NL7907862A - NEW THIAZOLIDINE DERIVATIVES, THEIR PREPARATION, PREPARATIONS CONTAINING THE NEW DERIVATIVES, AND METHODS FOR PREPARING THE SAME - Google Patents

Description

N.O. 28,310 "1"

New thiazolidine derivatives, their preparation, preparations containing the new derivatives, and processes for their preparation.

The present invention relates to new thiazolidine derivatives of the general formula 1, optionally their salts, their preparation, preparations containing the new derivatives, and the processes for the preparation of such preparations.

5 In general formula 1 R. | a hydrogen atom or a halogen atom on the 4 ~> 5- or 6-plate and

Eg an alkyl group of 2 to 4 carbon atoms, substituted at a position other than the 1-position ^ with an amino, alkylamino, dialkyl-10 amino (the alkyl of which shares with the nitrogen atom to which they are attached a saturated heterocyclic 5 "or 6-2" forms, optionally containing an ande heteroatom selected from a secondary or tertiary nitrogen atom, oxygen atom or sulfur atom), carbamoyl, alkyl carbamoyl, dialkyl carbamoyl (the alkyl moieties of which have the nitrogen atom to which they are attached), may form a saturated 5- or 6-membered heterocycle, optionally containing another heteroatom selected from a secondary or tertiary nitrogen atom, oxygen atom or sulfur atom) or cyano group j or a dialkyloxymethyl, bis (alkyl-thio) methyl, alkyl sulfonylmethyl, phenylthiomethyl, 1-phenylcyclo-20-propyl, 1-methylcyclohexyl, phenyl substituted (with an amino group in the 2 position or with two identical groups selected from hydroxy, methyl or methoxy), 1-naphthyl, heterocyclic (selected from 1,3-di-thiolanyl-2,5 * 6-dihydro-1,4-dithiinyl-2,3-thienyl or 2-, 3- or 4-pyridyl, alkanoyl or benzoyl group, except that the alkyl -25 groups and the alkanoyl group, as mentioned above, are straight or branched and, unless otherwise stated, contain 1-4 carbon atoms.

The products of the present invention may exist in one of the forms (IA) or (133) or as an equilibrium mixture of these two forms as a function of the internal parameters (the groups E ^ and Eg) or external parameters (in the especially the presence of a solvent), as will be shown below.

The existence of the two forms (i) and (iB) of the 4-hydroxythia-zolidinethiones-2 is known and is the subject of various publications, in particular of RWLamon et al., J.Org.Chem., £ 2, 55 (1964) 2146 and J. Het Chem., 4, (1967), 349.

In general, the general formula (IA) corresponds to 790 7 8 62 -2- «. % Predominant form, in the crystallized state, of the products for which: a) R 1 is defined as indicated above and an alkyl group having 2 to 4 carbon atoms, substituted according to the above definition, a dialkyloxymethyl group, alkylsulfonylmethyl group , phenylthiomethyl group, phenyl group, substituted with the groups methyl or methoxy, alkanoyl or benzyl, or b) R 1 represents a hydrogen atom and 10 Rg represents a 2-aminophenyl, 1,3-dithiolanyl-2, 3-thienyl or 2 - or 4 "represents pyridyl group.

In general, the formula (IB) corresponds to the predominant form, in the crystallized state of the products, for which: a) R 1 is a hydrogen or halogen atom, present at the 4, 5, or 6, 15 position and R 1 represents a 1-phenylcyclopropyl, 1-methylcyclohexyl, dihydroxyphenyl, 1-naphthyl, bis (alkylthio) methyl, 5 * 6-dihydro-1,4-dithiinyl-2- ° 3-pyridyl group, or b ) R 1 represents a halogen atom at the 4> 5 "or 6 position and R 2 represents a 2-aminophenyl, 1,3-dithiolanyl-2, 3-thienyl or 2 or 4-pyridyl group.

According to the invention, the compounds of the general formula 1 can be obtained by the action of a compound (which can be prepared in situ) of the general formula 2, in which Rg has the aforementioned meanings and X a halogen atom, preferably a bromine or chlorine atom, on esudithiocarbamate of the general formula 3> wherein R 2 has the above meanings and the symbols R 1 (which are identical or different) each represent an alkyl group of 1-4 carbon atoms.

In general, the reaction proceeds in an organic solvent (such as diffithylformamide or acetonitrile) in water or in an aqueous organic medium (for example a mixture of water and dimethylformamide or water and acetonitrile) at a temperature between -10 and + 30 ° C.

The dithiocarbamates of the general formula 3 can be obtained according to the method described by E. B. Zott, J. Chem. Soc.

1644-9 (1956), by the action of carbon disulfide in the presence of a tertiary amine on a 2-aminopyridine of the general formula 4, wherein R 1 has the above meanings or according to the method described in U.S. Pat. No. 3,726,880.

7907862 ‘-3- J» - »

The compounds of the general formula II can be prepared using various general methods, which have been described in the literature and which have been taken up in more detail in the examples.

The new compounds of the present invention can optionally be purified by physical methods such as crystallization or chromatography.

The new compounds of the invention may optionally be converted to addition salts with acids when Rg is an alkyl -10 group substituted | with an amino, alkylamino, dialkylamino (whose alkyl groups with the nitrogen atom to which they are bonded may form the previously defined heterocyclic ring) or dialkyl carbamoyl group, whose alkyl moieties with the nitrogen atom to which they are attached, a saturated heterocyclic or 6-ring, which ring represents another secondary or tertiary nitrogen atom, represents 2 or 2-aminophenyl group. The addition salts can be obtained by action of the compounds on acids in suitable solvents; the organic solvents used are, for example, alcohols, ketones, ethers or chlorinated solvents. The salt formed precipitates after any concentration of its solution; the salt is separated by filtration or decantation.

