JPS637186B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel imidazopyrazine derivatives represented by the following general formula (1), namely 1, 5, 6, 7, 8,
8a-Hexahydroimidazo[1.5-a]pyrazin-3(2H)one derivatives. (In the formula, R ¹ is a phenyl group or a phenyl group having a lower alkyl group, a lower alkoxy group, a halogen atom, or a trifluoromethyl group as a substituent, and R ² is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group. ) A lower alkyl group represented as a substituent of the phenyl group of R ¹ shown in the above general formula (1) and R ²
Preferred examples of the lower alkyl group represented by R ¹ include a chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl group, etc. Preferred examples of the lower alkoxy group represented as a substituent for the phenyl group include an alkoxy group having 1 to 6 carbon atoms, such as methoxy,
Examples of the halogen atom include ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, and the like, and examples of the halogen atom include fluorine, bromine, chlorine, and iodine. Preferred examples of the lower alkenyl group represented by ^R2 include chain or branched alkenyl groups having 2 to 5 carbon atoms, such as vinyl, allyl, butenyl, pentenyl, isopentenyl groups, and lower alkynyl groups. A preferred example is a carbon number of 2 to
Examples of the chain or branched alkynyl group of 5 include ethynyl, propynyl, butynyl, and pentynyl groups. The above-mentioned compound of the present invention is a novel compound that has not been described in any literature, has anti-inflammatory effect and analgesic effect, and is a compound useful as a medicine. The imidazopyrazine derivative according to the present invention is produced by the method exemplified below. [Method A] This method is characterized by ring-closing the piperazine derivative represented by the general formula (2), and is represented by the following reaction formula. (In the formula, R ¹ and R ² are the same as above. R ³ means a lower alkyl group) As the lower alkyl group in R ³ , the general formula
Specific examples include alkyl groups similar to the lower alkyl defined in (1). The ring-closing reaction of the piperazine derivative (2) is preferably carried out in a solvent in the presence of a base. Examples of preferred bases include sodium alcoholate and sodium hydride. The solvent is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and propanol, and hydrocarbons such as benzene, toluene, and xylene are preferably used. Although the amount of the base to be used may be selected as appropriate, it is generally advantageous to use an equimolar amount to the piperazine derivative (2). The reaction temperature and reaction time may be selected appropriately, but usually at about the boiling point of the solvent.
The reaction is fully completed in ~30 hours. Incidentally, in this reaction, the piperazine derivative (2) used as a starting material can be synthesized by various methods, and can be freely subjected to the ring-closing reaction without being isolated. [Method B] This method is characterized by reacting an imidazopyrazine derivative represented by the general formula (3) with a halide represented by the general formula (4), and is represented by the following reaction formula. (In the formula, R ¹ is the same as above. R ⁴ is a lower alkyl, lower alkenyl, or lower alkynyl group, and X is a halogen atom.) In the formula, R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, and X is a halogen atom. is the above general formula (1)
It has the same meaning as defined in . The reaction between the imidazopyrazine derivative (3) and the halide (4) is preferably carried out in a solvent in the presence of a base. Preferred bases include, for example, sodium alcoholate, sodium hydroxide, and the like. The solvent is not particularly limited as long as it does not participate in the reaction, but it usually includes hydrocarbons such as benzene, toluene, and xylene, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and N/N-dimethylformamide. , aprotic polar solvents such as dimethyl sulfoxide, etc. are used. The ratio of imidazopyrazine derivative (3) and halide (4) to be used may be selected as appropriate;
It is generally advantageous to use equimolar amounts. The reaction temperature and reaction time may be selected appropriately, but
Usually, the reaction is sufficiently completed in about 1 to 10 hours at room temperature to about the boiling point of the solvent. Isolation and purification of the compounds of the present invention obtained by the above methods A and B are carried out by conventional chemical operations such as concentration, extraction, distillation, recrystallization, column chromatography and the like. The following will further explain the production examples of the imidazopyrazine derivatives of the present invention and the results of anti-inflammatory and analgesic activity tests of the compounds of the present invention. Synthesis Example by Method A Example 1 7-(4-fluorophenyl)-1・5・6・
7.8.8a-Hexahydroimidazo [1.
