DK158734B - 1,2-DITHIOL-3-ON DERIVATIVES AND PHARMACEUTICAL PREPARATIONS WITH CONTENTS - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. 1,2-Dithiol-3-one derivative, characterized in that it corresponds to the general formula : see diagramm : EP0119895,P26,F1 in which - either R denotes a hydrogen or chlorine atom, A denotes an oxygen atom or an imino, alkylimino, alkylcarbonylimino or formylimino radical and Ar denotes a phenyl radical substituted by a cycloalkyl radical in which the alkyl part contains 3 to 7 carbon atoms, an alkenyl radical containing 2 to 4 carbon atoms as a straight or branched chain, an anilino, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl, 1,3-dioxolan-2-yl, dialkylaminomethyleneamino, trifluoromethylthio or alkylcarbonyloxy radical or an alkyl radical substituted by a hydroxy, alkoxy, carboxy, amino, alkylcarbonylamino, alkoxycarbonylamino, dialkylaminomethyleneamino, formamido, alkylureido, phenylsulphonyl, carbamoyl, alkylcarbamoyl, dialklylcarbamoyl, formul, semicarbazonomethyl, 1,3-dithiolan-2-yl or 1,3-dioxolan-2-yl radical or Ar denotes a pyridyl, quinolyl, isoquinolyl, indanyl or quinoxalinyl radical, - or R denotes a hydrogen atom, A denotes an oxygen atom or an amino, alkylimino, alkylcarbonylimino or formylimino radical and Ar denotes a phenyl radical substituted by an alkyl radical, - or R denotes a chlorine atom, A denotes an oxygen atom or an alkylcarbonylimino or formylimino radical and Ar denotes a phenyol radical substituted by an alkyl radical, it being understood that, unless specially mentioned, all the alkyl radicals and alkyl moieties contain 1 to 4 carbon atoms as a straight or branched chain, as well as, where these exist, its salts of addition with acids, its metal salts and its salts of addition with organic bases. For the Contracting State : AT 1. Process for the preparation of 1,2-dithiol-3-one derivative, of general formula : see diagramm : EP0119895,P28,F1 in which - either R denotes a hydrogen or chlorine atom, A denotes an oxygen atom or an imino, alkylimino, alkylcarbonylimino or formylimino radical and Ar denotes a phenyl radical substituted by a cycloalkyl radical in which the alkyl part contains 3 to 7 carbon atoms, an alkenyl radical containing 2 to 4 carbon atoms as a straight or branched chain, an anilino, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl, 1,3-dioxolan-2-yl, dialkylaminomethyleneamino, trifluoromethylthio or alkylcarbonyloxy radical or an alkyl radical substituted by a hydroxy, alkoxy, carboxy, amino, alkylcarbonylamino, alkoxycarbonylamino, dialkylaminomethyleneamino, formamido, alkylureido, phenylsulphonyl, carbamoyl, alkylcarbamoyl, dialklylcarbamoyl, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl or 1,3-dioxolan-2-yl radical or Ar denotes a pyridyl, quinolyl, isoquinolyl, indanyl or quinoxalinyl radical, - or R denotes a hydrogen atom, A denotes an oxygen atom or an amino, alkylimino, alkylcarbonylimino or formylimino radical and Ar denotes a phenyl radical substituted by an alkyl radical, - or R denotes a chlorine atom, A denotes an oxygen atom or an alkylcarbonylimino or formylimino radical and Ar denotes a phenyol radical substituted by an alkyl radical, it being understood that, unless specially mentioned, all the alkyl radicals and alkyl moieties contain 1 to 4 carbon atoms as a straight or branched chain, as well as, where these exist, its salts of addition with acids, its metal salts and its salts of addition with organic bases, characterized in that a) for the preparation of a product of general formula (I) in which A denotes an oxygen atom or an imino or alkylimino radical, R denotes a chlorine atom and Ar is defined as above except for denoting a phenyl radical substituted by a dialkylamino-methyleneamino radical or an alkyl radical substituted by a dialkylaminomethyleneamino radical, a product of general formula : Ar-A-H in which Ar and A have the corresponding definition, is reacted with 4,5-dichloro-1,2-dithiol-3-one of formula : see diagramm : EP0119895,P28,F2 and the product obtained is then isolated and converted, if appropriate, into a salt of addition with an acid, into a metal salt or into a salt of addition with a nitrogenous base, or in that b) for the preparation of a product of general formula (I) in which A denotes an alkylimino radical and the other symbols are defined as above, a product of general formula : R1 X in which R1 denotes an alkyl radical and X denotes a halogen atom or a reactive ester residue such as mesyloxy or tosyloxy, is reacted with a product of general formula (I), in which A denotes an imino radical and the other symbols are defined as above, that is to say a product of general formula : see diagramm : EP0119895,P29,F3 and the product obtained is then isolated and is converted, if appropriate, into a salt of addition with an acid, into a metal salt or into a salt of addition with an organic base, or in that c) for the preparation of a product of general formula (I) in which A denotes an alkylcarbonylimino or formylimino radical and the other symbols are defined as above, a mixed anhydride of general formula : R2 COOCOCH3 in which R2 denotes a hydrogen atom or an alkyl radical, is reacted with a product of general formula (I) in which A denotes an imino radical and the other symbols are defined as above, that is to say a product of general formula : see diagramm : EP0119895,P29,F4 and the product obtained is then isolated and is converted, if appropriate, into a salt of addition with an acid, into a metal salt or into a salt of addition with a nitrogenous base, or in that d) for the preparation of a product of general formula (I) in which R denotes a hydrogen atom and the other symbols are defined as above, a product of general formula (I) in which R denotes a chlorine atom and the other symbols are defined as above, that is to say a product of general formula : see diagramm : EP0119895,P29,F5 is dechlorinated and the product obtained is then isolated and is converted, if appropriate, into a salt of addition with an acid, into a metal salt or into a salt of addition with a nitrogenous base, or in that e) for the preparation of a product of general formula (I), in which Ar denotes a phenyl radical substituted by a 1,3-dithiolan-2-yl or 1,3-dioxolan-2-yl radical or an alkyl radical substituted by a 1,3-dithiolan-2-yl or 1,3-dioxolan-2-yl radical and the other symbols are defined as above, a product of general formula : H-Y(CH2 )2 -Y-H in which the symbols Y both denotes a sulphur or oxygen atom, is reacted with a product of general formula (I), in which Ar denotes a phenyl radical substituted by a formyl radical or by an alkyl radical substituted by a formyl radical, that is to say a product of general formula : see diagramm : EP0119895,P29,F6 in which Q denotes a valency bond or an alkylene radical containing 1 to 4 carbon atoms as a straight or branched chain, and the other symbols are defined as above, and the product obtained is then isolated, or in that f) for the preparation of a product of general formula (I), in which Ar denotes a phenyl radical substituted by a dialkylaminomethyleneamino radical or by an alkyl radical substituted by a dialkylaminomethyleneamino radical and the other symbols are defined as above, a product of general formula : see diagramm : EP0119895,P29,F7 in which the radicals R3 , R4 , R5 and R6 denote alkyl radicals is reacted with a product of general formula (I), in which Ar denotes a phenyl radical substituted by an amino radical or by an alkyl radical substituted by amino radical, that is to say a product of general formula : see diagramm : EP0119895,P29,F8 in which Q denotes a valency bond or an alkylene radical containing 1 to 4 carbon atoms as a straight or branched chain and the other symbols are defined as above, and the product obtained is then isolated and is converted, if appropriate, into a salt of addition with an acid, or in that g) for the preparation of a product of general formula (I), in which Ar denotes a phenyl radical substituted by an alkyl radical which is itself substituted by an alkylcarbonylamino or alkoxycarbonylamino radical and the other symbols are defined as above, a product of general formula : R7 X1 in which R7 denotes an alkylcarbonyl or alkoxycarbonyl radical and X1 denotes a halogen atom, is reacted with a product of general formula (I), in which A denotes a phenyl radical substituted by an alkyl radical substituted by an amino radical and the other symbols are defined as above, that is to say a product of general formula : see diagramm : EP0119895,P30,F9 in which Q' denotes an alkylene radical containing 1 to 4 carbon atoms as a straight or branched chain and the other symbols are defined as above, and the product obtained is then isolated, or in that h) for the preparation of a product of general formula (I), in which Ar denotes a phenyl radical substituted by an alkyl radical substituted by a formamido radical and the other symbols are defined as above, an alkyl formate of general formula : HCOOR8 in which R8 denotes an alkyl radical, is reacted with a product of general formula (I), in which Ar denotes a phenyl radical substituted by an alkyl radical which is itself substituted by an amino radical, that is to say a product of general formula : see diagramm : EP0119895,P30,F10 in which Q' denotes an alkylene radical containing 1 to 4 carbon atoms as a straight or branched chain and the other symbols are defined as above, and the product obtained is then isolated, or in that i) for the preparation of a product of general formula (I), in which Ar denotes a phenyl radical which is itself substituted by an alkyl radical substituted by a ureido radical and the other symbols are defined as above, an isocyanate of general formula : OCNR9 in which R9 denotes an alkyl radical, is reacted with a product of general formula (I), in which Ar denotes a phenyl radical substituted by an alkyl radical which is itself subst

Description

X

DK 158734 B

The present invention relates to novel 1,2-dithiol-3-one derivatives of the general formula is (I) -Lo wherein R is hydrogen or chloro, A is oxygen or imino, alkylimino or formylimino, and Ar is phenyl substituted with a cycloalkyl group wherein the cycloalkyl moiety contains 3-7 carbon atoms, straight or branched alkenyl with 2-4 carbon atoms, anilino, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl, 1,3-dioxolan-2-yl, dialkylaminomethylene -15 amino, trifluoromethylthio or alkyl substituted with hydroxy, alkyloxy, carboxy, amino, alkylcarbonylamino, alkyloxy-carbonylamino, dialkylaminomethylenamino, formamido, alkyl ureido, phenylsulfonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, formkyl-carbamoyl 2-yl or 1,3-dioxolan-2-yl, or Ar is pyridyl, quinolyl, isoquinolyl, indanyl or quinoxalinyl, or R is hydrogen, A is oxygen, or imino, alkylimino or formylimino, and Ar is phenyl substituent R is chlorine, A is oxygen or formylimino, and Ar is phenyl substituted with an alkyl group, all of the alkyl groups and alkyl moieties mentioned above or mentioned below being straight or branched and containing 1 -4 carbon atoms, 30 or addition salts with acids, metal salts or addition salts with organic bases.

The compounds of general formula I wherein A is oxygen or imino or alkylimino, R is chloro and Ar has the meaning given above other than phenyl substituted by dialkylaminomethylenamino or alkyl substituted by dialkylaminomethylenamino can be prepared

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2

by reacting a compound of general formula II

Ar '- A' - Η (II)

wherein Ar 'has the same meaning as Ar defined in connection with the general formula I, except phenyl substituted with dialkylaminomethylenamino or alkyl substituted with dialkylaminomethylenamino, and A' is oxygen, imino or alkylamino, with 4,5-dichloro-1,2 -dithiol-3-one of formula III

ci __ / Sss 10 I (III) GI Lo

It is usually employed in an organic solvent such as an alcohol such as methanol, a ketone such as acetone 15 or dimethylformamide (preferably dimethylformamide when A means oxygen), in the presence of a small excess relative to the theoretical amount of an acid acceptor such as an alkene. -lime metal carbonate or hydrogen carbonate, such as potassium carbonate or hydrogen carbonate, or an organic base such as nitro-nitro-tris- (2-propanol), at a temperature between 0 and 80 ° C, preferably near 20 ° C.

4,5-Dichloro-1,2-dithiol-3-one can be prepared according to the method described by F. Boberg, Ann. Chem. 681. 169 (1965).

The compounds of the general formula II can be prepared using or adapting known methods which are readily apparent to one skilled in the art.

The compounds of general formula I wherein A is alkylimino and the other symbols have the meaning given above can be prepared by reacting a compound of general formula IV

RXX (IV) wherein R 1 represents an alkyl group and X represents a halogen atom or a residue of a reactive ester such as mesyloxy or tosyloxy, with a compound of the general formula I wherein A represents an imino group and the other symbols have

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3

the meaning given above, i.e. a compound of the general formula V

Ar - HH - / \ bJLLo <v> wherein Ar and R have the meaning given above.

