DE3018670A1 - N-Alkyl-N-phenyl-O-phenyl-thiocarbamic acid derivs. - for local treatment of fungal skin infections, effective against e.g. Trichophyton mentagrophytes and Microsporum canis. - Google Patents

Abstract

Thiocarbamic acid esters of formula (I) are new. R1 is H, halo or alkyl hydroxyalkyl, alkoxy or alkylthio each with 1-4C in alkyl component; R2 is H, halo or alkyl, alkoxy or alkylthio, each with 1-4C in alkyl component; R3 is 1-4C alkyl; R4 is 2-6C straight chain, branched or cyclic alkyl substd. alkyl, alkylthio, hydroxyalkylthio, alkylsulphinyl, alkylcarbonyl, alkylcarbonyloxime, oxime (opt. substd.), alkyl carbonyl incorporating the benzene ring CN, carbamoyl, thiocarbamoyl, carboimidoether or carboimidothio ether. (I) are pharmaceuticals with an activity against fungal infections exceeding that of the known thiocarbamic acid ester, Tolnaflat. In vitro (I) are very effective against skin fungi such as Trichophyton mentagrophytes and Microsporum caris, or mould fungi such as Aspergillus niger. In vivo, e.g. experimental skin mycoses in guinea pigs, (I) are effective when used locally and can therefore be used to treat fungal diseases in humans and animals.

Description

Thiocarbamic acid esters, process for their first'Iung,

Medicinal products containing them and their uses From the Belgian Patent specification 627,322 discloses thiocarbamic acid esters with a fungistatic effect; in particular the N-methyl-N-3-tolyl-thiocarbamic acid-2-naphthyl ester (tolnaftate) to fight fungal infections of the skin.

The invention relates to thiocarbamic acid esters of the general formula I in which R¹ is hydrogen, alkyl, hydroxyalkyl, alkoxy, alkylthio each with 1 - 4 carbon atoms in the alkyl radical, in particular methyl, hydroxymethyl, methoxy, methylthio, or halogen, in particular fluorine or chlorine, where R1 is preferably in the 3 position, R2 is hydrogen, alkyl, alkoxy, alkylthio each with 1 - 4 carbon atoms in the alkyl radical, preferably methyl or halogen, where R2 is preferably in the 4- or 5-position, R3 alkyl, in particular methyl or ethyl, R4 alkyl, straight-chain, branched or cyclic with 2 to 6 carbon atoms, in particular ethyl, propyl, butyl, amyl, hexyl, substituted. Alkyl, in particular hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methylthiomethyl, methylthioethyl, N-dimethylaminomethyl, diethylaminomethyl, aminomethyl, aminoethyl, pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, N-methylpiperazinomethyl, N-methylpiperazinomethyl, N-methylpiperazinomethyl, alkylthiothio, in particular methyloxthioethyl, especially hydroxythiothio, in particular methyloxthioethyl, especially hydroxythiothio, especially methyloxthioethyl, especially hydroxythiothio, ethyloxthioethyl, especially hydroxythiomethyl, methylthioethyl, especially hydroxythiothio, methylthioethyl, N-dimethylaminomethyl, methylthioethio Methoxymethylthio, alkylsulfinyl, in particular methylsulfinyl, ethylsulfinyl, alkylcarbonyl, in particular propionyl, butyryl, alkylcarbonyloxime and substituted. Oxime, especially propionyloxime, butyryloxime, propionyl methoxime, propionyl ethoxime, propionyl-N-dimethylaminoethoxime, propionyl-N-diethylaminoethoxime, propionyl-morpholinoethoxime, alkylcarbonyl, including the benzene and oxime-oxime and oxime-oxime and oxime-substituted oxime-oxime and oxime-oxime, especially indethylaminoyl, tetroxime, especially indethylaminoyl, tetroxime, especially dimethylaminoyl , Cyano, carbamoyl, thiocarbamoyl, carboimido ether, or carboimidothioether, in particular carboimidomethyl, -ethylether, carboimidomethyl-, -äthylthioäther mean.