The novel compounds of the invention, and optionally their salts, are particularly effective as broad spectrum anthelmintics on nematodes.

In particular, their activity can be demonstrated in the mouse on Hematosuiroides dubius at doses between 5 and 200 mg / kg orally.

In addition, certain compounds of the invention have been shown to act on the filariose of the cotton rat docr hitomosoides carinii at doses between 25 and 50 mg / kg orally per day for 5 consecutive days of treatment. Certain compounds have also been shown to be effective in the dog at doses between 10 and 50 mg / kg orally on Ankylostoma caninum.

Between 2.5 and 50 mg / kg orally on Uncinaria stenocephale and between 5 and 50 mg / kg orally on Toxocara canis or Toxa-soaris leonina.

The toxicity of the compounds of the invention, expressed in their lethal dose of 50% (1> D), is between 400 mg / kg and higher than 1000 mg / kg orally in the mouse.

790 7 8 62 »s -4-

Because of their activity level, of particular interest are the compounds of the general formula 1, wherein: a hydrogen or chlorine atom in the 5 position Eg represents an alkyl group with 2-4 carbon atoms, substituted in a place other than the 1 position | with a dialkylamino, dialkylcarb-amioyl- (whose alkyl groups with the nitrogen atom to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, which may optionally contain another secondary or tertiary nitrogen atom) or cyano group j or a dialkyloxymethyl, bis (alkyl-10 thio) métiiyi, "» alkylsulfonylmethyl-, phenyl-tiamiamethyl, 1-phenylcyclopropyl, 1-methylcyclohexyl, phenyl, substituted (with an amino group in the 2- instead or with two identical groups selected from hydroxy or methoxy), 1-naphthyl, 3-thienyl, 3- or 4-pyzicLyl or alka-represents noyl groupy with the proviso that the above-mentioned alkyl groups are straight or branched and unless otherwise stated, the alkyl and alkanoyl groups and alkyl and alkanoyl moieties contain 1 or 2 carbon atoms.

Among these compounds, especially active on Nema-tospiroides dubius are the compounds of the general formula 1, wherein: R. R. represents a hydrogen or chlorine atom in the 5-position and

Eg an alkyl group with two or three carbon atoms, substituted at the end of the chain | with a dialkylamino, dialkylearbamoyl (whose alkyl groups may form a saturated six-membered heterocyclic ring, optionally containing another secondary or tertiary nitrogen atom) or cyano group j, bis (methylthio) methyl, methylsulfo. nylmethyl, phenylthiomethyl, phenyl, substituted (with an amino group in the 2-position or with 2 hydroxyl groups), 3- or 4-Pyridyl or acetyl group, or Rj a chlorine atom in the 5-position and 50 ^ 2 represent a 1-phenylcyclopropyl 1-methylcyclohexyl, 1-naphthyl or 3-thienyl group, with the proviso that the aforementioned alkyl groups contain 1 or 2 carbon atoms.

Among the products of which the symbols have the meanings given below 55, of particular interest (table) 7907862 -5- R1 '[R2'

OH

01-5 ^ 0H

H - -ch.ch.nCc.hJ, H- -4CHj) 3ZN (C "H |)" H - -CH2S02CH3

AA

0! -5 I jft J

Also shown to be of interest on the filariose of the katosnrat by Litomosoides oarinii, on subcutaneous worms in the macro and micro form, the compounds of the general formula 1 have been found, in which: R 1 represents a hydrogen atom and S 2 represents an alkyl group with 2- 4 carbon atoms substituted at a position other than the 1-position with a dialkylamino, dialkylcarbamoyl (the alkyl moieties of which may optionally form a saturated 5- or 6-membered heterocyclic ring with the nitrogen atom to which they are attached) optionally containing another secondary or tertiary nitrogen atom) or cyano group j or egg dialkyloxymethyl, methyl sulfonylmethyl, bis (methylthio) methyl, 2-aminophenyl, J or 4-pyxidyl or alkanoy 1 g 2 ^ p ^%% V 'provided that the above-mentioned alkyl groups are straight or branched and that, unless otherwise stated, the alkyl and alkanoyl groups and alkyl and alkanoyl moieties contain one or two carbon atoms and among these products, more in particular especially the products , in which the groups have the following meanings: (table) 7907862 -6-

R1 I V

H- - (CH2) 2N (C2H5) 2 H- - (CH2) 2CON (C2H5) 2 H- - (CH2) 2CO NQN-CH3

H- - (CH2) 2 CN

H- -CH (OCH3) 2 H- -CH (S CH3) 2 H- -CH2-S02 “CH3 <b ·« - -o H- -COCH3

The following examples, given as non-limiting, illustrate the present invention.

Example I.

