JP2778921B2 - Imidazopyrazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an imidazopyrazole derivative represented by the following general formula (1), which is useful as a medicament showing an analgesic, anti-inflammatory, anti-ulcer and anti-allergic action.

[0002]

The conventional analgesic and anti-inflammatory agents have a problem in that the side effects of gastrointestinal ulcer formation appear clinically.

The inventors of the present invention have conducted research on the development of an analgesic and anti-inflammatory agent having an inhibitory action on ulcer formation. The imidazopyrazole derivative represented by the following general formula (1) has such pharmacological activity. And completed the present invention.

[0004]

The present invention has a general formula

[0005]

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The present invention relates to a novel imidazopyrazole derivative or a salt thereof, and an analgesic and anti-inflammatory agent containing them as an active ingredient.

In the above formula, R ₁ represents an alkyl group, a lower alkenyl group, an aralkyl group or an aryl group which may be substituted by a fluorine atom, and R ₂ represents an aryl group or a nitrogen, oxygen or sulfur atom. Represents a 5- or 6-membered heteroaryl group containing from 3 to 3, R ₃ , R ₄ and R ₅
Represents a hydrogen atom.

In the general formula (1), when R ₁ is an “alkyl group”, the alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl,
linear or branched having 1 to 25 carbon atoms such as n-pentyl, isopentyl, n-hexyl, isohexyl, n-octyl, n-nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, and pentacosanyl; And an alkyl group of

When R ₁ is “an alkyl group substituted by a fluorine atom”, the substituted alkyl group includes fluoromethyl, trifluoromethyl, 2-fluoroethyl,
Examples thereof include an alkyl group having 1 to 3 carbon atoms and having a fluorine atom as a substituent, such as 2,2,2-trifluoroethyl.

When R ₁ is a “lower alkenyl group”, the alkenyl group may be allyl, 2-butenyl,
Alkenyl groups having 3 or 4 carbon atoms, such as -methylallyl.

When R ₁ is an “aralkyl group”, the aralkyl group may be benzyl, phenethyl, 3-phenylpropyl or 1-naphthylmethyl which may have a substituent described later on the aromatic ring. An aralkyl group having an alkylene moiety having 1 to 3 carbon atoms can be mentioned, and the substituent of the aromatic ring is methyl, ethyl, n-
Propyl, isopropyl such as a straight or branched alkyl group having 1 to 3 carbon atoms, methoxy,
A straight-chain or branched alkoxy group having 1 to 3 carbon atoms such as ethoxy, n-propoxy and isopropoxy, a trifluoromethyl group or a halogen atom such as fluorine, chlorine and bromine may be mentioned. These substituents may be the same or in combination, and may be substituted with 1 to 3 substituents.

When R ₁ or R ₂ is an “aryl group”, the aryl group may be phenyl, 1-naphthyl, or 2-naphthyl which may have the same substituent as the aralkyl group on the aromatic ring. And an aryl group having 6 or 10 carbon atoms such as

R ₂ is a “5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms”
When the heteroaryl group is furyl, thienyl, imidazolyl, thiazolyl, which may have 1 to 2 substituents identical to the aralkyl group in the heterocycle,
1 to 3 nitrogen, oxygen or sulfur atoms such as oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl and indolyl
And a 5- or 6-membered monocyclic or condensed heteroaryl group.

[0014] As a further preferred substituents in the general formula (1), R ₁ is, when it is methyl or ethyl group, R ₂ is a methyl group as a substituent, a trifluoromethyl group, a fluorine atom, chlorine Examples thereof include a phenyl group, a furyl group, and a thienyl group which may have an atom, a bromine atom, or a methoxy group.

Specific examples of the imidazopyrazole derivative having the general formula (1) of the present invention include the compounds shown in the following table.

[0016]

[Table 1]

[0017]

[Table 2]

[0018]

[Table 3]

The novel compound (1) of the present invention can be synthesized by the following method.

Manufacturing method (1)

[0021]

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Wherein R ₁ , R ₂ , R ₄ and R ₅ have the same meanings as described above.

[0023]

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(Wherein R ₁ and R ₂ have the same meanings as described above) in the presence of a base in the general formula

[0025]

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(Wherein X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group,> CＣY represents a carbonyl group or an acetal group, and R ₄ and R ₅ are as defined above. ( The first step ), and the obtained compound (4)

[0027]

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(Wherein R ₁ , R ₃ , R ₄ , R ₅ and> C
The = Y group has the same meaning as described above. ) Under acidic conditions ( second stage ).