Verbi7çFrven of the general formula I, in which R1 Methyl, methoxy or ethylthio, R2t. ^. 7hydrogen or methyl, R3 methyl 4 and R ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or isoamyl mean.

The invention also relates to a process for the preparation of the thiocarbamic acid esters of the general formula I, characterized in that a) an aniline of the general formula II in which R1, R2, R3 have the meanings given above, with a thiocarbonic acid ester compound of the general formula III in which R4 has the meaning given above and X is halogen, preferably chlorine, C1 to C4-alkylthio, preferably methylthio or phenylthio or p-tolylthio, or b) a thioaarbamic acid compound of the general formula IV in which R11, R2, R3, X have the meanings given above, with a phenol of the general formula V in which R4 has the meaning given above, or reacts with a corresponding alkali metal or ammonium phenolate.

The compounds of the formula II are known. Come as starting materials here for example in question 3-methyl-, 3-hydroxymethyl-, 3-methoxy-, 3-methylthio-, 3-fluoro, 3-chloro, 4-methyl, 3,4-dimethyl, 3, 5-dimethyl-N-methyl-aniline, -N-ethyl-aniline.

The compounds of the formula Iv can be substituted from those just listed Anilines of the formula II can be prepared by reaction with thiophosgene.

The compounds of the formula V are known. Come as starting materials here for example phenols which are substituted in the 4-position by one of the following radicals: ethyl, n-propyl, iso-propyl, cyclo-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclo-butyl, n-pentyl (amyl), iso-pentyl (amyl), neo-pentyl, cyclo-pentyl, n-hexyl, iso-hexyl, cyclo-hexyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, methylthio methyl, 1-methylthioethyl, 2-methylthioethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-dimethylaminomethyl, N-diethylaminomethyl, pyrrolidinomethyl, piperidinomethyl, Morpholinomethyl, N-methylpiperazinomethyl, 1 -N-dimethylaminoethyl, 2-N-dimethylaminoethyl, Methylthio, ethylthio, hydroxymethylthio, acetoxymethylthio, methoxymethylthio, Methylsulfinyl, ethylsulfinyl, propionyl, butyryl, propionyloxime, butyryloxime, propionyl methoxime, Propionylethoxime, propionyl-2-N-dimethylaminoethoxime, propionyl-2-N-diethylaminoethoxime, Cyano, carbamoyl, thiocarbamoyl, carbimidomethyl, -ethyl ether, carbimidomethyl-, Ethioether, or instead of phenols 5-hydroxyl indanone and 6-hydroxytetralone or oximes, methoximes or 2-N-dimethylaminoethoximes.

The compounds of the formula III can be substituted from those just listed Phenols of the formula V can be prepared by reaction with thiophosgene.

The process for the preparation of the compounds of the general formula I according to claim 2 are expediently carried out as follows.

The compounds of the formulas II and LII, or the formulas IV and V are expediently reacted in equimolar amounts. It is recommended the use of a solvent or dispersing agent. Preferred solvents are used in question ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, Amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, Hexamethylphosphoric triamide, also dimethyl sulfoxide, acetonitrile or chloroform.

The reaction times are a few minutes to a few hours. the Reaction temperatures are between 0 and 1000C, advantageously between 60 and 80C.

In the reactions of the reactants of the formulas II and III, or IV and V recommend the use of an acid-binding agent. As an acid-binding Agents come into question, for example, bases such as triethylamine, N-ethylmorpholine or Pyridine, alkali, alkaline earth carbonates or bicarbonates, hydroxides or alkoxides, e.g. sodium methoxide. Instead of the free phenols, their alkali metal or ammonium salts are used, in particular sodium or potassium phenolate.

The products of the process are isolated using customary methods by distilling off the solvents used or diluting the reaction solution with water.