The condensation of the compound of the general for flour IV with the compound of the general formula V is usually carried out in an organic solvent, such as acetonitrile, in the presence of a small excess of the theoretical amount of an alkaline condensing agent such as an alkali metal alcoholate. as sodium methylate, or an alkali metal hydride as sodium hydride, at a temperature between 15 and 60 ° C.

The compounds of general formula I wherein A represents formylimino and the other symbols having the meaning set forth above may be prepared by reacting a mixed anhydride with the general formula VI

HCOO COCH3 (VI) having a compound of the general formula V.

The reaction is usually carried out in an organic solvent, such as pyridine, at a temperature between 0 and 20 ° C.

The compounds of general formula I wherein R is a hydrogen atom and the other symbols have the meaning set forth above can be prepared by the dechlorination of a compound of general formula I wherein R is a chlorine atom and the other symbols have the above meaning given, ie. a compound of general formula VII

A

Ar-A— / S (VII)

C i_Uo

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4 wherein Ar and A have the meaning given above.

Dechlorination can be carried out by any method known to those skilled in the art to remove a chlorine atom without affecting the rest of the molecule. It is particularly advantageous to carry out the reaction by at least one mole of a trialkyltin hydride, such as tributyltin hydride, at a temperature near 20 ° C.

The compounds of general formula I wherein Ar means phenyl substituted with 1,3-dithiolan-2-yl, 1,3-10 dioxolan-2-yl or alkyl substituted with 1,3-dithiolan-2-yl or 1.3 -dioxolan-2-yl, and the other symbols having the meaning given above, can be prepared by reacting a compound of the general formula VIII

h-y- (ch 2) 2-y-h (VIII) wherein the symbols Y both represent an oxygen atom or a

sulfur atom, with a compound of general formula I wherein Ar means phenyl substituted with formyl or alkyl substituted with formyl, i. a compound of general formula IX

OHC-Q π H 1 - n wherein Q means a valence bond or a straight or branched alkylene group of 1-4 carbon atoms and A and R have the meaning given above.

The reaction is usually carried out in a chlorinated solvent, such as chloroform, in the presence of a catalytic amount of p-toluenesulfonic acid at a temperature between 30 ° C and the reflux temperature of the reaction mixture.

The compounds of general formula I wherein Ar means phenyl substituted by dialkylaminomethylenamino or alkyl substituted by dialkylaminomethylenamino, and the other symbols having the meaning given above, can be prepared by reacting a compound of general formula X

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5

Ri .OR5 (X) + N-CHC, R4 ^ XOR6

Wherein R 3, R 4, R 5 and R 6 are alkyl groups, with a compound similar to the general formula I, but wherein Ar is phenyl substituted with amino or alkyl substituted with amino, i. a compound of general formula XI

h2h-q -, 1 L «(XI) wherein Q means a valence bond or a straight or branched alkylene group of 1-4 carbon atoms and A and R have the meaning given above.

The reaction is usually carried out without solvent or in organic solvent, such as an alcohol (ethanol), a chlorinated solvent (methylene chloride) or dimethylformamide, at a temperature between 20 and 80 ° C.

The compounds of general formula I wherein Ar means phenyl substituted with alkyl substituted by alkylcarbonylamino or alkyloxycarbonylamino and the other symbols having the meaning given above, can be prepared by reacting a compound of general formula XII

R7X1 (XII)

wherein R7 is alkylcarbonyl or alkyloxycarbonyl, and X1 is halogen, with a compound of general formula I wherein Ar is phenyl substituted with alkyl substituted by amino and the other symbols have the meaning given above, i. a compound of general formula XIII

S

jT / A (l f (xiii) 35 -, Μ Lo

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6 wherein Q 'is a straight or branched alkylene group of 1-4 carbon atoms and A and R have the meaning given above.

The reaction is usually carried out in a solvent, such as pyridine, at a temperature between -20 and + 80 ° C.

The compounds of general formula I wherein Ar represents phenyl substituted by alkyl substituted by formamido and the other symbols having the meaning given above can be prepared by reacting an alkyl formate of general formula XIV

H-COO-R8 (XIV) wherein R8 represents an alkyl group, with a compound of the general parent XIII.

The reaction is usually carried out in an excess of alkyl formate of the general formula XIV at a temperature between 0 and 60 ° C.

The compounds of general formula I wherein Ar represents phenyl substituted by alkyl substituted by ureido and the other symbols having the meaning given above can be prepared by reacting an isocyanate of general formula XV

OCNR9 (XV) wherein R9 represents an alkyl group, with a compound of the general formula XIII.

The reaction is usually carried out in an organic solvent, such as a chlorinated solvent such as methylene chloride, at a temperature between 0 and 60 ° C.

The novel compounds of general formula 30I may be purified by conventional methods such as crystallization, chromatography or, where appropriate, successive extractions in acidic or basic medium.

The novel compounds of general formula I wherein the substituent Ar carries an amine function as defined above may optionally be converted to addition salts with acids by reaction with an acid in an organic solvent.

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7 such as an alcohol, a ketone, an ester or a chlorinated solvent. The salt precipitates, possibly after concentration of the solution, and is separated by filtration or decantation.

By analogy, the compounds of general formula I wherein Ar carries an acidic function as defined above can optionally be converted to metal salts or addition salts with organic bases.

It will be appreciated by those skilled in the art that, by using the methods described above, it may be necessary to introduce protecting groups for the functions present in the group Ar to avoid secondary reactions before one or other of the methods is initiated. The protecting group may subsequently be retained or removed depending on whether the compound prepared is a compound of the invention or not. Thus, when the group Ar carries an aldehyde function, it is advantageous to protect this function in e.g. form of a semicarbazone and then, if desired, remove the protecting group in alcoholic medium in the presence of copper sulfate. Likewise, when Ar carries an amino or alkylamino function, it is necessary to protect these functions by e.g. a tert-butyloxycarbonyl group and then releasing the amino function in acidic aqueous medium such as hydrochloric acid or, better yet, an acetic acid solution of hydrogen chloride gas. When Ar means a group carrying an acidic function, it is advantageous to protect this function in the form of e.g. an ester, such as an ethyl ester or a tert.butyl ester, and then release the acidic function by hydrolysis in acidic medium, e.g. hydrochloric acid or, which is better, an acetic acid solution of hydrogen chloride gas.

It is already known from DE patent specification no.

No. 1,242,324 and No. 1,278,701 and from Appendix No. 94,485 to U.S. Patent No. 1,498,374 1,2-dithiol-3-one derivatives of the general formula (A) 35

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8

* 1 / S

^ - W S

R2- (I) A3JJ-bo wherein R3 may be hydrogen or chlorine. Thus, these compounds 5 are different from the compounds of formula I. When R 2 is hydrogen, then R 2 is either non-aromatic (as opposed to the compounds of formula I) or a phenyl group substituted differently from the compounds of formula I. the compounds of formula (A) are stated to be fungicidal and bactericidal, while the compounds of formula I are effective against rheumatic diseases.

The novel compounds of the invention and their salts exhibit interesting pharmacological properties which make them suitable for use in the basic treatment of rheumatic diseases. They have been found to be active in concentration near 5 x 10-6 M in the sample to measure the activation of macrophages in vitro performed according to the method described by J. Schnyder and M. Baggiolini, J. Exp. With.

No. 148/1449 (1978).

In addition, the compounds of the general formula I exhibit low toxicity. Their DL50 is usually above 900 mg / kg by single administration by oral route to mice.

For medical use, the compounds of the invention can be used as they are or in the form of pharmaceutically acceptable salts, i.e. salts that are non-toxic in the doses used.

As pharmaceutically acceptable salts, there may be mentioned addition salts with inorganic acids such as hydrogen chlorides, sulfates, nitrates or phosphates, or with organic acids such as acetates, propionates, succinates, benzoates, fumarates, theophylline acetates, salicylates, phenolphthalein esters, methylene bis / 3-oxynaphthoates or substitution derivatives of these compounds. Further, as pharmaceutically acceptable salts may be mentioned salts with alkali metals such as sodium, potassium or lithium, alkaline earth metals such as calcium and magnesium, and addition salts with organic

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9 bases, such as salts of ethanolamine and lysines.

The present invention also relates to pharmaceutical compositions characterized in that they contain at least one compound of formula I or a salt thereof as defined above together with one or more compatible and pharmaceutically acceptable diluents or excipients.

In these compositions, the compound is associated with any other pharmaceutically compatible product which may be inert or physiologically active. The pharmaceutical compositions of the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (especially in gelatin capsules or cachets) or granules may be used. In these compositions, the active substance of the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica. These compositions may also comprise substances other than diluents, e.g. one or more lubricants, such as magnesium stearate or talc, a dye, a coating (coating) or a varnish.

As liquid preparations for oral administration, solutions, suspensions, emulsions, syrups 25 and elixirs which are pharmaceutically acceptable can be used and contain inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may also comprise substances other than diluents, e.g. wetting agents, sweeteners, diluents, 30 flavors or stabilizers.

Sterile preparations for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As the solvent or carrier, water, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, e.g. ethyl oleate, or other suitable

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10 organic solvents. These compositions may also contain adjuvants, particularly wetting agents, isotonicity agents, emulsifiers, dispersants and stabilizers. Sterilization can be performed in several ways, e.g. by sterile filtration, incorporation of sterilizing agents into the composition, irradiation or heating. The compositions may also be prepared in the form of solid sterile preparations which may be dissolved in a sterile injectable medium at the time of use.

The compositions for rectal use are suppositories or rectal capsules which contain, in addition to the active substance, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical application may e.g. be 15 creams, ointments, lotions, eye water, mouthwash, nasal drops or aerosols.

In the field of human therapy, the compounds of the invention are particularly useful for the basic treatment of rheumatic diseases. The doses depend on the desired effect and duration of treatment. They are generally between 50 and 1000 mg per day. day by oral administration to an adult in one or more portions.

As usual, the physician will determine the most appropriate dosage depending on the patient's age, body weight and other relevant factors.

The following examples illustrate compositions of the invention.

Example A

Generally, tablets are prepared with 50 mg of active substance having the following composition: 2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) - 50 mg -4-amino-phenyl] -propionamide starch 60 mg 35 lactose 50 mg magnesium stearate 2 mg

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Example B

An injectable solution containing 20 mg of active substance is prepared and has the following composition: 5- [4- (1-amino-2-propyl) phenylamino] - 22.4 mg of 5 -4-chloro-1,2-dithiol -3-one hydrochloride distilled water qsp 2 ml

The preparation of the compounds of the invention is illustrated by the following examples.

10

Example 1

To a suspension of 3.74 g of 4,5-dichloro-1,2-dithiol-3-one and 2.2 g of potassium hydrogen carbonate in 30 ml of methanol is added 2.92 g of 4-cyclopropylaniline. After stirring for 20 hours at a temperature near 20 ° C, 60 ml of distilled water is added to the reaction mixture. The insoluble product is separated by filtration and washed 3 times with a total of 30 ml of distilled water.

Recrystallization of the product thus obtained from 75 ml of ethyl acetate gives 3.8 g of 4-chloro-5- (4-cyclopropyl-phenyl-amino) -1,2-dithiol-3-one, m.p. 154 "C.

Example 2

To a suspension of 7 g of 4,5-dichloro-1,2-dithiol-3-one and 3.7 g of potassium hydrogen carbonate in 80 ml of methanol is added 5.5 g of 4-cyclobutylaniline. After stirring for 20 hours at a temperature near 20 ° C, 80 ml of distilled water is added to the reaction mixture. The resulting emulsion is extracted twice with a total of 160 ml of methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting product is then dissolved in 50 ml of methylene chloride and the resulting solution is poured onto 300 g of alumina gel in a column of 35 mm diameter.

ISLAND

12

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4.5 cm. First elute with 300 ml of methylene chloride and discard the eluate. The mixture is then eluted with 500 ml of methylene chloride and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Recrystallization of the residue thus obtained from 18 ml of acetonitrile gives 3.6 g of 4-chloro-5- (4-cyclobutyl-phenylamino) -1,2-di-thiol-3-one, m.p. 100 ° C.

4-Cyclobutylaniline can be prepared by hydrogenolysis of 14 g of 4- (1-hydroxy-cyclobutyl) -aniline dissolved in 70 10 ml of ethanol in the presence of 4.3 g of 10% palladium on carbon under a pressure of 310 kPa at a temperature near 20 ° C for 20 hours. After filtering off the catalyst, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting product is then dissolved in 20 ml of methylene chloride and the resulting solution is poured onto 300 g of alumina gel in a column of 3.4 cm diameter. Elute with 200 ml of a mixture of methylene chloride and cyclohexane in the 70:30 volume ratio and discard the eluate. The same mixture is then eluted with 500 ml of 20 and the eluate concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 5.5 g of 4-cyclobutylaniline in the form of a brown oil having an Rf value of 0.5 are obtained by thin layer chromatography on alumina gel with a mixture of methylene chloride and cyclohexane in the ratio of 70:30.

