GB2034712A - 4-substituted-4-hydroxy-3-pyridyl-thiazolidine-2-thione derivatives - Google Patents

4-substituted-4-hydroxy-3-pyridyl-thiazolidine-2-thione derivatives Download PDF

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GB2034712A
GB2034712A GB7937711A GB7937711A GB2034712A GB 2034712 A GB2034712 A GB 2034712A GB 7937711 A GB7937711 A GB 7937711A GB 7937711 A GB7937711 A GB 7937711A GB 2034712 A GB2034712 A GB 2034712A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07—ORGANIC CHEMISTRY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Abstract

Compounds of the general formula:- <IMAGE> [wherein R1 represents a hydrogen or halogen atom in the 4-, 5- or 6-position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms, substituted in a position other than the 1-position by an amino, alkylamino or dialkylamino radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms), a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms) or a cyano radical, or represents a dialkoxymethyl, bis-(alkylthio)methyl, alkylsulphonylmethyl, phenylthiomethyl, 1-phenylcyclopropyl or 1- methylcyclohexyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy, methyl and methoxy radicals), a naphth-1-yl radical, a radical selected from 1,3-dithiolan-2-yl, 5,6-dihydro-1,4-dithiin-2-yl, thien-3-yl and pyrid-2-, -3- and -4-yl radicals or an alkanoyl or benzoyl radical] and, when appropriate, non-toxic acid addition salts thereof, possess anthelmintic activity, having a broad spectrum of activity against nematodes.

Description

SPECIFICATION Thiazolidine derivatives This invention relates to new thiazolidine derivatives, a process for their preparation and therapeutic compositions containing them.
The thiazolidine derivatives of the present invention are those compounds of the general formula:
[wherein R, represents a hydrogen or halogen atom located in the 4-, 5- or 6- position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position other than the 1-position by an amino, alkylamino or dialkylamino radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms), a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated fiveor six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms) or a cyano radical, or represents a dialkoxymethyl, bis-(a lkylthio)methyl, alkylsulphonymethyl, phenylthiomethyl, 1-phenylcyclopropyl or 1methylcyclohexyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy, methyl and methoxy radicals), a naphth-i-yl radical, a heterocyclyl radical selected from 1 ,3-dithiolan-2-yl, 5,6-dihydro-1 ,4-dithiin-2-yl, thien-3-yl and pyrid2, -3- and -4-yl radicals or an alkanoyl or benzoyl radical, it being understood that the alkyl and alkanoyl radicals and alkyl moieties of any of the aforementioned groups have straight- or branched-chains and that, unless specifically indicated, they contain from 1 to 4 carbon atoms] and, when appropriate, nontoxic acid addition salts thereof.
The products according to the invention can exist in one of the forms I(A) or l(B) or an equilibrium mixture of these two forms, depending on internal parameters (the radicals R1 and R2) or external parameters (in particular, the presence of a solvent), as will be shown hereafter.
This existence of the two forms l(A) and l(B) of the 4-hydroxythiazolidine-2-thiones of general formula I is well known and forms the subject of various publications, especially those by R.W. Lamon et a/., J. Org. Chem., 29, 2146 (1964) and J. Het. Chem., 4,349 (1967).
The general formula l(A) generally corresponds to the preponderant form, in the crystalline state, of the products in which: a) R1 is as hereinbefore defined and R2 represents a substituted alkyl radical containing 2 to 4 carbon atoms as hereinbefore defined, or represents a dialkoxymethyl, alkysulphonylmethyl or phenylthiomethyl radical, a phenyl radical which is substituted by two methyl of two methoxy radicals, or represents an alkanoyl or benzoyl radical or in which b) R1 represents a hydrogen atom and R2 represents a 2-aminophenyl, 1 ,3-dithiolan-2-yl, thien-3-yl or pyrid-2- or-4-yl radical.
The general formula l(B) generally corresponds to the preponderant form, in the crystalline state, of the products in which: a) R, represents a hydrogen or halogen atom located in the 4-, 5-or 6-position of the pyridyl radical and R2 represents a 1 -phenylcyclopropyl, 1 -methylcyclohexyl, dihydroxyphenyl, naphth-l-yl, bis (alkylthio)methyl, 5,6-dihydro-1 ,4-dithiin-2-yl or pyrid-3-yl radical, or in which b) R1 represents a halogen atom located in the 4-, 5- or 6-position of the pyridyl radical and R2 represents a 2-aminophenyl, 1 ,3-dithiolan-2-yl, thien-3-yl or pyrid-2- or -4-yl radical.
According to a feature of the present invention, the compounds of general formula I are prepared by reacting a compound (which can be prepared in situ) of the general formula: R,-CO-CH,-X II (wherein R2 is as hereinbefore defined and X represents a halogen atom, preferably a bromine or chlorine atom) or, when appropriate, an acid addition salt thereof, with a dithiocarbamate of the general formula
wherein R, is as hereinbefore defined and the symbols R3 (which are identical or different) each represent an alkyl radical containing 1 to 4 carbon atoms.
The reaction is generally carried out in an organic solvent (for example dimethylformamide, acetonitrile or nitromethane), in water or in an aqueous-organic medium (for example in a mixture of water and dimethylformamide or water and acetonitrile), at a temperature between -10 and +500C.
The dithiocarbamates of general formula III can be obtained, in accordance with the method described by E. B. Knott, J. Chem. Soc., 1644-9 (1956), by reacting carbon disulphide, in the presence of a tertiary amine, with a 2-aminopyridine of the general formula:
wherein R, is as hereinbefore defined, or in accordance with the method described by D.B. Capps in United States Patent Specification 3,726,880.
The compounds of general formula II can be prepared by applying various general methods described in the literature, which are illustrated in greater detail in the Examples.
If necessary, the compounds of general formula I can be purified by physical methods such as crystallisation or chromatography.
The compounds of the invention, when R2 represents an alkyl radical which is substituted in a position bther than the I-position by an amino, alkylamino or dialkylamino radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms) or represents a dialkylcarbamoyl radical, the alkyl radicals of which form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring containing another secondary or tertiary nitrogen atom, or represents a 2-aminophenyl radical, can optionally be converted into acid addition salts.The salts can be obtained by reacting the compounds with acids in an appropriate solvent; examples of organic solvents which may be used are alcohols, ketones, ethers and chlorinated hydrocarbons. The salt which forms is precipitated if necessary after concentration of its solution and is separated by filtration or decanatation.
The compounds of general formula I and, when appropriate, their pharmaceutically acceptable salts are particularly active as anthelmintics which have a broad spectrum of activity against nematodes.
Their activity has been demonstrated, especially in mice, against Nematospfroides dubius at doses of between 5 and 200 mg/kg animal body weight, administered orally.