The substituent X in the starting compound having the general formula (3) is a halogen atom such as chlorine, bromine or iodine, a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy, or benzenesulfonyloxy. And an arylsulfonyloxy group such as paratoluenesulfonyloxy and an acetal group of> C = Y group include di-lower alkylacetal groups such as dimethylacetal and diethylacetal.

In carrying out the reaction of the first step of this method, as a solvent, halogenated hydrocarbons such as methylene chloride and chloroform, benzene, toluene,
Aromatic hydrocarbons such as xylene, acetonitrile,
Dimethylformamide and the like are used. Sodium hydride and triethylamine are preferably used as the base. The reaction is carried out at a temperature of from 10 ° C. to around the boiling point of the solvent used. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 10 hours. After completion of the reaction, the reaction mixture is poured into water, treated by a conventional method, and purified by column chromatography as needed.

In the ring closure reaction of the compound (4) obtained in the second step , organic solvents not involved in the reaction (for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, Alcohols such as methanol and ethanol) in the presence of sulfonic acids such as benzenesulfonic acid and paratoluenesulfonic acid, or acids such as mineral acids such as hydrochloric acid and sulfuric acid for about 5 minutes to 2 hours and at about room temperature. Heating is performed at around the boiling point of the solvent used. After completion of the reaction, the reaction mixture is poured into ice water, alkalified with ammonia or sodium bicarbonate, extracted with an organic solvent and treated by a conventional method to obtain the desired compound (1a). It can be purified by column chromatography, recrystallization method and the like.

Further, (1a) can be obtained by heating the intermediate compound (4) with PPA (polyphosphoric acid).

Production method (2 ) The imidazopyrazole derivative of the above (1a) has the general formula

[0034]

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Wherein R ₁ and R ₂ have the same meanings as described above.

[0036]

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(Where R_FourAnd R_FiveIs the same as above
Indicates significance. ) With a compound havingFirst stage
Floor), The obtained compound (4)

[0038]

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Is reacted under exactly the same conditions as the reaction in the second step of the production method (1), and purified to obtain the desired compound (1).
a) can be obtained.

In carrying out the first-stage reaction, the solvent may be alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene, toluene and xylene. , Acetonitrile, dimethylformamide and the like are used. The reaction is carried out by heating at a temperature of from 10 ° C. to around the boiling point of the solvent used. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 20 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture, and the residue can be purified by a recrystallization method or column chromatography, if necessary.

The starting compound (2) was synthesized according to the method of Takamizawa et al. (Pharmaceutical Magazine 84 , 1113 (1964)).

[0042]

The imidazopyrazole derivative (1) of the present invention and its salt have been shown by pharmacological tests to exhibit excellent analgesic, anti-inflammatory, anti-ulcer and 5-lipoxygenase inhibitory effects. Next, their analgesic, anti-inflammatory, and acute toxicity, anti-ulcer, and 5-lipoxygenase inhibitory activities are exemplified.

[0043]

[Table 4]

All the drugs were administered orally.

[Anti-inflammatory action (carrageenin edema method)] Carrageenan edema method was tested using Wistar rats. (CA Winter, E. et al.
A. Risley, G .; W. Nuss: J. Pharn
acol, Exp. Therap. , 141 , 369
(1963)). The edema inhibition rate (%) was determined.

[Anti-inflammatory Action (Reverse Passive Arthus Reaction)] S
Using a prague-Dawley rat, it is fasted for 17 hours, the back is shaved with a hair clipper, and 0.1 ml / site of anti-rat IgG rabbit serum is injected intradermally to cause inflammation. Two hours later, 1 ml of 1% Evans blue / physiological saline was injected into the tail vein of each individual, and 30 minutes later, the skin was exfoliated and the skin was exfoliated, and pigmentation of blue spots was performed. Extraction was performed by using the skin as a strip, extracting with 5 ml of the extract at room temperature for 2 days, and measuring the centrifuged supernatant with a spectrophotometer at an absorption wavelength of 605 nm. The inhibition rate of the drug administration group relative to the control group was determined. In the case of oral administration, the drug was administered immediately before inflammation.

