PL205167B1 - Novel 3-R-4-substitute derivatives of deltha-1,2,4-triazolin-5-thione and method of obtaining them - Google Patents

Description

Description of the invention

The subject of the invention is new 3-R-4-substituted- ² -1,2,4-tnazoline-5-thione derivatives of the general formula I, in which the symbol R represents pyrrolidine, morpholine, dimethylamine, diethylamine. dibutylamine and the symbol R 'means the group: C6H5, P-CH3C6H4, P-OCH3C6H4, p-BrC6H4, P-NO2C6H4 and the method of their preparation.

The new derivatives which are the subject of the invention show an antibacterial effect.

Based on reports from chemical literature, aminoguanidine salts have been used in reaction with isothiocyanates to prepare 3-amino-4-substituted-1,2,4-triazoline-5-thionium (British Patent, 736, 568, Sep.28 (1955)). 3-amino-1,2,4-triazoline-5-thionium derivatives show bacteriostatic activity (Ikizler A.A., Johansson C.B., Bekircan O., Celik C, Acta Polon. Pharm. 56, 283 (1999)).

The compounds according to the invention are obtained by reacting 2-amino-1-substituted guanidinium hydroiodides of the general formula 2 in which the symbol R has the above meaning with an isothiocyanate of the general formula 3 in which the symbol R 'is also as defined above.

The reaction of 2-amino-1-substituted guanidine hydroiodides with the indicated isothiocyanates according to the invention is carried out in anhydrous ethanol at a molar ratio of 1: 1 at 25-78 ° C for 3-24 hours. After completion of the reaction, ethanol is distilled off, the product obtained is washed thoroughly with diethyl ether and then with water, and the dried residue is recrystallized several times from anhydrous ethanol.

The starting material 2-amino-1-substituted guanidine hydroiodides are obtained by reacting 3-thiocarbazinic acid methyl ester with secondary amines: pyrrolidine, morpholine, dimethylamine, diethylamine, dibutylamine, in anhydrous methanol, leaving the substrates at room temperature for 48 hours.

Alternatively, the invention provides a method for the preparation of new compounds of general formula 1 in which R is as defined above, by reacting 2-amino-1-substituted guanidine hydroiodides of general formula 2 with an isothiocyanate of general formula 3 in which R 'is also the meaning given above.

In an alternative, the substrates used in a 1: 1 molar ratio are heated in N, N-dimethylacetamide at 60-100 ° C. After completion of the reaction, N, N-dimethylacetamide is distilled off, and the dry residue is washed with water, diethyl ether and, after drying, crystallized from alcohol as described above.

Example I. 2.3 g (0.01 mol) of 3-thiocarbazinic acid methyl ester hydroiodide and 0.71 g (0.01 mol) of pyrrolidine in 30 cm ^{3 of} anhydrous methanol were left in the flask for 48 hours at room temperature . The alcohol was then distilled off under reduced pressure (water pump) to 1/3 volume, and the residue was treated with anhydrous diethyl ether. The precipitated compound, after filtration and drying, was crystallized from ethanol.

2.12 g (83% of theory) of 2-amino-1-pyrrolidinoguanidine hydroiodide, mp 154-155 ° C were obtained. 2.56 g (0.01 mol) of the obtained hydroiodide and 1.65 g (0.01 mol) of 4-tolyl isothiocyanate in 20 cm ^{3 of} anhydrous ethanol were heated in a flask under reflux in an oil bath under the reflux temperature of the solvent for 3 hours. The reaction product was then washed thoroughly with water followed by diethyl ether. The dried product was crystallized several times from anhydrous ethanol. 1.69 g (65% of theory) of 3-pyrrolidine-4- (4-tolyl) -N ² -1,2,4-triazoline-5-thionium with a melting point of 183-185 ° C were obtained.

Example II. 2.56 g (0.01 mol) of 2-amino-1-pyrrolidinguanidine hydroiodide, prepared according to Example 1, and 1.65 g (0.01 mol) of 4-tolyl isothiocyanate in 20 cm ^{3 of} N, N-dimethylacetamide were heated to a temperature of 90 ° C for 5 hours. Then, N, N-dimethylacetamide was distilled to dryness, and the residue was washed with water, diethyl ether and, after drying, recrystallized several times from anhydrous ethanol.

1.69 g (65% of theory) of 3-pyrrolidine-4- (4-tolyl) -A were obtained. ² -1,2,4-triazoline-5-thion, m.p. 183-185 ° C.

Example III. 2.56 g (0.01 mol) of 2-amino-1-pyrrolidinoguanidine hydroiodide prepared according to Example 1 and 1.8 g (0.01 mol) of 4-nitrophenyl isothiocyanate in 20 cm ^{3 of} anhydrous ethanol were allowed to stand at room temperature for 24 hours. hours. The solution was then quenched with water. The precipitate formed is filtered off, washed with diethyl ether and, after drying, recrystallized several times from anhydrous ethanol.

PL 205 167 B1

1.88 g (68% of theory) of 3-pyrrolidine-4- (4-nitrophenyl) N '-1,2,4-triazoline-5-thionium with a melting point of 180-183 ° C were obtained.

The procedure described in Example 1 was used to obtain compounds listed in the table in items 2, 6, 7, 8, 9, 10, 16, 17, 18, 22, 24. Listed in items: compounds 1, 2, 6, 7, 8 , 9, 10, 12, 13, 16, 17, 18, 21, 22, 23, 24 were obtained according to example 2, and in positions: 3, 4, 5, 11, 14, 15, 19, 20 according to example 3.

