 2-pyridyl triethylammonium dithiocarbamate and 148 g phenacyl bromide in 1600 cm3 anhydrous acetonitrile between 18 and 25C. The reaction is continued for 2 hours at 20-25C. After recrystallization from 2000 cm3 of ethanol, 168.1 g of 4-hydroxy-phenyl-4 (pyridyl-2) -3 thiazo- are obtained.
lidinethione-2 melting at 135C.
When the product is examined in IR solution bromoformic we observe about 10% of pyridyl-2 dithio-phenacyl carbamate (carbonyl band at 1685 cm 1), On does not observe this band when the product is examined between lamellae in petroleum jelly.
; Example 43 -The procedure is as in Example 16 but from 38.3 g -de (5-chloro-pyridyl-2) triethylammonium dithiocarbamate and ; 30 of 24.9 g of phenacyl bromide in 250 cm3 of acetonitrile anhydrous between 20 and 25C. The reaction is continued for 30 minutes at 20C. After recrystallization in 200 cm3 1 ~ 9; i071 ~
of acetonitrile, 33.9 g of (5-chloro-pyridyl-2 are obtained phenacyl dithiocarbamate melting at 145C.
When the product is examined in IR solution chloro ~ ormique we observe about 95% of (chloro-5 pyridyl-2) -3 4-hydroxy-4-phenyl thiazolidinethione-2 (decrease in band carbonyle ~ 1690 cm 1) this ~ elm is not detectable when the product is examined between strips in petroleum jelly.
Example 44 -The procedure is as in Example 3 but ~ from 54.2 g . 10 of pyridyl-2 dithiocarbamate tri ~ thylammonium and 42.6 g of 2-bromo-phenyl-1 propanone-1 in 320 cm3 of acetonitrile anhydrous between 20 and 25C. The reaction is continued for 30 minutes at 20C. After recrystallization in 180 cm3 of acetonitrile, 46.5 g of 4-hydroxy-5-methyl-4-phenyl are obtained (2-pyridyl) -3 thiazolidinethione-2 melting at 150C.
When the product is examined in IR solution chloroformic we observe 1 to 3% of pyridyl-2 dithiocarbamate of (2-methyl-oxo-1 phenyl-1-propyl-2) (carbonyl band with 1680 cm 1) This band is not observed when the product is examined between lamellae in petroleum jelly.
~ Example 45 -We operate as in Example 3 but from 33.9 g 2-pyridyl-triethylammonium dithiocarbamate and 28.4 g 2-bromo-2-methylphenyl-1 propanone-1 in 175 cm3 of aceto-anhydrous nitrile between 20 and 25C. The reaction is continued for 30 minutes at 20C. After recrystallization in 120 cm3 of acetonitrile, 30.1 g of dimethyl-5.5 are obtained 4-hydroxy-phenyl-4 (pyridyl-2) -3 thiazolidinethione-2 fondant at 171C.

Example 46 -The procedure is as in Example 3 but ~ from 36.0 g 2-pyridyl triethylammonium dithiocarbamate and 31.0 g 1C ~ 9; ~ 0 ~ 8 of chloro-2 (chloro-3 phenyl) -l ethanone-1 in 300 cm3 anhydrous acetonitrile between 10 and 15C. The reaction is continued for 3 hours at 15-20C. After recrystallization in a mixture of 25 cm3 of ethanol and 300 cm3 of oxide isopropyl, 30.0 g of (3-chloro-phenyl) -4 are obtained hydrGxy-4 (pyridyl-2) -3 thiazolidinethione-2 fandant at 100C.

:
When the product is examined in IR solution : chloroform. 2 to 5% of pyridyl-2 dithiocarbamate is observed of (3-chloro-phenyl) -2 oxo-2 ethyl (carbonyl band at 1685 cm 1). This band is not observed when the product is examined between lamellae in petroleum jelly.
Chloro-2 (3-chloro-phenyl) -l ethanone-1 (PEo 4 =
: 110-115C) is prepared according to the method described by RE LUT ~
et al., J. Org. Chem., 12, 617 (1947).
Example 47 -:; Qn operates as in Example 3 but ~ from 40.0 g triethylammonium 2-pyridyl-dithiocarbamate and 34.6 g . 2-bromo-4-chloro-phenyl) -l ethane-1 in 500 cm3 of aceto-anhydrous nitrile between 15 and 20C. The reaction is continued for 3 hours at 20C. After 3 recrystallizations, successive-ment in 300 cm3 of ethanol (PF = 125C), then in 150 cm3 ethyl acetate (PF = 130C), then in 240 cm3 of acetate of ethyl, 17.3 g of (4-chloro-phenyl) -4 hydroxy-4 are obtained (2-pyridyl) -3 thiazolidinethione-2 melting at 147C.
~. ,.
When the product is examined by IR in chlorine solution roformique we observe approximately 10% of pyridyl-2 dithiocarbamate of (4-chloro-phenyl) -2 oxo-2 ethyl (carbonyl band at 1680 cm 1), ~; ~ We do not observe this band when the product is examined between lamellae in petroleum jelly.
Example 48 -The procedure is as in Example 3 but from 40.0 g pyrid ~ l-2 triethylammonium dithiocarbamate and 31.8 g "

. ~
.., ~,.