5-a] Pyrazin-3(2H)one (Compound 1)
Synthesis of sodium 0.1g (4.3 mmol) in ethanol
Dissolve in 20 ml, add 1.2 g (4.3 mmol) of 3-(N-ethoxycarbonylaminomethyl)-1-(4-fluorophenyl)piperazine, and reflux for 9 hours. The reaction mixture is cooled to room temperature, ethanol is distilled off under reduced pressure, water is added to the residue, and after neutralization with dilute hydrochloric acid, the precipitate is collected. Recrystallization from ethanol yields 0.54 g of the target compound with a melting point of 149-150°C (yield 65%). Elemental analysis value (as C ₁₂ H ₁₄ N ₃ OF) Calculated value (%) C: 61.27, H: 6.00, N: 17.86, Actual value (%) C: 61.22, H: 6.05, N: 17.79, Example 2 7-(3-methoxyphenyl)-1, 5, 6,
7.8.8a-Hexahydroimidazo [1.
5-a] Synthesis of pyrazin-3-(2H)one (compound 2). 0.6 g (26 mmol) of sodium in ethanol
Dissolve in 60 ml, add 7.6 g (26 mmol) of 3-(N-ethoxycarbonylaminomethyl)-1-(3-methoxyphenyl)piperazine, and reflux for 12 hours. The reaction mixture was cooled to room temperature, ethanol was distilled off under reduced pressure, water was added to the residue, and after neutralization with dilute hydrochloric acid, the precipitate was collected. Recrystallization from ethanol yields 4.5 g of the target compound having a melting point of 157-158°C (yield 71%). Elemental analysis value (as C ₁₃ H ₁₇ N ₃ O ₂ ) Calculated value (%) C: 63.14, H: 6.93, N: 16.99, Actual value (%) C: 63.36, H: 7.28, N: 17.03, Example 3 7-(3-trifluoromethylphenyl)-1.
Synthesis of 5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3(2H)one (compound 3). 0.6 g (26 mmol) of sodium in ethanol
Dissolve in 60 ml and add 8.6 g (26 mmol) of 3-(N-ethoxycarbonylaminomethyl)-1-(3-trifluoromethylphenyl)piperazine.
Reflux for 14 hours. Cool the reaction mixture to room temperature,
Ethanol was distilled off under reduced pressure, water was added to the residue, and after neutralization with dilute hydrochloric acid, the precipitate was collected. Recrystallization from ethanol-water yields 4.6 g of the target compound having a melting point of 145-147°C (yield 62%). Elemental analysis value (as C ₁₃ H ₁₄ N ₃ OF ₃ ) Calculated value (%) C: 54.94, H: 4.95, N: 14.73, Actual value (%) C: 54.91, H: 5.00, N: 14.78, Method B Synthesis Example Example 4 7-(4-fluorophenyl)-2-methyl-
Synthesis of 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3(2H)one (compound 4). 0.67 g (14 mmol) of sodium hydride (50% oil) was dissolved in 30 ml of tetrahydrofuran, and under stirring, 7-(4-fluorophenyl)-1.5.
6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-3(2H)one 3.3g (14
2 g (14 mmol) of methyl iodide are added and the mixture is refluxed for 7 hours. The solvent is distilled off under reduced pressure, and the residue is recrystallized from benzene-ligroin to obtain 3.0 g of the target compound having a melting point of 122-123°C (yield: 85%). Elemental analysis value (as C ₁₃ H ₁₆ N ₃ OF) Calculated value (%) C: 62.64, H: 6.47, N: 16.86, Actual value (%) C: 62.57, H: 6.45, N: 16.74, then the above The compounds of the present invention shown in Table 1 below were synthesized by the same method as in Examples 1 to 4.

