PL211768B1 - New derivatives of 1-aryl 6-substituted imidazo[1,2-a][1,3,5] triazines and the method of their obtaining - Google Patents

Description

Description of the invention

The invention relates to new 1-aryl 6-substituted imidazo [1,2-a] [1,3,5] triazine derivatives of the general formula I, where R is phenyl and its substituted analogs, in particular 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl and the method of their preparation.

In the known state of the art, and in particular in the patent description PL 190856 and PL 186228, there is a fused heterocyclic imidazo [1,2-a] [1,3,5] triazine system obtained by condensation of 1- (1-arylimidazolin-2- yl) -3-arylureas with phosgene or oxalic acid chloride. Compounds containing this system showed pharmacological activity in the Central Nervous System, especially depressive and analgesic.

The above-described heterocyclic system is also known from the patent description PL 196752, where appropriately substituted halogen hydrides of imidazoiidin-2-one hydrazones were condensed with oxalic acid diethyl ester.

The novel derivatives of the invention are the 1-aryl-6-ethoxycarbonylmethyl-5,7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine compounds of the general formula I, where R denotes phenyl and its substituted analogs, in particular 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl.

The compounds obtained according to the invention show pharmacological activity in the Central Nervous System and are characterized by a very low toxicity.

Compounds of the general formula I, where R is phenyl and its substituted analogs, especially 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, are obtained by the process of the invention by condensation of appropriately substituted 1- (1-arylimidazolines-2). ylidene) -3-ethoxycarbonylmethylurea of general formula 2 in which R is as defined above with carbonyldiimidazole of general formula 3. The condensation is carried out in an organic solvent, preferably dimethylformamide, at the reflux temperature of the solvent for a period of at least 4 hours. After completion of the reaction, the solvent is removed by distillation under reduced pressure. After cooling, the separated precipitate is filtered off and purified by crystallization from a polar solvent, preferably from a 1: 3 methanol-propan-2-ol mixture.

The compounds obtained according to the invention show pharmacological activity in the Central Nervous System, mainly manifested by a depressive effect, and are characterized by a very low toxicity (over 2000 mg / kg ^-1 ip). These compounds can be used both in human and veterinary medicine

Example 1: In a flask, okra g of L odennej 250 cm ³ Cooling cap equipped with a reflux cooler and a stirrer was placed 2.9 g (0.01 mol) of 1- (1-phenyl-imidazolidin-2-ylidene) -3-etoksykarbonylomocznika 1.6g (0.01 mol) carbonyldiimidazole and 30 cm ^{3 of} dimethylformamide. It was heated to the reflux temperature of the solvent for 6 hours. A small amount of precipitate was filtered off (unreacted carbonyldiimidazole). The solvent was distilled off under reduced pressure, and to the residue was added 20 cm ^{3 of} propan-2-ol, heated to reflux. Upon cooling, a precipitate appeared, 1-aryl-6-ethoxycarbonylmethyl-5,7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine, Formula 1 which was then filtered off and crystallized from 2-0l methanol-propane mixtures (1: 3 ratio).

1.77 g (56% of yield) of a solid with mp. 192-194 ° C

Elemental analysis for the C15H16N4O4 formula (MW 316.33)

Calculated:% C = 56.95% H = 5.10% N = 17.71

Determined:% C = 56.83% H = 4.99% N = 17.79

¹ H NMR spectrum (D6-DMSO, δ, ppm, TMS)?

7.12-7.85 (m, 5H, CHaromat); 4.48-4.56 (dd, 2H C4); 4.18-4.21 (dd, 2H, C5), 4.12-4.15 (m, 2H, CH2); 3.81-3.97 (m, 2H, CH2); 1.20-1.22 (s, 3H, CH3)

The physicochemical data of the remaining 1-aryl-6-ethoxycarbonylmethyl-5,7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine derivatives are presented in Table 1 in positions 1 to 4.

Detailed results of studies on the pharmacological activity of the new compounds were carried out on the example of 1-phenyl-6-ethoxycarbonylmethyl-5,7 (1H) dioxo-2,3-dihydroimidazo [1.2-a] [1,3,5] triazine, 1- (4 -methoxyphenyl) -6-ethoxycarbonylmethyl-5.7 (1H) dioxo-2,3-dihydroimidazo [1.2-a] [1,3,5] triazine. The results of the tests of the pharmacological activity of these compounds are presented in Table 2.

PL 211 768 B1

Table 2. Results of pharmacological studies of 1-aryl-6-ethoxycarbonyl methyl-5,7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine derivatives

Type of tests performed 1-phenyl-6- ethoxycarbonylmethyl5.7 (1H) dioxo-2,3-dihydroimidazo [1.2a] [1,3,5] triazine 1- (4-methoxyphenyl) -6-ethoxycarbonylmethyl 5.7 (1H) dioxo-2,3-dihydroimidazo [1 2a] [1,3,5] triazine LD ₅₀ (mg / kg) ip > 2000mg / kg > 2000mg / kg Influence on spontaneous mobility +++; and +++; _and Effect on amphetamine hyperactivity - - Effect on body temperature 30 '+++ ;, 6O' ++ j, 90 '++ ;, i20'+; _a 30 '; g, 6O'; g, 9O '; g, 120'+;, i50 '+; b 30 '+++ ;, 60' +++ ;, 9O '++; a 30 '+++ ;, 60' + ;, 90+ ;, 120 '+ ;, 150' + ;, iso +; b Protective effect in the pentetrazole convulsion test - - Moss coordination a) on a rotating rod - - Moss coordination b) in the chimney test - - Inhibition of 5-HTP induced "head shake" ; g J.G Antinociceptive activity a) in the "dragging" test + a, + b + a, ++ b, + c Antinociceptive activity b) in the naloxone drag test - -

Legend:

a - after administration of the compound at a dose corresponding to 1/10 LDsn. b - after administration of the compound at a dose corresponding to 1/20 LD ₅₀ . c after dosing of the compound at 1/40 LD ₅₀ . +++ -p <0.001.

I i -p <0.0L + - p <0.05.

I - lowering,

G result at the borderline of statistical significance.

- no impact.

PL 211 768 B1

PL 211 768 B1

Claims (3)

1. The new 1-aryl 6-substituted imidazo [1,2-a] [1,3,5] triazine derivatives of general formula I are 1-aryl-6-ethoxycarbonylmethyl-5.7 (1H) -dioxo-2 , 3-dihydroimidazo [1,2-a] [1,3,5] triazines where R is phenyl and its substituted analogs, especially 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl. 2. The method of obtaining new 1-aryl 6-substituted imidazo [1,2-a] [1,3,5] triazine derivatives of the general formula I, where R is phenyl and its substituted analogs, especially 4-methylphenyl, 4- methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, characterized in that the corresponding 1- (1-arylimidazolidin-2-ylidene) -3-ethoxycarbonylmethylureas of the general formula 2 in which R is as defined above is condensed with a carbonyldiimidazole of the general formula 3 , wherein the condensation is carried out in an organic solvent, preferably dimethylformamide, at the boiling point of the solvent for at least four hours, and after completion of the reaction, the solvent is removed by distillation under reduced pressure, and the separated precipitate is filtered off after cooling and purified by crystallization from polar solvent. 3. The method according to claim. 2. A method according to claim 2, characterized in that the separated precipitate is purified by crystallization from a 1: 3 methanol-propan-2-ol mixture.