~ Q ~ 378 chloro-2 (fluoro-3 phenyl) -l ethanone-l in 300 cm3 anhydrous acetonitrile between 15 and 20C. The reaction is continued for 3 hours at 20C. After recrystallization in 400 cm3 of ethanol, 31.0 g of (3-fluoro-phenyl) are obtained -4 hydroxy-4 (pyridyl-2) -3 thiazolidinethione-2 melting at 130C.
When the product is examined in IR solution chloroform is observed 5 to 8 / O of 2-pyridyl dithiocarbamate of (3-fluoro-phenyl) -2 oxo-2 ethyl (carbonyl band at 1690 cm 1), This band is not observed when the product is examined between lamellae in petroleum jelly.
Chloro-2 (3-fluoro phenyl) -l ethanone-1 (PF =
31C) is prepared according to the method described by L ~ G.
LEVI ~ OVSI ~ YA et al., I ~ him. Geterotsikl. Soedin. 6, 798 (1974).
Example 49 -The procedure is as in Example 3 but from 40.0 g 2-pyridyl-triethylan dithiocarbamate ~ onium and 31.8 g chloro-2 (4-fluoro phenyl) -l ethanone-1 in 325 cm3 anhydrous acetonitrile, between 10 and 15C. The reaction is continued for 4 hours at 15-20C. After recrystallization -tion in 250 cm3 of ethanol, we obtain 30.0 ~ of (fluoro-4 phenyl) -4 hydroxy-4 (pyridyl-2) -3 thiazolidinethione-2 fondant at 118C.
When the product is examined in IR solution chloroformic we observe about 10% of pyridyl-2 dithio-(4-fluoro-phenyl) carbamate -2 oxo-2 ethyl (carbonyl band at 1680 cm 1), We do not observe this band when the product is examined between lamellae in petroleum jelly.
Chloro-2 (4-fluoro phenyl) -l ethanone-1 (PF =
50C) is prepared according to the method described by RMI ~ ANN and JP WETHERILL, J. Wash. Acad. Sci. 24, 526 (1934).

- 109; ~ 078 Example 50 -We operate as in example 16 but starting from 40.0 g of 2-pyridyl triethylammonium dithiocarbamate and 31.5 g of bromo-2 (2-methylphenyl) -l ethanone-1 in 400 cm3 anhydrous acetonitrile at 20C. The reaction is continued for 3 hours at 20C. After recrystallization in 600 cm3 ethanol, 2 g, 9 g of 2-pyridyl dithiocarbamate are obtained (2-methylphenyl) -2 oxo-2 ethyl melting at 130C.
Bromo-2 (2-methylphenyl) -l ethanone-1 (PEo 5 =
116C) is prepared according to the method described by D. MERCER
et al., J. Chem. Soc., 997 (1935).
Example 51 -The procedure is as in Example 3 but from 40.0 g triethylammonium (2-pyridyl) dithiocarbamate and 31.5 g , ~ of bromo-2 (3-methylphenyl) -l ethanone-1 in 400 cm3 of aceto-nitrile anhydrous at 15-20C. The reaction is continued for 3 hours at 20C. After recrystallization dar) ~) crn3 of ethanol, 34.0 g of hydroxy-4 (3-methylphenyl) -4 (pyridyl-2) are obtained -3 thiazolidinethione-2 melting at 106C.
When the product is examined in IR solution chloroformic we observe about 10% of pyridyl-2 dithio-(3-methylphenyl) -2-oxo-ethyl carbamate (carbonyl band to 1685 cm 1) This band is not observed when the product is examined between lamellae in petroleum jelly.
Bromo-2 (3-methylphenyl) -1 ethanone-1 (PE94 =
105C) is prepared according to the method described by RMLAIRD and RE PARI ~ R, J.Am. Chem. Soc., 83, 4277 (1961).
Example 52 -The procedure is as in Example 16 but from 40.0 g 2-pyridyl triethylammonium dithiocarbamate and 31.5 g of 2-bromo (4-methylphenyl) -l ethanone-1 in 400 cm3 of aceto-`~ anhydrous nitrile between 15 and 20C. The reaction is continued `~ ' for 3 hours at 20C. After recrystallization in 300 cm3 of ethanol, 31.0 g of 2-pyridyl dithiocarbamate are obtained (m ~ thyl-4 phenyl) -2 oxo-2 ~ thyle melting at 133C.
When the product is examined by IR in solution chloroformic about 85-90% of hydroxy-4 (methyl-4 phenyl) - ~ (pyridyl-2) -3 thiazolidinethione-2 (-OH bands and -NH linked from 3100 to 3500 cm 1, decrease in intensity of carbonyl band at 1680 cm 1), This shape is not detected when the product is examined between strips in petroleum jelly.

