PL196752B1 - New 3-hydroxy-4-oxo-8-aryl-7, 8-dihydro-6h-imidazo[2, 1-c] [1, 2, 4] triazine and method for their manufacture - Google Patents

Abstract

1. New 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo [2,1-c] [1,2,4] triazines of general formula I, in which R is an aromatic substituent, preferably phenyl and its substituted analogs, especially 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl , 3,4-dichlorophenyl.

Description

(12) PATENT DESCRIPTION (19) PL (11) 196752 (13) B1 (21) Application number: 361373 ^{(51) Int.Cl.}

C07D 487/04 (2006.01) A61P 25/00 (2006.01) A61P 25/04 (2006.01) (22) Date of filing: 21/07/2003

REPUBLIC

POLAND

Patent Office of the Republic of Poland

(54) New 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazines and the method of their production (73) Patent holder: Prof. Feliks Skubiszewski Medical University, Lublin, Poland (43) The application was announced: 24.01.2005 BUP 02/05 (72) Inventor(s): Krzysztof Sztanke, Lublin, PL Dariusz Matosiuk, Lublin, PL Sylwia Fidecka, Lublin, PL (45) The patent was granted on: 31/01/2008 WUP 01/08 (74) Attorney: Anna Bełz, Professor F. Skubiszewski Medical University

⁽⁵⁷⁾ 1. New 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazines of the general formula 1, wherein R is an aromatic substituent, preferably phenyl and its substituted analogues, especially 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl.

PL 196 752 B1

Description of the invention

The subject of the invention are new 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazines and a method for their preparation.

The new compounds have pharmacological effects in the central nervous system, especially analgesic effects.

The previously known imidazo[2,1-c][1,2,4]triazine derivatives were obtained as cardiovascular agents, compounds with positive inotropic cardiac activity, stimulants of the central nervous system, 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 new 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazines of the general formula 1, wherein R is an aromatic substituent, preferably phenyl, and its substituted analogues, in particular 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, which are the subject of the invention, constitute a group of 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 phenyl and its substituted analogues, especially 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, and X is a halogen, preferably iodine, chlorine or bromine, with oxalic 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 the molar proportions of the starting materials 1:1, in the presence of basic substances that bind the evolved hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, sodium carbonate, 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 a mixture of polar solvents: protic, preferably methyl alcohol, isopropyl alcohol, and aprotic, preferably dimethylformamide, in a volume ratio of 1:1 to 1:5.

The new compounds obtained by the method according to the invention exhibit pharmacological effects in the central nervous system, particularly antinociceptive effects related to the opioid system due to the reversal of the analgesic effect by small doses of naloxone (5 mg/kg s.c.). The acute toxicity of the obtained compounds is relatively low, with LD50 ranging from 1100 mg/kg i.p. to above 2000 mg/kg i.p. The tested compounds did not exhibit neurotoxic effects in the rota-rod test or chimney test, and had no effect on spontaneous mobility or amphetamine hyperactivity.

Example 1. 6.1 g (0.02 mol) of 1-phenylimidazolidin-2-one hydrazone hydroiodide, 3.78 g (0.02 mol) of oxalic acid diethyl ester, 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 a 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 a mixture of methyl alcohol and dimethylformamide in a 1:3 volume ratio. 2.85 g (62% yield) of 3-hydroxy-4-oxo-8-phenyl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate was obtained, melting point 314-16°C.

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

11.78 (s, 1H, OH); 7.01-7.63 (m, 5H, aromatic protons); 4.05 (s, 4H, 2CH2)

Elemental analysis for the formula C11H10N4O2 (mol. 230.23)

Calculated: %C = 57.39 %H = 4.38 %N = 24.34

Marked: %C = 57.45 %H = 4.32 %N = 24.27

LD50 = 1400 mg/kg i.p.; analgesic effect at a dose of 0.1 LD50 reversed by naloxone;

hypothermic effect for 90 minutes.

Example 2. Following the same procedure as in Example 1, 1-(2'-methylphenyl-imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain

PL 196 752 B1

3.13 g (64% yield) of 3-hydroxy-4-oxo-8-(2'-methylphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate, melting point 241-3°C.