4- (1-Hydroxy-cyclobutyl) -aniline can be prepared as follows. 31.6 g of 4-bromo-N, N-bis (trimethylsilyl) aniline dissolved in 100 ml of ethyl ether are treated for 24 hours at a temperature near 20 ° C with 62 ml of a 1.6M solution of butyllithium in hexane. To the resulting solution is added at -10 ° C a solution of 7 g of cyclobutanone in 70 ml of ethyl ether, then stirred for 2 hours at a temperature near 20 ° C. The reaction mixture is then hydrolyzed with 210 ml of a 10% aqueous ammonium chloride solution.

The organic phase is extracted with 100 ml of 2N hydrochloric acid and the aqueous phase is washed twice with a total of 100 ml of ethyl acetate.

ISLAND

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13 ether, then basified to a pH of 8 by the addition of 4N aqueous sodium hydroxide solution. The resulting emulsion is extracted with 100 ml of ethyl ether and the organic phase is washed twice with a total of 200 ml of distilled water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 g of 4- (1-hydroxy-cyclobutyl) -aniline in the form of a brown oil having an Rf value of 0.36 is obtained by thin layer chromatography on silica gel with a mixture of methylene chloride 10 and methanol in a 95: 5 volume ratio as solvent.

Example 3

Proceeding in the same manner as in Example 1, but starting from 11.2 g of 4,5-dichloro-1,2-dithiol-3-one and 10.6 g of 4-cyclopentylaniline, is obtained after recrystallization. from ethanol 14.8 g of 4-chloro-5- (4-cyclopentyl-phenylamino) -1,2-dithiol-3-one, m.p. 119 ° C.

4-Cyclopentylaniline can be prepared according to P.V.

Hai, N.P. Buu-Hoi and N.D. Xuong, J. Org. Chem. 23 ^ 39 20 (19 5 8).

Example 4

Proceeding in the same manner as in Example 2 but starting from 5.6 g of 4,5-dichloro-1,2-dithiol-3-one and 4.9 g of 3-cyclopentylaniline, 9.8 are obtained. g of an oily crude product. This product is dissolved in 50 ml of methylene chloride and the resulting solution is poured onto 200 g of silica gel in a column with a diameter of 3.8 cm. First elute with 600 ml of methylene chloride and discard the eluate. It is then eluted with 1800 ml of methylene chloride and the eluate concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Recrystallization of the product thus obtained from a mixture of ethyl acetate and isopropyl ether in the 1: 2 volume ratio gives 4 g of 4-chloro-5- (3-cyclopentyl-35-phenylamino) -1,2-dithiol-3-one, m.p. 74 ° C.

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ISLAND

3- Cyclopentylaniline can be prepared in the same manner as described in Example 2 for the preparation of 4-cyclobutylaniline.

From 34 g of 3-bromo-N, N-bis (trimethylsilyl) -aniline and 9.1 g of cyclopentanone are obtained 5 g of 3-cyclopentylaniline in the form of a yellow oil used as it is at the o-friend of described synthesis.

Example 5 Proceeding in the same manner as in Example 1, but starting from 9.4 g of 4,5-dichloro-1,2-dithiol-3-one and 8.8 g of 4-cyclohexylaniline, is obtained. after recrystallization from acetonitrile 11 g of 4-chloro-5- (4-cyclohexyl-phenylamino) -1,2-dithiol-3-one, m.p. 160 ° C.

15

Example 6

Proceeding in the same manner as in Example 1, but starting from 7.4 g of 4,5-dichloro-1,2-dithiol-3-one and 7.5 g of 4-cycloheptylaniline, after recrystallization 20 acetonitrile 7.4 g of 4-chloro-5- (4-cycloheptyl-phenylamino) -1,2-dithiol-3-one, m.p. 160 ° C.

4- Cycloheptylaniline can be prepared in the same manner as described in Example 2 for the preparation of 4-cyclobutylaniline. From 22.2 g of 4-bromo-N, N-bis (trimethylsilyl) -25-aniline and 7.9 g of cycloheptanone are obtained 9.7 g of 4-cycloheptylaniline in the form of a brown oil used as it is in the synthesis described above.

Example 7 To a suspension of 15.6 g of 4-chloro-5- (4-cyclopeptyl-phenylamino) -1,2-dithiol-3-one prepared as in Example 3 in 200 ml of acetonitrile is added 4.1 g sodium methylate, after which the resulting suspension is stirred for 1 hour at a temperature near 20 ° C. Then 12.1 g and methyl iodide are added and stirred for 20 hours at a temperature near 20 ° C.

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The reaction mixture is then slowly poured into 2000 ml of distilled water and then extracted once with 500 ml and then twice with a total of 500 ml of ethyl ether.

The organic phases are combined and dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 60 ° C. The resulting oily residue is dissolved in 30 ml of methylene chloride and the resulting solution is poured onto 330 g of silica gel in a 4.5 cm diameter column. First elute with 500 ml of methylene chloride and discard the eluate. The mixture is then eluted with 700 ml of methylene chloride and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the resulting product from 50 ml of cyclohexane, 4.9 g of 4-chloro-5- (N-methyl-4-cyclopentyl-phenyl-amino) -1,2-dithiol-3-one is obtained, m.p. 73 ° C.

Example 8

Proceeding in the same manner as in Example 1, but starting from 9.4 g of 4,5-dichloro-1,2-dithiol-3-one and 10.8 g of 2- (4-aminophenyl) -1 3-Dithiolane, after recrystallization from a mixture of dimethylformamide and water in the 90:10 volume ratio, is obtained 10.1 g of 4-chloro-5- [4- (1,3-dithiolan-2-yl) phenylamino] -1,2-dithiol-3-one, m.p. 198 ° C.

2- (4-Aminophenyl) -1,3-dithiolane can be prepared as follows. To a suspension of 22.7 g of 2- (4-nitro-phenyl) -1,3-dithiolane and 42 g of iron powder in 250 ml of ethanol with 20% water is added with stirring at 60 ° C 3 ml of concentrated hydrochloric acid (d = 1 , 19). The reaction mixture is then heated to reflux for 30 minutes. The reaction mixture is then filtered hot and the filtrate concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. The resulting residue is dissolved in 250 ml of methylene chloride and the resulting solution is washed with 100 ml of 0.3N aqueous sodium hydroxide solution and then twice with a total of 100 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness while reducing.

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pressure (2.7 kPa) at 80 ° C. 18 g of 2- (4-aminophenyl) -1,3-dithiolane are obtained in this way, m.p. 69 ° C.

2- (4-Nitrophenyl) -1,3-dithiolane can be prepared by refluxing a suspension of 5 75.5 g of 4-nitrobenzaldehyde in 500 ml of methylcyclohexane containing 65.8 g of 1,2-ethanedithiol and 5 ml. boron trifluoride etherate for 3.5 hours while removing the water formed by azeotropic distillation. The resulting solution is then cooled to a temperature near 20 ° C and the insoluble product removed by filtration, washed twice with a total of 100 ml of methylcyclohexane and then dissolved in 500 ml of methylene chloride. The resulting solution is washed twice with a total of 500 ml of 1 N aqueous sodium hydroxide solution and then 3 times with a total of 600 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 80 ° C. 112 g of 2- (4-nitrophenyl) -1,3-dithiolane are thus obtained with m.p.

78 ° C.

Example 9

Proceeding in the same manner as in Example 1 but starting from 66.1 g of 4,5-dichloro-1,2-dithiol-3-one and 69.2 g of 4-aminobenzaldehyde semicarbazone, there is obtained after recrystallization from methanol 53.1 g of 4-chloro-5- (4-semi-carbazonomethyl-phenylamino) -1,2-dithiol-3-one, m.p.

193 ° C.

4-Aminobenzaldehyde semicarbazone can be prepared by catalytic hydrogenation of 104 g of 4-nitrobenzaldehyde - semicarbazone in ethanol in the presence of 3% palladium on 30 carbon at a temperature near 25 ° C under a pressure near 100 kPa for 2 hours. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 60 ° C. The residue thus obtained is washed with 100 ml of ethanol. After drying under reduced pressure (2.7 kPa), 69.3 g of 4-amino-benzaldehyde semicarbazone are obtained, m.p. 124 ° C.

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Example 10

Proceed as in Example 9, and then the aldehyde function for its protecting group is released as follows.

A solution of 36.4 g of 4-chloro-5- (4-semicarbazonomethyl-phenylamino) -1,2-dithiol-3-one and 138.2 g of copper sulphate pentahydrate in a mixture of 1850 ml of methanol, 1850 ml of tetrahydrofuran and 3700 ml of distilled water are heated to reflux for 5 hours. The resulting suspension is poured into 5000 ml of ethyl acetate and the aqueous phase is quenched. The organic phase is washed with a total of 3000 ml of distilled water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. In this way, 22.8 g of residue is obtained, which is then absorbed on 100 g of silica gel. The resulting mixture is deposited on 600 g of silica gel in a 5.5 cm diameter column. First elute with 6000 ml of methylene chloride and discard the eluate. It is then eluted with 7000 ml of methylene chloride and the eluate is concentrated to 20 dryness under reduced pressure (2.7 kPa) at 40 ° C. Recrystallization of the resulting residue from acetonitrile gives 6.5 g of 4-chloro-5- (4-formyl-phenylamino) -1,2-dithiol-3-one, which melts at 218 ° C with decomposition. 1 2 3 4 5 6 7 8 9 10 11

Example 11 2

A suspension of 5.7 g of 4-chloro-5- (4-formyl-phenylamino) -1,2-dithiol-3-one in 600 ml of chloroform contains 4 0.2 g of p-toluenesulfonic acid and 1, 43 g of ethylene glycol 5 is heated under reflux for 3 hours, removing the formed 6 water by azeotropic distillation. After cooling to 7 a temperature near 20 ° C, the reaction mixture is washed with 100 8 ml of distilled water, then the organic phase 9 is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the residue from methanol, 2.8 g of 4-chloro-5- [4- (1,3-dioxolan-2-yl) phenylamino] -1,2-dithiol-3-one is obtained. with m.p. 168 ° C.

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Example 12

Proceeding in the same manner as in Example 1, but starting from 4.88 g of 4,5-dichloro-1,2-dithiol-3-one and 4.8 g of 4-amino-diphenylamine, is obtained after recrystallisation. 5.5 g of acetonitrile, 4.9 g of 4-chloro-5- (4-phenylamino-phenylamino) -1,2-dithiol-3-one, m.p. 186 ° C.

4-Aminodiphenylamine can be prepared by catalytic hydrogenation of 6.8 g of 4-nitro-diphenylamine in ethanol in the presence of 0.3 g of 10% palladium on carbon at a temperature near 25 ° C under a pressure near 100 kPa for 1 hour. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. This gives 5.8 g of 4-amino-diphenylamine in the form of a violet blue oil having a 15 Rf value of 0.50 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the 90:10 volume ratio as eluent.

Example 13 Proceeding in the same manner as in Example 1, but starting from 30 g of 4,5-dichloro-1,2-dithiol-3-one and 21 g of 4-amino styrene, is obtained after recrystallization from acetonitrile 6.4 g of 4-chloro-5- (4-vinyl-phenylamino) -1,2-di-thiol-3-one, m.p. 185 ° C.

The 4-amino styrene can be prepared according to the method described by A.M. Shur and N.A. Barba, Chem. Abstr. 64, P 3383 h.

Example 14 Proceed as in Example 13 but replace the 4-amino styrene with 4- (2-propenyl) aniline. After recrystallization from isopropyl ether, 4-chloro-5- [4- (2-propenyl) phenylamino] -1,2-dithiol-3-one is obtained, m.p. 129 ° C.

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Example 15

Proceeding in the same manner as in Example 2, but starting from 65 g of 4,5-dichloro-1,2-dithiol-3-one and 57.6 g of 4- (1-hydroxy-1-methyl-ethyl) ) -aniline, 117 g of crude product 5 is obtained in the form of a red oil. This product is dissolved in 250 ml of methylene chloride and the resulting solution is poured onto 2500 g of silica gel in a 9 cm diameter column. First, elute with 16 liters of a mixture of methylene chloride and ethyl acetate in the volume ratio of 85:15 and discard the eluate 10. The mixture is then eluted with 5 liters of a mixture of methylene chloride and ethyl acetate in the volume ratio of 70:30, and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from acetonitrile, 5.1 g of 4-chloro-5- [4- (1-hydroxy-1-15-methyl-ethyl) -phenylamino] -1,2-dithiol-3-one is obtained, m.p.

