DE2944342A1 - NEW DERIVATIVES OF 4-HYDROXI-THIAZOLIDIN-2-THIONS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

New derivatives of 4-hydroxy-thiazolide-2-thione and the pharmaceutical compositions containing them

[Addition to patent (P 28 21 555.6)]

description

In the main patent are derivatives of 4-hydroxy-thiazolidine-2-thione of the general formula (I)

(A)

(B)

described in which

R .. means a hydrogen or Haigen atom in 4-, 5- or 6 position,

R _{2 is} a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms, an alleyl radical with 1 to 4 carbon atoms, which is substituted (by 1 to 3 halogen atoms or by a phenyl, hydroxyl, alkyloxy, alkylthio, carboxy,

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Alkyloxycarbonyl, alkyloxycarbonylalkyloxy, alkyloxycarbonylalkylthio, Acyloxy, acyloxyalkyloxy or aeyloxyalkylthio radical), a cycloalkyl radical having 3 to 6 carbon atoms, a cyclohexenyl radical, a phenyl radical (optionally substituted by a halogen atom or by an alkyl, alkyloxy, hydroxyl or nitro radical), a thien-2-yl radical or means an alkyloxycarbonyl radical,

R, a hydrogen atom, an alkyl, acyloxyalkyl, alkyloxycarbonylalkyl or is an alkyloxycarbonyl radical or forms an alkylene radical with 3 or 4 carbon atoms with Rg, in the chain of which two adjacent carbon atoms can form part of a benzene ring and

R- represents a hydrogen atom or an alkyl radical, it being possible for the abovementioned alkyl and aoyl radicals or parts to be straight or branched and, if nothing else indicated contain 1 to 4 carbon atoms.

The compounds of the general formula (I) can be in one of the forms (IA) or (IB) or as a mixture in the equilibrium of these two forms as a function of the internal parameters (in particular the radicals R ₁ and R ₂ ) or external parameters (in particular in the presence of a solvent) as mentioned below.

This existence of the two forms (IA) and (IB) of 4-hydroxithiazolidine-2-thione is known and forms the subject of various publications in particular by R.W. Lamon et al., J. Org. Chem. 29., 2146 (1964) and J. Het. Chem. 1, 349 (1967).

In general, the general formula (IA) corresponds to the predominant form in the crystallized state of the products for the:

a) Rp is a hydrogen atom or an alkyl radical with 1 to 3 Carbon atoms or η-butyl (in which these radicals are given-

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if by 1 "to 3 halogen atoms or by a phenyl, Hydroxi-, alkyloxy-, alkylthio-, carboxy-, alkyloxycarbonyl-alkyloxycarbonylalkyloxy-, Alkyloxycarbonylalkylthio, acyl

subscript. are oxy, acyloxyalkyloxy, acyloxyalkylthior QWbfy a straight or branched in a position different from the 1- or 2-position alkyl radical with 5 to 9 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a cyclohexenyl radical, a 3-nitro odex 4- Nitrophenyl radical or an alkyloxycarbonyl radical and

R, has the meanings given above with the exception of the formation of an alkylene radical with R ₂ , in the chain of which two adjacent carbon atoms form part of a benzene ring and

R. and R .. have the meanings given above; (b) R2 is a phenyl radical (optionally substituted in the 2-, 3- or 4-position by a halogen atom, in the 2- or 3-position by an alkyloxy radical in the 3- or 4-position by a hydroxy radical or in the 3-position by a Alkyl radical) and either R, an Y / hydrogen atom, an alkyl, acyloxy alkyl,

Alkyloxycarbonylalkyl or alkyloxycarbonyl radical or with Rp forms an alkylene radical with 3 or 4 carbon atoms, in the chain of which two adjacent carbon atoms form part of a benzene ring, R. has the meanings given above; and R .. means a hydrogen atom,
- or R, an Alley 1-, acyloxyalkyl-, alkyloxycarbonylelkyl-

or alkyloxycarbonyl radical or with Rp a Alkylene radical with 3 or 4 carbon atoms forms, in the chain of which two adjacent carbon atoms are part of a benzene ring form,

R, denotes an alkyl radical and
R _{1 represents} a halogen atom.

In general, the general formula (IB) corresponds to the above

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prevailing form in crystallized state of the products for the:

(a) R _{2 is} an alkyl radical with 4 "to 8 carbon atoms which is branched in the 1- or 2-position, a branched substituted butyl radical (substituted by 1 to 3 halogen atoms or a phenyl, hydroxyl, alkyloxy, alkylthio, Carboxy, alkyloxycarbonyl, alkyloxycarbonyl-alkyloxy, alkyloxycarbonylalkylthio, acyloxy, acyloxyalkyloxy, acyloxyalkylthio radical), a substituted phenyl radical (substituted in the 2-position by a hydroxy, alkyl or nitro radical or in the 4-position by an alkyl or alkyloxy radical) or a thien-2-yl radical,

R ~ has the meanings given above with the exception that with Rp an alkylene radical is formed which is optionally associated with a benzene ring and R- and R _{1 have} the meanings given above;

(b) Rp is a phenyl radical (optionally substituted in 2-,

3- or 4-position by a halogen atom, in 2- or 3-position by an alkyloxy radical, in the 3- or 4-position by a hydroxy radical or in the 3-position by an alkyl radical) is,

R, denotes a hydrogen atom, an alkyl, acyloxyalkyl, alkyloxycarbonylalkyl or alkyloxycartonyl radical or, together with Rp, forms an alkylene radical with 3 or 4 carbon atoms in whose chain two adjacent carbon atoms form part of a benzene ring
R _{1 is} a halogen atom and

R. means a hydrogen atom.
4th

According to the main patent, the compounds of the general formula (I) can be obtained by the action of a compound (which can be prepared in situ) of the general formula (II)

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(II)

where Rp »R * and R. are as defined above and X is Halogenatotn is preferably a bromine or chlorine atom (optionally in salt form if Rp is a carboxyalkyl radical represents), to a thiocarbamate of the general formula (III)

- NH CS-S ^, HN (

where R .. as defined above and the symbols R, - (which are identical or different), each represent an alkyl radical having 1 to 4 carbon atoms.

In general, the reaction takes place in an organic solvent such as dimethylformamide or acetonitrile, in water or an aqueous-organic medium (for example in a mixture of water-dimethylformamide or water-acetonitrile) at a temperature between -10 and +50 ⁰ C.

The dithiocarbamates of the general formula (III) can be prepared according to the method described by EB Knott, J.Chem.Soc. 164-4-9 (1956) described method ₇ by the action of carbon disulfide in the presence of a tertiary amine on a 2-aminopyridine of the general formula (IV)

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wherein R _{1 is} as defined above, or by the method described by DB Capps in U.S. Patent 3,726,880.