If necessary, the end products can be purified by recrystallization take place from a suitable solvent or solvent mixture.

The preparation of the starting materials according to the general formula III and IV takes place by reacting corresponding anilines of the general formula II, or phenols of the general formula V with thiophosgene. One sets equimolar Quantities of the two reactants around, but the use of one is recommended up to 10 dough excess of thiophosgene. Implementation is beneficial in a 2-phase system, e.g. chloroform / water. As a binding agent for hydrogen chloride An equivalent amount of alkali metal hydroxide is added to the aqueous phase. The reaction is expediently carried out at 0 to a maximum of + 100C. The isolation takes place in the usual way by distillation or crystallization. In most cases the raw products of the implementation can be further processed directly.

The new thiocarbamic acid esters according to the invention have a superior action against fungal infections to the initially mentioned tolnaftate.

They are very effective in vitro because of skin fungi such as Trichophyton mentagrophytes and Microsporum canis or molds such as Aspergillus niger. Also in vivo, e.g.

in experimental skin mycosis on guinea pigs, the compounds are very effective when applied locally and are therefore suitable for the treatment of Fungal diseases in humans and animals.

The compounds according to the invention are suitable for use for example in question solutions, jellies, creams or ointments, as well as aerosols in Form of spray.

The use concentration is generally 0.1-2 percent by weight.

The invention also includes pharmaceutical preparations which have a Compound of general formula I and a pharmaceutically suitable carrier or contain a diluent, as well as combinations and mixtures with others locally active substances against fungi.

Preparation examples: Example 1 (method a)) N-methyl-N- (3-tolyl) -0- (4-tert-butylphenylj-thiocarbamic acid ester To 12.1 g (0.1 mol) of 3-methyl-N-methylaniline, dissolved in 140 ml of dry acetone, 12.6 g (0.15 mol) of powdered sodium bicarbonate are added and added under Stirring 22.86 g (0.1 mol) of thiocarbonic acid (4-tert-butylphenyl) -sterchloride, dissolved in 60 ml of dry acetone, added dropwise. After that, the reaction mixture is 1 hour heated to reflux with stirring. After cooling it is in 2000 ml of water poured, the precipitated product filtered off, washed with water and the end Isopropanol / water recrystallized with the addition of charcoal.

25 g (80% of theory) of N-methyl-N- (3-tolyl) -O- (4-tert. -butylphenyl) thiocarbamic acid ester in the form of colorless crystals with the Melting point 1030C.

The thiocarbonic acid (4-tert-butylphenyl) ester chloride used as the starting material is made by known methods by converting molar amounts of thiophosgene in chloroform with tert-butyl-phenol in aqueous sodium hydroxide solution (two-phase system) at 0 - 150C shown. The crude product is obtained after the chloroform phase has been separated off and evaporated by stirring with petroleum ether or light gasoline of the remaining thiocarbonic acid bis (4th-tert-butylphenyl) ester freed, suctioned off, evaporated and directly reacted further.

The thiocarbonic acid (4-tert-butylphenyl) ester chloride obtainable in this way in very good yield is a yellowish oil, which can be distilled if necessary. But it is pure enough for further implementations.

Example 1 (method b)) N-Methyl-N- (3-tolyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester To 17.2 g (=. 1 mol) of sodium 4-tert-butylphenolate (prepared from 4-tert-butylphenol and sodium methylate) in 300 ml of dimethylformamide are stirred at 700C within 1 hour 20.06 g (=, 1 mol) of N-methyl-N-3-tolyl-thiocarbamic acid chloride in 100 ml Added dropwise chloroform. The reaction mixture is stirred for a further 15 minutes and evaporated to about half volume under reduced pressure. DLe solution becomes 2000 Poured ml of water, sucked off the precipitated product, washed with water and recrystallized from isopropanol / water with the addition of charcoal.

This gives 26.5 g (85% of theory) of N-methyl-N- (3-tolyl) - 0- (4-tert-Butylphenyl) -thiocarbamic acid ester of m.p. 1020C.