162 ° C.

4- (1-Hydroxy-1-methyl-ethyl) -aniline can be prepared by adding a solution of 54 g of 4-aminoacetophenone in 1000 ml of tetrahydrofuran to 1000 ml of a 1.2M solution of methyl magnesium iodide in tetrahydrofuran which kept at a temperature near 5 ° C. The resulting suspension is then stirred overnight at a temperature near 20 ° C and then poured into 5000 ml of saturated aqueous ammonium chloride solution. The organic phase is separated by decantation and the aqueous phase is extracted 3 times with a total of 3000 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 57.6 g of 4- (1-hydroxy-1-methyl-ethyl) -aniline in the form of a brown oil having an Rf value of 0.37 are obtained by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the 50:50 volume ratio as eluent.

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Example 16

Proceeding in the same manner as in Example I but starting from 13.1 g of 4,5-dichloro-1,2-dithiol-3-one and 9.6 g of 4-amino-benzyl alcohol, there is obtained after recrystallization 5 g of acetonitrile 4.5 g of 4-chloro-5- (4-hydroxymethyl-phenylamino) -1,2-dithiol-3-one, m.p. 168 ° C.

Example 17

To a suspension of 6 g of potassium hydrogen carbonate 10 and 10.1 g of 4,5-dichloro-1,2-dithiol-3-one in 75 ml of methanol is added 8.2 g of 2- (4-aminophenyl) ethanol. The reaction mixture is stirred at a temperature near 20 ° C for 20 hours, after which 75 ml of distilled water is added. The resulting emulsion is extracted with 75 ml of methylene chloride and the organic phase is washed with 20 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the product thus obtained from a mixture of ethyl acetate and isopropyl ether in 50:50 volume ratio, 5.3 g of 4-chloro-5- [4- (2-hydroxyethyl) phenylamino] -1,2- dithiol-3-one with m.p. 99 ° C.

2- (4-Aminophenyl) ethanol can be prepared by catalytic hydrogenation of 10 g of 2- (4-nitrophenyl) ethanol in 300 ml of ethanol in the presence of 0.9 g of 3% palladium on 25 carbon at a pressure close to 100 kPa for 14 hours at a temperature near 20 ° C. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 8.2 g of 2- (4-aminophenyl) ethanol are thus obtained with m.p. 109 ° C.

30

Example 18

Proceeding in the same manner as in Example 2 but starting from 10 g of 4,5-dichloro-1,2-dithiol-3-one and II, 35 g of 3-trifluoromethylthio-aniline stallization from a mixture of isopropyl ether and ethyl acetate in the 60:40 volume ratio 3.6 g of 4-chloro-5- (3-trifluoromethylthio-phenylamino) -1,2-dithiol-3-one, m.p.

160 ° C.

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Example 19

Proceeding in the same manner as in Example 2, but starting from 7.5 g of 4,5-dichloro-1,2-dithiol-3-one and 10.9 g of (4-aminobenzyl) phenylsulfone, after recrystallization from acetonitrile 2.2 g of 4-chloro-5- [(4- -phenylsulfonylmethyl) -phenylamino] -1,2-dithiol-3-one, m.p. 186 ° C.

(4-Aminobenzyl) phenylsulfone can be prepared according to the method described by W.R. Waldron and E.E. Reid, 10 J. Am. Chem. Soc. £ 5, 2399 (1923).

Example 20

A solution of 20.5 g of 3 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] -butyric acid ethyl ester in 360 ml of acetic acid containing 57.5 ml of 18N Sulfuric acid is heated at reflux for 30 minutes. The reaction mixture is cooled to a temperature near 20 ° C and poured into 1200 ml of distilled water. The insoluble product is separated by filtration and dried in the air at a temperature close to 20 ° C.

After recrystallization from ethanol, 10.1 g of 3 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] -butyric acid is obtained, m.p. 210 ° C.

3 - [(4-Chloro-3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -butyric acid ethyl ester can be prepared by proceeding in the same manner as in Example 1, but starting from 18.7 g of 4,5-dichloro-1,2-dithiol-3-one and 22.8 g of 3- (4-aminophenyl) -butyric acid ethyl ester. There is thus obtained 31.1 g of 3 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -butyric acid ethyl ester, m.p. 98 ° C.

3- (4-Aminophenyl) -butyric acid ethyl ester can be prepared by catalytic hydrogenation of 95.8 g of 3- (4-nitro-phenyl) -butene-2-acid ethyl ester in 3200 ml of ethanol in the presence of 3.7 g 10% palladium on carbon under a pressure near 100 kPa at a temperature near 25 ° C for 45 minutes. After separation of the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 83.4 g are thus obtained

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3- (4-Aminophenyl) -butyric acid ethyl ester in the form of a brown oil having an Rf value of 0.47 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate at 90:10 volume as eluent.

3- (4-Nitrophenyl) -butene-2-acid ethyl ester can be prepared by dropwise addition of 134.4 g of diethylphosphonoacetic acid ethyl ester dissolved in 200 ml of 1,2-dimethoxyethane to a suspension of 14.4 g sodium hydride in 300 ml of 1,2-dimethoxyethane at a temperature near 10 ° C. Then a solution of 99 g of 4-nitro-acetophenone in 500 ml of 1,2-dimethoxyethane is then added dropwise at a temperature near 10 ° C, then stirred for 3 hours at a temperature near 20 ° C. The reaction mixture is then poured into 3000 ml of distilled water and extracted 3 times with a total of 1500 ml of methylene chloride. The organic phases are combined and washed with 500 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting residue is dissolved in 100 ml of methylene chloride and the resulting solution is poured onto 1500 g of silica gel in a 7.5 cm diameter column.

First elute with 3400 ml of methylene chloride and discard the eluate. The mixture is then eluted with 5000 ml of methylene chloride and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 95.8 g of 3-25 - (4-nitrophenyl) -butene-2-acid ethyl ester in the form of a brown oil [IR spectrum (maximum at cm 2): 1720 and 1130 (CCXX ^), 1525 and 1345 (-NC2 / aromatic), 1635 (conjugated double bond)]. 1 2 3 4 5 6

Example 21 2

Proceeding in the same manner as in Examples 1, 3 but starting from 6.7 g of 4,5-dichloro-1,2-dithiol-3-one and 4 6.5 g of 3- (4-aminophenyl) - 1-methoxy-butane, after about 5 crystallization from cyclohexane 7.5 g of 4-chloro-5- [4- (1-6-methoxy-3-butyl) phenylamino] -1,2-dithiol-3 is obtained. on with m.p. 95 ° C.

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3- (4-Aminophenyl) -1-methoxy-butane can be prepared as follows. A suspension of 17.3 g of 1-methoxy-3- (4-tritylamino-phenyl) -butane in 350 ml of methanol containing 5.3 ml of concentrated hydrochloric acid (d = 1.19) is stirred at a temperature near 20 ° C. for 20 hours. The reaction mixture is then poured into 1500 ml of distilled water, and the resulting mixture is acidified to a pH of 2 by the addition of 4N hydrochloric acid and then extracted 3 times with a total of 750 ml of ethyl ether. The aqueous phase is made basic 10 to a pH of 9 by the addition of 4N aqueous sodium hydroxide solution and then extracted twice with a total of 400 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 15 g of 3- (4-aminophenyl) -1-methoxy-butane is obtained in the form of an orange oil having an Rf of 0.5 by thin-layer chromatography on silica gel with a mixture of leach chloride and ethyl acetate in the 90:10 volume ratio as eluent.

20-Methoxy-3- (4-tritylamino-phenyl) -butane can be prepared by adding 1.8 g of sodium hydride to a solution of 27.7 g of 3- (4-tritylamino-phenyl) -butanol and 11.4 g methyl iodide in 40 ml of 1,2-dimethoxyethane at a temperature near 20 ° C. The reaction mixture is stirred for 20 hours at a temperature close to 20 ° C and then concentrated to dryness under a pressure close to 100 kPa at a temperature of 100 ° C. The resulting solid is washed 4 times with a total of 400 ml of distilled water, dried in the air at a temperature close to 20 ° C and then recrystallized from a mixture of isopropyl ether and ethyl acetate in a 75:25 volume ratio. 17.3 g of 1-methoxy-3- (4-tritylamino-phenyl) -butane are thus obtained, m.p. 141 ° C.

3- (4-Tritylamino-phenyl) -butanol can be prepared as follows. A solution of 35.2 g of 3- (4-trityl-35-amino-phenyl) -butyric acid ethyl ester in 60 ml of tetrahydrofuran is added dropwise to a suspension of 5.1 g of potassium borohydride.

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and 4 g of lithium chloride in 80 ml of tetrahydrofuran at a temperature near 20 ° C. The reaction mixture is then stirred at reflux for 6 hours, then cooled to a temperature near 10 ° C. Then 70 ml of distilled water is added, the mixture is acidified to a pH near 3 by the addition of 10 ml of concentrated hydrochloric acid (d = 1.19) and finally it is made basic by the addition of 15 ml of 3.3N aqueous sodium hydroxide solution. The organic phase is decanted, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After washing the residue with 120 ml of petroleum ether and drying under reduced pressure (2.7 kPa), 27.7 g of 3- (4-trityl-amino-phenyl) -butanol are obtained with m.p. 114 ° C.

3- (4-Tritylamino-phenyl) -butyric acid ethyl ester can be prepared as follows. A solution of 10.1 g of triethylamine in 20 ml of dimethylformamide is added dropwise to a solution of 20.7 g of 3- (4-aminophenyl) -butyric acid ethyl ester and 28.8 g of triphenylmethyl chloride in 80 ml of dimethylformamide at a temperature close to 30 ° C. The reaction mixture is stirred for 20 hours at a temperature near 20 ° C, then poured into 1000 ml of distilled water and the resulting emulsion is extracted with 350 ml of chloroform. The organic phase is washed with 50 ml of distilled water, dried over magnesium sulfate, filtered and concentrated under reduced pressure 25 (0.7 kPa) at 60 ° C. After washing the residue with 60 ml of methanol and drying, 35.2 g of 3- (4-tritylamino-phenyl) -butyric acid ethyl ester are obtained with m.p. 130 ° C.

Example 22 Proceeding in the same manner as in Example 17, but starting from 12.9 g of 4,5-dichloro-1,2-dithiol-3-one and 15.3 g of tert-butyl-4-aminobenzylcarbamate , there is obtained 25.3 g of tert.butyl-4 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) amino] benzylcarbamate, m.p. 80 ° C.

35 To release the amine function from its protecting group, proceed as follows. 250 ml of one

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2N solution of gaseous hydrogen chloride in acetic acid is added dropwise over 30 minutes to the above-prepared tert.butyl - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-amino] - benzylcarbamate. The resulting suspension 5 is stirred for 6 hours at a temperature close to 20 ° C, after which the insoluble product is separated by filtration, washed 3 times with a total of 120 ml of isopropyl ether and then dried under reduced pressure (2.7 kPa). After recrystallization from water, 5.4 g of 5- (4-aminomethyl-phenylamino) -10 -4-chloro-1,2-dithiol-3-one hydrochloride is obtained, m.p. 291 ° C.

Tert.buty1-4-aminobenzylcarbamate can be prepared by catalytic hydrogenation of 18.1 g of tert.butyl-4-nitrobenzylcarbamate in 650 ml of ethanol in the presence of 0.75 g of 10% palladium on carbon under a pressure near 105 kPa. at a temperature near 25 ° C for 45 minutes. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 15.4 g of tert-butyl-4-aminobenzylcarbamate are thus obtained with m.p. 77 ° C.

Tert.butyl-4-nitrobenzylcarbamate can be prepared by adding, within 30 minutes, 14.2 g of ditert.butyldicarbonate dissolved in 35 ml of ethyl acetate to a suspension of 12.3 g of 4-nitrobenzylamine hydrochloride in 65 ml of ethyl acetate containing 6.6 g of triethylamine. The reaction mixture is stirred for 16 hours at a temperature close to 20 ° C and then poured into 100 ml of distilled water. The organic phase is decanted, washed 3 times with a total of 150 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

In this way, 15.7 g of tert-butyl-4-nitrobenzyl carbamate are obtained with m.p. 110 ° C.