The compounds described in the main patent and, if applicable their salts are particularly effective as broad spectrum anthelmintics against nematodes.

The present invention is a further development of the main patent and relates to further new derivatives of thiazolidines of the general formula (I), in which R, and R are hydrogen atoms, ie the general formula (I ¹ )

and optionally their salts and processes for their preparation.

In the above general formula (I ¹ ), R _{1 is} as defined in the main patent and R ₂ denotes an alkyl radical having 2 to 4 carbon atoms which is substituted in a position other than the 1-position [by an amino, alkylamino, dialkylamino- (whose alkyl parts together with the nitrogen atom to which they are attached form a saturated heterocycle with

cbilaen can,

5 or 6 chain links aVenthaitend optionally a further heteroatom selected from a secondary or tertiary nitrogen atom, oxygen or sulfur) - _; Carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (the alkyl parts of which can form a saturated heterocycle with 5 or 6 chain members with the nitrogen atom to which they are attached,

containing

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optionally another hetero atom selected from a secondary or tertiary nitrogen atom, oxygen or sulfur) or cyano radical], a dialkyloxymethyl, bis (alkylthio) methyl, alkylsulfonylmethyl, phenylthiomethyl, I-phenylcyclopropyl, i-I-ethylcyclohexyl, substituted phenyl radical (substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxi »methyl or methoxy), a 1-taplithyl, heterocyclyl (selected from 1,3-dithiolan-2-yl, 5, 6-dihydro-1, ^ - dithiin-2-yl, thien-3-yl or pyridyl-2, -3 or -A) - _t alkanoyl or benzoyl radical, the above-mentioned alkyl parts and the alkanoyl radical being straight or branched and unless otherwise indicated, they contain 1 to 4 carbon atoms.

The inventive compounds can under one of the forms (I ¹ A) or (I ¹ B) are present or as a mixture in the balance of these two forms in j unction internal? Parameters (R '. And R ₂₎ or external parameters (in particular in the presence of a solvent) as explained below.

In general, the general formula (I ¹ A) corresponds to the predominant form in crystallized! Condition of the products for which:

a) Ri is as defined in the main patent and R _{2 is} an alkyl radical with 2 to 4 carbon atoms, substituted according to the definition given above, a dialkyloxymethyl, alkylsulfonylmethyl, phenylthiomethyl, phenyl, alkanoyl or benzoyl radical disubstituted by methyl or methoxy radicals or

R ₁ . denotes a hydrogen atom and R ₂ denotes a 2-aminophenyl, 1,3-dithiolan-2-yl, thien-3-yl or pyridyl-2 or 4 radical.

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In general, the general formula (I ¹ B) corresponds to the predominant form in the crystallized state of the compounds for which:

a) R _{1 is} a hydrogen or halogen atom in the 4-, 5- or 6-position and

R _{2 is} I-phenylcyclopropyl-, I-methylcyclohaxyl-, dihydroxiphenyl-, 1 -ITaphthyl-, bis (alkylthio) -taethyl-, 5,6-dihydro-1,4-dithiin-2-yl- or pyridyl-3 -rest means or

b) R _{1 is} a halogen atom in the 4-, 5- or 6-position and R _{2 is} a 2-aminophenyl, 1 ^ -dithiolan ^ -yl-, thien-3-yl-

or is pyridyl-2- or -4-radical.

According to the invention, the new compounds of the general formula (I ¹ ) can be obtained by the method described in the main patent, by the action of a compound (which can be prepared in situ) of the general formula (II ")

R ₂ -CO- CH ₂ X (II ¹ )

wherein R _{2 is} as defined above and X is a halogen atom, preferably a bromine or chlorine atom, to a dithiocarbamate of the general formula (III),

The reaction is to achieve among those above for the main patent of the compounds of the general formula (I) from the compounds of the general formulas (II) and (III) Conditions causes.

The compounds of the general formula (II) can by application various general methods described in the literature are prepared, which is detailed in the examples is explained.

The new compounds according to the invention came where appropriate

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by physical methods such as crystallization or chromatography getting cleaned.

The new compounds according to the invention can optionally can be converted into acid addition salts with acids if R « a substituted alkyl radical [substituted by an amino, alkylamino, dialkylamino (whose alkyl group together with the Nitrogen atom to which they are bound can form the heterocycle defined above) - or dialkylcarbamoyl radical, whose Alkyl parts together with the nitrogen atom to which they are attached form a saturated heterocycle with 5 or 6 chain members containing a further secondary or tertiary nitrogen atom] or a 2-aminophenyl radical. The addition salts can by the action of the compounds obtained on acids in suitable solvents; organic solvents are used, for example, alcohols, Ketones, ethers or chlorinated solvents. The salt formed falls out of its solution after any concentration the end; it is separated by filtration or decantation.

The new compounds according to the invention and, if appropriate, their salts are particularly active as anthelmintics to a large extent Spectrum versus nematodes.

'Their activity was particularly evident in the mouse against Nematospiroides dubius in doses of about 5 and 200 mg / kg by oral route to be shown.

In addition, the compounds according to the invention have proven themselves as effective in the pilariasis (roundworm disease) of the cotton rat against Litomosoldes carinii in doses between 25 and 50 mg / kg orally per day during the course of treatment Proven for 5 consecutive days.

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-H-

Certain compounds have also been found to be effective in dogs in doses between 10 and 50 mg / kg by the oral route for Ankylostoma caninum, between 2.5 and 50 mg / kg by the oral route in Uncinaria stenocephale and between 5 and 50 mg / kg orally in Toxocara canis and Toxasaris leonina.

The toxicity of the compounds according to the invention, expressed as the lethal dose 50 # (DL _cn ), is between 400 mg / kg and a value above 1000 mg / kg by the oral route in the mouse.

Of particular interest because of their activity are the compounds of the general formula (I ¹ ) in which: R ₁ denotes a hydrogen or chlorine atom in the 5-position and

R _{2 is} an alkyl radical with 2 to 4 carbon atoms which is substituted in a position other than the 1-position [substituted by a dialkylamino, dialkylcarbamoyl (whose alkyl parts together with the nitrogen atom to which they are attached have a saturated heterocycle with 5 or 6 chain links, which may contain another secondary or tertiary nitrogen atom) - or cyano radical], or a dialkyloxyraethyl, bis (alkylthio) methyl, alkylsulfonylmethyl, phenylthiomethyl, 1-phenylcyclopropyl, 1- Ilethylcyclohexyl, substituted phenyl (substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxyl or ethoxy), 1-naphthyl, thien-3-yl, pyridyl-3- or -4- or alkanoyl radical denotes, where the mentioned alkyl radicals are straight or branched and, unless otherwise indicated, the alkyl and alkanoyl radicals and parts contain 1 or 2 carbon atoms.