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

11.46 (s, 1H, OH); 7.42-7.22 (m, 4H, aromatic protons); 4.09 (dd, 2H, CH2); 3.94 (dd, 2H,

CH2); 2.26 (s, 3H, CH3)

Elemental analysis for the formula C12H12N4O2 (mol. 244.26)

Calculated %C = 59.01 %H = 4.95 %N = 22.94

Marked %C = 59.22 %H = 5.02 %N = 22.79

Example 3. Following the same procedure as in Example 1, 1-(4-methylphenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3.3 g (67% yield) of 3-hydroxy-4-oxo-8-(4'-methylphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 330-2°C.

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

11.75 (s, 1H, OH); 7.46 (d, 2H, aromatic protons); 7.2 (d, 2H, aromatic protons); 4.02 (s, 4H, 2CH2); 2.26 (s, 3H, CH3).

Elemental analysis for the formula C12H12N4O2 (mol. 244.26)

Calculated: %C = 59.01 %H = 4.95 %N = 22.94

Marked: %C = 58.89 %H = 4.88 %N = 23.06

LD50 - 1800 mg/kg; analgesic effect at a dose of 0.1 LD50, not reversed by naloxone, hypothermic effect for 30 minutes, protective effect in the pentetrazolium convulsion model.

Example 4. Following the same procedure as in Example 1, 1-(2,3-dimethylphenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3.25 g (63% yield) of 3-hydroxy-4-oxo-8-(2',3'-dimethylphenyl)-7,8-dihydro-6H-imidazo-[2,1-c][1,2,4]triazine precipitate with a melting point of 307-310°C.

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

11.42 (s, 1H, OH); 7.24-7.13 (d, 3H, aromatic protons); 4.09 (dd, 2H, CH2); 3.91 (dd, 2H,

CH2); 2.26 (s, 3H, CH3); 2.14 (s, 3H, CH3)

¹³ C NMR spectrum (ppm):

152.98 (C-3); 145.23 (C-4); 40.99 (C-6); 48.61 (C-7); 154.09 (C-8a); 137.74 (C-9); 134.64 (C-10);

137.65 (C-11); 123.95 (C-12); 126.08 (C-13); 128.71 (C-14); 19.93 (C-15); 14.02 (C-16)

Elemental analysis for the formula C13H14N4O2 (mol. 258.28)

Calculated: %C = 60.45 %H = 5.46 %N = 21.69

Marked: %C = 60.49 %H = 5.37 %N = 21.78

Example 5. Following the same procedure as in Example 1, 1-(2-methoxyphenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3.12 g (60% yield) of 3-hydroxy-4-oxo-8-(2'-methoxyphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 248-251°C.

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

11.46 (s, 1H, OH); 7.46-7.94 (m, 4H, aromatic protons); 4.19 (dd, 2H, CH2); 4.04 (dd, 2H,

CH2) 3.9 (s, 3H, OCH3)

Elemental analysis for the formula C12H12N4O3 (mol. 260.26)

Calculated: %C = 55.38 %H = 4.64 %N = 21.53

Marked: %C = 55.44 %H = 4.70 %N = 21.65

LD50 = 1100 mg/kg; analgesic effect at a dose of 0.1 LD50 not reversed by naloxone.

Example 6. Following the same procedure as in Example 1, 1-(4-methoxyphenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain

3.54 g (68% yield) of 3-hydroxy-4-oxo-8-(4'-methoxyphenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate, melting point 302-3°C.

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

11.7 (s, 1H, OH); 7.52 (d, 2H, aromatic protons); 6.95 (d, 2H, aromatic protons); 4.02 (s, 4H, 2CH2); 3.73 (s, 3H, OCH3)

¹³ C NMR spectrum (ppm):

154.78 (C-3); 152.95 (C-4); 40.34 (C-6); 45.79 (C-7); 154.01 (C-8a); 132.8 (C-9); 119.16 (C-10 and C-14); 114.02 (C-11 and C-13); 143.34 (C-12); 55.23 (C-15);

PL 196 752 B1

Elemental analysis for the formula C12H12N4O3 (mol. 260.26)

Calculated: %C = 55.38 %H = 4.64 %N = 21.53

Marked: %C = 55.21 %H = 4.54 %N = 21.47

LD50 = 1500 mg/kg; analgesic effect in the dose range of 0.025-0.1 LD50 not reversed by naloxone, hypothermic effect for 90 minutes.