Example 23

Proceeding in the same manner as in Examples 1, 35 but starting from 104.5 g of 4,5-dichloro-1,2-dithiol-3-one and 132.2 g of tert-butyl-2- (4- aminophenyl) ethylcarbamate, available

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containing 150.6 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] ethylcarbamate, m.p. 147 ° C.

To release the amine function from its protecting group, proceed in the same manner as in Examples 22, 5 but proceed from 38.6 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol 5-yl) -4-aminophenyl] ethylcarbamate. This way, after recrystallization from a mixture of methanol and ethanol in the 50:50 volume ratio, 23 g of 5 - [4 - (2-aminoethyl) phenylamino] -4-chloro-1,2-dithiol-3-one hydro -10 chloride with m.p. 164 ° C.

Tert.Buty1-2- (4-aminophenyl) ethylcarbamate can be prepared by adding, during one hour, a solution of 122 g of tert.butoxycarboxylic anhydride in 920 ml of ethyl acetate to a solution of 76.1 g of 4- (2- aminoethyl) -aniline in 200 ml of ethyl acetate. The reaction mixture is stirred for 3 hours at a temperature near 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

118 g of tert.-butyl-2- (4-aminophenyl) -ethylcarbamate are obtained in this way, m.p. 71 ° C.

4- (2-Aminoethyl) -aniline can be prepared as follows. A solution of 200 g of aluminum chloride in 2000 ml of tetrahydrofuran is added dropwise to a suspension of 57 g of lithium aluminum hydride in 1500 ml of tetrahydrofuran at a temperature near 15 ° C. Then a solution of 99 g of (4-aminophenyl) acetonitrile in 500 ml of tetrahydrofuran is added dropwise 25 at a temperature near 20 ° C. The reaction mixture is stirred at ca. 20 ° C for 20 hours, then cool to a temperature near 5 ° C. There are added dropwise and successively 128 ml of distilled water, 98 ml of a 6N aqueous sodium hydroxide solution, 450 ml of distilled water and finally 340 ml of a 10N aqueous sodium hydroxide solution. The precipitate formed is separated by filtration and the filtrate is dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. By distillation of the residue under reduced pressure, 83.3 g of 4- (2-aminoethyl) -aniline are obtained in the form of a colorless oil which boils at 138-142 ° C under a pressure of 0.47 kPa.

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27 (4-Aminophenyl) -acetonitrile can be prepared by catalytic hydrogenation of 121.6 g (4-nitrophenyl) -acetonitrile in 2000 ml of ethanol in the presence of 7.5 g of 5% palladium on carbon under a pressure near 100 kPa at a temperature near 30 ° C for 1 hour. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C and 98.9 g (4-aminophenyl) -acetonitrile is obtained, m.p. 42 ° C.

Example 24

To a solution of 59.4 g of tert-butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] ethylcarbamate prepared as in Example 24 in 475 ml tetrahydrofuran at a temperature near 15 ° C is added dropwise 49 g of tributyltin hydride. The reaction mixture is then stirred for 20 hours at a temperature near 20 ° C, then poured into 1500 ml of distilled water. 200 ml of methylene chloride is then added and the aqueous phase is decanted. This is extracted again with 200 ml of methylene chloride. The organic phases are combined, washed with 200 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. The residue is dissolved in 100 ml of methylene chloride and the resulting solution is poured onto 1500 g of silica gel in a column of 7.5 cm diameter. First, elute with 10 liters of a mixture of methylene chloride and ethyl acetate in the 93: 7 volume ratio and then with 10 liters of a mixture of methylene chloride and ethyl acetate in the 88:12 volume ratio and discard the eluates. Then elute with 11 liters of a mixture 30 of methylene chloride and ethyl acetate in the volume ratio of 85:15 and concentrate the eluate to dryness under reduced pressure (2.7 kPa) at 40 ° C. 29.3 g of tert.butyl-2 - [(3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] ethylcarbamate are obtained in the form of a brown oil having an Rf of 0, 28 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the 80:20 volume ratio as eluent.

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To release the amine from its protecting group, proceed in the same manner as in Example 22, but proceed from 12 g of tert.butyl-2 - [(3-oxo-1,2-dithiol-5-yl) -4- aminophenyl] ethylcarbamate. Thus, after 5 crystallization from ethanol, 2.5 g of 5- [4- (2-aminoethyl) -phenylamino] -1,2-dithiol-3-one hydrochloride is obtained, m.p. 228 ° C.

Example 25

Proceed in the same manner as in Example 17, but 10 is based on 96.5 g of 4,5-dichloro-1,2-dithiol-3-one and 137 g of tert.butyl- [2- (4-aminophenyl) propyl] -carbamate. There is thus obtained 206 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl] propylcarbamate having an Rf of 0.32 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate at 90:10 volume as eluent.

To release the amine from its protecting group, proceed in the same manner as in Example 22, but proceed from 110 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-20-5). yl) -4-aminophenyl] propylcarbamate. In this way, after recrystallization from methanol, 41 g of 5- [4- (1- (amino-2-propyl) -phenylamino) -4-chloro-1,2-dithiol-3-one hydrochloride) is obtained, m.p. 194 ° C.

Tert.butyl [2- (4-aminophenyl) propyl] carbamate 25 can be prepared in the same manner as in Example 23. From 88.5 g of 2- (4-aminophenyl) propylamine and 111 g of tert.butoxy carboxylic anhydride is obtained 135.7 g of tert.butyl (4-amino-2-phenyl-propyl) -propylcarbamate in the form of a brown oil having an Rf value of 0.20 by thin layer chromatography on silica gel 30 with a mixture of methylene chloride and ethyl acetate in the 90:10 volume ratio as eluent.

2- (4-Aminophenyl) propylamine can be prepared in the same manner as in Example 24. From 80.3 g of 2- (4-aminophenyl) propionitrile 75.2 g of 2- (4-aminophenyl) propyl-35 are obtained. amine in the form of a brown oil having an Rf value of 0.50 by thin layer chromatography on silica gel with a mixture of

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methanol and concentrated ammonia (d = 0.92) in volume ratio 99: 1 as eluent.

2- (4-Aminophenyl) propionitrile can be prepared in the same manner as in Example 23. From 185 g of 2- (4-nitrophenyl) propionitrile 155 g of 2- (4-aminophenyl) propionitrile are obtained in the form of a brown oil having an Rf value of 0.26 by thin layer chromatography on silica gel with methylene chloride as eluant. 2- (4-Nitrophenyl) propionitrile can be prepared according to the method described by S. Opolski, 10 Z. Kowalski and J. Pilewski, Chem. Ber. 49, 2276 (1916).

Example 26

A suspension of 11.8 g of 5- (4-amino-phenylamino) -4-chloro-1,2-dithiol-3-one in 30 ml of dimethylformamide-dimethyl acetal is stirred for 3 hours at a temperature close to 25 ° C.

The insoluble product is separated by filtration, washed 3 times with a total of 75 ml of isopropyl ether and then dried under reduced pressure (2.7 kPa). The resulting product is dissolved in 300 ml of ethanol and to this solution is added 20 ml of a 3N solution of hydrogen chloride in ethyl ether.

The insoluble product is separated by filtration, washed twice with a total of 30 ml of ethanol and then dried under reduced pressure (2.7 kPa). After recrystallization from a mixture of water and dimethylformamide in the 50:50 volume ratio, 2.2 g of 4-chloro-5- (4-dimethylaminomethyleneamino-phenyl) -1,2-dithiol-3-one hydrochloride is obtained, m.p. 270 ° C.

5- (4-Amino-phenylamino) -4-chloro-1,2-dithiol-3-one can be prepared according to the method described in FR-A-1,498,374.

30

Example 27

Proceeding in the same manner as in Example 26, but starting from 4.1 g of 5- (4-aminomethyl-phenylamino) -4-chloro-1,2-dithiol-3-one, is obtained after recrystallization from a mixture of methanol and isopropyl ether in the 70:30 volume ratio 1.45 g of 4-chloro-5- (4-dimethylaminomethylenaminomethyl-phenylamino) -1,2-dithiol-3-one hydrochloride, m.p. 155 ° C.

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5- (4-Aminomethyl-phenylamino) -4-chloro-1,2-di-thiol-3-one can be prepared as in Example 22.

Example 28 Proceeding in the same manner as in Example 2, but starting from 63.5 g of 4,5-dichloro-1,2-dithiol-3-one and 89.8 g of tert-butyl-2- ( 4-aminophenyl) -butylcarbamate, 80.5 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-aminophenyl)] -butylcarbamate is obtained in the form of a red oil having a 10 Rf value of 0.47 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the volume ratio of 90:10 as eluent.

To release the amine from its protecting group, proceed in the same manner as in Example 22, but proceed from 80 g of tert.butyl-2 - [(4-chloro-3-oxo-1,2-dithiol ~ 5-- yl) -4-aminophenyl] -butylcarbamat. 24.5 g of 5- [4- (1-amino-2-butyl) -phenylamino] -4-chloro-1,2-dithiol-3-one hydrochloride, m.p. 230 ° C.

Tert.butyl 2- (4-aminophenyl) butyl carbamate can be prepared in the same manner as in Example 23. From 56.5 g of 2- (4-aminophenyl) butylamine and 74.7 g of tert.butoxycarboxylic anhydride are obtained. 89.8 g of tert.butyl 2- (4-aminophenyl) butylcarbamate. in the form of a red oil having an Rf value of 0.22 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the volume ratio of 90:10 as eluent.

2- (4-Aminophenyl) -butylamine can be prepared in the same manner as in Example 23. From 64 g of 2- (4-aminophenyl) -butyronitrile, 56.5 g of 2- (4-aminophenyl) -butylamine are obtained in the form of a brown oil having an Rf value of 0.25 by thin-layer chromatography on silica gel with a mixture of methanol and concentrated ammonia (d = 0.92) in 99: 1 volume ratio as eluent.

2- (4-Aminophenyl) -butyronitrile can be prepared in the same manner as in Example 23. From 149 g of 2- (4-nitrophenic acid)

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31 g of nyl) -butyronitrile 127 g of 2- (4-aminophenyl) -butyronitrile in the form of a yellow oil having an Rf of 0.21 are obtained by thin-layer chromatography on silica gel with methylene chloride as eluant.

2- (4-Nitrophenyl) -butyronitrile can be prepared according to the method described by E. Pourneau and, G. Sandules-co, Bull. Soc. Chim. France 41, 450 (1927).

Example 29 Proceeding in the same manner as in Example 24 but starting from 61.7 g of tert-butyl-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -1-propyl-carbamate and 49 g of tributyltin hydride, 14.2 g of tert-butyl-2 - [(3-oxo-1,2-dithiol-5-yl) -4- aminophenyl] propylcarbamate in the form of a brown oil having an Rf value of 0.41 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the volume ratio 80:20 as eluent.

To release the amine from its protecting group, proceed in the same manner as in Example 22, but proceed from 14.2 g of tert.butyl-2 - [(3-oxo-1,2-dithiol-5-yl) -4-phenyl-amino] propylcarbamate. There is thus obtained 6.7 g of 5 - [4- (1-amino-2-propyl) -phenylamino] -1,2-dithiol-3-one, m.p. 148 ° C. 1 2 3 4 5 6 7 8 9 10 11

Example 30 2

Proceeding in the same manner as in Examples 1, 3 but starting from 12.8 g of 4,5-dichloro-1,2-dithiol-3-one and 4 16.8 g of tert.butyl- [1- ( 4-aminophenyl) -2-propyl] carbamate, there is obtained 14.7 g of tert-butyl-1 - [(4-chloro-3-oxo-1,2-dithiol-6-5-yl) -4- amino-phenyl] -2-propyl-carbamate, m.p. 155 ° C.

7

To release the amine from its protecting group 8, proceed in the same manner as in Example 22, but 9 is based on 14.2 g of tert-butyl-1 - [(4-chloro-3-oxo-1,2-dithiol - (5-yl) -4-amino-phenyl] -2-propyl-carbamate. 9.5 g of 5- (4- (2- (aminopropyl) phenylamino) -4-chloro-1,2-dithiol-3-one hydrochloride, m.p. 149 ° C.