Among these, the products of the general formula (I ¹ ) are particularly active against Nematospiroides dubius, for which: RJ denotes a hydrogen or chlorine atom in the 5-position,

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Rg is an alkyl radical with 2 or 3 carbon atoms, which is on End of the chain is substituted [by a dialkylamino, dialkylcarbamoyl (whose alkyl parts together with the nitrogen atom, to which they are bound, a saturated heterocyclic

be able to load.

lus with 6 chain links optionally containing a further secondary or tertiary nitrogen atom) or cyano radical], bis (methylthio) methyl, methylsulfonylmethyl, phenyl thiomethyl, substituted phenyl (substituted by an amino radical in the 2-position or by two hydroxy radicals) I. > yridyl-3- or -4- or an acetyl radical or R _{1 is} a chlorine atom in the 5-position and

R ₂ denotes a 1-phenylcyclopropyl, 1-methylcyclohexyl, 1-naphthyl or thien-3-yl radical, the above-mentioned alkyl parts containing 1 or 2 carbon atoms, unless otherwise stated.

Particularly noteworthy among these compounds are those in the general formula of which the symbols have the following meanings:

^R 2 Cl-5
H -
H-
Cl-5
H- OH
- <^ ^ -OH
-CH ₂ CH ₂ N (C ₂ H ₅ ) ₂
(CH ₂ ) ₃ N (C ₂ H ₅ ) ₂
-CH ₂ SO ₂ CH ₃

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^{The following compounds of the general formula (I 1} ) have proven to be of particular interest in filariasis (roundworm disease) of the cotton rat against Litomosoides carinii against both macrofotworms and microfotworms, for which:

R ^ means a hydrogen atom and

R _{2 is} an alkyl radical with 2 to 4 carbon atoms which is substituted in a position other than the 1-position [by a dialkylamino, dialkylcarbamoyl (whose alkyl parts, optionally together with the nitrogen atom to which they are attached, form a saturated heterocycle with 5 or 6 chain links, optionally containing a further secondary or tertiary nitrogen atom) - or cyano radical], or a dialkyloxymethyl, I'lethylsulfonylmethyl, bis (methylthio) methyl, 2-aminophenyl, pyridyl-3- or -4 - or alkanoyl radical,

where the mentioned alkyl radicals are straight or branched and, unless otherwise indicated, the alkyl or alkanoyl parts and radicals ΐ or 2 carbon atoms; and among these compounds are particularly to be mentioned those compounds for which the radicals have the following meanings own:

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^R l ^R 2 H-
H- - (■ CH ₂ ) ₂ N (C2H ₅ ) ₂
- (CH ₂ ) ₂ CON (C2H ₅ ) 2 H- - (CH ₂ ) ₂ CO Vr N-CH ₃ H- - (CH ₂ ) ₂ CN H- -CH (OCH ₃ ) 2 H- -CH (SCH ₃ ) ₂ H- -CH ₂ SO ₂ CH ₃ H- O H- ο H- -COCH ₃ ;

The following examples are intended to explain the invention in more detail.

example 1

To a suspension of 5.42 g of triethylammonium-pyridyl-2-dithiocarbamate in 10 cc of anhydrous acetonitrile are 18-28 ⁰ C., a solution of 4.90 g of 1-bromo-3-phenylthiopropane-2-one in 50 cc acetonitrile . The reaction is continued währeud 2 hours at 20 to 28 ⁰ C. The insoluble triethylamine hydrobromide is removed by filtration and washed with 10 ecm acetonitrile. The acetonitrile is (20 mm Hg under reduced pressure, evaporated at 40 ⁰ C. The residual oil is dissolved in 50 cc of methylene chloride The organic solution is washed twice with a total of 100 cc of distilled water, and evaporated dried over sodium sulfate The product obtained (... 6.40 g) is dissolved in a mixture of 16 ml of ethyl acetate and 50 ml of cyclohexane The solution is passed over 40 g of Merck silicon dioxide (0.063 to 0.2 mm), which is poured into

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a column of 1.7 cm in diameter is distributed. It is eluted with a mixture of 40 ecm ethyl acetate and 100 ecm cyclohexane, then with a mixture of 25 ecm ethyl acetate and 75 ecm cyclohexane and then with a mixture of 30 ecm ethyl acetate and 70 ecm cyclohexane. One first Removes 250 cc of eluate is then collects 150 cc of eluate, which one (20 mm Hg) evaporated under reduced pressure at 40 ⁰ C and is dried at 30 ⁰ C under reduced pressure (0.2 mm Hg) ", wan receives ao 5 »50 g of 4-hydroxy-4-phenyl-thiomethyl-3- (pyridyl-2) -thiazolidine-2-thione.

NMR spectrum (60 MHz) resolved in about 10 $ deuterated Chloroform:

3.4 ppm: singlet (2H) -CH ₂ -SC ₆ H ₅

3.65 ppm: massive (2H) -CH ₂ -heterocycle 6.6 ppm: massive (1H) -OH

7.2 ppm: massive (6H) -CZH. ^ Plus -H ₁ -

7.5 ppm: doublet (1H) -H ₃ (J = 8)

7.65 ppm triplet of the doublet (IH) -H ₄ (J = 8 and 2) 8.35 ppm: doublet of the doublet (1H) -Hg (J = 5 and 2)

The Triäthylaramoniumpyridyl-2-dithiocarbamat (E = 95 ⁰ C) is according to the by EB Knott, J. Chem. Soc. 1644-49 (1956) described method.

The 1-bromo-3-phenylthio-propan-2-one (P = 45 ⁰ C) is produced in analogy to the production method of i-chloro-3-phenyl-thiopropan-2-one, which by V. Rossnati, Gazz. Chim. Ital. 99, Ms 64 (1969).

Example 2

The procedure is as indicated in Example 1, but starting from 121.9 g of! DriäthylammoniUfflpyrid-2-yl-dithiocarbamat and 88.7 g of 3-bromo-1, i-dimethyloxipropan-2-one in 1 1 of anhydrous

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Acetonltril 18-22 ⁰ C.The reaction is continued for 2 hours at 20 to 22 ⁰ C. The crude product obtained (98.6 g) is washed with 150 ecm methylcyclohexane. The obtained product (29,4g; F = 94 ⁰ C) is from 150 cc of a mixture of cyclohexane and ethyl acetate (1: 1) and then recrystallized a second time from 70 cc of the same Lösumgsmittelgemisches. This gives 15.7 g of 4-hydroxy-4-dimethoxymethyl-3- (2-pyridyl) thiazolidine-2-thione from F ■ = 100 ⁰ C.