Example 53 -The procedure is as in Example 16 but from 41.5 g 2-pyridyl triethylammonium dithiocarbamate and 33.0 g of 2-bromo (2-hydroxyphenyl) -l ethanone-1 in 400 cm3 anhydrous acetonitrile at 15C. The reaction is continued for 3 hours at 15-20C. After recrystallization in 200 cm3 ethanol, 34.0 g of 2-pyridyl dithiocarbamate are obtained (2-hydroxyphenyl) -2 oxo-2 ethyl melting at 128C.
Bromo-2 (2-hydroxyphenyl) - ethanone-1 (PEo 4 -117-119C) is prepared according to the method described by LC

KING and GI ~. OSTRUM, J. Org. Chem., 29, 3459 (1964).
Example 5 ~ -The procedure is as in Example 3 but from 45.0 g 2-pyridyl triethylammonium dithiocarbarnate and 38.0 g 2-bromo (2-methoxyphenyl) -l ethanone-1 in 400 cm3 of acetate anhydrous tonitrile at 15C. The reaction is continued for 3 hours at 15-20C. After recrystallization in 350 cm3 of ethyl acetate, 28.0 g of hydroxy-4 (2-methoxy) are obtained phenyl) -4 (pyridyl-2) -3 thiazolidinethione-2 melting at 148C.
When the product is examined in IR solution chloroformic we observe about 2% of pyridyl-2 dithio-(2-methoxyphenyl) carbamate -2 2-oxo-ethyl (carbonyl band at 16 ~ 30 cm 1). This band is not detected when the product is examined between lamellae in the vas ~ line.
Bromo-2 (2-methoxyphenyl) -l ethanone-1 (PF =
45C) is prepared according to the method described by S ~ J. sUCKMAN
et al., German patent application 1,174,017.
Example 55 -The procedure is as in Example 3 but starting from 40.0 g of 2-pyridyl-triethylammonium dithiocarbamate and 34.0 g of 2-bromo (3-methoxyphenyl) -l ethanone-1 in 400 cm3 anhydrous acetonitrile between 15 and 20C. The reaction is continued for 2 hours at 20C. After recrystallization in 300 cm3 of ethanol, 34.0 g of hydroxy-4 (methoxy-3) are obtained phenyl) -4 (pyridyl-2) -3 thiazolidinethione-2 melting at 114C.
When the product is examined in IF in solution chloroformic we observe about 10% of pyridyl-2 dithio-~ '(3-methoxyphenyl) carbamate -2-2-oxo-ethyl (carbonyl band at 1680 cm 1), We do not observe this band when the product is examined between lamellae in petroleum jelly.
Example 56 -The procedure is as in Example 16, but from 40.0 g 2-pyridyl triethylammonium dithiocarbamate and 34.0 g of 2-bromo (4-methoxyphenyl) -l ethanone-1 in 450 cm3 anhydrous acetonibrile between 1 ~ and 20C. The reaction is continued for 3 hours at 20C. After recrystallization in 300 cm3 of ethyl acetate, 20.0 g of pyridyl-2 are obtained ; (4-methoxyphenyl) -2 oxo-2 ethyl dithiocarbamate fondant at 135C.
When the product is examined in IR solution chloroformic we observe about 80% of hydroxy-4 (methoxy-4 phenyl) -4 (2-pyridyl) -3 thiazolidinethione-2 (-OH bands and - ~ H linked from 2700 to 3500 cm 1, decrease in intensity of the carbonyl strip ~ 1680 cm 1), This shape is not detected when the product is examined between lamellae in petroleum jelly.
- 37 -, .

: ~: ' : '' 1 ~ 9 ~ 078 Example 57 -We operate as ~ example 16 but ~ from 42.0 g 2-pyridyl triethylammonium dithiocarbamate and 38.0 g of bromo-2 (ni-tro-2 phenyl) -l ethanone-1 in 450 crn3 of aceto-anhydrous nitrile between 15 and 20C. The reaction is continued for 3 hours ~ 20C. The reaction is continued for 3 hours at 20C. After recrystallization from 600 cm3 of ethanol, 29.0 g of 2-pyridyl-dithiocarbamate (2-nitro) are obtained phenyl) -2 oxo-2 ethyl melting at 126C.