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Tert-butyl [1- (4-amino-phenyl) -2-propyl] carbamate can be prepared in the same manner as in Example 23. From 18.4 g of 1- (4-aminophenyl) -2-propylamine and 26.7 g of tert.-butoxycarboxylic anhydride, 20 g of tert.butyl [1- (4-amino-phenyl) -2-propyl] carbamate are obtained in the form of a red oil having an Rf value of 0.20 at thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate at 90:10 volume as eluent.

1- (4-Amino-1-phenyl) -2-propylamine can be prepared as follows. A solution of 26.3 g of a mixture of 1- (4-aminophenyl) -2-nitro-1-propene and 1- (4-aminophenyl) -2-nitro-propane in 200 ml of 1,2-dimethoxyethane is added dropwise to 440 ml of a 70% toluene solution of bis (2-methoxyethoxy) aluminum sodium hydride. The reaction mixture is heated to reflux for 1 hour and then cooled to a temperature near 10 ° C. 250 ml of distilled water and 250 ml of ethyl ether are then added. The insoluble product is separated by filtration, the filtrate is decanted and the aqueous phase is extracted 2 times 3 times with a total of 900 ml of ethyl ether and then 3 times with a total of 900 ml of chloroform. The organic phases are combined, dried over potassium carbonate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 18.4 g of 1- (4-aminophenyl) -2-25 -propylamine in the form of a brown oil having an Rf value of 0.12 are obtained by thin layer chromatography on silica gel with a mixture of methanol and concentrated ammonia ( d = 0.92) in volume ratio 99: 1 as eluent.

The mixture of 1- (4-aminophenyl) -2-nitro-1-propene and 1- (4-aminophenyl) -2-nitro-propane can be prepared by catalytic hydrogenation of 47 g of 2-nitro-1- (4 -nitro-phenyl-1-propene in 1500 ml of ethanol in the presence of 5 g of 5% palladium on carbon under a pressure near 100 kPa at a temperature near 50 ° C for 1.5 hours. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at

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50 ° C. 30 g of a mixture of 1- (4-aminophenyl) -2-nitro-2-propene and 1- (4-aminophenyl) -2-nitro-propane are obtained in the form of a brown oil having an Rf value of 0 , 81 and 0.54 by thin layer chromatography on silica gel with a mixture of 5 methylene chloride and ethyl acetate in the 50:50 volume ratio as eluent.

2-Nitro-1- (4-nitrophenyl) -1-propylene can be prepared according to the method described by B. Priebs, Liebig's Ann. 225, 319 (1884).

10

Example 31

Proceeding in the same manner as in Example 2, but starting from 5 g of 4,5-dichloro-1,2-dithiol-3-one and 8.6 g of tert-butyl-2- (4-methylamino-phenyl) ) -propylcarbamate, there is obtained 6.7 g of tert.butyl-2- [N- (4-chloro-3-oxo-1,2-dithiol-5--yl) -N-methyl-4-amino-phenyl ] -propylcarbamate in the form of a yellow oil having an Rf value of 0.59 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the volume ratio of 90:10 as eluent.

To release the amine from its protecting group, proceed in the same manner as in Example 22, but proceed from 6.8 g of tert-butyl-2- [N- (4-chloro-3-oxo-1,2- di-thiol-5-yl) -N-methyl-4-phenyl-amino] propylcarbamate. 4 g of N-25 - [4- (1-amino-2-propyl) phenyl] -N-methyl-5-amino-4-chloro--1,2-dithiol 3-one hydrochloride with m.p. 190 ° C.

Tert-butyl-2- (4-methylamino-phenyl) -propylcarbamate can be prepared in the same manner as in Example 23. From 9.9 g of 2- (4-methylamino-phenyl) -propylamine and 11.5 g of tert. butoxycarboxylic anhydride is obtained 8.6 g of tert.butyl [2- (4-methylamino-phenyl) -propyl] -carbamate in the form of a yellow oil having a Rf value of 0.5 by thin layer chromatography on silica gel with a mixture of methylene chloride and ethyl acetate in the 90:10 volume ratio as eluent.

2- (4-Methylamino-phenyl) -propylamine can be prepared as follows. A solution of 13.9 g of 2- (4-formyl)

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amino-phenyl) -propionitrile in 20 ml of tetrahydrofuran is added dropwise to a suspension of 12.2 g of lithium aluminum hydride in 120 ml of tetrahydrofuran at a temperature near 65 ° C. The reaction mixture is stirred for 2 hours under reflux and then for 16 hours at a temperature near 20 ° C. Then 12 ml of distilled water, 24 ml of 4N aqueous sodium hydroxide solution and 48 ml of distilled water are added dropwise. The insoluble product is separated by filtration and the filtrate is poured into a mixture of 100 ml of 10 4N hydrochloric acid and 100 ml of methylene chloride. The organic phase is decanted and the aqueous phase is washed with 100 ml of methylene chloride and then made basic by adding 50 ml of 10N aqueous sodium hydroxide solution. The resulting emulsion is extracted 3 times with a total of 300 ml of methylene chloride, 15 and the organic phases are combined, dried over potassium carbonate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 10.4 g of 2- (4-methylamino-phenyl) -propylamine in the form of a brown oil having an Rf value of 0.50 is obtained by thin layer chromatography 20 on silica gel with a mixture of methanol and ammonia in volume ratio 99 : 1 as eluent.

2- (4-Formylamino-phenyl) -propionitrile can be prepared as follows. A mixture of 5.7 ml of formic acid and 14.2 ml of acetic anhydride is heated for 2 hours to a temperature near 55 ° C, and after cooling to a temperature near 25 ° C, 14.6 g of 2- (4-aminophenyl) are added dropwise. ) - propionitrile. The reaction mixture is stirred for 20 hours at a temperature close to 20 ° C, then 30 ml of methylene chloride is added and the resulting solution is washed 2 times 30 with a total of 60 ml of distilled water and 2 times with a total of 60 ml of a saturated aqueous sodium hydrogen carbonate solution. it is dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) at 50 ° C. 14.4 g of 2- (4-formylamino-phenyl) -propionitrile in the form of a red oil having an Rf of 0.50 is obtained by thin layer chromatography on silica gel with a mixture

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of methylene chloride and ethyl acetate in the 50:50 volume ratio as eluent.

Example 32 Proceeding in the same manner as in Example 1, but starting from 39.5 g of 4,5-dichloro-1,2-dithiol-3-one and 34.6 g of 2- (4-aminophenyl) -propionamide, obtained after recrystallization from a mixture of acetonitrile and ethyl acetate in the 75:25 volume ratio 32.8 g of 2 - [(4-chloro-3-oxo-10 -1,2-dithiol-5-yl) -4- amino-phenyl] -propionamide, m.p.

195 ° C.

2- (4-Aminophenyl) propionamide can be prepared by catalytic hydrogenation of 51.4 g of 2- (4-nitrophenyl) propionamide in 700 ml of ethanol in the presence of 2.2 g of 5% palladium on carbon at a temperature near 35 ° C under a pressure near 100 kPa for 1 hour. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting residue is washed twice with a total of 200 ml of isopropyl ether 20 and then dried in the air at a temperature close to 20 ° C.

34.6 g of 2- (4-aminophenyl) propionamide are thus obtained with m.p. 126 ° C.

2- (4-Nitrophenyl) propionamide can be prepared as follows. A suspension of 52.8 g of 2- (4-nitrophenyl) -25-propionitrile in 150 ml of concentrated hydrochloric acid (d = 1.19) is heated for 1.5 hours to a temperature near 60 ° C. The resulting solution is cooled to a temperature near 10 ° C, then 150 ml of distilled water is added. The resulting precipitate is separated by filtration, washed 3 times with a total of 300 ml of distilled water, 2 times with a total of 300 ml of a saturated aqueous sodium hydrogen carbonate solution and 2 times with a total of 200 ml of distilled water and then dried in the air at a temperature close to 20 ° C. 48.8 g of 2- (4-nitrophenyl) propionamide are thus obtained with m.p.

35 117 ° C.

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Example 33

To a solution of 16.8 g of 5- [4- (1-amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one hydrochloride in 100 ml of pyridine is added temperature of -5 ° C 3.6 ml of acetyl chloride. The reaction mixture is kept for 10 minutes at a temperature near 0 ° C. Then, at the same temperature, a solution of 7 ml of triethylamine in 50 ml of pyridine is added. The reaction mixture is kept for 45 minutes at a temperature near 20 ° C. 450 ml of diethyl ether is then added and the supernatant is separated by decantation from the insoluble part. The organic phase thus obtained is washed with 100 ml of distilled water, treated with 1 g of decolorizing coal, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa).

Recrystallization of the residue thus obtained from 10 ml of acetonitrile gives 4.9 g of 5- [4- (1-acetylamino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one with a m.p. at 179 ° C and an Rf value of 0.4 by thin layer chromatography on silica gel with a mixture of chloroform and meth-2o hanol in the 80:20 volume ratio as eluent.

Example 34

Proceeding in the same manner as in Example 33, but starting from 10.1 g of 5- [4- (1-amino-2-propyl) -phenyl-25-amino] -4-chloro-1,2-dithiol -3-on hydrochloride and 2.9 ml of ethyl chloroformate, 7.5 g of a brown oil are obtained. This oil is dissolved in 40 ml of methylene chloride and the resulting solution is poured onto 150 g of silica gel in a 2.5 cm diameter column. First elute with 500 ml of methylene chloride and discard the eluate. It is then eluted with 1400 ml of methylene chloride and the eluate evaporated to dryness under reduced pressure (2.7 kPa) at a temperature near 40 ° C. The residue thus obtained is dissolved in 50 ml of methylene chloride and the resulting solution is washed with a mixture of 20 ml of water and 4 ml of 0.1N hydrochloric acid and then with 20 ml of water. The organic phase is separated by decantation.

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ring, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature near 60 ° C.

There are thus obtained 3.7 g of ethyl 2 - [(4-chloro-5 -3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -propylcarbamate in the form of a yellow maroon-like substance with an Rf value of 0.5 by thin layer chromatography on silica gel with a mixture of chloroform and methanol in the 80:20 volume ratio as eluent.

10

Example 35

A suspension of 12.0 g of 5- [4- (1-amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one in 300 ml of methyl formate is stirred at a temperature close to 25 ° C for 75 hours.

The reaction mixture is then filtered and the undissolved solid is washed with 150 ml of methyl formate. The filtrates are combined and the resulting organic solution is evaporated to dryness under reduced pressure (2.7 kPa) at a temperature near 40 ° C. Recrystallization of the residue thus obtained from 60 ml of acetonitrile gives 5.0 g of 4-chloro-5- [4- (1-formylamino-2-propyl) -phenylamino] -1,2-di-thiol-3 on with m.p. 143 ° C and an Rf value of 0.4 by thin layer chromatography on silica gel with a mixture of chloroform and methanol in the 80:20 volume ratio as eluent.

5- [4- (1-Amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one is prepared as follows. To a solution of 10.1 g of 5- [4- (1-amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one hydrochloride in 90 ml of water is added at temperature near 20 ° C 25 ml IN sodium hydroxide solution. The crystals obtained are separated by filtration, washed 3 times with a total of 90 ml of water and dried in the air for 24 hours. There is thus obtained 7.2 g of 5- [4- (1-amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one, m.p.

At 120 ° C and an Rf value of 0.3 by thin layer chromatography on silica gel with a mixture of chloroform and methanol in the 80:20 volume ratio as eluent.

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Example 36

To a suspension of 6.0 g of 5- [4- (1-amino-2-propyl) -phenylamino] -4-chloro-1,2-dithiol-3-one in 100 ml of methylene chloride is added at a temperature close to 20 DEG C. a solution of 1.1 g of methyl isocyanate in 25 ml of methylene chloride. The reaction mixture is kept for 30 minutes at a temperature near 20 ° C. The resulting precipitate is separated by filtration and washed 3 times with a total of 50 ml of methanol, then dried in the air for 16 hours. Recrystallization of the solid thus obtained from 60 ml of ethanol gives 3.4 g of N-2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -N'-methyl-propylurea with m.p. 176 ° C and an Rf value of 0.4 by thin layer chromatography on silica gel with a mixture of chloroform and methanol in volume ratio 80:20 as eluent.

Example 37

Proceeding in the same manner as in Example 24 but starting from 28.6 g of 4-chloro-5- (4-isopropyl-phenylamino) -20-1,2-dithiol-3-one and 32 g of tributyltin hydride, 6.3 g of 5- (4-isopropyl-phenylamino) -1,2-dithiol-3-one, m.p. is obtained after recrystallization from a mixture of isopropyl ether and ethyl acetate in the 70:30 volume ratio. 114 ° C.

