PL219640B1 - New derivatives of 1,6-disubstituted imidazo[1,2-a][1,3,5]triazines and process for their preparation - Google Patents

Description

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

In the known art, 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-arylamidazolin-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 imidazolidin-2-one hydrazones were condensed with oxalic acid diethyl ester.

The compounds obtained according to the invention show pharmacological activity in the Central Nervous System and are characterized by a very low toxicity. These compounds can be used in human and veterinary medicine.

The novel derivatives of the invention are the 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine compounds of the general formula 1, wherein R is as defined above.

Compounds of the general formula I, where R is an aromatic substituent, preferably phenyl, and the substituted analogs thereof, especially 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, are obtained by the process of the invention by condensation of appropriately substituted 1 - (1-arylimidazolidin-2-ylidene) -3-benzylurea of general formula 2 with a carbonyldiimidazole of general formula 3. The condensation is carried out in an organic solvent, preferably dimethylformamide, at the reflux temperature of the solvent for 6-8 hours. After completion of the reaction, the solvent is removed by distillation under reduced pressure, propan-2-ol is added to the residue and the mixture is heated. After cooling, the separated precipitate is filtered off and purified by crystallization from a polar solvent, preferably a methanol-propan-2-ol mixture.

Example 1: In a 250 cm round bottom flask equipped with a reflux condenser, 3.2 g (0.01 mol) of 1- (1-phenyimidazolidin-2-ylidene) -3- (4-chlorobenzyl) urea, 1 , 6 g (0.01 mol) of carbonyldiimidazole and 50 cm of dimethylformamide. It was heated to the reflux temperature of the solvent for 8 hours. A small amount of precipitate was filtered off (unreacted carbonyldiimidazole). The solvent was distilled off under reduced pressure, and 20 ml of propan-2-ol was added to the residue, which was heated to reflux. Upon cooling, a precipitate appeared, 1-phenyl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine, which was then filtered off and crystallized from a mixture of methanol-propan-2-ol (1: 3 ratio) formula 1.

2.18 g (50% of yield) of a solid with mp. 263-265 ° C.

Elemental analysis for the formula C18H15N4O2Cl (MW 320.36) calculated:% C = 60.93% H = 4.26% Cl = 9.99 Determined:% C = 60.63% H = 4.12% Cl = 9 , 80

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

3.69-4.10 (dd, 4H, C4 / C5), 4.69 (d, 2H, CH2 benzyl), 6.31-7.45 (m 9H, CHaromau),

The physicochemical data of the remaining 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine derivatives are presented in Table 1.

The compounds according to the invention were subjected to pharmacological tests for their effects on the Central Nervous System. The results of the pharmacological tests carried out on the example of 1- (2-methoxyphenyl) -6- (4-chloro-benzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5 ] the triazine is shown in Table 2.

The compounds according to the invention can be used as active substances in medicaments, especially in the treatment of disorders of the Central Nervous System. The analgesic activity of the tested derivatives is important. The 2-carbonylamino-, 1-arylimidazoline fragment present in the tested compounds due to its similarity to the analogous fragment (phenyl ring, carbonyl group) present in the painkiller BEZITRAMID, drugs of the FENTANYL group, PETYDIN may be responsible for the analgesic activity through the opioid system.

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T a b e l a 1 Physicochemical data of the obtained 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) -dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazines derivatives

Well R Formula Molecular Weight Yield% M.p. * C Analysis Calculated / Found ^l HNMR-5 (ppm) DMSO-ds % C % H % C1 1. 2-CH, C 1 H, N ₄ O 2 Cl 368.83 52 247-249 61.87 61.72 4.65 4.78 9.61 9.50 2.45 (s 3H.CH,) 3.99-4.33 (dd, 4H, H2 / H3), 4.92 (d, 211, CH, benzyl) 6.31-7.45 (m 8H, CH "), 2. 4-CH, C19H17N4O2Cl 368.83 43 225-227 61.87 61.94 4.65 4.35 9.61 9.52 2.80 (s 3H, CH 2) 4.05-4.12 (dd, 4H, H 2 / H 3 J, 4.90 (d, 2H, CH ₂ benzyl), 7.34-7.62 (m, 8H, CH "), 3. 2-OH, CHHI5N4O2C1 384.83 54 258-260 59.30 59.65 4.45 4.61 9.21 9.20 3.55 (s, 3H, OCH,), 3.69-4.22 (dd, 4H, H2ZH3), 4.65 (d, 2H, CH ₂ benzyl), 6.60-7.41 (m, 8H, CH ,,). 4. 4-OH, C "Hi7N.OjCI 384.83 58 260-261 59.30 59.56 4.45 4.68 9.21 9.17 3.53 (s, 3H, OCH,), 3.90-4.30 (m 4H, H2 / H3), 4.46 (d, 2H, CH ₂ benzyl), 6.83-7.14 (m, 8H, CH.,), 5 2-CI CwHnWfcCfe 389.26 64 196-197 55.54 55.69 3.63 3.89 18.22 18.20 4.15-4.24 (m 4H, H2 / H3), 4.96 (d, 2H, CH ₂ benzyl), 7,24-7.80 (m 8H, WD)

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TABLE 2 The results of pharmacological studies of 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazines derivatives based on the example 1- (2-methoxyphenyl) -6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine.