When the product is examined in IR solution chloroformic we observe approximately 50% of hydroxy-4 (nitro-2 phenyl) -4 (2-pyridyl) -3 thiazolidinethione-2 (-OH bands and -NH linked from 2500 to 3500 cm 1, decrease in intensity of carbonyl band at 1705 cm 1) This ~ elm is not detected when the product is examined between strips in petroleum jelly.
Bromo-2 (2-nitro-phenyl) -l ethanone-1 (PF =
54C) is prepared according to the method described by II. GEVEICOHT, Ann. Chem. 221, 323 (1883).
Example 58 -The procedure is as in Example 3 but from 42.0 g 2-pyridyl triethylammonium dithiocarbamate and 38.0 g of 2-bromo (3-nitro-phenyl) -l ethanone-1 in 450 cm3 of aceto-nitrile anhydrous between 15 and 20C. The reaction is continued for 3 hours at 20C. After recrystallization in 500 cm3 ethyl acetate, 34.7 g of hydroxy-4 ~ nitro-3 are obtained phenyl) -4 (pyridyl-2) -3 thiazolidinethione-2 melting at 155C.
Bromo-2 (3-nitro-phenyl) -l ethanone-1 (PF = 90C) is prepared according to the method described by HI ~ ORTEN e ~ t R. SCHOLL, Chem., Ber., 34 i901 (1901).

Example 59 -The procedure is as in Example 3 but from 42.0 g 2-pyridyl triethylammonium dithiocarbamate and 38.0 g 1t) 9; ~ 71 ~

of bromo-2 (nitro-4 phenyl) -l ~ thanone-l in 450 cm3 anhydrous acetonitrile between 15 and 20C. The reaction is continued for 3 hours at 20C. After recrystallization in 500 cm3 of ethyl acetate, 32.8 g of hydroxy-4 are obtained (4-nitro ph ~ nyl) -4 (pyridyl-2) -3 thiazolidinethione-2 fondant at 160C.
Example 60 -The procedure is as in Example 16 but starting with 46.5 g of 2-pyridyl-dithiocarbamate of triethylarnmonium and 35.2 g 2-bromo (2-thienyl) -1 ethanone-1 in 320 cm3 of acetonitrile anhydrous between 20 and 25C. The reaction is continued for 1 hour at 20C. After recrystallization from 180 cm3 of aceto-nitrile, 32.2 g of 2-pyridyl-oxo-2 dithiocarbamate are obtained (2-thienyl) -2 ethyl melting at 131C.
Ia bromo-2 (2-thienyl) -1 ethanone-l ~ PEo 05 =
112-114C) is prepared according to the method described by NP
BUU-MOI and NGUYEN-HOAN, Rec. 'rrav. Chim., 68, 441 (1949).
Exernple 61 -The procedure is as in Example 3 but from 40.0 g 2-pyridyl triethylammonium dithiocarbamate and 26.3 g 2-bromo cyclohexanone in 300 cm3 of anhydrous acetonitrile between 18 and 25C. The reaction is continued for 2 hours at 20-25C. After recrystallization in 250 cm3 ethanol, 23.4 g of hydroxy ~ 3a (pyridyl-2) -3 are obtained perhydrobenzothiazolethione-2 melting at 155C.
2-bromo cyclohexanone (PE25 = 110-120C) is prepared according to the method described by HC BROWN et al., J. Am. Chem. Soc. 90, 6218 (1968).
Example 62 -The procedure is as in Example 3 but from 54.2 g 2-pyridyl triethylammonium dithiocarbamate and 38.9 g 2-bromo indanone-1 in 350 cm3 of anhydrous acetonitrile 07l ~

20 DC. The reaction is continued for 45 minutes at 20C.
After recrystallization from 1250 cm3 of acetonitrile, we obtains 38.9 g of hydroxy-3a (pyridyl-2) -3 tetrahydro-3.3a, 8.8a 2H-2H-indeno / 1,2- ~ / thiazolethione-2 melting at 160C.
When the product is examined in IR solution chloroformic about 10-15% of pyridyl-2 dithio- is observed (oxo-l indanyl-2) carbamate (carbonyl band at 1710 cm 1) This band is not detected when the product is examined between lamellae in petroleum jelly.
2-bromo indanone-1 (PF = 40C) is prepared according to the method described by WSJOHNSON and WE SHELBERG, J.
Am. Chem. Soc. 67, 1745 (1945).
Example 63 -The procedure is as in Example 3 but from 79.8 g 2-pyridyl-dithiocarbamate sorting ~ thylammonium and 66.2 g 2-bromo-tetralone-1 in 750 cm3 of anhydrous acetonitrile 20C. The reaction is continued for 1 hour at 20C.
After recrystallization from 1 liter of acetonitrile, one obtains 64.5 g of hydroxy-9b (pyridyl-2) -1 tetrahydro-3a, 4,5,9b 1H-naphtho / 1,2- ~ Jthiazolethione-2 melting at 125C.
- When the product is examined by IR in solution chloroformic about 20% of pyridyl-2 dithio- is observed (oxo-l tetrahydro-1,2,3,4 naphthyl-2) carbamate (band carbonyl at 1685 cm 1). This band is not detected when the product is examined between strips in petroleum jelly.
2-bromo-tetralone-1 (PF = 40C) is prepared according to the method described by ALWILOS and JA JOHNSON, J.
Am. Chem. Soc. 68, 86 (1946).
Example 64 -The procedure is as in Example 3 but from 21.5 g chloro-5 pyridyl-2 di-thiocarbamate triethylammonium ~ t 8.5 g of chloro-l pentanone-2 in 175 cm3 of acetonitrile 7 ~