To a suspension of 5> 42 g of triethylammonium 2-pyridyldithio-carbamate in 10 ml of anhydrous acetonitrile, a solution of 4> 90 g of 1-bromo-3-phenylthiopropanone-2 in 50 ml of acetonitrile is added between 18 and 28 ° C. The reaction is continued at 20-28 ° C for 2 hours. The insoluble triethylamine bromohydrate is removed by filtration and washed with 10 ml of acetonitrile. The acetonitrile is evaporated under reduced pressure of 2.7 kPa at 40 ° C. The residual oil is dissolved in 50 ml of dichloromethane. The organic solution is washed twice with a total of 100 ml of distilled water, dried over sodium sulfate and evaporated. The product obtained (6.40 g) is dissolved in a mixture of 16 ml of ethyl acetate and 501 ml of cyclohexane. The solution is passed over 40 g of silica "Merck" (0.065-0.2 mm) distributed in a column with a diameter of 1.7 cm. Elution is carried out with a mixture of 40 ml of 790 7 8 62 -7-ethyl acetate and 160 ml of cyolohexane, then with a mixture of 25 ml of ethyl acetate and 75 µl of cyolohexane and then with a mixture of 50 ml of ethyl acetate and 70 ml of cyolohexane. 250 ml of eluate are first removed, then 150 ml of eluate are collected, evaporated at 40 ° C under a reduced pressure of 2.7 kPa and dried at 50 ° C under a reduced pressure of 0.027 kPa. 5.50 g of 4-hydroxy-4-phenylthiomethyl-5- (pyridyl-2) thiazolidinethion-2 are thus obtained.

The IRM spectrum (60 MHz) taken in about 10 percent solution in deuterated chloroform: 5.4 ppm: singlet (2H) -CHg-SCgH ^ 5.65 ppm: solid (2H) -CHg- heterocyclic 6.6 ppm : solid (1H) -0Ξ 7.2 ppm: solid (6H) -CgHj- plus -Hj.

7.5 ppm: doublet (1H) -H ^ (j = 8) 7.65 ppm: triplet of doublet (1H) -H ^ (J = 8 and 2) 8.55 ppm: doublet of doublet (1H) -Hg (J = 5 and 2)

The triethylammonium 2-pyridyl dithiocarbamate (mp 95 ° C) is prepared according to the method described by B. B. Enott, J. Chem.

Soc. 1644-49 (1956).

The 1-bromo-5-phenylthiopropanone-2 (melting point 45 ° C) is prepared by analogy with the preparation method of 1-chloro-3-phenylthiopropanone-2 described by Y. Hosnati, Gazz.Chim.Ital.99, ( 1969), 152-64.

Example II.

The procedure is as described in Example 1, but starting from 121.9 g of triethylammonium 2-pyridyldithiocarbamate and 88.7 g of 3-bromo-1,1-dimethoxypropanone-2 in 1 liter of anhydrous acetonitrile between 18 and 22 ° C. The reaction is continued at 20-22 ° C for 2 hours. The crude product (98.6 g) obtained is washed 50 with 150 ml of methylcyclohexane. The product obtained (29.4 gt, melting point 94 ° 0) is recrystallized from 150 ml of a mixture of equal parts of cyolohexane and ethyl acetate, followed by a second time in 70 ml of the same mixture of solvents. 15.7 g of 4-kydroxy-4-dimethoxymethyl-3- (P7ridyl-2) thiazolidinethion-2 are obtained, which melts at 55 ° C.

The 5-bromo-1,1-dimethoxypropanone-2 can be prepared by analogy to the bromination method of dissymetric ketones described by M. Gaudry and A. Marquet, Tetrahedron, 26 (1970), 5611-35 ^ by treating 118.0 g of 1.1 -dimethoxypropanone-2, dissolved in 800 ml of 40 methanol, with 160 g of bromine at a maximum of 5 ° C, ΐΐβΐΐ weld / fr, the reaction is 790 7 8 62 -8- /, continuants are obtained for 48 hours at 20 ° C. 95 S J-Dream 1.1-dimethoxypropanone-2 (boiling point g ^ ^ pa = 107-116 ° C)

Example III.

The procedure is as described in Example 1, but starting with 23 g of triethylammonium 2-pyridylthiocarbamate and 14.0 g of 1-bromobutanedione-2.3 in 170 ml of anhydrous acetonitrile between 18 and 20 ° C. The reaction is continued at 20 ° C for 4 hours.

The product obtained (15.0 g) is recrystallized from a mixture of 25 ml of ethanol and 80 ml of ethyl acetate, followed by a second 10 times in 85 ml of acetonium. 8.5 g of 4-aostyl-4-hydroxy-3 (pyridyl-2) thiazolidinethion-2 are obtained, which melts at 176 ° C.

The 1-bromobutanedione-2.3 (crumb point ^ kpa = 35 ° C) is prepared according to the method described in U.S. Pat. No. 2,821,555 Example IV.

The procedure is as described in Example 1, however, starting with 61 g of triethylammonium 2-pyridyldithiocarbamate and 29.6 g of 5-chloro-4-oxopentanitrile in 600 ml of anhydrous acetonitrile at a maximum of 2 ° C. The reaction is continued at 2 ° C for 2 hours.

After recrystallization from 150 ml of acetonitrile, 44.6 g of 34-hydroxy-3- (pyridyl-2) -2-thioxothiazolidinyl-4.7-propionitrile are obtained, which melts at 126 ° C. 2-5% 4-cyano-2-oxo-butyl-2-pyridyldithiocarbamate is observed in the infrared when the product is examined in the form of a tablet with kailum bromide ("carbonyl-25 band at 1720 cm"). This form is not found when the product is examined between slats in Vaseline.

The 5-chloro-4-oxopentanitrile is prepared by the action of 31.2 g of diazomethane at -10 ° C, followed by 50 ml of a solution of 12 N hydrochloric acid in water at 10-20 ° C, at 33> 0 g 3 -30 cyanopropanoyl chloride total 750 ml ether. 25.5 g of 5-chloro-4-oxopentanitrile are obtained. Melt at 68 ° C.