Furthermore, certain of the products according to the invention have been found to be active against filariosis in cotton rats due to litomosoides caring!, at doses of between 25 and 50 mg/kg animal body weight per day, administered orally, for a treatment lasting 5 consecutive days.
Certain of the compounds of the invention have also been found to be active in dogs, at doses of between 10 and 50 mg/kg animal body weight, administered orally, againstAnkylostoma caninum, at doses of between 2.5 and 50 mg/kg animal. body weight, administered orally, against Uncinaria stenocephale, and at doses of between 5 and 50 mg/kg animal body weight, administered orally, against Toxocara canis or Toxascaris leonina.
The toxicity to mice of the products according to the present invention, expressed as their 50% lethal dose (LDso) is between 400 mg/kg animal body weight and more than 1,or0 mg/kg animal body weight administered orally.
The compounds which are or particular value for their level of activity are those of general formula I in which: R1 represents a hydrogen or chlorine atom in the 5-position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position otherthan the 1-position by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a dialkoxymethyl, bis (alkylthio)methyl, alkylsulphonylmethyl, phenylthiomethyl, 1-phenylcyclopropyl or 1 -methylcyclohexyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy and methoxy radicals) or a naphth-1 -yl, thien-3-yl, pyrid-3- or -4-yl or alkanoyl radical, it being understood that the aforementioned alkyl radical containing 2 to 4 carbon atoms has a straight- or branched-chain and that, unless specifically indicated, the alkyl and alkanoyl radicals and alkyl moieties contain 1 or 2 carbon atoms.
Amongst these compounds, those which are more especially active against. Nematospiroides dubius are the compounds of general formula I in which: R1 represents a hydrogen or chlorine atom in the 5-position of the pyridyl radical and R2 represents an alkyl radical containing 2 or 3 carbon atoms, which is substituted on the terminal carbon atom by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atoms to which they are attached, a saturated six-membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a bis-(methylthio)methyl, methylsulphonylmethyl or phenylthiomethyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position br by two hydroxy radicals) or a pyrid-3- or -4-yl or acetyl radical, or in which R represents a chlorine atom in the 5-position of the pyridyl radical and R2 represents a 1phenylcyclopropyl, 1-methylcyclohexyl, naphth-1-yl or thien-3-yl radical, it being understood that the aforementioned alkyl moieties contain 1 or2 carbon atoms.
Amongst such compounds those of general formula I wherein the symbols have the meanings indicated below in Table I are of particular interest; TABLE I
R1 R2 5-Cl 3,4-dihydroxyphenyl H 2-diethyiaminoethyl H - 3-diethylarninopropyl H methylsulphonylmethyl 5-Cl naphth-1-yl The compounds of general formula I which have also been found to be of value for their activity against filariosis in cotton rats due to Litomosoides carinii, both against macrofilariae and microfilariae, are those of general formula I in which:: R, represents a hudrogen atom and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position other than the 1-position by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached a saturated five- or six-membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a dialkoxymethyl, methylsulphonylmethyl, bis-(methylthio)-methyl, 2aminophenyl, pyrid-3- or -4-yl or alkanoyl radical, it being understood that the aforementioned alkyl radical containing 2 to 4 carbon atoms has a straight- or branched-chain and that, unless specifically indicated, the alkyl and alkanoyl radicals and alkyl moieties contain 1 or2 carbon atoms.
Amongst such compounds those of general formula I wherein the symbols have the meanings indicated below in Table II are of particular interest: TABLE II
R2 H - 2-diethylaminoethyl H - e-(N,N-diethy Icarbamoyl)ethyl H - 3-(4-methy Ipi peraz in-1-y I )-3-oxopropy I H - 2-cyanoethyl H - dimethoxymethyl H - bis-(rnethylthio)-rnethyl H - methylsulphonylmethyl H - pyrid-3-yl H - pyrid-4-yl H - acetyl The following Examples illustrate the present invention.
EXAMPLE 1 A solution of 1 -bromo-3-phenyithiopropan-2-one (4.90 g) in acetonitrile (50 cc) is added, at between 1 8 and 280C, to a suspension of triethylammonium pyrid-2-yldithiocarbamate (5.42 g) in anhydrous acetonitrile (10 cc). The reaction is allowed to proceed for 2 hours at 20--280C. The insoluble triethylamine hydrobromide is removed by filtration and washed with acetonitrile (10 cc). The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 400 C. and the residual oil is dissolved in methylene chloride (50 cc). The organic solution is washed twice with distilled water (100 cc in total), dried over sodium sulphate and evaporated. The resulting product (6.40 g) is dissolved in a mixture of ethyl acetate (16 cc) and cyclohexane (50 cc).The product in solution is purified by chromatography on Merck silica (0.063-0.2 mm) (40 g) in a column of diameter 1.7 cm. Elution is carried-out with a mixture of ethyl acetate (40 cc) and cyclohexane (160 cc), then with a mixture of ethyl acetate (25 cc) and cyclohexane (75 cc) and then with a mixture of ethyl acetate (30 cc) and cyclohexane (70 cc). The first 250 cc of eluate are discarded and 150 cc of eluate are then collected, evaporated under reduced pressure (20 mm Hg) at 400C and dried under reduced pressure (0.2 mm Hg) at 300C. 4-Hydroxy-4-phenylthiomethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (5.50 g) is thus obtained.
NMR spectrum (60 MHz) of an approximately 10% (w/v) solution in deuterated chloroform: 3.4 ppm: singlet (2H) -CH2-SC6H5 3.65 ppm: hump (2H) heterocyclic H2- 6.6 ppm: hump (1 H) -OH 7.2 ppm:- hump (6H) -C6H5 plus-H5 7.5 ppm: doublet (1 H) -H3 (J = 8) 7,65 ppm: triplet of doublets (1 H) -h4 (J = 8 and 2) 8.35 ppm: doublet of doublets (1 H)-H6(J = 5 and 2) Triethylammonium pyrid-2-yldithiocarbamate (m.p. 950C) is prepared in accordance with the method described by E.B. Knott, J. Chem. Soc., 1644--49 (1956).
1 -Bromo-3-phenylthiopropan-20ne (m.p. 450C) is prepared by a method analogous to that for the preparation of 1 -chloro-3-phenylthiopropan-2-one, described by V. Rosnati, Gazz. Chim. Ital., 99, 152-64(1969).
EXAMPLE 2 The procedure of Example 1 is followed, but triethylammonium pyrid-2-yldithiocarbamate t121.9 g) and 3-bromo-1,ldimethoxypropan-2-one (88.7 g) in anhydrous acetonitrile (1 litre) are used as thestarting materials at between 1 8 and 220C. The reaction is allowed to proceed for 2 hours at 20-220C. The resulting crude product (98.6 g) is washed with methylcyclohexane (150 cc).The resulting product (29.4 g; m.p. 940 C) is recrystallised from a mixture of cyclohexane and ethyl acetate (1 :1) (150 cc) and then a second time from the same mixture of solvents (70 cc).4-Hydroxy-4- dimethoxy-metjyl-3-(pyrid-2-yl)-thiazolidine-2-thione (15.7 g), which melts at 1000C, is obtained.