The N-methyl-N-3-tolyl-thiocarbamic acid chloride used as the starting material is made by known methods by converting molar amounts of thiophosgene in chloroform with N-methyl-N-3-tolylamine hydrochloride in water (two-phase system) with addition of aqueous soda solution at 0 - 150C. After separation of the chloroform phase and evaporation, the crude product is obtained by stirring with petroleum ether or light gasoline freed from residual bis (N-methyl-N-3-tolyl) thiourea, filtered off with suction, evaporated and implemented directly.

The N-methyl-N-3-tolylthiocarbamic acid chloride obtainable in this way in very good yields is a yellow oil which can be distilled if necessary (bp 3 mm -13QoC). But it is pure enough for further implementations.

Following the procedures described in Example 1, those in the following Examples listed compounds are shown with good yields: From 3-methyl-N-methyl-aniline and phenols corresponding to the thiocarbonic acid ester chlorides: N-methyl-N- (3-tolyl) -0- (4-ethylphenyl) thiocarbamic acid ester, m.p. 380C N-methyl-N- (3-tolyl) -0- (4-n-propylphenyl) thiocarbamic acid ester, Oil N-methyl-N- (3-tolyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, 780C N-methyl-N- (3-tolyl) -0- (4-cyclopropylphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-n-butylphenyl) thiocarbamic acid ester, 1040C N-methyl-N- (3-tolyl) -0- (4-iso-butylphenyl) thiocarbamine- acid esters, 900C N-methyl-N- (3-tolyl) -0- (4-sec-butylphenyl) thiocarbamic acid ester, oil N-methyl-N- (3-tolyl) -0- (4-cyclo-butylphenyl) thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-n-pentylphenyl) -thiocarbamic acid ester, 840C N-methyl-N- (3-tolyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester, 770C N-methyl-N- (3-tolyl) -0- (4-cyclo-pentylphenyl) -thiocarbamic acid ester, 800C N-methyl-N- (3-tolyl) -0- (4-n-hexylphenyl) -thiocarbamic acid ester, N-methyl-N-13-tolyl) -0- (4-iso-hexylphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-cyclo-hexylphenyl) -thiocarbamic acid ester, 820C N-methyl-N- (3-tolyl) -O-t4-hydroxymethylphenyl) -thiocarbamic acid ester, Oil N-methyl-N- (3-tolyl) -O- / 4- (1-hydroxyethyl) -phenyl / -thiocarbamic acid ester, oil N-methyl-N- (3-tolyl) -O- / 4- (2-hydroxyethyl) -phenyl / -thiocarbamic acid ester, N-methyl-N- (3-tolyl) -0- (4-methoxymethylphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- / 4- (1-methoxyethyl) phenyl / thiocarbamic acid ester N-methyl-N- (3-tolyl) -O- / 4- (2-methoxyethyl) - phenyl / thiocarbamic acid ester N-Methyl-N- (3-tolyl) -0- (4-methylthiomethilphenyl) -thiocarbamic acid ester, Oel N-Methy N- [3-tolyl) -O- / 4- (1-methylthioethyl) -phenyl / -thiocarbamic acid ester tS w2teChyl-N- (3-tolyl) -O-} / 4- (2-methylthioethyl) -phenyl / -thio - carbamic acid ester N-methyl-N- (3-tolyl) -0- (4-aminomethylphenyl) -thiocarbamic acid ester hydrochloride, M.p. 2700C N-methyl-N- (3-tolyl) -O- / 4- (1-aminoethyl) -phenyl / -thiocarbamic acid ester hydrochloride, Mp. 2090C N-methyl-N- (3-tolyl) -O- / 4- (2-aminoethyl) -phenyl / -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-N-dimethylaminomethylphenyl) thiocarbamic acid ester hydrochloride, M.p. 21 50C N-methyl-N- (3-tolyl) -0- (4-N-diethylaminomethylphenyl) thiocarbamic acid ester hydrochloride, M.p. 2000C N-methyl-N- (3-tolyl) -0- (4-pyrrolidinomethylphenyl) -thiocarbamic acid ester hydrochloride, M.p. 2060C N-Methyl-N- (3-tolyl) -0- (4-piperidinomethylphenyl) -thiocarbamic acid ester. M.p. 770C N-methyl-N- (3-tolyl) -0- (4-piperidinomethylphenyl) -thiocarbamic acid ester hydrochloride, M.p. 21 20C N-methyl-N- (3-tolyl) -0- (4-morpholinomethylphenyl) -thiocarbamic acid ester hydrochloride, Mp. 2510C, N-Methyl-N- (3-tolyl) -0- (4-N-methylpiperazinomethylphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -O- / 4- (1-N-dimethylaminoethyl) -phenyl / -thiocarbamic acid ester, Oil N-methyl-N- (3-tolyl) -O- / 4- (2-N-diethylaminoethyl) -phenyl / -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester, 870C N-methyl-N- (3-tolyl) -0- (4-ethylthiophenyl) -thiocarbamic