The 3-bromo-1, i-dimethoxypropan-2-one can be prepared in analogy to the method of the bromination of asymmetric ketones described by M. Gaudry and A. Marquet, Tetrahedron, 2,6, 5611-35 (1970) " : by 118.0 g 1,1-dimethoxypropane-2-one dissolved in 800 cc of methanol with 160 g Erotu at a maximum of 5 ⁰ C and treated can continue the reaction for 48 hours at 20 ⁰ C, to obtain 95 g of 3- Bromo-1,1-dimethoxypropan-2-one (KP ₂₀ = 107 to 116 ⁰ C).

Example 3

The procedure is as given in Example 1, but starting from 23.0 g of triethylammonium-pyridyl-2-dithiocarbamate and 14.0 g of 1-bromo-butan-2,3-dione in 170 cc of anhydrous acetonitrile 18-20 ^0C The reaction is continued ^{at 20 ° C. for 4 hours.} The product obtained (15 »O g) is recrystallized from a mixture of 250 ecm ethanol and 80 ecm ethyl acetate and then a second time from 85 ecm acetonitrile. This gives 8.5 g of 4-acetyl-4-hydroxy-3- (2-pyridyl) thiazolidine-2-thione F = 176 ⁰ C.

The 1-bromo-butan-2,3-dłoń (KP _{Q 15} = 35 ⁰ C) is prepared according to the method described by MP Doerner in U.S. Patent 2,821,555 method.

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Example 4:

The procedure is as given in Example 1, but starting from 61 g TriäthylatniDonium-pyridyl-2-dithiocar'bainat and 29.6 g of 5-chloro-4-oxo-pentanenitrile in 600 cc of anhydrous acetonitrile at maximum 2 ⁰ C. The reaction is continued ^{at 2 °} C. for 2 hours. After recrystallization from 150 ecm of acetonitrile, 44.6 g of 3- [4-Hydroxi-3- (pyridyl-2) -2-thioxo-thiazolidin-4-yl] propionitrile with a melting point of 126 ° C. are obtained,

In the infrared, 2 to 5 % 4-cyano-2-

oxo-butyl-pyridyl-2-dithiocarbamate when the product is in compressed Form is tested with potassium bromide (carbonyl band at 1720 cm "). This form is not detected if the Product is tested between lamellas in Vaseline.

The 5-chloro-4-oxo-pentanenitrile is by the action of 31.2 g of diazomethane at about -10 ⁰ C and then 50 com 12IT an aqueous hydrochloric acid solution at 10 to 20 ⁰ C to 33.0 g of 3-cyano-propanoyl produced in a total of 750 ecm of ether. This gives 25.3 g of 5-chloro-4-oxo-pentanenitrile from F = 68 ⁰ C.

The 3-cyanopropanoyl chloride (KP _{0 2} = 82 to 84 ⁰ C) is prepared by the _{method described by L 5} J. Dolby, J. Org. Chem. 31, 4510-11 (1968).

Example 5:

Using the procedure described in Example 1, but starting from 62 g of triethylammonium-pyridyl-2-dithiocarbamate and 47 * 4 g of 5-chloro-N, N-diethyl-4-oxo-pentanamide in 600 cc of anhydrous acetonitrile 20-25 ⁰ C The reaction is continued for 2 hours at 20-25 ° C. After recrystallization from 200 ecm of acetonitrile, 56.5 g of N, N-diethyl

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[4-hydroxy-3- (pyridyl-2) -2-thioxo-thiazolidin-4-yl] p-topionamide from F = 125 ° C.

When the product is examined in the infrared in chloroform solution, "about 2 to 5% A-diethylaminocarbonyl ^ -oxobutyl-pyrldyl-2-aithiocarbamate (carbonyl band at 1720 cm ~) is observed. This shape is not detected if the product is between lamellae is checked in petroleum jelly.

The S-chloro-NjN-diethyl-A-oxo-pentanamide is obtained by the action of 59 g of dicyclohexylcarbodiimide in 20.6 g of diethylamine on 44.8 of 5-chloro-4-oxo-pentanoic acid in 770 ecm of methylene chloride at 20 to 25 ° C produced during 2 hours. Wan receives 47.6 g of 5-chloro-N, N-diethyl-4-oxo-pentanamide (KP _{Q 2} = 140 to H5 ° C.).

The 5-chloro-4-oxo-pentanoic acid (F = 71 ⁰ C) is prepared by the VM Rodionov and MA Gubareva, Chem. Abst. 4J9, 926D (1955) besciiriebenen method.

Example 6:

The procedure is as described in Example 1, but starting from 28.2 g of triethylammonium pyridyl-2-ethiocarbamate and 25.2 g of 1- (5-chloro-1 _; 4-dioxo-pentyi; -4-methylpiperazine in 300 ecm of anhydrous acetonitrile at a maximum of 2 C. The reaction is continued for 2 hours at 2 ⁰ C. The resulting oily product (32.0 g) is dissolved in 150 cc of ethanol and a maximum with a solution of 10.1 g fumaric acid in 30 cc of dimethylformamide at treated 30 ⁰ C. After 2 hours, cooling at 2 ⁰ C the arisen crystals are separated by filtration, washed three times with a total of 90 cc of ethanol and dried under reduced pressure (0.2 mm Hg) at 50 ⁰ C., giving 31.5 g of 4-hydroxy-4- [3- (4-methylpiperazin-1-yl) -3-oxo-propyl] -3- (2-pyridyl) thiazolidine-2-thione fumarate by F = 150 ⁰ C.

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The 1- (5-chloro ~ 1,4-dioxo-pentyl) -4-methyl-piperazine can on produced in the following way:

- Preparation of 5-chloro-4-oxo-pentanoic acid (F = 71 C) as described in Example 5 ",

- Production of 34 g of 5-ChIOr-S-ChI ormethyl ^^ - dihydro ^ H-furan-2-one (KP _n , = 88 to 89 ⁰ C) by the action of 35.0 6 thionyl chloride on 36.9 g 5- Chloro-4-oxo-pentanoic acid in 240 ecm chloroform at reflux temperature for 1 1/2 hours,

- Production of 25.2 g of 1- (5-chloro-1,4-dioxo-pentyl) -4-methyl-piperazine (P = 95 ⁰ C) by the action of 36.4 g of 1-methyl-piperazine on 30, 8 g S-

hydro-3H-furan-2-or in 300 cc of anhydrous acetone for 1 hour at 2 ⁰ C.