The 3-cyanopropanoyl chloride (bottleneck n = 82-84 ° 0)

v) Uu (iCjtcL

is prepared according to the method described by L.J. Dolby, J.Org.

Chem. ], 4510-11 (1968).

35 Example V.

The procedure is as described in Example 1, but starting from 62 g of triethylammonium 2-pyridyldithiocarbamate and 47 4 S 5-chloro-N.N-diethyl-4-oxopentanamide in 600 ml anhydrous acetonitrile between 20 and 25 ° C. The reaction is continued at 20-25 ° C for 2 hours. After recrystallization from 200 ml of acetonitrile 7 * 90 7 8 62. 56.5 S of N.N-diethyl-4-hydroxy-3- (pyridyl-2) -2-thioxothiazolidinyl-4 -7 propionamide is obtained, which melts at 125 ° C.

When the product is examined in the infrared in a chloroform solution, about 2-5% of 4-di-hylaminocarbonyl-1,5-oxobutyl-2-pyridyldithiocarbamate (carbonyl tape at 1720 cm) is observed. This form is not detected when the product is examined between slats in Vaseline.

The 5-chloro-NN-diethyl-4-oxopentanamide is prepared by the action of 59 S dicyclohexylcarbodiimide and 20.6 g diethylamine on 10 44.8 g 5-chloro-4-oxopentanoic acid in 770 ml dichloromethane at 20-25 ° C for 2 hours. 47.6 g of 5-chloro-N, N-diethyl-4-oxopentanamide (boiling point Qlpa = 140-145 ° C) are obtained.

The 5-chloro-4-oxopentanoic acid (melting point = 71 ° C) is prepared according to the method described in 7.M. Rodionov and M.A.Gubareva, 15 Chem. Abst. & (1955), 926d.

Example 71.

The procedure is as described in Example 1, but starting from 28.2 g of triethylammonium 2-pyridyldithiocarbamate and 25.2 g of 1- (5-chloro-1,4-dioxopentyl) -4-nonhylpiperazine in 300 ml of anhydrous acetonitrile maximum 2 ° C. The reaction is continued at 200C for 2 hours. The resulting oily product (32.0 g) is dissolved in 150 ml of ethanol and treated with a solution of 10.1 g of fumaric acid in 30 ml of dimethylformamide at a maximum of 30 ° C. After cooling to 2 ° C for 2 hours, the appeared crystals are separated by filtration, washed three times a total of 90 ml of ethanol and dried under a reduced pressure of 0.027 kPa at 50 ° C. 31.5 S of 4-hydroxy-4-J / -3- (4-phenyl-piperazinyl-1) -3-oxo-propyl-7-3- (pyridyl-2) thiazolidinethion-2 fumarate are obtained, which is 150 ° C melt.

The 1- (5-chloro-1,4-dioxopentyl) -4-methylpiperazine can be prepared in the following manner; - preparation of 5-chloro-4-oxopentanoic acid (melting point 71 ° C) as described in example 7, - preparation of 34 S 5-chloro-5-chloromethyl-4 »5-chlorhydro-3H-furanone-2 35 (boiling point q papa = 88-89 ° C) by action of 35.0 g of thionyl chloride on 36.9 S of 5-chloro-4-oxopentanoic acid in 240 ml of chloroform, at the reflux temperature for 1.5 hours, preparation of 25.2 g of 1- (5-chloro-1,4-dioxopentyl) -4-methylpiperazin-40 ne (melting point 95 ° C) by action of 36.4 S 1-methylpiperazine on 790 7 8 62 -10-30, 8 g of 5-chloro-5-chloromethyl-4 * 5-dihydro-3H-furanone-2 in 300 ml of anhydrous acetone for 1 hour at 2 ° C.

Example VII.

To a suspension of 27.1 g of triethylammonium 2-pyridyldithio-5 carbamate in 100 ml of water, a loading of 30.3 g of 1-bromo-4-diethylaminobutanone-2 bromohydrate in 30 ml of water is added at 20 ° C.

The reaction is continued at 20 ° C for 1 hour. It is treated with 1.0 g of decolorizing carbon, filtered and washed with 10 ml of water. The filtrate is dried under reduced pressure of 2.7 kPa at 50 ° C to a residual volume of about 60 ml. After cooling to 2 ° C for 2 hours, the appeared crystals are separated by filtration, washed with 10 ml of ice water and 10 ml of ethanol and dried at 45 ° C under a reduced pressure of 0.027 kPa. This gives 18.7 g of 4- (2-diethylaminoethyl) -4-hydroxy-3- (pyridyl-2) thiazolidine-15 thion-2 bromohydrate, which melts at 148 ° C. The 1-bromo-2-diethyl-aminobutanone-2 bromohydrate (melting point 80 ° C) is prepared according to the method described by C. Djerassi et al., J. Org.Chem.15 (1950), 700-06.

Example VIII.

The procedure is as described in Example 1, although starting from 52 g of triethylammonium (5-chloropyridyl-2) dithio-carbamate and 33.1 g of 1-chloro-2- (1-phenylcyclopropyl) ethanone-2 500 ml anhydrous acetonitrile at 20 ° C. The reaction is continued at 20 ° C for 2 hours. After recrystallization from 160 ml of acetoni-25 trile, 48.1 g of 2- (1-phenylcyclopropyl) -2-oxoethyl (5-chloropyridyl-2) dithiocarbamate are obtained, which melts at 127 ° C.

