CS200101B1 - Substituted 0-/5-pyrimidinyl/thiocarbamates and process for preparing them - Google Patents

Description

(54) Substituted O - (5-pyrrolidinyl) thiocarbamates A process for their preparation

The invention relates to substituted O- (5-pyrimidinyl) thiokerbamates of the general formula I-I

* 3 (I) wherein R 1 represents C 1 -C 4 alkylthio, R 4 C 1 -C 4 alkyl, R 4 alkyl and C 1 -C 4 alkyl or phenyl optionally substituted by one or two halogen atoms, especially chlorine, one or two methyl or methoxy groups, or the substituents Rg-Rj, taken together, form a four to six-membered polymethylene chain which may be interrupted by one oxygen, sulfur or nitrogen atom. The invention also relates to a process for the preparation of compounds of the formula I.

The substituted δ (5-pyrimidinyl) thiocarbamates of the formula I are novel hitherto undescribed compounds which have been found to have significant antifungal activity against various dermatophytes in vitro, as shown in the following table:

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The antifungal efficacy of the disclosed compounds, expressed as a minimum inhibitory concentration / µg / ml

Substance TM TR TV TSch MG MA MC BF O- (2-Methylthio-5-pyrimidinyl) -N- -methyl-N-phenylthio carbamate 0.8 0.6 0.5 1,2 6.2 3.1 2.6 1.5 O- (2-Methylthio-5-pirimidinyl) -N- -methyl-N-p-chlorophenylthio carbamate 0.3 0.3 0.1. 0.6 3.1 • 2.6 1,2 0.7 O- (2-Methylthio-5-pyrimidinyl) -N- -methylthi-N-m-cyclophenylthio carbamate; 0.07 0.07 0.05 0.1 0.6 ^U , 1 0.1 0.2 O- (2-Methylthio-5-pyrimidyn) -N- methyl N-p-methoxyphenylthiocarbamate 0.6 0.5 0.3 1,2 2.6 1,8 1,2 2.2 O- (2-Methylthio-5-pyrimidinyl) -N- methyl-N-p-tolylthiocarbamate m.p. 0.3 0.2 0.1 0.5 3.1 2.6 1,2 0.5 O- (2-Methylthio-5-pyrimidinyl) -N- methyl N-m-tolylthiocarbamate 0.06 0.05 0.03 0.06 0.4 0.1 0.1 ^υ , 15 O- (2-Methylthio-5-pyrimidinyl) -N- -methyl-N- (3,4-dichlorophenyl) thiocarbamate 0.15 0.1 0.07 0.15 0.5 0.1 0.1 0.3

O- (2-Methylthio-5-pyrimidinyl) -N-methyl-N- (3,5-dichlorophenyl) thiocarb-

mát 0.05 0.04 0.03 0.06 0,4 0,1 0.1 0.15 O- (2-Methylthio-5-pyrimidinyl) -N-methyl-N- (3,4-dimethylphenyl) thio carbamate 0.09 0.06 0.03 θ » ¹ 0,5 0,1 0.1 0.2 O- (2-Methylthio-5-pyrimidinyl) -N- methyl-N- (3,5-dimethylphenyl) thiocar- bamát 0.07 0.04 0.02 0.07 0,4 0,1 0.1 ^V , 15

Tested microorganisms j

TM Triohophyton Mentagrophytes, TR Jric, Hophyton Rubrum, TV ®riohophyton verrucosum, TSch

Triohophyton sohoenleinii, MG Nicopsis gypseum, MA Microsporum audouinii, MG Miorosporum canla, EF Epidermophyton floccosum.

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According to the invention, the compounds of the formula I can be prepared by converting to the ω-bis (5-pyrimidinyl) thiocarbonate of the formula II

in which R1 denotes the same as in formula I, acts with a secondary amine of formula III / ^R3

HN 1 (III) ^R 2 in which R g and R 2 denote the same as in formula I, in a water or inert organic solvent such as ethanol, acetone, dioxane, diidopropyl ether or dimethylsulfoxide, at a temperature of 0 to 100 ° C, preferably 10 to 50 ° C.

Typically, a thiocarbonate of formula (H) is introduced into a solution of the secondary amine (111) in the selected solvent and the reaction mixture is allowed to either stand at room temperature (in the case of strongly basic aliphatic amines or heterocyclic bases such as piperidine). , morpholine, N-methylpiperazine, and the like) or the reaction mixture is heated or boiled as necessary in the case of weak bases such as N-alkylanilines. In this reaction, 1 mole of the corresponding 5-hydroxypyrimidine is liberated, which, after isolation of the thiocarbamate of formula I, can easily be regenerated from the mother liquor and reused to prepare the starting thiocarbonate of formula II.

Details of the process for the preparation of the novel compounds of the formula I as well as the intermediates, if their preparation is not known from the literature, are given in the following examples.

EXAMPLES Example 1

A solution of 91.0 g of 2-methylthio-5-hydroxypyrimidine in 48.5 ml of 5% sodium hydroxide solution is added dropwise with stirring to a solution of 77.0 g of thiophosgene in 500 ml of chloroform at a temperature below 30 [deg.] C. Heat briefly to reflux. After cooling, the precipitated crystalline solid was washed with water and acetone to give 50.0 g of crude O, O-bis- (2-ethyl) -thio-5-pyrimidinyl) thiocarbonate with m.p. 168 DEG-169.5 DEG C. (carbon tetrachloride).

Analogously prepared from thiophosgene and 2-isobutylthio-5-hydroxy-pyrimidine is O-bis- (2-isobutylthio-5-pyrimidinyl) thiocarbonate with m.p. 98 DEG-101 DEG C. (ethanol).

