PL196751B1 - New ethyl esters of (54) 7,8-dihydro-6H-imidazo [2,1-c] [1,2,4] triazine-4-oxo-3-formic acids and their preparation - Google Patents

Abstract

1. New ethyl esters of 7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acids of the general formula 1, wherein R is an aromatic substituent, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl.

Description

(12) PATENT DESCRIPTION (19) PL (11) 196751 (13) B1 (21) Application number: 361167 ^{(51) Int.Cl.}

C07D 487/04 (2006.01) A61P 25/00 (2006.01) A61P 25/04 (2006.01) (22) Filing date: 09/07/2003 ₍₅₄₎ New ethyl esters of ⁽⁵⁴⁾ 7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acids and a method for their preparation

(73) Patent holder: (43) The application was announced: Prof. Feliks Skubiszewski Medical University, Lublin, Poland 10/01/2005 BUP 01/05 (72) Inventor(s): Krzysztof Sztanke, Lublin, PL (45) The patent was granted on: 31/01/2008 WUP 01/08 (74) Attorney: Anna Bełz, Professor Feliks Skubiszewski Medical University

⁽⁵⁷⁾ 1. New ethyl esters of 7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acids of general formula 1, wherein R is an aromatic substituent, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl.

PL 196 751 B1

Description of the invention

The invention relates to new ethyl esters of 7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acids and a method for their preparation. The new compounds exhibit pharmacological activity in the central nervous system, particularly analgesic activity.

The previously known imidazo[2,1-c]triazine derivatives were obtained as cardiovascular agents, compounds with positive cardiac inotropic activity, stimulants of the central nervous system, herbicides, bactericides and Maillard reaction inhibitors, according to European patent no. 531 812 they are used in the prevention of chronic diabetic complications such as arteriosclerosis, coronary heart disease, cerebrovascular disease, neuropathy, nephropathy and cataract.

The new ethyl esters of 7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acids of the general formula 1, being the subject of the invention, wherein R is an aromatic substituent, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl, constitute a group of new compounds not described in the source literature so far.

The compounds of general formula 1 according to the invention are obtained by condensation of an appropriately substituted imidazolidine-2-one hydrazone hydrohalide, i.e. a compound of general formula 2, where R is an aromatic substituent, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl, and X is a halogen, preferably iodine, chlorine or bromine, with isonitrosomalonic acid diethyl ester, i.e. a compound of general formula 3. The condensation is carried out in an organic solvent, preferably an aliphatic alcohol, especially ethyl, propyl, isopropyl, butyl or dimethylformamide, at the boiling point of the solvent for 1-7 hours, using a molar ratio of the substrates of 1:1, in the presence of basic substances that bind the evolved hydrogen halide, preferably in the presence of triethylamine, pyridine, alkoxides alkali metals, sodium or potassium carbonate. After the reaction is complete, the precipitate is separated from the solvent and washed with water or alcohol to remove salts containing chemically bound hydrogen halide. Then, after separating the solution, the precipitate is crystallized from an organic solvent, preferably methyl alcohol, isopropyl alcohol, dimethylformamide, or a mixture of polar solvents: protic, preferably methyl alcohol, isopropyl alcohol, and aprotic, preferably dimethylformamide, in a volume ratio of 1:1 to 6:1.

The new compounds obtained by the method according to the invention exhibit pharmacological activity in the central nervous system, particularly analgesic activity, and are characterized by low toxicity. Their acute toxicity, expressed as LD50, is above 2000 mg/kg i.p.

Example 1:

15.91 g (0.05 mol) of 1-(4'-methylphenyl)-imidazolidin-2-one hydrazone hydroiodide, 9.45 g (0.05 mol) of isonitrosomalonic acid diethyl ester, 5 ml of triethylamine, and 80 ml of isopropanol were placed in a 250 ml round-bottomed flask equipped with a reflux condenser and mechanical stirrer and heated for 6 hours at the boiling point of the solvent. After cooling, the separated precipitate was filtered off and washed with cold methanol. The precipitate was recrystallized from dimethylformamide. 9.2 g (61% yield) of 8-(4'-methylphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acid ethyl ester was obtained, melting point 205-8°C.