Example 7t

To a suspension of 27.1 g of triethylammonium-pyridyl-2-dithiocarbamate in 100 cc of water are added at 2O ⁰ C a solution of 30.3 g of 1-Brora-4-diethylamino-butan-2-onr-hydro-broniid in 30 ecm of water. The reaction is continued for 1 hour at 20 ⁰ C, is treated iiachher r.?it 1.0 g of decolorizing carbon was filtered and washed with 10 cc water. The filtrate is under reduced pressure (20 mm Hg) evaporated at 50 ⁰ C up to a residual volume of about 60 cc. After about 2 hours of cooling at 2 ° C., the crystals that have formed are separated off by filtration, washed with 10 ecm of ice water and 10 ecm of ethanol and dried at 45 ° C. under reduced pressure (0.2 mm Hg). This gives 18.7 g of 4- (2-diethylamino-ethyl) -4-hydroxy-3- (pyridyl-2) - thiazolidine-2-thione hydrobromide from F = 148 ⁰ C.

The 1-urom-2-diethylamino-butan-2-one hydrobromide (F = 80 ⁰ C) is according to the CD Djerassi et al. J. Org. Chem. 15 i 700-06 (1950).

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Example 8t

The procedure is as described in Example 1, but starting from 52 g of triethylaiDnioniuni- (5-chloro-pyridyl-2) -dithiocarbanate and 33 »1 g of 1-chloro-2- (1-phenyl-cyclopropyl) -ethan-2-one in 500 cc of anhydrous acetonitrile at 20 ⁰ C. Tie reaction is continued for 2 hours at 20 ⁰ C. Recrystallization from 160 cc of acetonitrile to obtain 48.1 g of 2- (i-phenylcyclopropyl) -2-oxo-ethyl (5-chloro-pyridyl-2) dithiocarbamate of F = 127 ⁰ C.

48.0 g of 1-chloro-2- (1-phenyl-cyclopropyl) -ethan-2-one (KP _{0 4} = 106 ⁰ C; F = 45 ⁰ C; by the action of 25.2 g of diazomethane between- 15 and -5 ⁰ C and then 1CO ecm of an aqueous 12N hydrochloric acid solution between 0 and 10 ⁰ C, on 48.7 g of 1-phenyl-cyclopropanecarbonyl chloride in 600 ecm of ether.

The 1-phenyl-cyclopropanecarbonyl chloride (KPq ₂ = 82 ⁰ C) is according to the method described by AW Weston, J. Am. Chem. Soc. 68, 2347 (1946) described method.

Example 9:

The procedure is as described in Example 1, but starting from 80.5 g of triethylammonium (5-chloropyridyl-2) dithiocarbamate and 46.0 g of 1-chloro-2- (i-methyl-cyclohexyl) -ethane-2 -one in 650 cc of anhydrous acetonitrile at 20 C. The reaction is continued for 2 hours at 20 ⁰ C. Fold recrystallization from 400 cc of acetonitrile are obtained 66.1 g of 2- (1-methyl-cyclohexyt) -2-oxo-ethyl (5-chloro-pyridyl-2) -äiiWocarbamat from F = 102 ⁰ C.

The 1-chloro-2- (1-methyl-cyclohexyl) -ethan-2-one (KP _{n Q} = 70 to

ο ♦

75 C), according to the T.A. Magee in DT-PS 2,216,838 Method made.

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Example 10;

The procedure is as described in Example 1, but starting from 10.9 g of triethylammonium pyridyl ^ -dithiocarbamate and 8.6 g of 1- (2-aminophenyl) -2-broni-ethan-1-one in 60 ecm of anhydrous acetonitrile between 22 and 28 ^° C. The reaction is continued ^{at 20 to 28 ° C. for 2 hours.} After recrystallization cus 90 cc of acetonitrile to obtain 8.4 g of 4- (2-aminophenyl) -4-hydroxy-3- (2 pyridyl) thiazolidine-2-thione from P = 130 ⁰ C.

If the product is tested in the infrared in chloroform solution, about 30 ° 2- (2-aminophenyl) -2-oxo-ethyl- (pyridyl-2) -dithiocarbamate (carbonyl band at 1650 cm -1) is observed. This shape is not detected when the product is checked between slats in Yaseline.

The 1- (2-amino-phenyl) -2-broüj-ethan-1-one (P = 63 ° C) is after that of P. Ruggli and H. Reichwein, HeIv. Chim. Acta 20, 913 (1937) described method.

Example 11;

The procedure is as described in Example 1, but starting from 40.0 g of triethylammonium (5-chloropyridyl-2) dithiocarbanate and 24.2 g of 2-chloro-1- (3,4-dihydroxyphenyl) -ethane-1 -one in 450 cc of anhydrous acetonitrile 15-20 ⁰ C. The reaction is continued for 4 hours at 20 ⁰ C. After recrystallization from a mixture of 1000 ecm acetonitrile, 500 ecm ethyl acetate and 25 ecm dimethylformamide, 21.0 g of 2- (3,4-dihydroxiphenyl) -2-oxo-ethyl- (5-chloro-pyridyl-2) are obtained ) -dithiocarbaaat of ^F = 195 ⁰ C).

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29U342

Example 12;

The procedure is as in Example 1, but starting from 40.0 g of iDriäthylammonium- (5-chloro-pyridyl-2) -dithiocar "bamate and 33.8 g of 2-bromo ~ 1- (2,5-dimethoxyphenyl) - ethane-1-one in 450 cc of anhydrous acetonitrile 15-20 ¹ O. The reaction is continued at 20 ⁰ C for 4 hours. " After recrystallization from 500 cc of acetonitrile to obtain 35 »0 g of 3- (5-chloro-pyridyl-2-4- (2,5-dimethoxy-phenyl) -4-hydroxithiazolidin-2-thione from F = 168 ⁰ C. .

Example 13:

The procedure is as described in Example 1, but starting from 18.0 g of 'i'riäthylammonium- (5-chloro-pyridyl-2) -dithiocarcamat and 45.0 g of 2-bromo-1- (naphthyl-1) -ethane- 1-one in 250 cc of anhydrous acetonitrile at 20 ⁰ C. The reaction is continued for 4 hours at 20 ⁰ C, ifach recrystallization from a mixture of 500 cc of ethanol and 100 cc of ethyl acetate to obtain 13.0 g of 2- (naphthyl 1) ~ 2-oxo-ethyl- (5-chloropyridyl-2) -dithiocarbamate from F = H6 ° C.

When the product is examined in the infrared in chloroform solution, about 90 to 95 # 3- (5-chloro-pyridyl-2) -4-hydroxy-4- (naphthyl-1) -thiazolidine-2-thione is observed (Decrease in the intensity of the carbonyl band at 1690 cm "). This Shape is not detected when the product is examined between lamellas in petroleum jelly.

The 2-bromo-1- (naphthyl-i) -ethan-1-one (KP _{0 1} = 145 to 155 ° C) is after that of CB. Radcliffe et al. J. Chem. Soc. 2293 (1931) described method.