Example 7. Following the same procedure as in Example 1, 1-(2-chlorophenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3 g (57% yield) of 3-hydroxy-4-oxo-8-(2'-chlorophenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 307-9°C.

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

11.53 (s, 1H, OH); 7.67-7.33 (m, 3H, aromatic protons); 4.16 (dd, 2H, CH2); 3.95 (dd, 2H, CH2)

Elemental analysis for the formula C11H9ClN4O2 (mol. 264.68)

Calculated: %C = 49.92 %H = 3.43 %Cl = 13.40 %N = 21.17

Marked: %C = 50.04 %H = 3.51 %Cl = 13.45 %N = 21.25

Example 8. Following the same procedure as in Example 1, 1-(3-chlorophenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3.1 g (59% yield) of 3-hydroxy-4-oxo-8-(3'-chlorophenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 316-18°C.

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

11.86 (s, 1H, OH); 7.85-7.08 (m, 4H, aromatic protons); 4.05 (s, 4H, 2CH2)

Elemental analysis for the formula C11H9ClN4O2 (mol. 264.68)

Calculated: %C = 49.92 %H = 3.43 %Cl = 13.40 %N = 21.17

Marked: %C = 49.77 %H = 3.47 %Cl = 13.27 %N = 21.23

LD50 >2000 mg/kg i.p.; strong analgesic effect in the dose range of 0.00625-0.1

LD50 reversed by naloxone, hypothermic effect for 60 minutes.

Example 9. Following the same procedure as in Example 1, 1-(4-chlorophenyl)imidazolidine-2-one hydrazone hydroiodide and oxalic acid diethyl ester were used in the reaction to obtain 3.8 g (72% yield) of 3-hydroxy-4-oxo-8-(4'-chlorophenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 346-9°C.

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

11.8 (s, 1H, OH); 7.51 (d, 2H, aromatic protons); 7.26 (d, 2H, aromatic protons); 4.02 (s, 4H, 2CH2)

Elemental analysis for the formula C11H9ClN4O2 (mol. 264.68)

Calculated: %C = 49.92 %H = 3.43 %Cl = 13.40 %N = 21.17

Marked: %C = 49.95 %H = 3.50 %Cl = 13.26 %N = 21.09

LD50 > 2000 mg/kg i.p.; no analgesic effect, hypothermic effect for 60 minutes, reduction in the number of head shaking episodes after administration of 5-hydroxytryptophan.

Example 10. Following the same procedure as in Example 1, 1-(3,4-dichlorophenyl)imidazolidine-2-one hydrazone and oxalic acid diethyl ester were used in the reaction to obtain 3.7 g (62% yield) of 3-hydroxy-4-oxo-8-(3',4'-dichlorophenyl)-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazine precipitate with a melting point of 323-4°C.

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

11.89 (s, 1H, OH); 7.99 - 7.44 (m, 3H, aromatic protons); 4.06 (s, 4H, 2CH2)

Calculated: %C = 44.17 %H = 2.70 %Cl = 23.71 %N = 18.73

Marked: %C = 44.07 %H = 2.64 %Cl = 23.64 %N = 18.67

Claims (2)

Patent claims 1. New 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo [2,1-c] [1,2,4] triazines of general formula I, wherein R is an aromatic substituent, preferably phenyl and its substituted analogs, especially 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl. 2. A method for the preparation of new 3-hydroxy-4-oxo-8-aryl-7,8-dihydro-6H-imidazo- [2,1-c] [1,2,4] triazines of general formula 1, in which R represents an aromatic substituent, preferably phenyl and its substituted analogs, especially 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2-methoxyphenyl, 4-methoxy phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, characterized in that a compound of the general formula II, in which R is as defined above and X is halogen, preferably iodine, chlorine or bromine, is reacted with oxalic acid diethyl ester, i.e. a compound of the general formula 3 in the presence of basic substances binding the evolving hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, sodium or potassium carbonate, and the process is carried out in an organic solvent environment, preferably an aliphatic alcohol, especially ethyl, propyl, isopropyl, butyl or dimethylformamide in the environment boiling point with a solvent for 1-7 hours, using molar proportions of the reactants 1: 1, and 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 a mixture of polar solvents: protic, preferably methyl, isopropyl and aprotic, preferably dimethylformamide in a volume ratio of 1: 1 to 1: 5.