Example 2

To a solution of 8.7 g of morphine in 150 ml of acetone at 0-10 ° C was added portionwise 32.6 g of O, O-bis- (2-methylthio-5-pyrimidinyl) thiocarbonate, and the mixture was stirred for 2 h at room temperature. room temperature. ^When the reaction mixture is poured into 1000 ml of cold water, the precipitated product is filtered off with suction and washed with water. & Iška 25.0 g of 0- (2-methylthio-5-pyrimidinyl) -N _' N- (3-oxapentamethylene) thiocarbamate & Bt 14 to 148,5 ° C (ethanol).

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In analogy, these compounds are prepared from O, N-bis- (2-methylthio-5-pyrimidinyl) thiocarbonate and the corresponding and corresponding secondary amines.

N- (2-methylthio-5-pyrimidinyl) -N, N-dimethylthiocarbamate with m.p. 100-101 ° C (water), O- (2-methylthio-5-pyrimidinyl) -N, N-pentamethylene thiocarbamate, m.p. 70.5 to 71.5 ° C (60% ethanol),

N- (2-methylthio-5-pyromidinyl) -N, N- (3-thiapentamethylene) thiocarbamate with m.p. 99.5 to 100.5 ° C (60% ni ethanol), *

O - (2-methylthio-5-pyrimidinyl) -N, N- (3-methyl-3-azapentamethylene) thiocarbamate with m.p. 128 DEG-129 DEG C. (30% methanol).

Example 3

To a solution of 12.9 g of di-n-butylamine in 15O mL of acetone at ⁰ DEG to 10 DEG C. was added portionwise 32.6 g 0, ^0-bis- (2-methylthio-5-pyrimidinyl) thiocarbonate, and the mixture Stir 2.5 h at room temperature. The reaction mixture was poured into 1000 ml of cold water and the product was extracted twice with 400 ml of ether each time. After drying the ether extract, the ether was evaporated and the oily residue was purified by distillation. 20.0 g of O- (2-methylthio-5-pyrimidinyl) -N, N-di-n-butylthiocarbamate having a bp of 183-186 DEG C./0.7 mbar were obtained.

Example 4

To a solution of 14.2 g of N-methyl-m-chloroaniline in 200 ml of acetone at 0 DEG to 20 DEG C. is added in small portions with stirring 32.6 g of O, O-bis (2-methylthio-5-pyrimidinyl) thiocarbonate and the mixture slowly warms to reflux. After 1 1/2 h, the reaction mixture was cooled and poured into 1000 mL cold water. The precipitated crude O (2-methylthio-5-pyrimidynil) -N-methyl-N-m-halophenylthiocarbamate is filtered off with suction and washed with water. 8.1 g of compound are obtained and m.p. 93-95 ° C (ethanol).

Analogously from O, O-bis (2-methylthio-5-pyrimidinyl) thiocarboxylate, respectively. O-bis (2-isobutylthio-5-pyrimidinyl) thiocarbonate and the corresponding N-methylanilines will prepare these compounds »

O (2-methylthio-5-pyrimidinyl) -N-methyl-N-phenylthiocarbamate βbt 157.5-158 ° C (ethanol), O- (2-methylthio-5-pyrimidinyl) -N-methyl-N-3,4 —Dichlorophenyl thiocarbamate with bt 122.5 to 123 ° C (90% ethanol),

O (2-methylthio-5-pyrimidyl) -N-methyl-R-3,5-dichlorophenylthiocarbamate, m.p. 160-172 ° C (ethanol),

N- (2-methylthio-5-pyrimidinyl) -N-methyl-N-methyl-N-m-tolylthiocarbamate and m.p. 112-114 ° C (ethanol),

O (2-methylthio-5-pyrimidinyl) -N-methyl-N-3,5-dimethylphenylthiocarbamate β m.p. 147.5-149 ° C (85% ethanol),

N- (2-methylthio-5-pyrimidinyl) -N-methyl-N-p-methoxyphenylthiocarbamate with m.p. 102.5 to 103 ° C (80% ethanol),

N- (2-methylthio-5-pyrimidinyl) -N-methyl-N-3,4-dimethylphenylthiocarbamate with m.p. 115.5-117 ° C (90% ethanol),

N- (2-methylthio-5-pyrimidinyl) -N-methyl-N-p-tolylthiocarbamate β m.p. 109-111 ° C (ethanol),

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O- (2-methylthio-5-pyrimidinyl) -N-methyl-N-p-chlorophenylthiocarbamate β m.p. 143.5-145 ° C (70% ethanol),

N- (2-isobutylthie-5-pyrimidinyl) -N-methyl-N-m-tolylthiocarbamate β m.p. 62 ei 65 ° C (carbon tetrachloride),

Claims (2)

SUBJECT OF THE INVENTION Substituted δ- (5-pyrimidinyl) + thiocarbamates of the general formula I (I) in which R 1 denotes C 1 -C 4 alkylthloscycline, R 8 -C 1 -C 4 alkyl and R 1 -C 1 -C 4 alkyl or phenyl, optionally substituted by one or two halogen atoms, in particular chlorine, by one or two methyl or methoxy groups, or the substituents R 8 and R 6 taken together form a four to six membered polymethylene chain which may be interrupted by one oxygen, sulfur or nitrogen atom · 2. A process for the preparation of substituted Q1 (5-pyrimidiayl) thiocarbate of the general formula I according to claim 1, characterized in that to the O, O-bis (5-pyrimidinyl) thiocarbonate of the general formula II (II) in which denotes the same in formula I, with a secondary amine of formula III X ^R 3 HN (III) R. wherein R 8 and R 8 denote the same as in formula I in a medium of water or an inert organic solvent, for example ethanol, acetone, dioxane, diisopropyl ether or dlmethylsulfoxide, at a temperature of 0 to 100 ° C, preferably 10 to 50 ° C.