acid ester, 600C N-methyl-N- (3-tolyl) -0- (4-hydroxymethylthiophenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-acetoxymethylthiophenyl) -thiocarbamic acid ester, M.p. 830C, N-Methyl-N- (3-tolyl) -0- (4-methoxymethylthiophenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-methylsulfinylphenyl) -thiocarb- amic acid ester, M.p. 1170C N-methyl-N- (3-tolyl) -0- (4-ethylsulfinylphenyl) thiocarbamic acid ester, M.p. 920C N-Methyl-N- (3-tolyl) -0- (4-propionylphenyl) -thiocarbamic acid ester, m.p. 680C N-methyl-N- (3-tolyl) -0- (4-butyrylphenyl) -thiocarbamic acid ester, oil N-methyl-N- (3-tolyl) -O-- (1-hydroxyimino-propion-1 -yl) -phenyl2-thiocarbamic acid ester, 1 770C N-Methyl-N- (3-tolyl) -O-g4- (1-hydroxyimino-butyr-1-yl) -phenylT-thiocarbamic acid ester N-Methyl-N- (3-tolyl) -O- £ 4- (1-methoxyimino-propion-1 -yl) -phenyl-2-thiocarbamic acid ester N-methyl-N- (3-tolyl) -O-fi4- (1-ethoxyimino-propion-1-yl) -phenyl-thiocarbamic acid ester N-methyl-N- (3-tolyl) -O-fi4- (N-dimethylaminoeth-oxyimino-propion-1-yl) -phenyl-2-thiocarbamic acid ester N-methyl-N- (3-tolyl) -O-S4- (N-diethylaminoethoxyimino-propion-1-yl) -phenyl7-thiocarbamic acid ester, Oil N-Methyl-N- (3-tolyl) -0- (4-cyanophenyl) -thiocarbamic acid ester, m.p. 1120C N-Methyl-N- (3-tolyl) -0- (4-carbamoylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-tolyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester, m.p. 1250C N-methyl-N- (3-tolyl) -O (4-carbimidomethoxyphenyl) -thiocarbamic acid ester, N-methyl-N- (3-tolyl) -0- (4-carbimidoethoxyphenyl) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -0- (4-carkimidomethylthio-phenyl) -thiocarbamic acid ester hydroiodide, Mp. 1 580C N-Methyl-N- (3-tolyl) -0- (4-carbimidoethylthio-phenyl) -thiocarbamic acid ester N-Methyl-N- (3-tolyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester, m.p. 1280C N-methyl-N- (3-tolyl) -O- (tetralon-1-yl-6) -thiocarbamic acid ester, Mp 940C N-methyl-N- (3-tolyl) -0- (1-hydroxyimino-indanon-1-yl-5) -thiocarbamic acid ester, M.p. 1700C N-methyl-N- (3-tolyl) -0- (1-hydroxyimino-tetralon-1-yl-6) -thiocarbamic acid ester, 146 ° C N-Methyl-N- (3-tolyl) -0- (1-methoxyimino-indanon-1-yl-5) -thiocarbamic acid ester N-Methyl-N- (3-tolyl) -O- (1-methoxyimino-tetralon-1-yl-6) -thiocarbamic acid ester N-methyl N- (3-tolyl) -O- (N-dimethy] aminoethoxyimino-indanon-1-yl-5) -thiocarbamic acid ester N-methyl-N- (3-tolyl) -O- (N-dimethylaminoethoxyimino-tetralon-1-yl-6) -thiocarbamic acid ester From 3-hydroxymethyl-N-methyl-aniline and the tricarbonic acid ester chlorides corresponding Phenols: N-methyl-N- (3-hydroxymethylphenyl) -0- (4-ethylphenyl) thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4 -n-propylphenylthiocarbamic acid ester, Oil N-methyl-N- (3-hydroxymethylphenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, Oil N-methyl-N- (3-hydroxymethylphenyl) -0- (4-n-butylphenyl) thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4-iso-butylphenyl) thiocarbamic acid ester N-Methyl-N- (3-hydroxymethylphenyl) -0- (4-sec-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, Oil N-methyl-N- (3-hydroxymethylphenyl) -0- (4-iso-pentylphenyl) thiocarbamic acid ester N-Methyl-N- (3-hydroxymethylphenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4-methylthiomethylphenyl) thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4-methylthiophenyl) thiocarbamic acid ester, m.p. 950C N-methyl-N- (3-hydroxymethylphenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester N-methyl-N- (3-hydroxymethylphenyl) -0- (4-thiocarbamoylphenyl) thiocarbamic acid ester, N-methyl-N- (3-hydroxymethylphenyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester N-Methyl-N- (3-hydroxymethylphenyl) -O- (tetralon-1-yl-6) -thiocarbamic acid ester Aus 3-methoxy-N-methyl-aniline and phenols corresponding to the thiocarbonic acid ester chlorides: N-methyl-N- (3-methoxyphenyl) -0- (4-ethylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methoxyphenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester, Oil