anhydrous ~ at 30C maximum. The reaction is continued for 2 hours at 20-30C. The product is purified by chromatography on 150 g of silica (0.06-0.20 mm) r ~ part in a column 2.8 cm in diameter. Eluted with a mixture formed of 480 cm3 of cuclohexane and 120 cm3 of ethyl acetate which is eliminated, then with a melanye formed from 1040 cm3 of cyclohexane and 360 cm3 of ethyl acetate which is evaporated under reduced pressure (20 mm of mercury) at 50C. After recrystallization of the product purified (16.5 g) in a mixture of 30 cm 3 of acetonitrile and 60 cm3 of isopropyl ether, 10.6 g of (5-chloro-pyridyl-2) -3 hydroxy-4 propyl-4 -thiazolidinethione-2 melting at 93C.
When the product is examined in IR solution chloroformic about 2 to 3% of chloro-5 pyridyl-2 is observed oxo-2 pentyl dithiocarbamate (carbonyl band at 1710 cm 1) This form is not detected when the product is examined between lamellae in petroleum jelly ~
Example 65 -The procedure is as in Example 3 but from 14.4 g of 5-chloro-2-pyridyl-dithiocarbamate of triethylammonium and 6.35 g of chloro-l hexanone-2 in 120 cm3 of acetonitrile anhydrous at 30C maximum. The reaction is continued for 2 hours at 20-30C. The product is purified by chromatography on 150 g of silica (0.06-020 mm) distributed in a column 2.8 cm in diameter. Eluted with a mixture formed of 320 cm3 cyclohexane and 80 cm3 of ethyl acetate which is eliminated, then with a mixture formed of 1480 cm3 of cyclohexane and 520 cm3 of ethyl acetate which is evaporated under pressure reduced (20 mm of mercury) to 50C. After recrystallization purified product (12.5 g) in a mixture formed of 10 cm3 of acetonitrile and 100 cm3 of isopropyl ether, we obtain

9.2 g of butyl-4 (chloro-5 pyridyl-2 ~ -3 hydroxy-4 thiazolidine-7 ~

thione-2 melting at 85C ~
When the product is examined in IR solution chloroform is observed about 2 to 3% of c ~ loro-5 pyridyl-2 oxo-2 hexyl dithiocarbamate (carbonyl band at 1710 cm 1), This form is not detected when the product is examined between lamellae in petroleum jelly.
Example 66 -We operate cor ~ me in Example 3 but from 22.9 g ; of 5-chloro-2-pyridyl-dithiocarbamate of triethylammonium and 11.0 g of 2-chloropentyl-2-ethanone-2 in 180 cm3 anhydrous acetonitrile at 30C maximum. The reaction is continued for 2 hours at 20-30C. After recrystallization in 240 cm3 of acetonitrile, 21.4 g of (5-chloro) are obtained pyridyl-2) -3 cyclopentyl-4 hydroxy-4 thiazolidinethione-2 melting at 147C.
When the product is examined in IR solution chloroform there are approximately 5 to 8% of (5-chloro pyridyl-2) 2-cyclopentyl-2-oxo-ethyl dithiocarbamate (band carbonyl at 1710 cm 1), We do not observe this band when the product is examined between strips in petroleum jelly.
Example 67 -The procedure is as in Example 16 but from 61.1 g of 5-chloro-2-pyridyl-dithiocarbamate of triethylammonium and 34.5 g of chloro-2 (4-fluoro-phenyl) -l ethanone-1 in 600 cm3 of anhydrous acetonitrile at 20C. The reaction is continued for 1 hour at 20C. After recrystallization in 300 cm3 of acetonitrile, 30.4 g of chloro-5 are obtained 2-pyridyl (4-fluoro-phenyl) 2-oxo-ethyl dithiocarbamate melting at 146C ~