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Example 14:

17.2 g of 2-bromo-1- (pyridyl-4_) -ethan-1-one are added at a maximum of 15.degree. C. to a suspension of 23.4 g of triethylammonium pyridyl-2-dithiocarbamate in 500 ecm of nitromethane. The reaction is continued at 15 to 20 ^{° C. for 2 hours.} The nitromethane is evaporated at 45 ° C. under reduced pressure (20 min Hg). The pasty residue obtained is washed with 100 ecm of distilled water and then with 500 ecm of ethyl acetate. The crystals obtained (12.0 g; P = 175 ° C.) are purified by recrystallization from a mixture of 20 ecm dimethylformamide and 50 ecm ethanol. I-Ian receives

5.7 g of 4-Hydroxi-3- (pyridyl-2) -4- (pyridyl-4) thiazolidine-2-

thion from F = 175 ⁰ O.

24.1 g of 2-bromo-1- (pyridyl-4) -ethan-1-one with a P = 190 ⁰ O are obtained by the action of 16.0 g of bromine on a solution of 12.2 g of 1- (Pyr ± dyl-4) ethan-1-one in 60 ecm of methanol at 18 and 29 C and then of 50 ecm of a concentrated aqueous sodium hydrogen carbonate solution.

Example 15:

To a suspension of 38.0 g of triethylammonium-pyridyl-2-dithiocarbamate in 260 cc of anhydrous acetonitrile is added between 0 and 5 ⁰ C, a solution of 38 g of i-bromo-3-methylsulfonyl-propan-2-one (80 frlg) in 120 ecm anhydrous acetonitrile. The reaction is continued ^{at 2 ° C. for 2 hours.} The acetonitrile is (20 mm Hg) evaporated under reduced pressure at a maximum of 50 ⁰ C. The remaining oil is dissolved in 400 ecm of ethylene chloride. The organic solution is washed four times with a total of 600 ecm of distilled water, treated with decolorizing charcoal, dried over anhydrous sodium sulfate and evaporated. The product obtained (40 g) is in 400 ccn

0300 1 9/0938

2344342

Dissolved chloroform. The solution is chromatographed on 400 g of Merck silicon dioxide (0.2 to 0.5 mc) contained in a column 5 cm in diameter. (g 20.0; P about 130 ⁰ C) 2 1 chloroform is evaporated at 50 ⁰ C under reduced pressure (20 mm Hg) "the product obtained.. is purified by recrystallization from 120 cc of ethyl acetate, giving 7.6 g of 4-hydroxy-4-methylsulfonylmethyl-3- (2-pyriäyl) -thiazolidine-2-thione from P = 148 ⁰ C.

The 1-bromo-3-methylsulfonyl-propan-2-one can have the following Way to be made:

- Production of methylsulfonylacetic acid (P = 114 ⁰ C) according to that of JM Carpenter and Mi tar Td. , J. Chera. Soc.

2016 Ms 22 (1970) described method;

- Preparation of 36.9 g Methylsulfonylacetylchlorid (oily) by the action of 130 cc sulfinyl chloride to 32.6 g Methylsulf onylessigsäure at about 60 ⁰ C in the presence of 0.3 cc of dimethylformamide;

- Production of 38.4 g of 1-bromo-3-methylsulfonyl-propan-2-one (pasty; purity about 80 $>) by the action of a solution of 24.2 g of diazomethane in 600 ecm of anhydrous ether on a solution of 36, 9 ecm Methylsulfpnylacetylchlorid in 100 cc of methylene chloride at about -10 ⁰ C, then the action of 45 cc of an aqueous 48 #igen hydrobromic acid (d = 1.49) on the "l3) iazo-3-methylsulfonyl-propan-2-one formed in situ between 0 and 20 ⁰ C.

Example 16;

The procedure is as described in Example 15, but starting from 40.5 g of triethylammonium pyridyl 2-dithiocarbamate and 28 g of 1-chloro-3 »3 ^ bis (methylthio) propan-2-one in 400 ecm of anhydrous acetonitrile between 15 and 20 ^° C. The reaction is continued ^{at 20 ° C. for 16 hours.} The received

030019/0936

Product (75 g) is dissolved in 500 ecm of ethyl acetate and the solution is washed twice with a total of 200 ecm of distilled water, treated with decolorizing charcoal, dried over anhydrous sodium sulfate and evaporated. The product (60 g) obtained is in a (mixture of 300 ecm of cyclohexane and 200 ecm of ethyl acetate are dissolved and the solution is chromatographed on 600 g of Merck silica (0.2-0.5 mm) contained in a column 5 cm in diameter, eluting with a mixture of 900 ecm of cyclohexane and 600 cc of ethyl acetate to give the corresponding eluate is removed, then with a mixture of 600 cc of cyclohexane and 4-00 cc of ethyl acetate. It is the second eluate (20 mm Hg) the product (30 obtained is evaporated under reduced pressure at 50 ⁰ C. g ) is purified by recrystallization from 100 ecm boiling diisopropyl ether, giving 11 g of 3,3-bis (methylthio) -2-oxo-propylpyridyl-2-dithiocarbamate with a melting point of 127 ° C.

If the product is tested in a chloroform solution in the infrared, about 90% 4-Hydroxi-4-bis- (methylthio) -methyl-3- (pyridyl-2) -thiazolidine-2-thione is discovered (very significant reduction in the intensity of the carbony! band at 1705 cm ~). This shape is not observed when the product is tested between lamellas in petroleum jelly.

The 1-chloro-3,3-bis (methylthio) propan-2-one can have the following Way to be made:

-Production of 2,2-bis- (methylthio) -acetic acid (F = 77 ° C) after that of A.Tananger, Arkiv. Kerai, Mineral.Geol. 24, A, 10-18 (1947) described method;

-Production of 28.4 g of bis (methylthio) acetyl chloride (EP ₂₀

= 105 ° C) by the action of a solution of 3 0 »4 g of 2,2-bis (methylthio) acetic acid in 350 ecm anhydrous diethyl ether to a solution of 19 ecm oxalyl chloride in 100 ecm anhydrous diethyl ether in the presence of 1 ecm dimethylformamide at about 0 C;

0300 19/0936

-Preparation of 28 g of 1-chloro-3,3-bis (methylthio) -propan-2-one (non-distillable orange-colored oil) by the action of a solution of 17.2 g of diazomethane in 480 ecm of anhydrous diethyl ether on a solution of 28 , 4 g bis (methylthio) acetylchloride in 50 ecm anhydrous diethyl ether
about -30 C and then exposure to 35 ecm of an aqueous
12N hydrochloric acid solution on 1-diazo-3 »3-bis (methylthio) propan-2-one formed in situ between 0 and 20 ^° C.