48.0 g of 1-chloro-2- (1-phenylcyclopropyl) ethanone-2 (boiling point = Pa = 106 ° C; melting point about 45 ° C) are obtained by the action of 25.2 g of diazomethane between -15 and -5 ° C, followed by 100 ml of a solution of 12 l of hydrogen chloride in water between 0 and 10 ° (S) on 48.7 g of 1-phenylcyclopropanecarbonyl chloride in 600 ml of ether.

The 1-phenylcyclopropanecarbonyl chloride (boiling point papa = 82 ° C) is prepared according to the method described by A.W. Weston, J.Am.Chem.Soc. 68, (1946), 2347-35 Example IX.

The procedure is as described in Example 1, but starting from 80.5 g of triethylammonium (5-chloropyridyl-2) dithio-carbamate and 46.0 g of 1-chloro-2- (1-methylcyclohexyl) ethanone-2 650 ml anhydrous acetonitrile at 20 ° C. The reaction is continued at 20 ° C for 2 hours. After recrystallization from 400 ml of aceto-790 7 8 62 -11-nitile, 66.1 g of 2- (1-methylcyclohexyl) -2-oxoethyl (5-chloropyridyl-2) dithiocarbamate are obtained, which melts at 102 ° C.

The 1-chloro-2- (1-methylcyclohexyl) ethanone-2 (boiling point 1 = 70-75 c) is prepared according to the method described in German Pat. No. 2,216,838.

7907862 -12-

Example X.

The procedure is as described in Example 1, however starting from 10.9 g of triethylammonium 2-pyridyldithiocarbamate and 8.6 g of 1- (2-aminophenyl) -2-bromoethanone-1 in 60 ml of anhydrous acetonitrile between 22 and 28 ° C. The reaction is continued at 20-28 ° C for 2 hours. Recrystallization from 90 ml of acetonitrile gives 8.4 g of 4- (2-aminophenyl) -4-hydroxy-3- (pyridyl-2) thiazolinethione-2, which melts at 130 ° C.

When the product is examined in the infrared in a chloroform solution, about 30% 2- (2-aminophenyl) -2-oxoethyl (pyridyl-2) dithiocarbamate (carbonyl tape at 1650 cm-1) is observed. This form is not detected when the product is examined between slats in Vaseline.

The 1- (2-aminophenyl) -2-bromoethanone-1 (melting point 63 ° c) is prepared according to the method described by P. RUGGLI and H. REICHWEIH, Helv. Chim. Acta 20, (1937) 913

Example XI

The procedure is as described in Example 1, however, starting from 40 g of triethylammonium (5-chloropyridyl-2) dithio-20 carbamate and 24.2 g of 2-chloro-1- (3,4-dihydroxyphenyl) ethanone. 1 in 450 ml anhydrous acetonitrile between 15 and 20 ° 0. The reaction is continued at 20 ° C for 4 hours. After recrystallization from a mixture of 1000 ml of acetonitrile, 500 ml of ethyl acetate and 25 ml of dimethylformamide, 2-TrO 2 g of 2- (3-4-dihydroxyphenyl) -25 2-oxoethyl (5-chloropyridyl-2) dithiocarbamate melts at 195 ° C. Example XII

The procedure is as described in Example 1, but starting from 4 °, 0 g of triethylammonium (5-chloropyridyl-2) dithiocarbamate and 33.8 g of 2-bromo-1- (2,5-dimethoxyphenyl) ethanone-1 in 450 ml 30 anhydrous acetonitrile between 15 and 20 ° C. The reaction is continued at 20 ° C for 4 hours. After recrystallization from 500 ml of acetonitrile, 35.0 g of 3- (5-chloropyridyl-2) -4- (2,5-dimethoxy-phenyl) -4-hydroxythiazolidinethion-2 are obtained, which melts at 168 ° C.

Example XIII

The procedure is as described in Example 1, but starting from 18.0 g of triethylammonium (5-chloropyridyl-2) dithio-carbamate and 15.0 g of 2-bromo-1- (1-naphthyl) ethanone-1 in 250 ml anhydrous acetonitrile at 20 ° C. The reaction is continued at 20 ° C for 4 hours. After recrystallization from a mixture of 500 ml of ethanol and 100 ml of ethyl acetate, 13.0 g of 2- (1-naphthyl) - 790 7 8 62 -13-2-oxoethyl (5-chloropyridyl-2) dithiocarbamate, which is obtained at 146 ° C melts.

When the product is examined in the infrared in a chloroform solution, about 90 to 95% of 3- (5-chloro-pyridyl-2) -4-hydroxy-4- (1-naphthyl) thiazolidinethione-2 is observed (reduction of the intensity of the carbonyl tape at 1690 cm ”).

This form is not detected when the product is examined between slats in Vaseline.

The 2-bromo-1- (1-naphthyl) ethanone-1 (boiling point = 145-

UjUlp iCir8, 155G) is prepared according to the method described by C.B. RADCLIFFE 10 et al., J. Ghem. Soc., 2293 (1931).

Example XIV

To a suspension of 23> 4 S triethylammonium 2-pyridyldithio-carbamate in 500 ml nitromethane, 17 µg of 2-bromo-1- (4-pyridyl) ethanone-1 is added at a maximum of 15 ° C. The reaction is continued at 15-20 ° C for 2 hours. The nitromethane is evaporated at 45 ° C under a reduced pressure of 2.7 kPa. The resulting paste-like residue is washed with 100 ml of distilled water and then with 500 ml of ethyl acetate. The crystals obtained (12.0 g, melting point = 175 ° C) are purified by recrystallization from a mixture of 20 ml of dimethylformamide and 50 ml ethanol. 5.7 g of 4-bydroxy-3- (2-pyridyl) -4 (4-pyridyl) thiazolidine-thione-2 are obtained, which melts at 175 ° C.