L.p. Relationship name Performance [g =%] Melting point [° C] 1 3-pyrrolidine-4-phenyl-? ² -1,2,4-triazoline-5-thion 1.48 = 60 179-180 2 3-pyrrolidine-4- (4-tolyl) -A ² -1,2,4-triazoline-5-thion 1.69 = 65 183-185 3 3-pyrrolidine-4- (4-methoxyphenyl) -A ² -1,2,4-triazoline-5-thion 1.93 = 70 168-170 4 3-pyrrolidine-4- (4-bromophenyl) -A ² -1,2,4-triazoline-5-thion 2.99 = 92 174-175 5 3-pyrrolidine-4- (4-nitrophenyl) -A ² -1,2,4-triazoline-5-thion 1.88 = 68 180-183 6 3-morpholino-4-phenyl-? ² -1,2,4-triazoline-5-thion 2.23 = 85 144-145 7 3-morpholino-4- (4-tolyl) -A ² -1,2,4-triazoline-5-thion 2.21 = 80 148-150 8 3-morpholino-4- (4-methoxyphenyl) -A ² -1,2,4-triazoline-5-thion 2.48 = 85 161-163 9 3-morpholino-4- (4-bromophenyl) -A ² -1,2,4-triazoline-5-thion 2.80 = 82 176-177 10 3-morpholino-4- (4-nitrophenyl) -A ² -1,2,4-triazoline-5-thion 2.86 = 93 166-168 11 3- (N, N-dimethylamino) -4-phenyl-A ² -1,2,4-triazoline-5-thion 1.67 = 76 185-187 12 3- (N, N-dimethylamino) -4- (4-tolyl) -A ² -1,2,4-triazoline-5-thion 1.76 = 75 223-224 13 3- (N, N-dimethylamino) -4- (4-methoxyphenyl) -A ² -1,2,4-triazoline-5-thion 1.75 = 70 135-137 14 3- (N, N-dimethylamino) -4- (4-bromophenyl) -A ² -1,2,4-triazoline-5-thion 2.18 = 73 191-193 15 3- (N, N-dimethylamino) -4- (4-nitrophenyl) -A ² -1,2,4-triazoline-5-thion 2.25 = 85 182-184 16 3- (N, N-diethylamino) -4-phenyl-A ² -1,2,4-triazoline-5-thion 1.93 = 78 60-61 17 3- (N, N-diethylamino) -4- (4-tolyl-A ² -1,2,4-triazoline-5-thion 1.91 = 73 81-82 18 3- (N, N-diethylamino) -4- (4-methoxyphenyl) -A ² -1,2,4-triazoline-5-thion 1.95 = 70 60-62 19 3- (N, N-diethylamino) -4- (4-bromophenyl) -A ² -1,2,4-triazoline-5-thion 3.01 = 92 98-99 twenty 3- (N, N-diethylamino) -4- (4-nitrophenyl) -A ² -1,2,4-triazoline-5-thion 2.55 = 87 167-169 21 3- (N, N-dibutylamino) -4-phenyl-A ² -1,2,4-triazoline-5-thion 2.13 = 70 128-130 22 3- (N, N-dibutylamino) -4- (4-tolyl-A ² -1,2,4-triazoline-5-thion 2.00 = 63 78-80 23 3- (N, N-dibutylamino) -4- (4-methoxyphenyl) -A ² -1,2,4-triazoline-5-thion 2.77 = 83 166-168 24 3- (N, N-dibutylamino) -4- (4-bromophenyl) -A ² -1,2,4-triazoline-5-thion 3.33 = 87 101-103

Patent claims

Claims (3)

1. New 3-R-4-substituted N-1,2,4-triazoline-5-thione derivatives of general formula 1, shown in the figure, in which R is pyrrolidine, morpholine, dimethylamine, diethylamine, dibutylamine and R 'is group: C6H5, P-CH3C6H4, p-OCH3C6H4, p-BrC6H4, p-NO2C6H4. 2. The method for the preparation of new 3-R-4-substituted- ² -1,2,4-triazoline-5-thione derivatives of general formula 1, in which R is pyrrolidine, morpholine, dimethylamine, diethylamine, dibutylamine and R 'is the group : C6H5, p-CH3C6H4, P-OCH3C6H4, p-BrC6H4, p-NO2C6H4, characterized in that 2-amino-1-substituted guanidine hydroiodide of the general formula 2 in which the symbol R is as defined above is reacted with isothiocyanates with formula general 4 In 3, in which the symbol R 'has the meaning given above, where the reactions are carried out with a molar ratio of the reactants of 1: 1 in anhydrous ethanol at a temperature of 25-78 ° C for 3-24 hours, then ethanol is distilled off to dryness, and the residue is washed with water, ether and crystallized from ethanol. ₂ 3. The method for the preparation of new 3-R-4-substituted N-1,2,4-triazoline-5-thione derivatives of general formula I, in which R is pyrrolidine, morpholine, dimethylamine, diethylamine, dibutylamine and R 'is the group: C6H5, p-CH3C6H4, p-OCH3C6H4, p-BrC6H4, p-NO2C6H4, characterized in that 2-amino-1-substituted guanidine hydroiodide of the general formula 2 in which the symbol R is as defined above is reacted with isothiocyanates of Formula 3, in which the symbol R 'is as defined above, wherein the reactions are carried out with a molar ratio of the starting materials of 1: 1 in N, N-dimethylacetamide at a temperature of 60-100 ° C for about 5 hours, then N, N- dimethylacetamide is distilled off and the reaction product is washed with water, ether and crystallized from ethanol.