When the product is examined in IR solution chloroformic about 80% of (5-chloro-pyridyl-2) -3 is observed (4-fluoro-phenyl) -4 hydroxy-4 thiazolidinethione-2 (decrease band intensity ca ~ bonyle at 1685 cm). This shape is not detected when the product is examined between slides in petroleum jelly.
Example 68 -The procedure is as in Example 16 but starting from 38.2 g of 5-chloro-pyridyl-2 dithiocarbamate of tri-thylammonium and 28.6 g of 2-bromo (4-methoxyphenyl) -l ethanone-1 in 500 cm3 of anhydrous acetonitrile at 20C. The reaction is for-followed for 1 hour at 20C. After recrystallization in lOOO cm3 of acetonitrile, 38.1 g of (5-chloro pyridyl-2) (4-methoxyphenyl) dithiocarbamate -2 2-oxo-ethyl fondant at 159 ~ C.
The present invention also relates to medicinal compositions usable in therapy which contain at least one product of formula g. ~ neral (I) (possibly in the form of non-toxic salt) in combination with one or more compatible diluents or adjuvants and . pharmaceutically acceptable and possibly with others compatible and physiologically active products. These composi-tions can be used orally, parenterally or rectal.
As compositions for oral administration, use tablets, pills, powders, capsules, or granules. In these compositions the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions may also include substances other than thinners, for example a lubricant such as stearate magnesium.
: 30 As liquid compositions for administration oral, emulsions can be used pharmaceutically solutions, solutions, suspensions, syrups and 1 ~ 9 ~ `7 ~

elixirs containing inert diluents such as water or paraffin oil ~ These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
The compositions for parenteral administration can be aqueous or non-aqueous sterile solutions, suspensions or emulsions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants, in especially wetting agents, emulsifiers and dispersants.
Sterilization can be done in several ways, by example using a bacteriological filter, incorporating to the composition of sterilizing agents, or by heating.
They can also be prepared as a compound.
sterile conditions which can be dissolved at the time of employment in sterile water or any other sterile injectable medium.
The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.
The compositions according to the invention are useful as anthelmintic compositions.
In veterinary medicine, the products according to the invention - tion can be used in the treatment of helminthiasis with bovine, ovine, equine and caprine nematodes at doses between 5 and 50 mg / kg orally during treatments of 1 to 3 days, or between 2.5 and 25 mg / kg of weight body of the animal in spun doses, as well as for elimination tion of sheep gastrointestinal strongles and nematodes intestines of the dog.
In human medicine, the products according to the invention lQ ~ 78 can be used to remove the eel, roundworms and hookworms at doses between 5 and 50 mg / kg orally during treatments 1 to 3 days.
The compositions according to the invention may be also particularly useful in therapy in the treatment and prevention of human ilarioses: filariasis skin-o-dermal (onchocerciasis, loasis, dracunculiasis), lymphatic filariasis (wuchereriosis, brugiasis).
In human therapy, the doses depend on the desired effect and the duration of treatment, they are ge '~ generally between 10 and 50 mg / kg per day per channel oral and between 5 and 15 mg / kg per day by intramuscular route for an adult during treatments lasting from 1 to 30 days.
Of a ~ ac, on general, the doctor or the v, térinaire determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.
The following examples, given without limitation, illustrate compositions according to the invention.
Example A -We prepare according to the usual technique of tablets dosed at 25 mg having the following composition:
- 5-chloro-pyridyl-2-dimethyl-3,3 dithiocarbamate 2-oxo-butyl ..... 25 mg - wheat starch ..... 125 mg - colloidal silica ..... 45 mg - magnesium stearate ..... 5 mg Example B -We prepare according to the usual technique of tablets dosed at 25 mg having the following composition:
hydroxy-4 methyl-4 (pyridyl-2) -3 thia ~ olidinethione-2 ... 25 mg 7 ~

- wheat starch ~ ... 125 mg - colloidal silica ... 4S mg - magnesium stearate ... 5 mg

Claims (10)