4-Chloro-5- (4-isopropyl-phenylamino) -1,2-dithiol-25-3-one can be prepared according to the method described in FR-A-1,498,374.

Example 38

To a solution of 13.5 g of 4-chloro-5- (4-isopropyl-phenylamino) -1,2-dithiol-3-one in 165 ml of pyridine is added over 31 minutes to 31.2 g of mixed anhydride of acetic acid and formic acid at a temperature close to 5 ° C. The reaction mixture is stirred at this temperature for 3 hours, then it is poured into 1650 ml of distilled water. The resulting emulsion is extracted twice with a total of 500 ml of methylene chloride. The organic phases are combined and washed with 100 ml

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distilled water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 60 ° C. The resulting residue is taken up in a mixture of ethyl ether and isopropyl ether at 50:50, 5 by volume, and the resulting crystals are separated by filtration and recrystallized from isopropyl ether. 8.9 g of 4-chloro- (N-formyl-N-5 - [(4-isopropyl-phenyl) -amino]-1,2-dithiol-5-one are obtained in this way, mp 72 ° C .

Example 39

A suspension of 13.8 g of potassium carbonate in a solution of 18.7 g of 4,5-dichloro-1,2-dithiol-3-one, 13.2 g of 4-isopropylphenol and 0.5 g of 4-dimethylamino-pyridine in 150 ml of dimethylformamide is stirred for 20 hours at a temperature 15 near 20 ° C. The reaction mixture is then poured into 1500 ml of a 5% aqueous solution of ammonium chloride and the resulting emulsion is extracted once with 400 ml and then 3 times with a total of 300 ml of methylene chloride. The organic phases are combined and washed twice with a total of 500 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 70 ° C. The resulting residue is dissolved in 100 ml of methylene chloride and the resulting solution is poured onto 650 g of silica gel in a column of 5.5 cm diameter. First, elute with 1400 ml of methylene chloride and discard the eluate. Then elute with 1200 ml of methylene chloride and concentrate the eluate to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, after recrystallization from isopropyl ether, 11.7 g of 4-chloro-30- (4-isopropyl-phenoxy) -1,2-dithiol-3-one is obtained with m.p. 94 ° C.

Example 40

To a solution of 18.8 g of 3-amino-pyridine and 38.2 g of nitrilo tris (2-propanol) in 1000 ml of acetone at a temperature near 0 ° C is added 37.4 g of 4,5-dichloro-1 , 2-dithiol-3-one, and the mixture is stirred at a temperature near 0 ° C

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16 hours. The insoluble product is separated by filtration and washed twice with a total of 100 ml of acetone. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure 5 (2.7 kPa) at 40 ° C. The resulting residue is placed on 750 g of silica gel in a column of 6.5 cm diameter. First, elute with 2.4 liters of a mixture of ethyl acetate and methanol in a 95: 5 volume ratio and discard the eluate. The mixture is then eluted with 800 ml of a mixture of 10 ethyl acetate and methanol in a 95: 5 volume ratio, and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting residue is taken up with 500 ml of acetonitrile and the insoluble product is separated by filtration. After recrystallization from 470 ml of methyl iso-butyl ketone, 4.65 g of 4-chloro-5- (3-pyridylamino) -1,2-di-thiol-3-one is obtained, m.p. 235 ° C.

Example 41

To a solution of 28.2 g of 2-amino-pyridine, 57.3 20 g of nitrilo tris (2-propanol) and 1.5 g of 4-dimethylamino-pyridine in 1200 ml of acetone at a temperature near 0 ° C 56.1 g of 4,5-dichloro-1,2-dithiol-3-one are added with stirring. The reaction mixture is then stirred at a temperature near 0 ° C for 17 hours, after which the insoluble product formed is separated by filtration and washed twice with a total of 100 ml of acetone. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting residue is placed on 1500 g of silica gel in a column of 30 cm diameter. First elute with 12.6 liters of methylene chloride and discard the eluate. The mixture is then eluted with 1200 ml of a mixture of methylene chloride and ethyl acetate in a 90:10 volume ratio, and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Recrystallization of the resulting residue from 170 ml of acetic acid gives 2.84 g of 4-chloro-5- (2-pyridylamino) -1,2-di-thiol-3-one, m.p. 248 ° C.

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Example 42

To a solution of 28.8 g of 6-amino-quinoline and 38.2 g of nitrilo tris (2-propanol) in 1000 ml of acetone at a temperature near 5 ° C is added 37.4 g of 4,5-dichloro-1, 2-dithiol-5 -3-one and the reaction mixture is stirred at a temperature near 5 ° C for 70 hours. The reaction mixture is then evaporated to dryness under reduced pressure (2.7 kPa) at 70 ° C and the residue taken up with a mixture of 2000 ml of methylene chloride and 2000 ml of distilled water. The suspension thus obtained is stirred for 1 hour at a temperature near 20 ° C and the remaining insoluble product is separated by filtration. The filtrate is decanted and the organic phase is washed with 1500 ml of distilled water, dried over magnesium sulfate in the presence of decolorizing coal, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue thus obtained is placed on 800 g of silica gel in a column of 6 cm diameter. First, elute 7200 ml of a mixture of methylene chloride and ethyl acetate in the 90:10 volume ratio and discard the eluate. The mixture is then eluted with 2400 ml of a mixture of methylene chloride and ethyl acetate in the 75:25 volume ratio and the eluate is discarded. The mixture is then eluted with 16000 ml of a mixture of methylene chloride and ethyl acetate in the 60:40 volume ratio, and the eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the residue thus obtained from 3000 ml of a mixture of acetonitrile and methylene chloride in the 80:20 volume ratio, 15 g of 4-chloro-5- (6-quinolylamino) -1,2-dithiol-3-one with mp. 232-234 ° C.

30

Example 43

To a solution of 28.8 g of 5-amino-isoquinoline and 38.2 g of nitrilo tris (2-propanol) in 1000 ml of acetone at a temperature of 5 ° C is added 37.4 g of 4,5-dichloro-1, 2-di-thiol-3-one and the reaction mixture is stirred at a temperature near 5 ° C for 48 hours. The formed insoluble product

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42 is separated by filtration and washed 3 times with a total of 600 ml of acetone. The organic filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue thus obtained is placed on 800 g of 6 silica gel in a column of 6 cm diameter. First elute with 11 liters of a mixture of methylene chloride and ethyl acetate in the 80:20 volume ratio and discard the eluate. Then, elute with 3.6 liters of a mixture of methylene chloride and ethyl acetate in the volume ratio of 80:20 10 and then with 1800 ml of a mixture of methylene chloride and ethyl acetate in the volume ratio of 70:30 and finally with 6.4 liters of a mixture of methylene chloride and ethyl acetate in 50:50 volume ratio, and the eluates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the resulting residue from 900 ml of acetic acid, 10.5 g of 4-chloro-5- (5-isoquinolylamino) -1,2-dithiol-3-one is obtained, m.p. 251-253 ° C with decomposition.

Example 44

To a solution of 18.8 g of 8-amino-quinoline and 24.8 g of nitrilo tris (2-propanol) in 650 ml of acetone at a temperature near 6 ° C is added 24.4 g of 4,5-dichloro-1, 2-dithiol-3-one and the reaction mixture is stirred at a temperature 25 near 5 ° C for 24 hours. The insoluble product formed is separated by filtration, washed with 50 ml of acetonitrile and dried in the air at a temperature close to 20 ° C. This product is then taken up with a mixture of 1000 ml of ethanol and 2000 ml of methylene chloride and the resulting suspension is stirred at a temperature near 20 ° C for 1 hour. The insoluble product is separated by filtration and dried in the air at a temperature close to 20 ° C. After recrystallization from 900 ml of acetic acid, 10.0 g of 4-chloro-5- (8-quinolylamino) -1,2-dithiol-3-one is obtained, m.p. 230 ° C.

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Example 45

To a solution of 34 g of 5-amino-quinoline, 45 g of nitrilo tris- (2-propanol) and 1 g of 4-dimethylamino-pyridine in 1000 ml of acetone at a temperature of 0 ° C is added 44.1 g of 5 4, 5-dichloro-1,2-dithiol-3-one and the reaction mixture is stirred at a temperature near 0 ° C for 88 hours. The insoluble product formed is separated by filtration and washed 3 times with a total of 15 ml of acetone. The product thus obtained is placed on 1500 g of silica gel in a column with a diameter of 10 meters of 10 cm. First, elute with 8 liters of a mixture of methylene chloride and ethyl acetate in the 80:20 volume ratio and discard the eluate. It is then eluted with 9 liters of a mixture of methylene chloride and ethyl acetate in the 80:20 volume ratio and then with a mixture of methylene chloride and ethyl acetate in the 40:60 volume ratio, and the eluates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization of the residue from 220 ml of acetic acid, 11.8 g of 4-chloro-5- (5-quinolylamino) -1,2-dithiol-3-one is obtained, m.p. 241-242 ° C under decomposition.

Example 46

To a solution of 8 g of 5-amino-indane and 11.2 g of 4,5-dichloro-1,2-dithiol-3-one in 300 ml of methanol is added 6.6 g of sodium bicarbonate and the reaction mixture is stirred for 24 hours. at a temperature near 20 ° C. The insoluble product formed is separated by filtration and washed with distilled water until the aqueous filtrate is free of chlorine ions and then dried in the air at a temperature near 20 ° C. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C and the residue is taken up with 250 ml of methylene chloride. The solution thus obtained is washed 4 times with a total of 600 ml of distilled water, dried over magnesium sulfate in the presence of decolorizing coal, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue thus obtained

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44 is combined with the insoluble product separated as described above and recrystallized from 190 ml of acetonitrile. 14.0 g of 4-chloro-5- (5-indanyl-amino) -1,2-dithiol-3-one is obtained in this way, m.p. 150-152 ° C 5

Example 47

To a solution of 17.4 g of 6-amino-quinoxaline and 22.9 g of nitrilo tris (2-propanol) in 600 ml of acetone at a temperature near 5 ° C is added 22.5 g of 4,5-dichloro-1, 2-dithiol-10 -3-one and the reaction mixture is stirred at a temperature near 5 ° C for 48 hours. The reaction mixture is then evaporated to dryness under reduced pressure (2.7 kPa) at 70 ° C and the residue is washed with distilled water until the filtrate is free of chlorine ions and then dried in the air at a temperature near 20 ° C. This product is then placed on 1000 g of silica gel in a column of 8 cm diameter. 6000 ml of methylene chloride, 4200 ml of a mixture of methylene chloride and ethyl acetate in volume ratio 95: 5, 4000 ml of a mixture of methylene chloride and ethyl acetate in volume ratio of 90:10, 2000 ml of a mixture of methylene chloride and ethyl acetate are successively eluted. in the volume ratio 85:15, 2250 ml of a mixture of methylene chloride and ethyl acetate in the volume ratio 80:20 and finally 2000 ml of a mixture of methylene chloride and ethyl acetate in the volume ratio of 75:25 and all these eluates are discarded. Then 7200 ml of a mixture of methylene chloride and ethyl acetate in the volume ratio of 60:40 and then with 2600 ml of a mixture of methylene chloride and ethyl acetate in the volume ratio of 50:50 are combined and concentrated to dryness under reduced pressure. (2.7 kPa) at 40 ° C. After recrystallization of the residue thus obtained from 400 ml of acetic acid, 10 g of 4-chloro-5- (6-quinoxalinylamino) -1,2-dithiol-3-one is obtained, m.p. 244 ° C.

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Example 48

Proceed in the same manner as in Example 1, but proceed from 5.64 g of 4,5-dichloro-1,2-dithiol-3-one and 6.7 g of 2- (4-aminophenyl) -butyramide, and After recrystallization from methanol, 2 g of 2- [(4-chloro-3-oxo-1,2-dithiol-5--yl) -4-amino-phenyl] -butyramide are obtained in the form of pale yellow crystals, m.p. 196 ° C.

2- (4-Aminophenyl) -butyramide can be prepared by a method analogous to that described in Example 32 for the preparation of 2- (4-aminophenyl) propionamide, but from 6.95 g of 2- (4- nitrophenyl) butyramide. 6.7 g of 2- (4-aminophenyl) -butyramide is thus obtained in the form of a white powder, m.p. 126 ° C.

2- (4-Nitrophenyl) -butyramide may be prepared by a method analogous to that described in Example 32 for the preparation of 2- (4-nitrophenyl) propionamide, but from 19 g of 2- (4-nitrophenyl) -butyronitrile. There is thus obtained 6.95 g of 2- (4-nitrophenyl) -butyramide in the form of beige crystals with m.p. 139 ° C.