N-methyl-N- (3-methoxyphenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, M.p. 630C N-Methyl-N- (3-methoxyphenyl) -0- (4-n-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methoxyphenyl) -0- (4-iso-butylphenyl) thiocarbamic acid ester, N-methyl-N- (3-methoxyphenyl) -0- (4-sec-butylphenyl) thiocarbamic acid ester N-Methyl-N- (3-methoxyphenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, m.p. 880C N-Methyl-N- (3-methoxyphenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methoxyphenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methoxyphenyl) -0- (4-methylthiomethylphenyl) thiocarbamic acid ester N-Methyl-N- (3-methoxyphenyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester N-Methyl-N- (3-methoxyphenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester, N-Methyl-N- (3-methoxyphenyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methoxyphenyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester, N-methyl-N- (3-methoxyphenyl) -O- (tetralon-1-yl-6) -thiocarbamic acid ester From 3-fluoro-N-methyl-aniline and the thiocarbonic acid ester chlorides corresponding Phenols: N-methyl-N- (3-fluorophenyl) -0- (4-ethylphenyl) -thiocarbamic acid ester, N-methyl-N- (3-fluorophenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-fluorophenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, m.p. 1130C N-methyl-N- (3-fluorophenyl) -0- (4-n-butylphenyl) thiocarbamic acid ester, N-methyl-N- (3-fluorophenyl) -0- (4-iso-butylphenyl) thiocarbamic acid ester N-methyl-N- (3-fluorophenyl) -0- (4-sec-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-fluorophenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, M.p. 1380C N-Methyl-N- (3-fluorophenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-fluorophenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-fluorophenyl) -0- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-methyl-M- (3-fluorophenyl) -o- (4-methylthiophenyl) -thiocarb amic acid ester N-Methyl-N- (3-fluorophenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester N-Methyl-N- (3-fluorophenyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester, N-Methyl-N- (3-fluorophenyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester N-Methyl-N- (3-fluorophenyl) -O- (tetralon-1-yl-6) -thiocarbamic acid ester From 3-chloro-N-methyl-aniline and phenols corresponding to the thiocarbonic acid ester chlorides: N-methyl-N- (3-chlorophenyl) -0- (4-ethylphenyl) thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-methyl] .- N- (3-chlorophenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, M.p. 980C N-methyl-N- (3-chlorophenyl) -0- (4-n-butylphenyl) thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (4-iso-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (4-sec-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, M.p. 1250C N-Methyl-N- (3-chlorophenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester, N-methyl-N- (3-chlorophenyl) -0- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-chlorophenyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester, N-Methyl-N- (3-chlorophenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester N-Methyl-N- (3-chlorophenyl) -0- (4-thiocar.bamoylphenyl) -thiocarbamic acid ester N-methyl-N- (3-chlorophenyl) -0- (indanon-1-yl-5) -thiocarbamic acid ester, N-methyl-N- (3-chlorophenyl) -O- (tetralone-1-v1-6) -thiocarbamic acid ester From 3-methylthio-N-methyl-aniline and the thiocarbonic acid ester chlorides corresponding Phenols: N-methyl-N- (3-methylthiophenyl) -0- (4-ethylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methylthiophenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methylthiophenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, M.p. 550C N-Methyl-N- (3-methylthiophenyl) -0- (4-n-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3-methylthiophenyl) -0- (4-iso-butylphenyl) -thiocarbamic acid ester, N-methyl-N- (3-methylthiophenyl) -0- (4-sec-butylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester , M.p. 810C N-Methyl-N- (3-methylthiophenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl) -0- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester N-methyl-N- (3-methylthiophenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester N-methyl-N- (3-methylthiophenyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester N-Methyl-N- (3-methylthiophenyl-O- (tetralon-1-yl-6) -thiocarbamic acid ester From 4.