Example 17;

To a solution of 18.4 g of triethylamraonium pyridyl-2-dithiocarbamate in 150 ecm of distilled water is added between
18 and 22 ⁰ C a solution of 19.0g of 2-bromo-1 - (? Yridyl-3) -ethanone hydrobromide in 350 ecm of distilled water. The reaction is continued at 20 to 22 ^{° C. for 16 hours.}
The crude product is separated off by filtration, three times with a total of 300 ecm of distilled water and then with 100 ecm
Washed isopropyl ether and air dried. The product obtained (13.0 g; F = 185 ⁰ C) is dissolved in 100 cc of boiling ethyl acetate. After filtering the boiling solution and then 4 hours of cooling at ⁰ C 2 v / ground the arisen crystals separated by filtration, washed three times with a total of 30 cc of ice-cooled ethyl acetate GeV / waste and under reduced pressure (0.2 mm Hg) at 40 ⁰ C dried. You get so
10.5 g of 2-0x0-2- (pyridyl-3) -ethyl- (pyridyl-2 -) - ethiocarbamate
from F = 190 ° C.

The triethylammonium (pyridyl-2) - dithiocarbamate is after
that of EB Knott, J. Chem. Soc. 1644-9 (1956) described method.

The 2-bromo-1- (pyridyl-3) - ethanone is made according to the method of A. Dornow, H. Machens and K. Bruncken, Chem. Ber. 84., 147-50 (1951) Method made.

0300 1 9/0936

Example 18:

The procedure is as described in Example 15 ", but starting from 25.6 g of triethylamine (5-chloropyridyl-2) dithiocarbamate and 17.2 g of 1-bromo-3- (thien-3-yl) propane -2-one in 150 cc of anhydrous acetonitrile 15-20 ⁰ C. The reaction is continued for 30 Hinuten at 20 ⁰ C. The product obtained (25.0 g; P = 145 ⁰ C). is by recrystallization from acetonitrile 280 ecm 21.7 g of (thenoyl-3) methyl (5-chloro-pyridyl-2) dithiocarbamate at P = H8 ° C. are obtained.

If the product is tested in a chloroform solution in the infrared, the 3- (5-chloro-pyridyl-2) -4-hydroxy-4- (thien-3-yl) -thiazolidine-2-thione is predominantly observed (reduction in the intensity of the carbonyl band at 1680 cm " ) .

The 1-bromo-3- (thien-3-yl) -prnpan-2-one (P = 55 ⁰ C) according to the DWHi of McDowell and TD Greenwood, J.Het. Chera. 2_, 46 (1965) described method.

Example 19t

To a solution of 27.1 g of triethylammonium (pyridyl-2) dithiocarbamate in 150 cer? distilled water was added 15 to 20 ⁰ C 30.3 g of 1-Broro-5-diethylamino-pentan-2-on-h: 7diO bromide. The reaction is continued at 20 to 25 ^{° C. for 2 hours.} After filtering the reaction mixture under reduced pressure, the water is obtained residue under 20 mm Hg at 70 ⁰ C evaporated is dissolved in 200 cc of boiling ethanol.

After adding 2 g of decolorizing charcoal to the boiling solution, it is filtered at the boiling point and allowed to cool to 20 ^{° C. for 2 hours.} The crystals that have occurred are collected by filtration and ice-cream twice with a total of 40 ecm

030019/0936

29U342

cooled ethanol and dried under reduced pressure (0.2 mm Hg) at 45 ⁰ C dried.

Are thus obtained 11.6 g of 4- (3-diethylamino-propyl-1) -4-hydroxy-3- (pyridyl-2) (thiazolidine-2-thione hydrobromide from I ¹ = ⁰ 175 C structure determined by IR Spectrum in petroleum jelly).

The 1-bromo-5-diethylaraino-pentan-2-one hydrobromide can have the following V / can be produced:

To a solution of 15.7 g 5-diethylamino-pentan-2-one in 20 cc of acetic acid there between 20 and 25 ⁰ C 25 cc of an about 35 $ strength hydrogen bromide in acetic acid and then 15 to 20 ⁰ C, a solution which was formed by dissolving 16g of bromine in 30 ecm of acetic acid. The reaction is continued ^{at 20 °} C. to 25 ^{° C. for 16 hours.} The acetic acid is evaporated under 20 mm Hg at 70 ⁰ C, and then under 0.2 mm Hg at 50 ⁰ C. The remaining oil is washed three times with a total of 1500 cc of diethyl ether and then under reduced pressure (0.2 Hg ram) dried at 45 ⁰ C. This gives 30 g of i-bromo ^ diethylamino-pentane ^ -one hydrobromide (oily).

The Sriäthylammonium-pyridyl-2-dithiocarbamat (F = 95 ⁰ C) is according to the by EB Knott, J. Chem. Soc. 1644-9 (1956) described method.

030019/0936

The invention "also relates to the medicinal compositions which can be used in therapy and which contain at least one product of the general formula (I ¹ ) (optionally in the form of a non-toxic salt) together with one or more compatible and pharmaceutically acceptable diluents or auxiliaries and optionally with other compatible and physiologically active compounds These compositions can be used orally, parenterally or rectally.

As compositions for oral administration one can use tablets, Use pills, powders, capsules, or granules. The compound according to the invention is mixed in these compositions with one or more inert diluents such as sucrose, lactose or starch. The compositions can also contain substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions Substances other than diluents, for example wetting agents, sweeteners or flavoring agents, can also be used contain.

The compositions for parenteral administration can be sterile, be aqueous or non-aqueous solutions, suspensions or emulsions. Propylene glycol, Use polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters such as ethyl oleate Compositions can also contain auxiliaries, in particular agitating agents, lubricants and dispersants Sterilization can take place in various ways, for example by means of a bacteriological filter by

030019/0936

sterilizing agents are incorporated into the composition or by heating. They can also be in the form of sterile compositions which are injectable in sterile water or any other injectable at the moment of use sterile environment can be dissolved.

The compositions for rectal administration are suppositories, which, in addition to the active product, can contain carriers such as cocoa butter or soup wax.

In these different compositions, the active ingredient is if it is not dissolved, it is advantageously contained in micronized form.

The compositions of the invention are as anthelmintic Compositions useful.

In veterinary medicine, the products according to the invention can be used in the treatment of helminthiases in nematodes of cattle, sheep, horses and goats in doses between 5 and 50 mg / kg orally during a treatment of 1 to 3 days or between 2.5 and 25 mg / kg body weight of the animal in decaying doses as well as for the removal of gastrointestinal pests in sheep and intestinal ilematodes in dogs.

In human medicine, the compounds according to the invention can be used to remove roundworms, roundworms and hookworms at doses between 5 and 50 mgAg orally used over the course of 1 to 3 day treatments.