[Analgesia] Wistar
The rats were tested by the Randall-Celitt method. (LO Randall, JJ Selitt)
o; Arch, int. Pharmacodyn, 11
1 , 409 (1957)).

[Acute toxicity] Using a ddy male mouse (5 weeks old), the drug was suspended in a 0.5% CMC solution and orally administered, followed by observation for 7 days.

[Stomach secretion inhibitory action] The Shay method [H. S
Hay; Gastroenterology, Vol. 5, 4
3 (1945)] as follows.
Five male SD rats weighing about 180 g were used per group. They were fasted for 24 hours before the experiment and had free access to water. The abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound suspended in a 0.5% carboxymethylcellulose solution was administered into the duodenum. After 4 hours, the rats are killed with carbon dioxide,
The stomach was removed and the gastric fluid volume was measured.

Further, the gastric juice was titrated with 0.01 N sodium hydroxide to pH 7.0, the acidity was determined, and the amount of excreted acid per animal was calculated.

The inhibition rate (R) with respect to the control group was calculated by the following equation.

R = (1−B / A) × 100 A: Gastric acid excretion (μEq / h) in the control group B: Gastric acid excretion (μEq / h) in the sample administration group Table 2 Test compounds (Example No.) Dose (mg / kg) Inhibition rate (%) 4 10 67 30 100 Cimetidine 10 62 30 58 [5-Riboxygenase inhibitory action]
The method of Barra [Sbarra A. et al. J. and K
Arnovsky, M .; L. : J. Biol. Che
m. 234 , 1355-1362 (1959)]. A 2% casein solution was administered intraperitoneally to a male guinea pig (Hartley type) weighing 400 to 500 g,
After 4 to 16 hours, polymorphonuclear leukocytes were obtained from the peritoneal cavity.

The enzyme was prepared according to the method of Yoshimoto et al. [Yoshimoto, T .; , Furukawa,
M. , Yamamoto, S .; , Horie, T .; an
d Watanabe-Kohno, S .; : Bioch
em. Biophys. Commun. 116 , 612
-618 (1983)]. The extracted polymorphonuclear leukocytes were subjected to 10% ethylene glycol and 1 mM EDT.
A in 50 mM phosphate buffer (pH 7.4) containing A
The cells were suspended so as to have a density of × 10 ⁸ cells / ml. After sonicating it twice at 20 kHz for 30 seconds,
After centrifugation at 00 × g for 10 minutes, the supernatant was stored at −80 ° C. as an enzyme fraction.

The enzyme assay was performed according to the method of Ochi et al. [Oc
hi, K .; , Yoshimoto, T .; , Yamamo
to, S. Taniguchi, K .; and Miy
amoto, T .; : J. Biol. Chem. 258 ,
5754-5758 (1983)]. The enzyme reaction solution was 2 mM CaCl ₂ , 1 mM glutathione, 2 mM ATP (adenosine-5 ′).
-Triphosphate, 16 μM [ ¹⁴ C] -arachidonic acid (0.16 μCi: dissolved in 5 μl ethanol), a test compound (dissolved in 4 μl DMSO) and a 50 mM phosphate buffer (pH 7.0) containing an enzyme (200 μg in terms of protein). In 4), the total volume was 200 μl. Pretreatment of the test compound and the enzyme was performed at 30 ° C. for 5 minutes, and the reaction was performed at 30 ° C. for 30 minutes after the addition of arachidonic acid. Then 50μl
Was added to stop the reaction, and the reaction product was extracted with ethyl acetate. The extract was concentrated under a nitrogen stream and subjected to thin-layer chromatography. The developing solvent is diethyl ether: petroleum ether: acetic acid = 85: 15:
0.1 was used. 5-hydroxyei on plate
cosatetraenoic acid (5-HET
E) Fractions were identified with a radioactive scanner and radioactivity was measured. The inhibitory activity of the test compound was determined by the inhibition rate of control against 5-HETE production.

[0055] As is clear from the above pharmacological test results, the compound having the general formula (1) has an anti-inflammatory effect, an analgesic effect, and an antipyretic effect, for example, rheumatoid arthritis, osteoarthritis, lumbago, shoulder It is useful as an agent for improving and treating periarthritis, cervico-brachial syndrome, upper respiratory tract inflammation, etc., and also has a gastric secretion inhibitory action, an ulcer formation inhibitory action, a 5-lipoxygenase inhibitory action and an antiallergic action.