1- (2-methoxyphenyl) -6- (4-chiorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5 J-triazine ED 50 (mg / kg) i.p. 2000 Effects on mobility ** 4a spontaneous ** 4b Effect on hyperactivity amphetamine - 60 '* 4.90' *** 1, 120'-150 '** 4 a Effect on body temperature 60'-90 '*** 4, 120' ** 4 b Protective effect in the seizure test pentetrazoles Motor coordination -

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a) on a rotating rod b) in the chimney test Impact on episodes of 'head shaking induced by 5-HTP t ns Antinociceptive activity a) in the drag test * a b) in the "drag" test z naloxone *

a - after administration of the compound at a dose corresponding to 0.1 ED _SO b - after administration of the compound at a dose corresponding to 0.05 ED50 *** pO.OOl ** p <0.01 * p <0.05 | - reduction, | - increase - no influence

The compounds obtained according to the invention are characterized by a very low toxicity. Dose

ED ₅₀ for both compounds, determined on the basis of the observation of the loss of the righting reflex among the tested animals, is 2000 mg / kg ip In the performed tests, the compound 1- (2-methoxyphenyl) -6- (4-chloro-benzyl) -5.7 (1H ) dioxo-2,3-di-hydroimidazo [1,2-a] [1,3,5] triazine strongly lowered the body temperature of normothermic animals from 60 to 150 minutes after administration (0.1 ED50) and from 60 to 120 min (0.05 ED50), inhibited the spontaneous mobility of animals, and clearly, though not statistically significantly increased the episodes of head shaking caused by the administration of 5-hydroxy-L-tryptophan, which may suggest the involvement of the serotonin system in the depressive effect on the CNS . It also showed antinociceptive activity in the "writhing" test, manifested by a statistically significant inhibition of dragging episodes. This activity was reversed by administration of naloxone, which may suggest a relationship with the opioid system. However, the compound did not affect the hyperactivity caused by amphetamine administration, it did not disturb the coordination in both tests (the rota-rhodium test and the chimney test) and showed no protective effect in the pentetrazole convulsion model.

The compound was tested in the following tests:

- the locomotor activity was measured in photoresistors for 30 min as

a) spontaneous mobility

b) amphetamine hyperactivity: mice were administered subcutaneously (s.c.) 5 mg / kg amphetamine min before the test;

the body temperature of the normothermic mice was measured in the rectum of the mice with a thermistor thermometer;

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- pentetrazole convulsions (PTZ, 110 mg / kg) were assessed in mice showing clonic, tonic convulsions and death;

- the coordination was measured in the tests of: a) rotating rod b) chimney;

- head shakes after L-5-HTP (180 mg / kg) were recorded in 6 two-minute intervals (4-6, 14-16, 24-26, 34-36, 44-46, 54-56 min);

- the antinociceptive activity was assessed in the "drag" test, where the number of dragging episodes was recorded for 10 min, starting 5 min after intraperitoneal administration of 0.6% acetic acid solution;

the effect of naloxone (5 mg / kg) on the antinociceptive effects of the compounds was assessed in the "drag" test.

The compound was administered at doses corresponding to 0.1, 0.05, 0.025 ED50.

Claims (3)

1. 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo- [1,2-a] [1,3,5] triazine derivatives of general formula 1, where R is preferably an aromatic substituent, phenyl and its substituted analogs, especially 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl. 2. A method for the preparation of 1-aryl-6- (4-chlorobenzyl) -5.7 (1H) dioxo-2,3-dihydroimidazo [1,2-a] [1,3,5] triazine of general formula 1, where R is an aromatic substituent, preferably, phenyl and its substituted analogs, in particular 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, characterized in that the compound of general formula II, wherein meaning, it is reacted with a carbonyldiimidazole of the general formula 3, the reaction is carried out in an organic solvent, preferably dimethylformamide, at the reflux temperature of the solvent for 6 - 8 hours, using a molar ratio of 1: 1, and after completion of the reaction, the solvent is distilled off and the separated the precipitate is purified by crystallization from a polar solvent. 3. The method according to p. 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.