3-Bromo-1,1 -dimethoxypropan-2-one can be prepared by a method analogous to that for the bromination of asymmetric ketones, described by M. Gaudry and A. Marquet, Tetrahedron, 26, 5,611-35(1970); by treating a solution of 1,1-dimethoxypropan-2-one (118.0 g) in methanol (800 cc) with bromine (160 g), at a maximum of 50C, and then allowing the reaction to proceed for 48 hours at 200C, 3-bromo-l,l -dimethoxypropan-2-one (b.p. 107-11 60C/20mm Hg) (95 g) is obtained.
EXAMPLE 3 The procedure of Example 1 is followed, but triethylammonium pyrid-2-yldithiocarbamate (23.0 g) and 1 -bromobutane-2,3-dione (14.0 g) in anhydrous acetonitrile (170 cc) are used as the starting materials at between 1 8 and 200 C. The reaction is allowed to proceed for 4 hours at 200 C. The resulting product (15.0 g) is recrystallised from a mixture of ethanol (250 cc) and ethyl acetate (80 cc) and then a second time from acetonitrile (85 cc). 4-Acetyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2thione (8.5 g), which melts at 1 760C, is obtained.
1-Bromobutane-2,3-dione (b.p. 350C/0.15 mm Hg) is prepared in accordance with the method described by M.P. Doerner in United States Patent Specification 2,821,555.
EXAMPLE 4 The procedure of Example 1 is followed, but triethylammonium pyrid-2-yldithiocarbamate (61 g) and 5-chloro-4-oxopentane-nitrile (29.6 g) is anhydrous acetonitrile (600 cc) are used as the starting materials at a maximum of 20C. The reaction is allowed to proceed for 2 hours at 20C. After recrystallisation from acetonitrile (1 50 cc), 3-[4-hydroxy-3-(pyrid-2-yl)-2-thioxothiazolidin-4-yl]- propionitrile (44.6 g), which melts at 1 260 C, is obtained.
When the product is examined by infra-red spectroscopy in a potassium bromide disc, 2 to 5 % of 4-cyano-2-oxobutyl pyrid-2-yldithiocarbamate is observed (carbonyl band at 1,720 cm1). This form is not detected when the product is examined between plates in petroleum jelly.
5-Chloro-4-oxopentane-nitrile is prepared by reacting diazomethane (31.2 g), at about -1 00C, and then a 1 2N aqueous solution of hydrochloric acid (50 cc), at 1 0-200 C, with 3-cyanopropanoyl chloride (33.0 g) in diethyl ether (750 cc in total). 5-Chloro-4-oxopentane-nitrile (25.3 g), which melts at 689C, is obtained.
3-Cyanopropanoyl chloride (b.p. = 82-840C/0.2 mm Hg) is prepared in accordance with the method described by L.J. Dolby, J. Org. Chem., 33, 4,51 (#11(1968).
EXAMPLE 5 The procedure of Example 1 is followed, but triethylammonium pyrid-2-yldithiocarbamate (62 g) and 5-chloro-N,N-diethyl-4-oxopentanamide (47.4 g) in anhydrous acetonitrile (600 cc) are used as the starting materials at between 20 and 250C. The reaction is allowed to proceed for 2 hours at 2O-250C. After recrystallisation from acetonitrile (200 cc), N,N-diethyl-[4-hydroxy-3-(pyrid-2-yl)-2thioxothiazolidin-4-yl]-propionamide (56.5 g), which melts at 1250C, is obtained.
When the product is examined by infra-red spectroscopy in chloroform solution, about 2 to 5 % of 4-diethylaminocarbonyl-2-oxobutyl pyrid-2-yldithio-carbamate is observed (carbonyl band at 1 ,720 cm-1). This form is not detected when the product is examined between plates in petroleum jelly.
5-Chloro-N,N-diethyl-4-oxopentanamide is prepared by reacting dicyclohexylcarbodiimide (59 g) and diethylamine (20.6 g) with 5-chloro-4-oxopentanoic acid (44.8 g) in methylene chloride (770 cc) at 2O-250C for 2 hours. 5-Chloro-N,N-diethyl-40xopentanamide (b.p. 140-1 450C/0.2mm Hg) (47.6 g) is obtained.
5-Chloro-4-oxopentanoic acid (m.p. 71 0C) is prepared in accordance with the method described by V.M. Rodionov and M.A. Gubareva, Chem. Abstracts, 49, 926d (1955).
EXAMPLE 6 The procedure of Example 1 is followed, but triethylammonium pyrid-2-yldithiocarbamate (28.2 g) and 1 -(5-chloro-1 ,4-dioxopentyl)-4-methylpiperazine (25.2 g) in anhydrous acetonitrile (300 cc) are used as the starting materials at a maximum of 2"C-. The reaction is allowed to proceed for 2 hours at 20C. The resulting oily product (32.0 g) is dissolved in ethanol (1 50 cc) and treated with a solution of fumaric acid (10.1 g) in dimethylformamide (30 cc) at a maximum of 300C.After cooling for 2 hours at 20C, the crystals which have appeared are filtered off, washed three times with ethanol (90 cc in total) and dried under reduced pressure (0.2 mm Hg) at 500C. 4-Hydroxy-4-[3(4-methylpiperazin-lyl)-3- oxopropyl]-3-(pyrid-2-yl)-thiazolidine-2-thione fumarate (31.5 g), which melts at 1 500C, is obtained.
1 (5-Chloro-1 ,4-dioxopentyl)-4-methylpiperazine can be prepared in the following manner: preparation of 5-chloro-4-oxopentanoic acid (m.p. 71 0C) as described in Example 5; preparation of 5-ch loro-5-chloromethyl-4,5-dihydro-3H-furan-2one (b.p, 88--89 OC/0.3 mm Hg; 34 g) by reacting thionyl chloride (35.0 g) with 5-chloro-4-oxopentanoic acid (36.9 g) in chloroform (240 cc) at the reflux temperature for 1 1/2 hours, and preparation of 1 -(5-chloro-1 ,4-dioxopentyl)-4-methylpiperazine (m.p. 950C; 25.2 g) by reacting 1 -methylpiperazine (36.4 g) with 5-chloro-5-chloromethyl-4,5-dihydro-3H-furan-2-one (30.8 g) in anhydrous acetone (300 cc) at 20C for 1 hour.