2- (4-Nitrophenyl) -butyronitrile can be prepared according to the method described by E. Fourneau and G.

Sandulesco, Bull. Soc. Chim. France 41, 450 (1927).

Example 49 Proceeding in the same manner as in Example 1, but starting from 12.7 g of 4,5-dichloro-1,2-dithiol-3-one and 10.3 g of (4-aminophenyl) acetonitrile , after recrystallization from acetic acid, 12.7 g of 4 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -amino] -phenyl-acetamide in the form of yellow crystals with mp. 230 ° C.

(4-Aminophenyl) -acetonitrile can be prepared by a method analogous to that described in Example 32 for the preparation of 2- (4-aminophenyl) propionamide starting from 18 g of (4-nitrophenyl) acetamide. 35 g (4-aminophenyl) acetamide is obtained in the form of beige crystals with m.p. 156 ° C.

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Example 50

Proceed in the same manner as described in Example 1, but proceed from 7.13 g of 4,5-dichloro-1,2-dithiol-3-one and 6.26 g of 3- (4-aminophenyl) propionamide. 2.85 g of 3 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -propionamide is obtained in the form of a yellow powder after 5 crystallization from dioxane. mp. 197 ° C.

3- (4-Aminophenyl) propionamide can be prepared by catalytic hydrogenation of 30.4 g of 4-nitro-cinnamic acid amide 10 in 450 ml of methanol in the presence of 1.6 g of 5% palladium on carbon at a temperature near 30 ° C under a pressure close to 100 kPa for 3 hours. After separating the catalyst by filtration, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. There is thus obtained 24.8 g of 3- (4-aminophenyl) propionamide in the form of white crystals, m.p. 134 ° C.

4- Nitro-cinnamic acid amide can be prepared according to the method described by L. Chiozza, Ann. Chim. Phys. [3] 39, 196 (1853).

20

Example 51

Proceeding in the same manner as in Example 1, but starting from 8.9 g of 4,5-dichloro-1,2-dithiol-3-one and 8.5 g of 2- (4-aminophenyl) -Ν, Ν-Dimethylacetamide, after recrystallization from a mixture of ethyl acetate and ethanol in volume ratio 83:17, is obtained 4.7 g of 2 - [(4-chloro-3-oxo-1,2-di-thiol-5-yl) ) -4-amino-phenyl] -Ν, Ν-dimethylacetamide in the form of a yellow powder, m.p. 165 ° C.

2- (4-Aminophenyl) -Ν, Ν-dimethylacetamide can be prepared in a manner analogous to that described in Example 32 for the preparation of 2- (4-aminophenyl) propionamide, starting from from 10.2 g of N, N-dimethyl-2- (4-nitrophenyl) acetamide. 8.6 g of 2- (4-aminophenyl) -Ν, Ν-dimethylacetamide are thus obtained in the form of a brown powder with m.p. 103 ° C.

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N, N-Dimethyl-2- (4-nitrophenyl) acetamide can be prepared according to the method described by H.J. Taverne,

Rec. Trav. Chim. des Pays-Bas, 16_, 38 (1897).

Example 52

Proceeding in the same manner as in Example 1, but starting from 11.4 g of 4,5-dichloro-1,2-dithiol-3-one and 10.9 g of 2- (4-aminophenyl) -2- methyl propionamide, after recrystallization from acetic acid, 6.2 g of 2 - [(4-chloro-3-10-oxo-1,2-dithiol-5-yl) -4-amino-phenyl] -2-methyl propion amide in the form of a yellow powder with m.p. 193 ° C.

2- (4-Aminophenyl) -2-methyl-propionamide can be prepared by a method analogous to that described in Example 32 for the preparation of 2- (4-aminophenyl) propionamide, starting from 28 , 4 g of 2-methyl-2- (4-nitrophenyl) propionamide. 23.9 g of 2- (4-aminophenyl) -2-methyl-propionamide are obtained in the form of a white powder, m.p. 124 ^ (second

2-Methyl-2- (4-nitrophenyl) -propionamide may be prepared in a manner analogous to that described in Example 32 for the preparation of 2- (4-nitrophenyl) -propionamide, starting from 39 , 3 g of 2-methyl- (4-nitrophenyl) -propionitrile. 28.8 g of 2-meth-hy1-2- (4-nitrophenyl) propionamide are thus obtained in the form of white crystals, m.p. 104 ° C.

2-Methyl (4-nitrophenyl) propionitrile can be prepared as follows. To 180 ml of 93% aqueous nitric acid maintained at a temperature near 0 ° C is added dropwise over approx. 50 minutes 39.6 g of 2-methyl-2-30-phenyl-propionitrile. The reaction mixture is stirred for 20 hours at a temperature near 20 ° C and then poured into 2 liters of ice water. The formed precipitate is separated by filtration, washed with 5 x 100 ml of distilled water and dried. In this way, 40.5 g of 2-methyl- (4-nitrophenyl) -propionitrile is obtained in the form of a white powder, m.p. 78 ° C.

2-Methyl-2-phenyl-propionitrile can be prepared

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48 according to the method described by L. B. Taranko and R.H.

Perry, Jr.; J. Org. Chem. 34/226 (1969).

Example 53

Proceeding in the same manner as in Examples 39, 5 but obtained from 9 g of 4,5-dichloro-1,2-dithiol-3-one and 7.3 g of 2- (4-hydroxyphenyl) acetamide are obtained. after recrystallization from acetonitrile 3.5 g of 2 - [(4-chloro-3-oxo-1,2-dithiol-5-yl) -4-oxa-phenyl] -acetamide in the form of a yellow powder, m.p.

168 ° C.

2- (4-Hydroxyphenyl) acetamide can be prepared according to the method described by H. Salkowski, Chem. Ber. 22, 2137 (1889).

BIOLOGICAL ACTIVITY

15 1 - Measurement of activation of macrophages in vitro In sterile petri dishes commonly used for cell cultures, 2 x 10 6 peritoneal macrophages of stimulated mice are placed. After attaching the cells for approx. For 2 hours, two washes are performed with isotonic phosphate buffer 20 to remove non-adherent cells, then 2 ml of Dulbecco medium containing 15% serum of newborn calves (SVN) is added.

Then, the compound tested dissolved in 100 μΐ of water or 5 μΐ of dimethylformamide or dimethyl sulfoxide (depending on the solubility of the compound) is added so that the solvent constitutes 0.25% of the reaction medium. Then incubate at 37 ° C for 18 hours in an atmosphere containing 10% CO 2.

After washing with isotonic phosphate buffer 30, the incubation medium is replaced with 2 ml of a 0.04% suspension of zymosan in Dulbecco medium containing 15% SVN and then the compound to be tested is added as described above. Finally, 0.5 µl of 14 C 2 glucose contained in 100 µΐ of a 0.05% ethanolic solution is added and the phagocytose is allowed to proceed for 30 minutes at 37 ° C in an atmosphere containing 10% CO 2 .

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The consumption of glucose during the activation of the pentose-phosphate pathway is accompanied by a release of the This 14 CO 2 dissolved in the medium is released and intercepted to measure the radioactivity in a scintillation counter.

5 5 petri dishes are used per day. the dose of compounds to be tested and relative to comparative cultures carried out under the same conditions, the percent inhibition of the activation of the pentose pathway of macrophages is determined by the following formula: number of com T x 100

number of cpm Z - number of cpm T

wherein 1% is the percent inhibition, cpm is counts per minute. X is the average for samples of the tested compound at a given concentration, T is the average for the comparison samples, and Z is the average for zymosan-treated samples.

2 - Acute toxicity in mice.

20 The dose of the compound which, after oral administration to mice, determines that 50% of these dies (DL50) ·

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ACHIEVED RESULTS

TOXICITY ACTIVATION OF MACROPHAGES

(mouse)% inhibition at the 5 Ex. No._DLrq (mg / kq / p.o.) concentration indicated

1 63% at 5 x 10 “6M

2 non-toxic at 900 - 78% at 5 x 10-¾ 3 non-toxic at 900 - 50% at 4 x 10-¾ 4 non-toxic at 900 - 14% at 5 x 10-¾ 10 5 non-toxic at 900 - 50% at 2 x 10-¾ 6 nontoxic at 900 - 100% at 5 x 10-¾ 8 nontoxic at 900 - 50% at 5 x 10-¾ 9 nontoxic at 900 - 65% at 10-¾ 10 nontoxic at 900 - 45% at 2f5 x 10-¾ 15 11 - - 76% at 5 x 10-¾ 12> 1000 - 50% at 2 x 10-¾ 13 non-toxic at 900 - 52% at 2.5 x 10-¾ 15 non-toxic at 900 - 50% at 1.25 x 10-¾ 16 300 - 900 - 68% 2.5 X 10-¾ 20 17 non-toxic at 900 - 55% at 5 x 10-¾ 18 non-toxic at 900 - 50% at 2 x 10-¾

20> 900 - 75% at 10-5M

21> 900 - 37% at 5 X 10 6M

22 300 - 900 - 50% at 6.5 x 10-¾

25 23 300 - 900 - 58% at 10-5M

25 1200 - 50% at 7.5 x 10-¾ 26> 900 - 50% at 5 x 10-¾ 27 non-toxic at 300 - 40% at 5 x 10-¾ 28 300 - 900 - 50% at 2.5 x 10-¾ 30 29 non-toxic at 900 - 29% at 5 x 10-¾

30 300 - 900 - 49% at 10_5M

31 300 - 900 - 31% at 10-5M

32 non-toxic at 900 - 50% at 5 x 10-¾

33 non-toxic at 900 - 97% at 10-5M

35 34 non-toxic at 900 - 45% at 5 x 10-¾ 35 non-toxic at 900 - 55% at 5 x 10-¾

36 non-toxic at 900 - 80% at 10-5M

?

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TOXICITY ACTIVATION OF MACROPHAGES

(mouse)% inhibition by it

Ex. No._DLkn (mg / kq / p. o.) - concentration indicated

5 37 non-toxic at 900 - 77% at 10 ~ 5M

38 non-toxic at 900 - 92% at 10 - ¾

39 non-toxic at 900 - 72% at 10 ”5M

40 non-toxic at 900 - 84% at 10 ”5M

41 non-toxic at 900 - 22% at 5 x 10 ”6M

10 42 non-toxic at 900 - 50% at 2 x 10-6M

43 non-toxic at 900 - 50% at 7.5 x 10 ”6M

44 non-toxic at 900 - 50% at 10-6M

45 non-toxic at 900 - 20% at 5 x 10-6M

46 non-toxic at 900 - 75% at 10-5M

15 47 non-toxic at 900 - 58% at 10-5M

48> 900 - 50% at 5 x 10-6M

49 non-toxic at 900 - 57% at 10 ”5M

50 non-toxic at 900 - 60% at 10 "M

51 non-toxic at 900 - 65% at 10 "5M

20 52> 900 - 67% at 5 x 10 6 M

53 non-toxic at 900 - 50% at 3 x 10 ”6M

Claims (2)

Ar is O __ / S j_L wherein R is hydrogen or chlorine, A is oxygen or imino, 10 alkylimino or formylimino, and Ar is phenyl substituted with a cycloalkyl group wherein the cycloalkyl moiety contains 3-7 carbon atoms, straight or branched alkenyl of 2-4 carbon atoms, anilino, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl, 1,3-dioxolan-2-yl, dialkylaminomethylenamino, trifluoromethylthio or alkyl substituted by hydroxy, alkyloxy, carboxy, amino, alkylcarbonylamino, alkyloxycarboxylic acid dialkylaminomethylenamino, formamido, alkylureido, phenylsulfonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, formyl, semicarbazonomethyl, 1,3-dithiolan-2-yl or 1,3-20 dioxolan-2-yl, or Ar means pyridyl, quinolyl, isoquino indanyl or quinoxalinyl, or R is hydrogen, A is oxygen or imino, alkylimino or formylimino, and Ar is phenyl substituted with an alkyl group, or R is chlorine, A is oxygen or formylimino, and Ar is means phenyl substituted with an alkyl group, all of the alkyl groups and alkyl moieties being straight or branched and containing 1-4 carbon atoms, or being addition salts with acids, metal salts or addition salts with organic bases. Pharmaceutical composition, characterized in that it contains at least one compound according to claim 1 together with one or more compatible and pharmaceutically acceptable diluents or excipients.