The compositions according to the invention can also particularly be useful in treatment and prevention or /. prevention of nematode diseases in humans: Cutan-dernisehe Filariasis (Onchocercosis, Loase, Dracunculosis), lymphatic

030019/0936

Pilarioses (usury, brugias).

In human therapy, the doses depend on the desired Effect and the duration of treatment. They are generally between 10 and 50 mg / kg per day for oral administration and between 5 and 15 mg per kg per day for intramuscular administration for adults in the course of treatments from 1 to 30 days.

In general, the physician or veterinarian will determine the posology that appears most suitable to him With regard to age, weight and other factors, de.ra patients own pactors.

The following examples are intended to illustrate the compositions of the invention explain in more detail:

Example A:

The following tablets of 25 mg are prepared according to the usual technique Composition ago:

2- (3,4-Dihydroxi-phenylJ-2-oxo-ethy1- (5-chloro-

pyridyl-2) dithiocarbamate 25 mg

Grain starch ·· «··· 125 mg

colloidal silicon dioxide 45 mg

Magnesium stearate 5 mg

Example B:

If, in the usual manner with 25 mg tablets having the following composition is prepared:

030019/0936

4-Hydroxi-4- (2-diethylanino-ethyl) -3-

(pyridyl-2) -thiazolidine-2-thione 25 mg

Corn starch 125 mg

colloidal silicon dioxide 45 mg

Magnesia stearate ··. ···· 5 mg

Example Ct

Injectable ampoules are produced using conventional methods, which contain a 10 # solution of the active product and have the following compositions:

4-Hydroxi-4- (2-diethylamino-ethyl) -3-

(pyridyl-2) -thiazolidine-2-thione .- 0.25 mg

injectable saline solution 2.5 ecm

030019/0936

Claims (5)

Dr. F. Zumstein Sr. - Dr. E. Assriaon · Dr. R. Koeniqsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Kl * nc; «3eison - Or. F Zumstein jun. ΘΟ0Ο Munich 2 - Brauhausstrasse 4 - Telephone collective No. 32 5341 ■ Telegrams Zumpat - Telex 5 29979 SC 4657/4681
10 / We Claims i New derivatives of 4-Hydroxi-thiasolidin-2-thione of the general formula wherein R ₁ denotes a water or halogen atom in the 4-, 5- or 6-position and R ₂ denotes an alkyl radical with 2 "to 4 carbon atoms which is substituted in a position other than the 1-position [by an amino, alkylamino, dialkylamino (the alkyl moieties of which together with the nitrogen atom to which they are bonded, one Saturated heterocycle with 5 or 6 chain links T> £ Lden, optionally containing another heteroatom selected from a secondary or tertiary nitrogen atom, oxygen or sulfur) -, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (its alkyl parts together with the nitrogen atom, an that they are bound, a saturated hetero- be able to form a counter cycle with 5 or 6 chain links, containing / optionally another heteroatom selected from a secondary one 03001 9/0936 or tertiary nitrogen atom, oxygen or sulfur) or a cyano radical] or a dialkyloxymethyl radical, bis (alkylthio) methyl radical, alkylsulfonylmethyl radical, phenylthiomethyl radical, 1-phenyl-cyclopropyl radical, 1-methylcyclohexyl radical> a substituted phenyl radical (substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxyl, methyl or methoxy), a 1-naphthyl radical, heterocyclyl radical (selected from> 1 _f 3-dithiolan-2-yl, 5 »6-dihydro-1,4-dithiin-2-yl, Thien-3-yl or pyridyl-2, -3 or -4), an alkanoyl or benzoyl radical, where the above-mentioned alkyl parts and the alkanoyl radical are straight or branched and where 3ie, unless otherwise stated, contain 1 to 4 carbon atoms and optionally their salts when R _{2 is} an alkyl radical [substituted by an amino-, alkylamino-dialkylamino- (its Alkyl parts together with the nitrogen atom to which they are bonded can form the above-mentioned heterocycle) or a dialkylcarbamoyl radical, the alkyl parts of which together with the nitrogen atom to which they are bonded form a saturated heterocycle with 5 to 6 chain members containing a further secondary or tertiary one Nitrogen atom, form] or a 2-aminophenyl radical. 2. derivative of 4-hydroxi-thiazolidine-2-thione according to claim 1, characterized in that its predominant form in the crystallized state corresponds to the general formula (A), wherein: a) R _{1 is} a hydrogen or halogen atom in the 4-, 5- or 6-position and R _{2 is} an alkyl radical with 2 to 4 carbon atoms, substituted according to the above definition, a dialko-xy- methyl, alkylsulfonylmethyl, phenylthiomethyl or phenyl radical substituted by two methyl or methoxy radicals, an alkanoyl or benzyol radical or b) R «denotes a hydrogen atom and R _{2 is} a 2-aminophenyl-, 1,3-dithiolan-2-yl-, thienyl-3- or 03001 9/0936 29U342 Pyridyl-2- or -4-radical "means, 3. derivative of 4-hydroxi-thiazolidine-2-thione according to claim 1, characterized in that the predominant form is crystallized State corresponds to the general formula (B), in which: a) R _{1 is} a V / water or halogen atom in the 4-, 5- or 6-position "and R _{2 is} I-phenylcyclopropyl, 1-methylcyclohexyl, dihydroxiphenyl, 1-naphthyl, bis (alkylthio ) -methyl, 5,6-dihydro-1,4-dithiin-2-yl or pyridyl-3 radical "means or b) R .. is a halogen atom in the 4-, 5- or 6-position and R _{2 is} a 2-aminophenyl, 1,3-dithiolan-2-yl, thienyl-3-, or pyridyl-2- or -4 -rest means. 4. A method for producing a compound according to claim 1, characterized in that a compound of the general formula R ₂ - COCH ₂ X wherein Rp is as defined in claim 1 and X is a halogen atom means with a dithiocarbamate of the general formula HN wherein R _{1 is} as defined in claim 1 and the symbols R, which can be identical or different, each represent an alkyl radical having 1 to 4 carbon atoms, and that the product obtained is then optionally converted into an addition salt with an acid when R _{2 is} a substituted alkyl radical [substituted by 030 0 19/0936 -A- an amino, alkylamino, dialkylamino (its alkyl part together with the nitrogen atom to which they are bound can form the above-defined ileterocycle) - or one Dialkylcarbamoylrest, whose alkyl parts together with the nitrogen atom, to which they are bound, a saturated heterocycle with 5 or 6 cat members containing another form secondary or tertiary nitrogen atom] or a 2-aminop!: enyl radical. 5. Medicaments consisting of a compound according to claim in the pure state or together with one or more compatible and pharmaceutically acceptable diluents or auxiliaries. 030019/0936