EXAMPLE 7 A solution of 1 -bromo-4-diethylaminobutan-2-one hydrobromide (30.3 g) in water (30 cc) is added, at 200 C, to a suspension of triethylammonium pyrid-2-yldithio-carbamate (27.1 g) in water (100 cc). The reaction is allowed to proceed for 1 hour at 200C. The mixture is treated with decolourising charcoal (1.0 g) and filtered and the solid is washed with water (10 cc). The filtrate is concentrated under reduced pressure (20mm Hg) at 500C until a residuai volume of about 60 cc is obtained.After cooling for 2 hours at 20C, the crystals which have appeared are filtered off, washed with ice-cooled water (10 cc) and ethanol (10 cc) and dried under reduced pressure (0.2mm Hg) at 450 C. 4-(2-Diethyla minoethyl)-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione hydrobromide (18.7 g), which melts at 1 480C, is thus obtained.
1-Bromo-2-diethylaminobutan-2-one hydrobromide (m.p. 800C) is prepared in accordance with the method described by C. Djerassi et al., J. org. Chem., 15, 700--06(19 (1950).
EXAMPLE 8 The procedure of Example 1 is followed, but triethylammonium 5-chloropyrid-2-yldithiocarbamate (52 g) and 1-chloro-2-(phenylcyclopropyl)-ethan-2-one (33.1 g) in anhydrous acetonitrile (500 cc) are used as the starting materials at 200C. The reaction is allowed to proceed for 2 hours at 200 C. After recrystallisation from acetonitrile (160 cc), 2(1-phenylcyclopropyl)-2-oxoethyl 5-chloropyrid-2yldithiocarbamate (48,1 g), which melts at 1270C, is obtained.
1-Chloro-2-(1-phenylcyclopropyl)-ethan-2-one (b.p. 1060 C/0.4mm Hg; m.p. about 450C; 48.09) is obtained by reacting diazomethane (25.2 g), at between -15 and -50C, and then a 1 2N aqueous solution of hydrochloric acid (100 cc), at between 0 and 1 OOC, with 1 -phenylcyclopropanecarbonyl chloride (48.7 g) in diethyl ether (600 cc).
1-Phenylcyclopropanecarbonyl chloride (b.p. 820C/0.2mm Hg) is prepared in accordance with the method described by A.W. Weston, J. Amer. Chem. Soc., 68,2,347 (1946).
EXAMPLE 9 The procedure of Example 1 is followed, but triethylammonium 5-chloropyrid-2-yldithiocarbamate (80.5 g) and 1-chloro-2-(1-methylcyclohexyl)-ethan-2-one (46.0 g) in anhydrous acetonitrile (650 cc) are used as the starting materials at 200 C. The reaction is allowed to proceed for 2 hours at 200 C. After recrystallisation from acetonitrile (400 cc), 2-(1-methylcyclohexyl)-2-oxo-ethyl 5-chloropyrid-2yldithiocarbamate (66.1 g), which melts at 1020C, is obtained.
1-Chloro-2-(1-methylcyclohexyl)-ethan-2-one (b.p. 70-750C/0.8mm Hg) is prepared in accordance with the method described by T.A. Magee in German Patent Specification 2,21 6,838.
EXAMPLE 10 The procedure of Example 1 is followed, buttriethylammonium pyrid-2-yldithiocarbamate (10.9 g) and 1 -(2-aminophenyl)-2-bromoethan-1-one (8.6 g) in anhydrous acetonitrile (60 cc) are used as the starting materials at between 22 and 280 C. The reaction is allowed to proceed for 2 hours at 20--280C. After recrystallisation from acetonitrile (90 cc),4-(2-aminophenyl)-4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (8.4 g), which melts at 1300C, is obtained.
When the product is examined by infra-red spectroscopy in chloroform solution, about 30 % of 2 (2-aminophenyl)-2-oxoethyl pyrid-2-yldithiocarbamate is observed (carbonyl band at 1 ,650 cm'). This form is not detected when the product is examined between plates in petroleum jelly.
1-(2-Aminophenyl)-2-bromoethan-1-one (m.p. 630C) is prepared in accordance with the method described by Pl Ruggli and H. Reichwein, Helv. Chim. Acta 20,913 (1937).
EXAMPLE 11 The procedure of Example 1 is followed, but triethylammonium 5-chloropyrid-2-yldithiocarbamate (40.0 g) and2-chloro-1-(3,4-dihdroxyphenyl)-ethan-1-one (24.2 g) in anhydrous acetonitrile (450 cc) are used as the starting materials at between 1 5 and 200 C. The reaction is allowed to proceed for 4 hours at 200 C. After recrystallisation from a mixture of acetonitrile (1,000 cc), ethyl acetate (500 cc) and dimethylforma mide (25 cc), 2-(3-,4-dihydroxyphenyl)-2-oxoethyl 5-chloropyrid-2 yldithiocarbamate (21.0 g), which melts at 1 950 C, is obtained.
EXAMPLE 12 The procedure of Example 1 its followed, but triethylammonium 5-chloropyrid-2-yldithiocarbamate (40.0 g) and 2-bromo-1-(2,5-dimethoxyphenyl)ethan-1-one (33.8 g) in anhydrous acetonitrile (450 cc) are used as the starting materials at between 1 5 and 200 C. The reaction is allowed to proceed for 4 hours at 200C. After recrystallisation from acetonitrile (500 cc), 3-(5-chlornpydd-2-yl)-4A2,5- dimethoxyphenyl)-4-hydroxy-thiazolidine-2-thione (35.0 g), which melts at 1 68 "C, is obtained.
EXAMPLE 13 The procedure of Example 1 is followed, byt triethylammonium 5-chloropyrid-2-yldithiocarbamate (18.0 g) and 2--brnmo-1 -(naphthi-yl)-ethan-1 ne (15.0 g) in anhydrous acetonitrile (250 cc) are used as the starting materials at 200C. The reaction is allowed to proceed for 4 hours at 200 C. After recrystallisation from a mixture of ethanol (500 cc) and ethyl acetate (100 cc), 2-(naphth-l -yl)-2- oxoethyl 5-chloropyrid-2-yldithiocarbamate (13.0 g), which melts at 1 46 OC, is obtained.
When the product is examined by infra-red spectroscopy in chloroform solution, about 90 to 95% of 3-(5-chloropyrid-2-yl)-4-hydroxy-4-(naphth-1 -yl)-thiazolidine-2-thione is observed (reduction in the intensity of the carbonyl band at 1,690 cm'). This form is-not detected when the product is examined between plates in petroleum jelly.
2-Bromo- 1 -(naphth-1 -yl)-ethan-1 -one (b.p. 145-1 550 C/ 0.1 mm Hg) is prepared in accordance with the method described by C.B. Radcliffe etna!., J. Chem. Soc., 2,293(1931).