24.1 g of 2-bromo-1- (4-pyridyl) ethanone-1 (melting point = 190 ° C) are obtained by the action of 16.0 g of bromine on a solution of 12.2 g of 25 1- (4-pyridyl) ethanone-1 in 60 ml of methanol between 18 and 29 ° C, followed by 50 ml of a concentrated aqueous solution of sodium hydrogen carbonate.

Example XV

To a suspension of 38> 0 g of triethylammonium 2-pyridyldithio-30 carbamate in 260 ml of anhydrous acetonitrile, a solution of 38 g of 1-bromo-3-methylsulfonylpropanone-2 (80%) in 120 ml is added between 0 and 5 ° 0. anhydrous acetonitrile. The reaction is continued at 2 ° G for 2 hours. The acetonitrile is evaporated under a reduced pressure of 2.7 kPa at a maximum of 50 ° C. The residual oil is dissolved in 400 ml of dichloromethane. The organic solution is washed 4 times with a total of 600 ml of distilled water, treated with decolorizing charcoal, dried over anhydrous sodium sulfate and evaporated. The product obtained (40 g) is dissolved in 400 ml of chloroform. The solution is chromatographed over 400 g of silica "MERCK1" (0.2-0.5 mm) taken up in a column with a diameter of cm. 7907862-5. Elution is carried out with 4 µl of chloroform, which is removed, followed by 1.2 L of chloroform, which is evaporated at 50 ° C under a reduced pressure of 2.7 kPa.

The product obtained (20.0 g, melting point about 150 ° C) is purified by recrystallization from 120 ml of ethyl acetate. 1.6 g of 4-b-hydroxy-4-methylsulfonylmethyl-3- (pyridyl-2) thiazolidinethion-2 are obtained, which melts at 148 ° C.

The 1-bromo-3-methylsulfonylpropanone-2 can be prepared in the following manner: - preparation of ethylsulfonyl acetic acid (melting point 114 ° 0) according to the method described by J.M. CAKPMTER et al., J. Chem. Soc. 2016-22 (1970), - preparation of 36.9 methanesulfonylacetyl chloride (oily) by the action of 130 ml sulfinyl chloride on 32.6 g methylsulfonyl acetic acid at about 60 ° C in the presence of 0.3 ml dimethylformamide, - preparation of 38 »4 S 1-bromo-3-methylsulfonylpropanone-2 (pasty; purity about 80%) by acting a solution of 24> 2 g diazomethane in 600 ml anhydrous ether on a solution of 36.9 ml methylsulfonylacetyl chloride in 200 ml of dichloromethane at -10 ° C, followed by the action of 45 ml of a 48% aqueous solution of hydrogen bromide (density 1.49) on the 1-diazo-3-methylsulfonylpropanone-2 formed in situ between 0 and 20 ° C .

7907862 -15-

Example XVI

The procedure is as described in Example XV, however, starting from 40.5 g of triethylammonium 2-pyridyldithiocarba and 28 g of 1-chloro-3,3- (methylthio) propanone-2 in 400 ml of water-5 free acetonitrile between 15 and 20 ° C. The reaction is continued at 20 ° C for 16 hours. The product obtained (75 g) is dissolved in 500 ml of ethyl acetate and the solution is washed twice with a total of 200 ml of distilled water, treated with decolorizing charcoal, dried over anhydrous sodium sulfate and evaporated. The product obtained (60 g) was dissolved in a mixture of 300 ml of cyclohexane and 200 ml of ethyl acetate and the solution was chromatographed on 600 g of silica "MERCK" (0.2 - 0.5 mm) contained in a column with a diameter of 5 cm. Elution is carried out with a mixture of 900 ml of cyclohexane and 600 ml of ethyl acetate while removing the corresponding eluate, followed by a mixture of 600 ml of cyclohexane and 400 ml of ethyl acetate. The second eluate is evaporated under a reduced pressure of 2.7 kPa at 50 ° C. The product obtained (30 g) is purified by recrystallization from 100 ml of boiling diisopropyl ether. 11 g of 3 · 3-bis- (methylthio) -2-oxopropyl-2-pyridyldithiocarbamate are melted in this manner, which melts at 127 ° C.

When the product is examined in infrared in a chloroform solution, about 90% of 4-hydroxy-4-bis (methylthio) methyl-3- (2-pyridyl) thiazolidinethion-2 (very marked reduction in intensity is observed) of the carbonyl tape at 1705 cm). This form is not detected when the product is examined between slats in Vaseline.

The 1-chloro-3,3-bis (methylthio) propanone-2 can be prepared in the following manner: - preparation of 2,2-bis (methylthio) acetic acid (melting point TJ ° C) according to the method described by A. TANAtJGER, Arkiv. Kemi, Mineral, Geol., 24 A, (1947) 10-18, - preparation of 28.4 g bis (methylthio) acetyl chloride (boiling point 2.7 kPa = 105 ° c) cL ° or action of a solution of 30, 4 g 2.2- ^ 13 35 (methylthio) acetic acid in 350 ml anhydrous diethyl ether on a solution of 19 ml oxalyl chloride in 100 ml anhydrous diethyl ether in the presence of 1 ml dimethylformamide at 0 ° C, - preparation of 28 g 1-chloro-3.3- bis (methylthio) propanone-2 (non-distillable orange colored oil) by acting a solution of 17> 2 g diazomethane in 480 ml anhydrous diethyl ether on 790 7 8 2 ✓ * -16- a solution of 28.4 g bis (methyl) acetyl chloride in 50 ml of anhydrous diethyl ether at -30 ° C, followed by action of 55 ml of an aqueous solution of 12 N hydrochloric acid on 1-diazo-3,3-bis (methylthio) propanone-2, which is in situ is formed, between 0 and 20 ° C.