MS (ionization energy - 70 eV) in %: M ⁺ = 300 (75.37); 256 (84.29); 228 (43.70); 200 (100.00); 172 (22.43); 145 (67.56); 91 (42.89)

^1H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS): 7.72 (d, 2H, aromatic protons); 7.24 (d, 2H, aromatic protons); 4.16-4.36 (m, 6H, 3CH2); 2.32 (s, 3H, CH3); 1.29 (t, 3H, CH3)

Elemental analysis for the formula C15H16N4O3 (mol. 300.32)

Calculated: %C = 59.99 %H = 5.37 %N = 18.66

Marked: %C = 59.86 %H = 5.41 %N = 18.71

Example 2:

Proceeding analogously to Example 1, 1-(4'-methoxyphenyl)-imidazolidine-2-one hydrazone hydroiodide and isonitrosomalonic acid diethyl ester were used in the reaction to obtain 10.6 g (67% yield) of 8-(4'-methoxyphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acid ethyl ester with a melting point of 149-151°C.

MS (ionization energy - 70 eV) in %: M ⁺ = 316 (100.00); 272 (21.85); 216 (92.95); 161 (42.98); 107 (4.71)

^1H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS): 7.72 (d, 2H, aromatic protons); 7.06 (d, 2H, aromatic protons); 4.35-4.17 (m, 6H, 3CH2); 3.78 (s, 3H, OCH3); 1.31 (t, 3H, CH3)

PL 196 751 B1

Elemental analysis for the formula C15H16N4O4 (mol. 316.32)

Calculated %C = 56.96 %H = 5.10 %N = 17.71

Marked %C = 57.22 %H = 5.07 %N = 17.67

Example 3:

Proceeding analogously to Example 1, 1-(3'-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and isonitrosomalonic acid diethyl ester were used in the reaction to obtain 10.4 g (65% yield) of 8-(4'-chlorophenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine-4-oxo-3-formic acid ethyl ester with a melting point of 189-191°C.

MS (ionization energy - 70 eV) in %: M ⁺ = 320 (26.83); 276 (100.00); 248 (44.86); 220 (72.93); 165 (31.40); 111 (31.09)

^1H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS): 8.12-7.25 (m, 4H, aromatic protons); 4.37-4.17 (m, 6H, 3CH2); 1.3 (t, 3H, CH3)

Elemental analysis for the formula C14H13ClN4O3 (mol. m. 320.75)

Calculated %C = 52.43 %H = 4.09 %Cl = 11.05 %N = 17.47

Marked %C = 52.45 %H = 4.11 %Cl = 10.94 %N = 17.39

Claims (2)

Patent claims 1. New ethyl esters of 7,8-dihydro-6H-imidazo [2,1-c] [1,2,4] triazine-4-oxo-3-formic acids of the general formula 1, in which R is an aromatic substituent, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl. 2. The method of obtaining new ethyl esters of 7,8-dihydro-6H-imidazo [2,1-c] [1,2,4] triazine-4-oxo-3-formic acids of general formula 1, in which R is a substituent aromatic, preferably 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-chlorophenyl, characterized in that the compound of general formula 2, in which R is as defined above and X is halogen, preferably iodine, chlorine or bromine, is reacted with isonitrosomalonic acid diethyl ester, i.e. a compound of general formula III in the presence of basic substances which bind the evolving hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, sodium or potassium carbonate and in an organic solvent, preferably an aliphatic alcohol , especially ethyl, propyl, isopropyl, butyl or dimethylformamide at the boiling point of the solvent for 1-7 hours, using a molar ratio of the reactants of 1: 1, and after completion of the reaction, a precipitate is isolated p separated from the solvent, washed with water or alcohol, and then crystallized from an organic solvent, preferably from methyl, isopropyl alcohol, dimethylformamide or from a mixture of polar solvents: protic, preferably methyl, isopropyl and aprotic alcohol, preferably dimethylformamide in a 1: 1 volume ratio up to 6: 1.