-Methyl-N-methyl-aniline and phenols corresponding to the thiocarbonate chlorides: N-methyl-N- (4-tolyl) -0- (4-ethylphenyl) -thiocarbamic acid ester, N-methyl-N- (4-tolyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-Methyl-N- (4-tolyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, m.p. 1200C N-Methyl-N- (4-tolyl) -0- (4-n-butylphenyl) -thiocarbamic acid ester N-methyl-N- (4-tolyl) -0- (4-iso-butylphenyl) -thiocarbamic acid ester, N-methyl-N- (4-tolyl) -0- (4-sec-butylphenyl) -thiocarbamic acid ester N-methyl-N- (4-tolyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, m.p. 1470C N-methyl-N- (4-tolyl) -0- (4-iso-pentylphenyl) - thiocarbamic acid ester N-methyl-N- (4-tolyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester, N-methyl-N- (4-tolyl) -0- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-methyl-N- (4-tolyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester N-methyl-N- (4-tolyl) -0- (4-cyanophenyl) -thiocarbamic acid ester, N-Methyl-N "(4-tolyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester N-Methyl-N- (4-tolyl) -0- (indanon-1 -yl-5) -thiocarbamic acid ester N-Methyl-N- (4-tolyl) -O- (tetralon-1-yl-6) -thiocarbamic acid ester From 3,4-dimethyl-N-methyl-aniline and the thiocarbonic acid ester chlorides corresponding Phenols: N-methyl-N- (3, 4-dimethylphenyl) -0- (4-ethylphenyl) thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-methyl-N- (3f4-dimethylphenyl) -0- (4-iso-propylphenyl} -thiocarbamic acid ester, M.p. 820C, N-Methyl-N- (3,4-dimethylphenyl) -0- (4-n-butylphenyl) thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -0- (4-iso-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -0- (4-sec-butylphenyl) - thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, M.p. 1080C N-Methyl-N- (3,4-dimethylphenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester, N-methyl-N- (3,4-dimethylphenyl) -0- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-methyl-N- (3m4-dimethylphenyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester, N-methyl-N- (3,4-dimethylphenyl) -O- (4-cyanophenyl) -thiocarbamic acid ester N-Methyl-N- (3,4-dimethylphenyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester N-methyl-N- (3,4-dimethylphenyl) -O-vndanon-1-yl-5) -thiocarbamic acid ester, N-methyl-N- (3,4-dimethylphenyl) -O- (tetralon-1-yl-6 ) thiocarbamic acid ester the end 3,5-dimethyl-N-methyl-aniline and the thiocarbonic acid ester chlorides corresponding Phenols: N-methyl-N- (3,5-dimethylphenyl) -0- (4-ethylphenyl) -thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -0- (4-n-propylphenyl) -thiocarbamic acid ester N-methyl-N- (3, 5-dimethylphenyl) -0- (4-iso-propylphenyl) -thiocarbamic acid ester, M.p. 720C N-Methyl-N- (3,5-dimethylphenyl) -0- (4-n-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -0- (4-iso-butylphenyl) -thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -0- (4-sec-butylphenyl) - thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -0- (4-tert-butylphenyl) -thiocarbamic acid ester, M.p. 980C N-Methyl-N- (3m5-dimethylphenyl) -0- (4-iso-pentylphenyl) -thiocarbamic acid ester N-methyl-N- (, 5-dimethylphenyl) -0- (4-neo-pentylphenyl) -thiocarbamic acid ester, N-methyl-N- (3,5-dimethylphenyl) -O- (4-methylthiomethylphenyl) -thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -0- (4-methylthiophenyl) -thiocarbamic acid ester, N-methyl-N- (3,5-dimethylphenyl) -0- (4-cyanophenyl) -thiocarbamic acid ester N-Methyl-N- (3,5-dimethylphenyl) -0- (4-thiocarbamoylphenyl) -thiocarbamic acid ester N-methyl-N- (3,5-dimethylphenyl) -O- (indanon-1-yl-5) -thiocarbamic acid ester N-methyl-N- (3t5-dimethylphenyl) -O- (tetralon-1-yl-6) thiocarbamic acid ester.