Example XVII

To a solution of 18.4 g of triethylammonium 2-pyridyldithio-carbamate in 150 ml of distilled water, a solution of 19> 0 g of 2-bromo-1 "(3-pyridyl) ethanone bromo-10 hydrate is added between 18 and 20 ° C. in 350 ml of distilled water. The reaction is continued at 20-22 ° C for 16 hours. The crude product is separated by filtration, washed 3 times with a total of 300 ml of distilled water and then with 100 ml of diisopropyl ether and air dried. The product obtained (13.0 g, melting point 185 °) is dissolved in 100 ml of boiling ethyl acetate. After filtration of the boiling solution, followed by cooling at 2 ° C for 4 hours, the appeared crystals are separated by filtration, washed 3 times with a total of 30 ml of ice-cold ethyl acetate and dried at 40 ° C under a reduced pressure of 0.027 kPa. 10.5 g of 2-oxo-2 ((3-pyridyl) ethyl 2-pyridyl carbamate melting at 190 [deg.] C. are thus obtained.

The triethylammonium 2 pyridyl dithiocarbamate is prepared according to the method described by E.B, KNOTT, J. Chem. Soc., 1644-9 (1956). ------------ The 2-bromo-1- (3-pyridyl) ethanone bromohydrate is prepared according to the method described by A. D0EN0W, Ξ. MACHENS and K. BRUNCHEN, Chem. Ber., 84, 147-50 (1951).

Example XVIII

The procedure is as described in Example XV, but starting from 25.6 g of triethylammonium 5-chloro-2-pyridyl dithiocarbamate and 17.2 g of 1-bromo-3- (3-thienyl) propanone-2 in 150 ml anhydrous acetonitrile between 15 and 20 ° C. The reaction is continued at 20 ° C for 30 minutes. The product obtained (25.0 g, melting point 145 ° C) is purified by recrystallization with 280 ml of acetonitrile. 21.7 g of (3-thenoyl) methyl (5-chloropyridyl-2) dithiocarbamate are obtained, which melts at 148 ° C.

When the product is examined in the infrared in chloroform solution, the 3- (5-chloro-pyridyl-2) -4-hydroxy-4- (3-thienyl) thiazolidinethion-2 (intensity reduction) is predominantly obtained.

- * J

40th carbonyl band at 1680 cm ”).

790 7 8 62 -17-

The 1-bromo-3- (5-thienyl) propanone-2 (melting point 55 ° C) is prepared according to the method described by D.W.H. Mac DOWELL and T.D. GREENWOOD, J. Het. Chem. 2, 46 (1965).

Example 7TX

5 To a solution of 27.1 g of triethylammonium (2-pyridyl) dithio-

carbamate in 150 ml of distilled water is added between 15 and 20 ° C

30.3 g of 1-bromo-5-diethylaminopentanone-2 bromohydrate. The reaction is continued at 20-25 ° for 2 hours. After filtration of the reaction mixture under a reduced pressure: the water is evaporated under a pressure of 2.7 kPa at 70 ° C. The resulting residue is dissolved in 200 ml of boiling ethanol.

After adding 2 g of decolorizing carbon to the boiling solution, it is filtered boiling and allowed to cool to 20 ° C for 2 hours. The chalks appearing are separated by filtration, washed 5 times with total 40 ml / ethanol and dried under a reduced pressure of 0.027 kPa at 45 ° G.

11.6 g of 4- (3-diethylaminopropyl-1) -4-hydroxy-3- (2-pyridyl) thiazolidinethion-2 bromohydrate are melted in this manner, melting at 175 ° (structure determined according to the infrared spectrum in Vaseline ).

The 1-bromo-5-diethylaminopentanone-2 bromohydrate can be prepared in the following manner:

To a solution of 15> 7 g of 5-diethylaminopentanone-2 in 20 ml of acetic acid is added between 20 and 25 ° C, 25 ml of an approximately 25 35-percent hydrogen bromide solution in acetic acid, followed by, between 15 and 20 ° G , a solution formed by a solution of 16 g of bromine in 30 ml of acetic acid. The reaction is continued at 20-25 ° C for 16 hours. The acetic acid is evaporated under a pressure of 2.7 kPa at 70 ° C and then under a pressure of 0.027 kPa at 50 ° C. The residual oil is washed 3 times with a total of 1500 ml of diethyl ether and then dried at 45 ° C under a reduced pressure of 0.027 kPa. 30 g of 1-bromo-5-diethylaminopentanone-2 bromohydrate (oily) are thus obtained.

The triethylammonium 2-pyridyl dithiocarbamate (melting point 3595 ° C) is prepared according to the method described by E.B. ΚΗ0ΤΤ, J. Ohem. Soc., 1644-9 (1956).

The present invention also relates to therapeutically applicable pharmaceutical preparations comprising at least one product of the general formula (1 ') (optionally in the form of a n-toxic salt) together with one or more compatible pharmaceutical 790 7 8 62 -18- contain acceptable diluents or additives and optionally with other compatible and physiologically active compounds. These preparations can be used orally, parenterally or rectally.

As preparations for oral administration, tablets, pills, powders, dragées or granules can be used. In these preparations, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or amidone. These preparations may also contain products other than the diluents, for example a lubricant such as magnesium stearate.