【table】

[Table] Example 5 Synthesis of 7-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-(2H)one (Compound 11) (Method A
synthesis) 0.51 g (22 mmol) of sodium in ethanol
Dissolve in 50 ml of 5.3 g of 3-(N-ethoxycarbonylaminomethyl)-1-phenylpiperazine (20
mmol) and reflux for 13 hours. The reaction mixture was cooled to room temperature, ethanol was distilled off under reduced pressure, water was added to the residue, and the precipitate was collected after neutralization with dilute hydrochloric acid. Melting point after recrystallization from ethanol-ether
Obtain 2.4 g of the target compound at 163-166°C (yield 56
%). Elemental analysis value (as C ₁₂ H ₁₅ N ₃ O) Calculated value (%) C: 66.34 H: 6.96 N: 19.34 Actual value (%) C: 66.55 H: 6.90 N: 19.20 Example 6 Same as Example 5 above The compound of the present invention shown below was synthesized by the method described above. 7-(4-methoxyphenyl)-1・5・6・
7.8.8a-Hexahydroimidazo [1.5
-a] Pyrazine-3-(2H)one (Compound 12) Melting point 175-177℃ Elemental analysis value (as C ₁₃ H ₁₇ N ₃ O ₂ ) Calculated value (%) C: 63.14 H: 6.93 N: 16.99 Actual value (%)C: 63.40 H: 7.18 N: 17.07 7-(4-methylphenyl)-1.5.6.7.
8.8a-hexahydroimidazo [1.5-a]
Pyrazine-3-(2H)one (Compound 13) Melting point 176-178℃ Elemental analysis value (as C ₁₃ H ₁₇ N ₃ O) Calculated value (%) C: 67.51 H: 7.41 N: 18.17 Actual value (%) C :67.43 H:7.57 N:18.20 The anti-edema effect, analgesic effect and acute toxicity of the compounds of the present invention were measured by the methods shown below, and the results are shown in Table 2. Test method for anti-edema effect: Female Wistar rats weighing approximately 130 g were used in groups of 5, and after fasting for 18 hours, they were given food for 1 hour, and then the test drug was orally administered. One hour after administration, 0.1 ml/rat of 1% carrageenan was subcutaneously injected into the left hind footpad, and the volume of the left hind paw was then measured at 1 hour intervals for up to 5 hours. The edema rate was determined by the volume increase rate with respect to the hindlimb volume before carrageenin treatment, and the inhibition rate was calculated from the average edema rate of the control group and the test drug administration group. The inhibition rate in the table represents the maximum inhibition rate when administered at 100 mg/Kg. Test method for analgesic effect 1: Acetic acid stretching method A group of 10 DDY male mice weighing approximately 18 g were given 0.6% acetic acid 0.1 30 minutes after oral administration of the test drug.
ml/10g was injected intraperitoneally. Stretching symptoms were observed for 5 minutes starting 25 minutes after the acetic acid injection.
(Number of animals showing no symptoms ÷ Number of animals used) x 100
The efficacy rate was calculated using the Litchfield-Wilcoxon method, and the 50% effective dose (ED50) and its 95% confidence limit were calculated using the Litchfield-Wilcoxon method. In addition, for test drugs for which ED50 values could not be obtained, the pain response was observed and the dose (mg/Kg)
- Expressed as inhibition rate (%). 2 Modified Hafner method A group of 10 male mice weighing around 19 g was used.
30 minutes after oral administration of the study drug, morphine hydrochloride 2 mg/
Kg was injected subcutaneously. 15 minutes to 15 minutes after morphine injection
The base of the mouse tail was pinched with Kotsuheru forceps four times at minute intervals to measure the presence or absence of a pain response. The efficacy rate was determined by (number of animals that do not cause a pain response ÷ number of animals used) x 100, the maximum efficacy rate of 4 measurements was taken, and the 50% effective dose was calculated using the Litchfield-Wilcoxon method ( ED ₅₀ ) and its 95% confidence limits were calculated.
For test drugs for which ED ₅₀ values could not be obtained, pain reactions were observed and expressed as dose (mg/Kg) - inhibition rate (%). Acute toxicity test method: Using male DDY mice weighing around 19g,
Groups of 4 to 6 animals were observed for 72 hours after oral administration of the test drug, and the number of dead animals/number of animals used at each dose (mg/Kg) was displayed.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a phenyl group or a phenyl group having a lower alkyl group, a lower alkoxy group, a halogen atom, or a trifluoromethyl group as a substituent, and R ² is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group. imidazopyrazine derivative represented by