When the compound (1) is used as such a medicament, it is used alone or as appropriate, mixed with a pharmacologically acceptable carrier, excipient, diluent, and powders, granules, tablets, capsules, injections. , Suppositories, ointments, patches and the like can be safely administered orally or parenterally. The dosage varies depending on the target disease, symptoms, administration target, administration method, and the like. For example, in the case of oral administration to an adult, a dose of 0.025 to 0.5 g is administered once to three times a day. Is preferred.

Next, the present invention will be described more specifically with reference to Examples and Preparation Examples.

[0058]

Example 1 6- (4-trifluoromethylphenyl) -1H-imi
Dazo [1,2-b] pyrazole 3-amino-5- (trifluoromethylphenyl) pyrazole (1.0 g) and N, N-dimethylformamide (5 ml) (hereinafter abbreviated as DMF) are treated with sodium hydride (0 .15 g), a suspension of DMF (15 ml) was added at room temperature,
The mixture was dropped slowly with stirring, and stirred for 1 hour.
Dimethoxyethyl bromide (1.06 g) was added dropwise at room temperature with stirring, and the mixture was stirred at 70 to 80 ° C for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off to give 3-amino-2, the desired intermediate. -Dimethoxyethyl-5- (4-trifluoromethylphenyl) pyrazole (700 mg) was obtained as an oil. After stirring a mixture of the intermediate (700 mg) and polyphosphoric acid (7.0 g) at 100 ° C. for 30 minutes, the reaction product was poured into ice water, neutralized with sodium hydrogen carbonate, and then added to ethyl acetate. To extract. The extract is dried over magnesium sulfate, and the solvent is distilled off to obtain crude crystals of the desired product. The crude crystals were isolated by silica gel chromatography, and recrystallized from a mixture of ethyl acetate and hexane to give 6- (4-trifluoromethylphenyl).
0.3 g of light brown needles of -1H-imidazo [1,2-b] pyrazole was obtained. Mp 134-135 ° C. Elemental analysis: C H N F Calculated as _{C 12 H 8 N 3 F 3} : 57.37 3.21 16.73 22.69 Found: 57.80 3.35 16.79 22 .14 The following compounds were synthesized as in Example 1.

[0059]

[Table 5]

[0060]

Example 6 6- (4-Fluorophenyl) -1H-imidazo [1,
2-b] pyrazole 3-amino-5- (4-fluorophenyl) pyrazole (2.0 g) and DMF (10 ml) were stirred in a suspension of sodium hydride (0.3 g) and DMF (20 ml) at room temperature. Then, the mixture is slowly added dropwise, and the mixture is stirred for 1 hour. Then, 2,2-dimethoxyethyl bromide (2.1 g) is added dropwise with stirring at room temperature, and the mixture is stirred at 80 to 90 ° C. for 3 hours.
The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off to give 3-amino-2, the desired intermediate.
-Dimethoxyethyl-5- (4-fluorophenyl) pyrazole (1.2 g) was obtained as an oil. After refluxing a mixture of the intermediate (1.2 g), 4N-dioxane hydrochloride (10 ml) and ethanol (5 ml) for 30 minutes,
The solvent of the mixture was distilled off, the residue was partitioned between ethyl acetate and an aqueous solution of sodium hydrogen carbonate, the ethyl acetate layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off to give crude crystals of the desired product. Get. The crude crystals were isolated by silica gel chromatography, and recrystallized from a mixture of ethyl acetate and hexane to give 6- (4-fluorophenyl)-
0.5 g of pale purple needles of 1H-imidazo [1,2-b] pyrazole was obtained. Melting point: 225-227 ° C Elemental analysis: C ₁₁ H ₈ N ₃ F CH NF Calculated: 65.67 4.01 20.88 9.44 Found: 65.97 4.25 20.99 9. 22 The following compounds were synthesized as in Example 6.