EXAMPLE 14 2-Bromo-1 -(pyrid-4-yl)-ethan-1 -one (17.2 g) is added, at a maximum of 1 50C, to a suspension of triethylammonium pyrid-2-yldithiocarbamate (23.4 g) in nitro-methane (500 cc). The reaction is allowed to proceed for 2 hours at 1 5--200C. The nitromethane is evaporated off under reduced pressure (20mm Hg) at 45"C. The resulting pasty residue is washed with distilled water (-100 cc) and then with ethyl acetate (500 cc). The resulting crystals (12.0 g; m.p. 1 750C) are purified by recrystallisation from a mixture of dimethylformamide (20 cc) and ethanol (50 cc). 4-Hydroxy-3-(pyrid- 2-yl)-4-(pyrid-4-yl)-thiazolidine-2-thione (5.7 g), which melts at 1 750C, is obtained.
2-Bromo-1-(pyrid-4-yl)-ethan-1-one tm.p. 1900C; 24.1 g) is obtained by reacting bromine (16.0 g) with a solution of 1 -(pyrid-4-yl)-ethan-1 -one (12.2 g) in methanol (60 cc), at between 1 8 and 290C, and then reacting a concentrated aqueous solution of sodium bicarbonate (50 cc) with the resulting mixture.
EXAMPLE 15 A solution of 1-bromo-3-methylsulphonylpropan-2-one (80 % pure; 38 g) in anhydrous acetonitrile (120 cc) is added, at between 0 and 50 C, to a suspension of triethylammonium pyrid-2 yldithiocarbamate (38.0 g) in anhydrous acetonitrile (260 cc). The reaction is allowed to proceed for 2 hours at 20C. The acetonitrile is evaporated off under reduced pressure (20mm Hg) at a maximum of 500C. The residual oil is dissolved in methylene chloride (400 cc). The organic solution is washed four times with distilled water (600 cc in total), treated with decolourising charcoal, dried over anhydrous sodium sulphate and evaporated. The resulting product (40 g) is dissolved in chloroform (400 cc).The solution is chromatographed on Merck silica (0.2-0.5 mm; 400 g) contained in a column of diameter 5 cm. Elution is carried out with chloroform (4.2 litres), this eluate being discarded, and then with chloroform (1.2 litres), this eluate being evaporated under reduced pressure (20mm Hg) at 500C. The resulting product (20.0 g; m.p. about 1300C) is purified by recrystallisation from ethyl acetate (120 cc).
4-Hydroxy-4-methylsulphonylmethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (7.6 g), which melts at 1 480C, is obtained.
1 -Bromo-3-methylsulphonylpropan-2-one can be prepared in the following manner: preparation of methylsulphonylacetic acid (m.p. 11 40C) in accordance with the method described by J.M. Carpenter et al., J. Chem Soc., 2,01 6--22 (1970), preparation of methylsulphonylacetyl chloride (oily; 36.9 g) by reacting sulphinyl chloride (130 cc) with methylsulphonylacetic acid (32.6 g) at about 600C in the presence of dimethylformamide (0.3 cc), and preparation of 1 -bromo-3-methylsulphonylpropan-2-one (pasty; purity about 80 %; 38.4 g) by reacting a solution of diazomethane (24.2 g) in anhydrous diethyl ether (600 cc) with a solution of methylsulphonylacetyl chloride (36.9 g) in methylene chloride (100 cc), at about -1 OOC, and then by reacting a 48 % (w/v) aqueous solution of hydrobromic acid (d 1.49; 45 cc) with the 1-diazo-3methylsulphonylpropan-2-one formed in situ, at between O and 2O0C.
EXAMPLE 16 The procedure of Example 1 5 is foilowed, but triethylammonium pyrid-2-yldithiocarbamate (40.5 g) and 1 -chloro-3,3-bis(methylthio)-propan-2-one (28 g) in anhydrous acetonitrile (400 cc) are used as the starting materials at between 1 5 and 200C. The reaction is allowed to proceed for 1 6 hours at 2O0C. The resulting product (75 g) is dissolved in ethyl acetate (500 cc) and the solution is washed twice with distilled water (200 cc in total), treated with decolourising charcoal, dried over anhydrous sodium sulphate and evaporated.The resulting product (60 g) is dissolved in a mixture of cyclohexane (300 cc) and ethyl acetate (200 cc) and the solution is chromatographed on Merck silica (0.2-0.5 mm) (600 g) contained in a column of diameter 5 cm. Elution is carried out with a mixture of cyclohexane (900 cc) and ethyl acetate (600 cc), the corresponding eluate being discarded, and then with a mixture of cyclohexane (600 cc) and ethyl acetate (400 cc). The second eluate is evaporated under reduced pressure (20mm Hg) at 500 C. The resulting product (30 g) is purified by recrystallisation from boiling diisopropyl ether (100 cc).3,3-Bis-(methylthio)-2-oxopropyl pyrid-2-yldithiocarbamate (11 g), which melts at 1210C, is thus obtained.
When the product is examined by infra-red spectroscopy in chloroform solution, about 90 % of 4 hydroxy-4-bis-( methylthio)-m ethyl-3-(pyrid-2-yl)-thiazolidine-2-thione is observed (very distinct reduction in the intensity of the carbonyl band at 1,705 cm-'). This form is not detected when the product is examined between plates in petroleum jelly.
1-Chloro-3,3-bis-(methylthio)-propan-2-one can be prepared in the following manner: preparation of 2,2-bis-(methylthio)-acetic acid (m.p. 770C) in accordance with the method described by A. Tananger, Arkiv. Kemi, Mineral. Geol., 24 A,. 10-18 (1947).
preparation of bis-(methylthio)-acetyi chloride (b.p. 1050C/20 mm Hg; 28.4 g) by reacting a solution of 2,2-bis-(methylthio)-acetic acid (30.4 g) in anhydrous diethyl ether (350 cc) with a solution of oxalyl chloride (19 cc) in anhydrous diethyl ether (100 cc), in the presence of dimethylformamide (1 cc), at about OOC, and preparation of 1 -chloro-3,3-bis-(methylthio)-propan-2-one (orange oil which cannot be distilled) (28 g) by reacting a solution of diazomethane (17.2 g) in anhydrous diethyl ether (480 cc) with a solution of bis-(methylio)-acetyl chloride (28.4 g) in anhydrous diethyl ether (50 cc), at about -300C, and then by reacting a 1 2N aqueous solution of hydrochloric acid (35 cc) with the 1 -diazo-3,3-bis (methylthio)-propan-2-one formed in situ, at between 0 and 200 C.