The embodiments of the invention, over which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of hydroxy-4 derivatives thiazolidinethione-2, corresponding to the general formula:
(A) (B) in which:
R1 represents a hydrogen or halogen atom located in position -4, -5 or -6;
R2 represents a hydrogen atom or a radical alkyl containing 1 to 8 carbon atoms, an alkyl radical containing 1 to 4 substituted carbon atoms (by 1 to 3 atoms halogen or by a phenyl, hydroxy or alkyloxy radical, alkylthio, carboxy, alkyloxycarbonyl, alkyloxycarbonyl-alkyloxy, alkyloxycarbonylalkoylthio, acyloxy, acyloxy-alkyloxy or acyloxyalkoylthio), a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a phenyl radical (optionally substituted by an atom halogen or an alkyl, alkyloxy, hydroxy or nitro), a 2-thienyl radical or an alkyloxycarbonyl radical R3 represents a hydrogen atom, a radical alkyl, acyloxyalkyl, alkyloxycarbonylalkyl or alkyl-oxycarbonyl, or forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 atoms adjacent carbon can be part of a benzene ring, and R4 represents a hydrogen atom or a radical alkyl, it being understood that the radicals and alkyl portions and acyls mentioned above are straight or branched and that, except special mention, they contain from 1 to 4 carbon atoms, and their pharmaceutically acceptable salts when R2 represents a carboxyalkyl radical, characterized in that we act a .alpha.-halogenoketone of formula general:
in which R2, R3 and R4 have the abovementioned meanings and X represents a halogen atom, on a dithiocarbamate of general formula:
in which R1 has the abovementioned meaning and the symbols R5, which are the same or different, each represents an alkyl radical containing 1 to 4 carbon atoms, then optionally transforms the product obtained into addition salt with a nitrogen or metal salt base when R2 represents a carboxyalkyl radical. 2. Method according to claim 1, characterized in that :
- R1 represents a hydrogen atom:
- R3 and R4 represent a hydrogen atom, and - R2 represents a hydrogen atom, or a radical alkyl containing 1 to 8 carbon atoms, an alkyl radical containing 1 or 2 carbon atoms (substituted by 1 to 3 atoms halogen or by a phenyl, hydroxy or alkyloxy radical, alkylthio, carboxy, alkyloxycarbonyl or acyloxy), a radical cycloalkyl containing 3 to 6 carbon atoms a radical cyclohexenyl, a phenyl radical (optionally substituted by a halogen atom or by a methyl or methoxy radical, hydroxy or nitro), a thienyl-2 radical or an alkyloxy-carbonyl, or - R3 represents an alkyl radical (optionally substituted by an acyloxy radical) or an alkyloxycarbonyl radical le, R4 represents a hydrogen atom or an alkyl radical and R2 represents a hydrogen atom, an alkyl radical or a phenyl radical, or - R3 forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 atoms of adjacent carbon can be part of a benzene ring and R4 represents a hydrogen atom, it being understood that the alkyl radicals are straight or branched and that, unless otherwise stated, the radicals and alkyl portions contain 1 or 2 carbon atoms. 3. Method according to claim 1, characterized in that R1 represents a halogen atom, R2 represents an alkyl radical containing 1 to 4 carbon atoms or phenyl and R3 and R4 represent hydrogen atoms. 4. Method according to claim 1, characterized in that :
- R1 and R4 each represent a hydrogen atom, and - R3 represents a hydrogen atom, and R2 represents an alkyl radical containing 1 to 8 carbon atoms, a radical alkyl containing 1 or 2 carbon atoms (substituted by a phenyl, alkyloxy, alkylthio, methoxycarbonyl or carboxy), a cycloalkyl radical containing 5 or 6 atoms of carbon, a phenyl radical (optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy radical or nitro), a 2-thienyl radical, an alkyloxycarbonyl radical, or a trifluoromethyl radical; or - R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl or phenyl radical; or - R3 forms with R2 a tetramethylene radical in the chain of which the carbon atoms located in .alpha. and .beta. of the atom of carbon bearing R2 belong to a benzene ring, it being understood that the radicals are straight or branched and that, unless otherwise noted, radicals and portions alkyl contain 1 or 2 carbon atoms. 5. Method according to claim 1, characterized in that :
- R1 and R4 each represent a hydrogen atom, and - R3 represents a hydrogen atom, and R2 represents a straight or branched alkyl radical containing 1 to 8 atoms of carbon an alkyl radical containing 1 or 2 carbon atoms substituted (by a phenyl, hydroxyalkyloxy, alkylthio radical, alkyloxycarbonyl, acetoxy or carboxy), a cyclohexyl radical, a phenyl radical (optionally substituted by an atom halogen, or by a methyl, methoxy or hydroxy radical), a 2-thienyl radical, an alkyloxycarbonyl radical or a trifluoromethyl radical; or - R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl radical; or - R3 forms with R2 a tetramethylene radical;
the radicals and alkyl portions above comprising 1 or 2 carbon atoms. 6. Derivatives of 4-hydroxy thiazolidinethione-2, corresponding to the general formula:

(A) (B) in which:
R1 represents a hydrogen or halogen atom located in position -4, -5 or -6;
R2 represents a hydrogen atom or a radical alkyl containing 1 to 8 carbon atoms, an alkyl radical containing 1 to 4 substituted carbon atoms (by 1 to 3 atoms halogen or by a phenyl, hydroxy or alkyloxy radical, alkylthio, carboxy, alkyloxycarbonyl, alkyloxycarbonyl-alkyloxy, alkyloxycarbonylalkoylthio, acyloxy, acyloxy-alkyloxy or acyloxyalkoylthio), a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexenyl radical, a phenyl radical (optionally substituted by an atom halogen or an alkyl, alkyloxy, hydroxy or nitro), a thienyl-2 radical or an alkyloxycarbonyl radical;
R3 represents a hydrogen atom, a radical alkyl, acyloxyalkyl, alkyloxycarbonylalkyl or alkyl-oxycarbonyl, or forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 atoms adjacent carbon can be part of a benzene ring;
and R4 represents a hydrogen atom or a radical alkyl;
it being understood that the radicals and alkyl portions and acyls mentioned above are straight or branched and that, except special mention, they contain from 1 to 4 carbon atoms;

and their pharmaceutically acceptable salts when R2 represents a carboxyalkyl radical, whenever they are obtained by a process according to claim 1 or its equivalents manifest slow chemicals. 7. Derivatives according to claim 6, characterized in that :
- R1 represents a hydrogen atom;
- R3 and R4 represent a hydrogen atom, and - R2 represents a hydrogen atom, or a radical alkyl containing 1 to 8 carbon atoms, an alkyl radical containing 1 or 2 carbon atoms (substituted by 1 to 3 atoms halogen or by a phenyl, hydroxy or alkyloxy radical, alkylthio, carboxy, alkyloxycarbonyl or acyloxy), a cycloalkyl radical containing 3 to 6 carbon atoms a cyclohexenyl radical, a phenyl radical (optionally substituted by a halogen atom or by a methyl radical, methoxy, hydroxy or nitro), a 2-thienyl radical or a radical alkyloxycarbonyl; or - R3 represents an alkyl radical (optionally substituted by an acyloxy radical) or an alkyloxy radical carbonyl, R4 represents a hydrogen atom or a radical alkyl and R2 represents a hydrogen atom, a radical alkyl or a phenyl radical; or - R3 forms with R2 an alkylene radical containing 3 or 4 carbon atoms in the chain of which 2 atoms of adjacent carbon can be part of a benzene ring and R4 represents a hydrogen atom, it being understood that the alkyl radicals are straight or branched and that, unless otherwise stated, the radicals and alkyl portions contain 1 or 2 carbon atoms, each once they are obtained by a process according to claim 2 or its obvious chemical equivalents. 8. Derivatives according to claim 6, characterized in what R1 represents a halogen atom, R2 represents a alkyl radical containing 1 to 4 carbon atoms or phenyl and R3 and R4 represent hydrogen atoms, each time that they are obtained by a process according to claim 3 or its obvious chemical equivalents. 9. Derivatives according to claim 6, characterized in that :
- R1 and R4 each represent a hydrogen atom; and - R3 represents a hydrogen atom, and R2 represents an alkyl radical containing 1 to 8 carbon atoms, a radical alkyl containing 1 or 2 carbon atoms (substituted by a phenyl, alkyloxy, alkylthio, methoxycarbonyl or carboxy), a cycloalkyl radical containing 5 or 6 atoms of carbon, a phenyl radical (optionally substituted by a halogen atom or by a methyl, methoxy, hydroxy radical or nitro), a 2-thienyl radical, an alkyloxycarbonyl radical, or a trifluoromethyl radical; or - R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl or phenyl radical, or - R3 forms with R2 a tetramethylene radical in the chain of which the carbon atoms located in .alpha. and .beta. of the atom of carbon bearing R2 belong to a benzene ring, it being understood that the radicals are straight or branched and that, unless otherwise stated, alkyl radicals and portions 1 or 2 carbon atoms, each time they are obtained by a process according to claim 4 or their equivalents manifest slow chemicals. 10. Derivatives according to claim 6, characterized in that :
- R1 and R4 each represent a hydrogen atom, and - R3 represents a hydrogen atom, and R2 represents a straight or branched alkyl radical containing 1 to 8 atoms of carbon an alkyl radical containing 1 or 2 carbon atoms substituted (by a phenyl, hydroxyalkyloxy, alkylthio radical, alkyloxycarbonyl, acetoxy or carboxy), a cyclohexyl radical, a phenyl radical (optionally substituted by an atom halogen, or by a methyl, methoxy or hydroxy radical), a 2-thienyl radical, an alkyloxycarbonyl radical or a trifluoromethyl radical; or - R3 represents a methyl or methoxycarbonyl radical and R2 represents a methyl radical; or - R3 forms with R2 a tetramethylene radical; the radicals and alkyl portions above comprising 1 or 2 atoms of carbon, each time they are obtained by a process according to claim 5 or their chemical equivalents festes.