PL201047B1 - New 8-substituted-3-imino-2,3,7,8-tetrahydroimidazo [2,1-c] [1,2,4] triazine-4 (6H) -ones and their preparation - Google Patents

Abstract

The invention relates to new 8-substituted-3-imino-2,3,7,8-tetrahydroimidazo-[2,1-c]-[1,2,4]triazin-4(6H)-ones of the general formula 1, wherein R is an aromatic substituent, preferably phenyl, and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, exhibiting effects on the central nervous system. The compounds being the subject of the invention are obtained by condensation of appropriately substituted imidazolidine-2-one hydrazone hydrohalides with ethyl oxamate in an organic solvent (aliphatic alcohol) in the presence of basic substances that bind the evolved hydrogen halide. The product is purified by crystallization from dimethylformamide.

Description

(12) PATENT DESCRIPTION (19) PL (11) 201047 (13) ^B1 ( ²¹ ) Application number: 3 ⁷ 3355 ( ⁵⁾ ) ^|nt ·^

C07D 487/04 (2006.01) A61P 25/00 (2006.01) A61P 29/00 (2006.01) (22) Date of filing: 03/03/2005

New 8-substituted-3-imino-2,3,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones and method for their preparation

(73) Patent holder: (43) The application was announced: Medical University of Lublin, Lublin, PL 04/09/2006 BUP 18/06 (72) Inventor(s): Krzysztof Sztanke, Lublin, PL (45) The patent was granted on: 31/03/2009 WUP 03/09 (74) Attorney: Anna Bełz, Medical University

(57) The invention relates to new 8-substituted-3-imino-2,3,7,8-tetrahydroimidazo-[2,1-c][1,2,4]triazin-4(6H)-ones of the general formula 1, wherein R represents an aromatic substituent, preferably phenyl, and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, exhibiting effects on the central nervous system. The compounds being the subject of the invention are obtained by condensation of appropriately substituted hydrohalides of imidazolidine-2-one hydrazones with ethyl oxamate in an organic solvent (aliphatic alcohol) in the presence of basic substances that bind the evolved hydrogen halide. The product is purified by crystallization from dimethylformamide.

PL 201 047 B1

Description of the invention

The subject of the invention are new 8-substituted-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-ones of the general formula 1, where R is an aromatic substituent, preferably phenyl, and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, having pharmacological activity in the central nervous system, especially analgesic, and a method for obtaining them.

The previously known imidazo[2,1-c][1,2,4]triazine derivatives were obtained as cardiovascular agents, compounds with positive cardiac inotropic activity, central nervous system stimulants, herbicides, bactericides and Maillard reaction inhibitors, according to European patent no. 531 812 used in the prevention of chronic diabetic complications such as arteriosclerosis, coronary heart disease, cerebrovascular disease, neuropathy, nephropathy and cataract.

The 8-substituted-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-ones of the general formula 1 which are the subject of the invention are new compounds not described in the source literature so far.

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 phenyl and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and X is halogen, preferably iodine, chlorine or bromine, with ethyl oxamate, 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 alcohol, at the boiling point of the solvent for 4-8 hours, using molar proportions of the substrates 1:1, in the presence of basic substances binding the evolved hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, 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. After the reaction is complete, the solvent is removed, and the residue is purified by crystallization from dimethylformamide.

The new compounds obtained by the method according to the invention have pharmacological effects in the central nervous system, especially analgesic effects.

Example 1

6.08 g (0.02 mol) of 1-phenylimidazolidine-2-one hydrazone hydroiodide, 2.34 g (0.02 mol) of ethyl oxamate, 2 ml of triethylamine, and 40 ml of n-butanol were placed in a 250 ml round-bottomed flask equipped with a reflux condenser and mechanical stirrer and heated for 6 hours at the solvent's boiling point. After cooling, the separated precipitate was filtered off and washed with cold methanol. The precipitate was recrystallized from dimethylformamide. 3.12 g (68% yield) of 8-phenyl-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-one precipitate was obtained, melting point 307-10°C.

¹ H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS):

8.3 (s, 1H, NH); 7.89 (s, 1H, NH); 7.02-7.65 (m, 5H, aromatic protons); 4.2 (s, 4H, 2CH ₂ )

Elemental analysis for the formula C11H11N5O (mol. 229.24)

Calculated: %C = 57.63 %H = 4.84 %N = 30.55

Marked: %C = 57.8 %H = 4.8 %N = 30.4

Example 2

Proceeding analogously to Example 1, 1-(4-methylphenyl)-imidazolidine-2-one hydrazone hydroiodide and ethyl oxamate were used in the reaction to obtain 3.55 g (73% yield) of 8-(4-methylphenyl)-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-one precipitate with melting point 297-299°C.