As liquid preparations for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These preparations may also contain products other than the diluents, for example, wetting agents, sweeteners or flavorings.

790 7 8 62 i- ~ -19-

The preparations for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As the solvent or carrier, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, such as ethyl oleate, can be used. These preparations may also contain additives, in particular wetting agents, emulsifying agents and dispersing agents. Sterilization can be performed in various ways, for example, using a bacteriological filter, incorporating sterilizing agents into the composition, or by heating. The formulations can also be prepared in the form of sterile formulations, which can be dissolved at the time of use in sterilized 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 supplements.

In these various preparations, the active product, when not dissolved, is expediently in a comminuted form.

The preparations according to the invention are used as anthelmintic preparations.

In veterinary medicine, the products according to the invention can be used for the treatment of helmet intiases caused by nematodes in cattle, sheep, equidae and goats at doses between 5 and 50 mg / kg orally during treatments of 1 to 3 days, or between 2.5 and 25 mg / kg body weight of the animal in long-acting doses, as well as for the elimination of intestinal worms in the sheep and intestinal nematodes in the dog.

In human medicine, the products of the invention can be used for the elimination of nematodes, rinse worms and curved worms at dosages between 5 and 50 mg / kg orally during treatments of 1 to 3 days.

The compositions according to the invention can also be used particularly therapeutically for the treatment and prevention of human filariose: cutaneous dermal filarioses (onchocercosis, loase, dracunculosis), lymphatic filariose (wucheriosis, bridgese).

In human therapy, dosages depend on the intended effect and duration of treatment; the dosages are generally between 10 and 50 mg / kg per day by the oral route and between 5 and 15 mg / kg per day by the intramuscular route for an adult during treatments lasting from 1 to 30 days.

Generally, the physician or veterinarian will determine the posology he deems most appropriate as a function of age, weight, and all other factors peculiar to the individual to be treated.

The following examples, which are not limiting, illustrate compositions of the invention.

10 Example A.

Tablets of a dose of 25 mg with the following composition are prepared in the following manner: s 2- (3,4- <iib.hydroxyphenyl) -2-oxoethyl 5-chloro-2-pyridyl dithiocarbamate ... 25 mg wheat starch ... 125 mg of colloidal silicon dioxide ... 45 mg of magnesium stearate ... 5 mg

Example B.

Tablets with a dosage of 25 mg with the following composition are prepared according to the usual technique: 4-hydroxy-4- (2-diethylaminoethyl) -3- (pyridyl-2) -thiazolidinethione-2 ... 25 mg wheat starch. .125 mg colloidal.silicon dioxide -------- ... 45 mg 25 magnesium stearate ... 5 mg

Example 0

Injectable ampoules containing a 10% solution of the active product and of the following composition are prepared by the usual methods: 4-hydroxy-4- (2-diethylaminoethyl) -3- (pyridyl-2) -thiazolidinethione-2 ... 0.25 mg injectable solute ... 2.5 ml 790 7 8 62

Claims (4)

5 Eg represents a 2-aminophenyl, 1,3-dithiolanyl-2-, 3-thienyl or 2- or 4-pyridyl group. 4-Hydroxythiazolidinethion-2 derivative according to claim 1, characterized in that its predominant form in the crystallized state corresponds to the general formula 10 (TE), wherein a) Ej represents a hydrogen or halogen atom at the 4-> 5 "or 6 position and Eg represents a 1-phenylcylopropyl, 1-methylcyclohexyl, dihydroxyphenyl, 1-naphthyl, dialkylthiomethyl, 5 * 6-dihydro-1,4-di-thinnyl-2 or 3-pyridyl group or 15 b) EJ represent a halogen atom in the 4-> 5- or 6-position and Eg a 2-amino-phenyl, 1,3-dithiolanyl-2-, 3-thienyl or 2- or 4-pyridyl group. 4. Process for the preparation of thiazolidine derivatives, characterized in that compounds of formula 1, in which the symbols have the meanings stated in claim 1, are prepared in a manner known per se. 5. A process for the preparation of thiazolidine compounds, characterized in that compounds of the general formula 1, in which the symbols have the meanings stated in claim 1, are prepared by preparing a compound of the general formula 2, in which Eg the compounds of claim 1 has the meanings mentioned and X represents a halogen atom feed reacting with a di-thiocarbamate of the general formula 3 wherein E ^ has the meanings stated in claim 1 and the symbols E ^, which are the same or different, each have an alkyl group with 1 to 4 carbon atoms, then optionally converting the resulting product to an addition salt with an acid, when Eg is an alkyl group substituted with an amino, alkylamino, dialkylamino (the alkyl moieties of which have the nitrogen atom to which they are attached). 35 previously defined heterocyclic ring) or dialkylearbamoyl group, the alkyl parts of which with the nitrogen atom to which they are attached form a saturated h can form a 5- or 6-membered e-cyclic ring containing another secondary or tertiary nitrogen atom representing 2-aminophenyl group, 6. Pharmaceutical preparation, characterized by the presence of one or more compounds of the general formula 1 in the pure state or: together with one or more diluents or additives, which are compatible and are pharmaceutically acceptable. A method of preparing a pharmaceutical preparation, characterized in that one or more compounds of formula 1, wherein the symbols are as claimed in claim. 1, in a form suitable for such application. «790 7 8 62 _1_ (Υί ^ Η rYA, Vj“ NVLJ Μ η V OH 0 (A) (B) 2, r2-co-ch2 — X 3. Λ R-- © © '^ Nj * -NHC5- S, HN (R3) 3 -L · V. V "NH2 7907862