Claims (4)

Claims: Thiocarbamic acid ester of formula 1 in which R1 is hydrogen, alkyl, hydroxyalkyl, alkoxy, alkylthio each with 1 - 4 carbon atoms in the alkyl radical or halogen, R² is hydrogen, alkyl, alkoxy, alkylthio each with 1 to 4 carbon atoms or halogen, R³ is alkyl, with 1 - 4 carbon atoms, R4 alkyl, straight-chain, branched or cyclic with 2 to 6 carbon atoms, substituted. Alkyl, alkylthio, hydroxyalkylthio, alkylsulfinyl, alkylcarbonyl, alkylcarbonyloxime and substituted oxime, alkyl carbonyl including the benzene ring, oximes or substituted oximes, cyano, carbamoyl, thiocarbamoyl, carbamido ethers or carboimidothio ethers. 2. Process for the preparation of thiocarbamic acid esters of the formula I in claim 1, characterized in that a) an aniline of the general formula II wherein R1, R, R have the meanings given in claim 1, with a tFìokoh] .enoic acid ester compound of the general formula III wherein R4 has the meaning given in claim 1 and X is halogen, C1 to C4-alkylthio or phenylthio or p-polythio or b) a thiocarbamic acid compound of the general formula IV in which R1, R2, R3, X have the meaning given in claim 1, with a phenol of the general formula V. in which R4 has the meaning given above. 3. Medicinal product, characterized by a content of a thiocarbamic acid ester of formula I in claim 1. 4. Use of thiocarbamic acid ester of the formula I in claim 1 for the treatment of fungal infections.