¹ H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS):

8.08 (s, 1H, NH); 7.68 (s, 1H, NH); 7.21 (d, 2H, aromatic protons); 7.47 (d, 2H, aromatic protons); 4.38/4.54 (J=9.1 Hz, J'=7.6 Hz, dd, 4H, 2CH2 ₎ ; 2.27 (s, 3H, CH3)

Elemental analysis for the formula C^H^NsO (mol. 243.27)

Calculated: %C = 59.25 %H = 5.39 %N = 28.79

Marked: %C = 59.1 %H = 5.4 %N = 28.7

PL 201 047 B1

Example 3

Proceeding analogously to Example 1, 1-(2-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and ethyl oxamate were used in the reaction to obtain 3.43 g (65% yield) of 8-(2-chlorophenyl)-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-one precipitate with a melting point of 215-218°C.

¹ H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS):

8.13 (s, 1H, NH); 7.73 (s, 1H, NH); 7.3-7.61 (m, 4H, aromatic protons); 3.96/4.17 (J=9Hz, J'=7.6Hz, dd, 4H, 2CH2)

Elemental analysis for the formula CnH^ClNsO (mol. molar mass 263.68)

Calculated: %C 50.11 %H = 3.82 %Cl = 13.44 %N = 26.56

Marked: %C 49.9 %H = 3.8 %Cl = 13.5 %N = 26.6

Example 4

Proceeding analogously to Example 1, 1-(3-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and ethyl oxamate were used in the reaction to obtain 3.16 g (60% yield) of 8-(3-chlorophenyl)-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-one precipitate with a melting point of 253-256°C.

¹ H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS):

8.36 (s, 1H, NH); 7.95 (s, 1H, NH); 7.08-7.80 (m, 4H, aromatic protons); 4.2 (s, 4H, 2CH2)

Elemental analysis for the formula _CnH10ClN5O (mol. molar mass 263.68)

Calculated: %C = 50.11 %H = 3.82 %Cl = 13.44 %N = 26.56

Marked: %C = 50.2 %H = 3.7 %Cl = 13.3 %N = 26.7

Example 5:

Proceeding analogously to Example 1, 1-(4-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and ethyl oxamate were used in the reaction to obtain 3.32 g (63% yield) of 8-(4-chlorophenyl)-3-imino-2,3,7,8-tetrahydro-imidazo[2,1-c][1,2,4]triazin-4(6H)-one precipitate with a melting point of 282-284°C.

¹ H NMR spectrum (δ, ppm, DMSO-d6 vs. TMS):

8.31 (s, 1H, NH); 7.91 (s, 1H, NH); 7.21 (d, 2H, aromatic protons); 7.53 (d, 2H, aromatic protons); 4.18 (s, 4H, 2CH2)

Elemental analysis for the formula _CnH10ClN5O (mol. molar mass 263.68)

Calculated: %C = 50.11 %H = 3.82 %Cl = 13.44 %N = 26.56

Marked: %C = 50.2 %H = 3.9 %Cl = 13.3 %N = 26.5

Claims (4)

Patent claims 1. New 8-substituted-3-imino-2,3,7,8-tetrahydro-imidazo [2,1-c] [1,2,4] triazin-4 (6H) -ones of general formula 1, in wherein R is an aromatic substituent, preferably phenyl and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl. 2. The method of preparation of the new 8-substituted-3-imino-2,3,7,8-tetrahydro-imidazo [2,1-c] [1,2,4] triazin-4 (6H) -ones of general formula 1 wherein R is an aromatic substituent, preferably phenyl and its substituted derivatives, especially 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, characterized in that the compound of general formula II, in which R is as defined above, and X is halogen, preferably iodine, chlorine or bromine, is reacted with ethyl oxamate, i.e. a compound of general formula 3 in the presence of basic substances which bind the evolving hydrogen halide, and the process is carried out in an organic solvent at the boiling point of the solvent for a period of 4 -8 hours using 1: 1 molar ratio of substrates. After completion of the reaction, the separated precipitate, after separation from the solvent, is washed with water or alcohol, and then purified by crystallization from dimethylformamide. 3. The method according to p. The process of claim 2, wherein the reaction is carried out in the presence of basic substances such as triethylamine, pyridine, alkali metal alkoxides, sodium carbonate or potassium. 4. The method according to p. A process as claimed in claim 2, characterized in that the reaction is carried out in an aliphatic alcohol, especially ethyl, propyl, isopropyl, butyl alcohol.