EXAMPLE 17 A solution of 2-bromo-1 -(pyrid-3-yl)-ethanone hydrobromide (19.0 g) in distilled water (350 cc) is added, at between 1 8 and 220C, to a solution of triethylammonium pyrid-2-yldithiocarbamate (1 8.4 g) in distilled water (1 50 cc). The reaction is allowed to proceed for 16 hours at 20-220C. The crude product is filtered off, washed three times with distilled water (300 cc in total) and then with diisopropyl ether (100 cc) and dried in air. The resulting product (13.0 g; m.p. 1 85 OC) is dissolved in boiling ethyl acetate (100 cc). After filtering the boiling solution and then cooling for 4 hours at 20C, the crystals which have appeared are filtered off, washed three times with ice-cooled ethyl acetate (30 cc in total) and dried under reduced pressure (0.2 mm Hg) at 400 C. 2-Oxo-2-(pyrid-3-yl)-ethyl pyrid-2yldithiocarbamate (10.5 g), which melts at 1 9O0C, is thus obtained.
Triethylammonium pyrid-2-yldithiocarbamate is prepared in accordance with the method described by E.B. Knott, J. Chem. Soc., 1,644-9 (1956).
2-Bromo-1 -(pyrid-3-yl)-ethanone hydrobromide is prepared in accordance with the methods described by A. Dornow, H. Machens and K. Bruncken, Chem. Ber., 84, 147-50 (1951).
EXAMPLE 18 The procedure of Example 1 5 is followed, but triethylammonium 5-chloropyrid-2 yldithiocarbamate (25.6 g) and 1 -bromo-3-(thien-3-yl)-propan-2-one (17.2 g) in anhydrous acetonitrile (150 cc) are used as the starting materials at between 1 5 and 200 C. The reaction is allowed to proceed for 30 minutes at 200 C. The resulting product (25.0 g; m.p. 1450 C) is purified by recrystallisation from acetonitrile (280 cc). 2-Oxo-2-(thien-3-yl)-ethyl 5-ch loropyrid-2-yldithiocarbamate (21.7 g), which melts at 1480C, is obtained.
When the product is examined by infra-red spectroscopy in chloroform solution, the major compound observed is 3-(5-chlornpyrid-2-yl)-4-hydrnxy-4-(thien-3-yl)-thiazolidine-2-thione (reduction in the intensity of the carbonyl band at 1,680 cm-l).
1 -Bromo-3-(thien-3-yl)-propan-2-one (m.p. 550C) is prepared in accordance with the method described by D.W.H. MacDowell and T.D. Grnenwood, J. Het. Chem.,2,46 (1965).
EXAMPLE 19 1 -Bromo-5-diethylaminopenta n-2-one hydrobromide (30.3 g) is added, at between 1 5 and 200 C, to a solution of triethylammonium pyrid-2-yldithiocarbamate (27.1 g) in distilled water (150 cc). The reaction is allowed to proceed for 2 hours at 20--250C. After filtering the reaction mixture under reduced pressure, the water is evaporated off under a pressure of 20mm Hg at 700C. The resulting residue is dissolved in boiling ethanol (200 cc).
After decolourising charcoal (2 g) has been added to the boiling solution, the mixture is filtered at the boil and the filtrate is left to cool for 2 hours at 200C. The crystals which have appeared are filtered off, washed twice with ice-cooled ethanol (40 cc in total) and dried under reduced pressure (0.2mm Hg) at 450C.
4-(3-Diethylaminoprop-1 -yl)-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione hydrobromide (11.6 g), which melts at 1 750C, is thus obtained (structure determined by infra-red spectroscopy in petroleum jelly).
1 -Bromo-5-diethylaminopentan-2-one hydrobromide can be prepared in the-following manner: an approximately 35 % (w/v) solution of hydrobromic acid in acetic acid (25 cc) is added, at between 20 and 250C, to a solution of 5-diethylaminopentan-2-one (15.7 g) in acetic acid (20 cc), and a solution formed by dissolving bromine (16 g) in acetic acid (30 cc) is then added at between 15 and 200 C. The reaction is allowed to proceed for 16 hours at 20-250 C. The acetic acid is evaporated off under a pressure of 20mm Hg at 700C and then under a pressure of 0.2mm Hg at 500C. The residual oil is washed three times with diethyl ether (1,500 cc in total) and then dried under reduced pressure (0.2mm Hg) at 450C. 1 -Bromo-5-diethylaminopentan-2-one hydrobromide (oily; 30 g) is thus obtained.
Triethylammonium pyrid-2-yldithiocarbamate (m.p. 950C) is prepared in accordance with the method described by E.B. Knott, J. Chem. Soc., 1,644-9 (1956).
The present invention includes within its scope therapeutic compositions (for use in human or animal medicine) which comprise, as active ingredient, at least one of the compounds of general formula I or - when appropriate -- a non-toxic salt thereof, in association with one or more compatible and pharmaceutically acceptable carriers, and optionally with other compatible and physiologically active products. The invention includes- especially such preparations made up for oral, parenteral or rectal administration.
Solid compositions for oral administration include tablets, pills, e.g. sugar-coated pills, powders and granules. In such solid compositions the active compound is admixed with at least one inert diluent süch as sucrose, lactose or starch. The compositions may also comprise, as is normal practise, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water or liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting, emulsifying and suspending agents, and sweetening, flavouring and aromatizing agents. The compositions according to the invention,. fororal administration, also include capsules of absorbable material such as gelatin containing the active substance with or without the addition of diluents or excipients.
Compositions according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilizing agents, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Compositions for rectal administration are suppositories which contain, in addition to the active substance, excipients such as cacao butter or a suitable wax base.
In the compositions of the invention, the active ingredient, when it is not in solution, is advantageously in the micronised form.
The compositions according to the invention are useful as anthelmintic compositions.
In veterinary medicine, the compounds according to the invention can be used in the treatment of helminthiases caused by nematodes in cattle, sheep, horses and goats, at doses, administered orally, of between 5 and 50 mg/kg animal body weight, for treatments of 1 to 3 days, or at doses of between 2.5 and 25 mg/kg animal body weight for treatments over more prolonged periods, as well as for the removal of gastro-intestinal strongyles in sheep and intestinal nematodes in dogs.
In human medicine, the compounds according to the invention can be used for eliminating anguillulae, ascarides and ankylostomes, at doses of between 5 and 50 mg/kg weight, administered orally, for treatments lasting from 1 to 3 days.
The compositions according to the invention can also be particularly useful in therapy in the treatment and prevention of human filarioses, namely cutaneo-dermic filarioses (onchocerosis, loasis and dracunculosis) and lymphatic filarioses (wuchereriasis and brugiasis).
In human therapy, the doses depend on the desired effect and the duration of the treatment; for an adult, they are generally between 10 and 50 mg/kg body weight per day, administered orally, and between 5 and 1 5 mg/kg body weight per day, administered intramuscularly, for treatments lasting from 1 to 30 days.
In general the physician or the veterinary surgeon will determine the posology considered appropriate, taking into account the age and weight and all other factors intrinsic to the subject being treated.
The following Examples illustrate therapeutic compositions according to the invention.
EXAMPLE 20 Tablets containing 25 mg of active compound and having the following composition are prepared in accordance with the usual technique: 2-(3,4-dihydroxyphe nyl)-2-oxoethyl 5-chloropyrid-2-yldithiocarbamate 25 mg corn starch 125 mg colloidal silica 45 mg magnesium stearate 5 mg EXAMPLE 21 Tablets containing 25 mg of active ingredient and having the following composition are prepared in accordance with the usual technique: 4-hydroxy-4-(2-diethylaminoethyl) 3-(pyrid-2-yl)-thiazolidine-2-thione 25 mg corn starch 125 mg colloidal silica 45 mg magnesium stearate 5 mg.
EXAMPLE 22 Injectable ampoules containing a 10% (w/v) solution of active ingredient and having the following composition are prepared in accordance with the usual technique: 4-hydroxy-4-(2-diethylaminoethyl)- 3-(pyrid-2-yl)-thiazolidine-2-thione 0.25 mg injectable solution 2.5 cc

Claims (30)

1. Compounds of the general formula:
[wherein R1 represents a hydrogen or halogen atom located in the 4-, 5- or 6-position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position other than the 1-position by an amino, alkylamino or dialkylamino radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms), a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms, and oxygen and sulphur atoms) or a cyano radical, or represents a dialkoxymethyl, bis-(alkylthio)methyl, alkylsulphonylmethyl, phenylthiomethyl, 1 -phenylcyclopropyl or 1-methylcyclohexyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy, methyl and methoxy radicals), a naphth-1 -yl radical, a heterocyclyl radical selected from 1,3-dithiolan-2-yl, 5,6-dihydro-1,4-dithiin-2-yl, thien-3-yl and pyrid-2, -3- and -4-yl radicals or an alkanoyl or benzoyl radical, it being understood that the alkyl and alkanoyl radicals and alkyl moieties of any of the aforementioned groups have straight- or branchedchains and that, unless specifically indicated, they contain from 1 to 4 carbon atoms] and, when appropriate, non-toxic acid addition salts thereof.
2. Compounds according to claim 1 wherein R1 represents a hydrogen or halogen atom located in the 4-, or 6-position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms which is substituted in a position other than the 1-position by an amino, alkylamino or dialkylamino radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms and oxygen and sulphur atoms) a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another hetero-atom selected from secondary and tertiary nitrogen atoms and oxygen and sulphur atoms) or a cyano radical or represents a dialkoxymethyl, phenylthiomethyl, 1 -phenylcyclopropyl or 1 methylcyclohexyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy, methyl and methoxy radicals) a naphth-1 -yl, pyrid-4-yl, alkanoyl or benzoyl radical, it being understood that the alkyl and alkanoyl radicals and alkyl moieties of any of the aforementioned groups have straight- or branched-chains and that, unless specifically indicated, they contain from 1 to 4 carbon atoms and, when appropriate, non-toxic acid addition salts thereof.
3. Compounds according to claim 1 wherein R, represents a hydrogen or halogen atom located in the 4-, 5- or 6-position of the pyridyl radical and R2 represents an alkylsulphonylmethyl, bis (alkylthio)methyl, or heterocyclyl radical selected from 1 ,3-dithiolan-2-yl, 5,6-dihydro- 1 ,4dithien-2l, thien-3-yl and pyrid-2- or -3-yl radicals, the alkyl moieties of the aforementioned groups having straight- or branched-chains and containing from 1 two 4 carbon atoms.
4. Compounds according to claim 1 which, in preponderent form in the crystalline state, correspond to general formula l(A) in which (a) R, is as defined in claim 1 and R2 represents a substituted alkyl radical containing 2 to 4 carbon atoms as defined in claim 1, or represents a dialkoxymethyl, alkylsulphonylmethyl or phenylthiomethyl radical, a phenyl radical which is substituted by two methyl or two methoxy radicals, or represents an alkanoyt or benzoyl radical, or in which (b) Ri represents a hydrogen atom and R2 represents a 2-aminophenyl, 1 ,3dithiolan-2-yl, thien-3-yl or pyrid-2- or -4-yl radical.
5. Compounds according to claim 1 which, in preponderant form in the crystalline state, correspond to general forumla l(B) in which (a) R, represents a hydrogen or halogen atom located in the 4-, or 6-position of the pyridyl radical and R2 represents a t-phenylcyclopropyl,1 1-methylcyclohexyl, dihydroxyphenyl, naphth- 1 -yl, bis-(alkylthio)methyl, 5,6-dihydro- 1 ,4-dithiin-2-yl or pyrid-3-yl radical, or in which (b) R, represents a halogen atom located in the 4-, 5- or 6-position of the pyridyl radical and R2 represents a 2-aminophenyl, 1 ,3-dithiolan-2-yl, thien-3-yl or pyrid-2- or -4-yl radical.
6. Compounds according to claim 1 wherein R, represents a hydrogen or chlorine atom in the 5position of the pyridyl radical and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position other than the 1-position by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six-membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a dialkoxymethyl, bis-(alkylthio)methyl, alkylsulphonymethyl, phenylthiomethyl, 1 -phenylcyclopropyl or 1-methylcyclohexyl radical, a phenyl radical (which is subsituted by an amino radical in the 2-position or by two identical radicals selected from hydroxy and methoxy radicals) or a naphth-1 -yl, thien-3-yl, pyrid-3- or -4-yl or alkanoyl radical, it being understood that the aforementioned alkyl radical containing 2 to 4 carbon atoms has a straight- or branched-chain and that, unless specifically indicated, the alkyl and alkanoyl radicals and alkyl moities contain 1 or 2 carbon atoms.
7. Compounds according to claim 6 wherein R, represents a hydrogen or chlorine atom in the 5position of the pyridyl radical and R2 represents an alkyl radical containing 2 or 3 carbon atoms, which is substituted on the terminal carbon atom by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated six-membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a bis-(methylthio)methyl, methylsulphonylmethyl or phenylthiomethyl radical, a phenyl radical (which is substituted by an amino radical in the 2-position or by two hydroxy radicals) or a pyrid3- or -4-yl or acetyl radical, or in which R, represents a chlorine atom in the 5-position of the pyridyl radical and R2 represents a 1 -phenylcyclopropyl, 1 -methylcyclohexyl, naphth-1 -yl or thien-3-yl radical, it being understood that the aforementioned alkyl moieties contain 1 or 2 carbon atoms.
8. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents an alkyl radical containing 2 to 4 carbon atoms, which is substituted in a position other than the 1-position by a dialkylamino or dialkylcarbamoyl radical (the alkyl radicals of which may form, with the nitrogen atom to which they are attached, a saturated five- or six- membered heterocyclic ring which may contain another secondary or tertiary nitrogen atom) or a cyano radical, or represents a dialkoxymethyl, methylsulphonylmethyl, bis-(methylthio)methyl, 2-aminophenyl, pyrid-3- or -4-yl or alkanoyl radical, it being understood that the aforementioned alkyl radical containing 2 to 4 carbon atoms has a straightor branched-chain and that, unless specifically indicated the alkyl and alkanoyl radicals and alkyl moieties contain 1 or2 carbon atoms.
9. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents a 2diethylaminoethyl radical and pharmaceutically acceptable acid addition salts thereof.
1 0. The compound according to claim 9 which is 4(2-diethylaminoethyl)-4-hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione hydrobromide.
11. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents a methysulphonylmethyl radical.
12. The compound according to claim 11 which is 4-hydroxy-4-methylsulphonylmethyl-3-(pyrid2-yl)-thiazolidine-2-thione.
1 3. Compounds according to claim 1 wherein R, represents a chlorine atom in the 5-position of the pyridyl radical and R2 represents a 3,4-dihydroxyphenyl or naphth-1 -yl radical.
14. The compounds according to claim 13 which are 2-(3,4-dihydroxyphenyl)-2-oxoethyl 5ch loropyrid-2-yldith iocarbamate and 2-(naphth- 1 -yl)-2-oxoethyl 5-ch loropyrid-2-yldithiocarba mate.
1 5. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents the 3-diethylaminopropyl radical and pharmaceutically acceptable acid addition salts thereof.
16. The compound according to claim 15 which is 4-(3-diethylaminoprop-1-yl)-4-hydroxy-3 (pyrid-2-yl)-thiazolidine-2-thione hydrobromide.
1 7. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents a 2-(N,N-diethylca rbamoyl)ethyl, 3-(4-methylpiperazin- 1 -yl)-3-oxopropyl, 2-cya noethyl, dimethoxymethyl, pyrid-4-yl or acetyl radical and, when appropriate, pharmaceutically acceptable acid addition salts thereof.
18. The compounds according to claim 1 7 which are N,N-diethyl-[4-hydroxy-3-(pyrid-2-yl)-2 thioxothiazolidin-4-yl]-propiona mide,4-hydroxy-4-[3-(4-methylpiperazi n- 1 l)-3-oxoprnpyl]-3-(pyrid-2- yl)-thiazolidine-2-thione fu ma rate, 3-[4-hydroxy-3-(pyrid-2-yl)-2-thioxothiazolidin-4-ylj-propionitrile, 4- hydroxy-4-dimethoxymethyl-3-(pyrid-2-yl)-thiazolidine-2-thione, 4-hydroxy-3-( pyrid-2-yl)-4-(pyrid-4yl)-thiazolidine 2-thione and 4-acetyl-4-hydroxy-3-( pyrid-2-yl)-thiazolidine-2-thione.
1 9. Compounds according to claim 1 wherein R, represents a hydrogen atom and R2 represents a bis-(methylthio)methyl or pyrid-3-yl radical.
20. The compounds according to claim 19 which are 3,3-bis-(methylthio-2-oxopropyl pyrid-2 yldithiocarba mate and 2-oxo-2-(pyrid-3-yl)ethyl pyrid-2-yldithiocarbamate.
21. Compounds according to claim 1 identified by name in any of the foregoing Examples and not claimed in any one of claims 9 to 20 and, when appropriate, acid addition salts thereof.
22. A process for the preparation of a compound of general formula I specified in claim 1, and acid addition salts thereof, which comprises reacting a compound of the general formula: R2-CO-C H 2-X II (wherein R2 is as defined in claim 1 and X represents a halogen atom) or, when appropriate, an acid addition salt thereof, with a dithiocarbamate of the general formula:
[wherein R, is as defined in claim I and the symbols R3 (which are identical or different) each represent an alkyl radical containing 1 to 4 carbon atoms] and optionally, when appropriate, converting the compound of general formula I obtained into an acid addition salt thereof.
23. Process according to claim 22 in which the reaction is carried out in an organic solvent, in water or in an aqueous-organic medium at a temperature between -10 and 500C.
24. Process according to claim 23 in which the organic solvent is dimethylformamide, acetonitrile or nitromethane and the aqueous-organic medium is a mixture of water and dimethylformamide or water and acetonitrile.
25. Process according to claim 22, 23 or 24 in which X represents a bromine or chlorine atom.
26. A process for the preparation of a compound of general formula I specified in claim I substantially as hereinbefore described with especial reference to any one of Examples 1 to 19.
27. Compounds of general formula I specified in claim 1 and, when appropriate, acid addition salts thereof when prepared by the process claimed in any one of claims 22 to 26.
28. Therapeutic compositions which comprise, as active ingredient, at least one compound of general formula I specified in claim I or, when appropriate, a pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims 1 to 21 and 27 in association with a pharmaceutically accepatble carrier or coating, and optionally with other compatible and physiologically active products.
29. Therapeutic compositions according to claim 28 substantially as hereinbefore described with especial reference to Example 20, 21 or 22.
30. A compound as claimed in any one of claims 1 to 21 and 27 or, when appropriate, a pharmaceutically acceptable salt thereof, when used as a medicament and, more particularly, as an anthelmintic agent.
GB7937711A 1978-11-02 1979-10-31 4-substituted-4-hydroxy-3-pyridyl-thiazolidine-2-thione derivatives Withdrawn GB2034712A (en)

Applications Claiming Priority (2)

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FR7831039A FR2440368A2 (en) 1978-11-02 1978-11-02 3-Pyridyl-4-hydroxy-thiazolidine-2-thione derivs. - useful as anthelmintic agents, esp. against nematodes
FR7922793A FR2464954A2 (en) 1979-09-12 1979-09-12 3-Pyridyl-4-hydroxy-thiazolidine-2-thione derivs. - useful as anthelmintic agents, esp. against nematodes

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5246948A (en) * 1991-05-10 1993-09-21 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5246948A (en) * 1991-05-10 1993-09-21 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
US5389658A (en) * 1991-05-10 1995-02-14 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
US5457106A (en) * 1991-05-10 1995-10-10 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
US5561147A (en) * 1991-05-10 1996-10-01 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
US5767121A (en) * 1991-05-10 1998-06-16 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use

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ATA706679A (en) 1981-04-15
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IL58610A0 (en) 1980-02-29
IT7927015A0 (en) 1979-11-02
AU5237779A (en) 1980-05-08
LU81843A1 (en) 1980-05-07
ES485652A2 (en) 1980-06-16

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