[0061]

[Table 6]

[0062]

[Table 7]

[0063]

Example 20 6- (2-thienyl) -1H-imidazo [1,2-b]
Pyrazole 6- (2-thienyl) -3-aminopyrazole (1.0
g), a solution of dimethylformamide (5 ml)
Sodium hydride (0.26g), DMF (15ml)
Was slowly added dropwise to the suspension at room temperature with stirring, and after stirring for 1 hour, 2,2-dimethoxyethyl bromide (1.3
g) was added and reacted at 50-600 ° C. for 3 hours, then partitioned between ethyl acetate and water, the organic layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography. 0.9 g of the desired intermediate was obtained as an oil. After refluxing a mixture of the intermediate (0.9 g), 4N-dioxane hydrochloride (5 ml) and ethanol (3 ml) for 10 minutes, the reaction solution was poured into ice water, made basic with ammonia water, and then ethyl acetate. Extraction, the extract was washed with brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography.
Recrystallize with hexane to give the desired product as colorless needles 0.3
5 g were obtained. Melting point: 199-203 ° C Elemental analysis: C ₉ H ₇ N ₃ S Calculated for CH NS: 57.12 3.73 22.21 16.94 Found: 57.09 3.69 22.08 17. 05

[0064]

Embodiment 217-methyl-6- (2-thienyl) -1H-imidazo
[1,2-b] pyrazole

[0065]

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4-methyl-5- (2-thienyl) -3-
A solution of aminopyrazole (1.9 g) and DMF (15 ml) was added to 55% sodium hydride (0.5 g), DMF
(10 ml), the mixture was slowly dropped into the suspension at room temperature with stirring, stirred for 1 hour, 2,2-dimethoxyethyl bromide (2.0 g) was added, and the mixture was reacted at 60 to 70 ° C. for 4 hours. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 0.4 g of the desired intermediate as an oil. After refluxing a mixture of the intermediate (0.4 g), 4N-dioxane hydrochloride (4 ml) and ethanol (1.5 ml) for 10 minutes, the reaction solution was poured into ice water, made basic with ammonia water, and ethyl acetate was added. The extract was washed with brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography.
The crystals were recrystallized from ethyl acetate-hexane to obtain 0.14 g of the target compound as light brown needles. Mp 205 to 208 ° C. Elemental analysis: C H N S Calculated as _{C 10 H 7 N 3 S:} 59.09 4.46 20.67 15.77 Found: 59.12 4.49 20.52 16. 06

[0067]

Example 22 6- (2-furyl) -1H-imidazo [1,2-b] pi
Lazole 5- (2-furyl) -3-aminopyrazole (2.0
g) and a solution of DMF (5 ml) were slowly dropped into a suspension of 55% sodium hydride (0.59 g) and DMF (15 ml) with stirring at room temperature.
2-Dimethoxyethyl bromide (2.7 g) was added,
After reacting at 60 to 70 ° C. for 4 hours, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and dried over magnesium sulfate.
The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 1.2 g of the desired intermediate as an oil. Intermediate (1.2 g), 4N-dioxane-hydrochloric acid (10 ml),
After refluxing a mixture of ethanol (4 ml) for 20 minutes,
Pour the reaction solution into ice water, make it basic with ammonia water,
The mixture was extracted with ethyl acetate, the extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, recrystallized from ethyl acetate-hexane, and obtained as pale brown needles. 0.44 g of the desired product was obtained. Mp 186-188 ° C. Elemental analysis: C ₉ H ₇ N ₃ O as C H N Calculated: 62.42 4.07 24.27 Found: 62.36 4.23 24.14 Example 20 to 22 Similarly, the following compounds were synthesized.

[0068]

[Table 8]

[0069]

Example 26 1-ethyl-6- (3-trifluoromethylphenyl)
-1H-imidazo [1,2-b] pyrazole hydrochloride 6- (3-trifluoromethylphenyl) -1H-imidazo [1,2-b] pyrazole (800 mg), DMF
(5 ml) in sodium hydride (76 mg), DMF
(10 ml) was slowly added dropwise to the suspension at room temperature under stirring, and the mixture was stirred for 30 minutes. Ethyl bromide was added dropwise under ice-water cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was
After washing with brine and drying over magnesium sulfate, the solvent was distilled off and the residue was isolated by silica gel chromatography to obtain the desired oily product. This oil was converted into a hydrochloride with 4N-dioxane hydrochloride, and recrystallized from a mixture of acetone and ether to give 1-ethyl-6- (3-trifluoromethylphenyl) -1H-imidazo [1,2- b] 750 mg of light brown prisms of pyrazole-hydrochloride were obtained. 135-141 ° C. Elemental analysis: C ₁₄ H ₁₃ N ₃ ClF ₃ CH N Cl F Calculated: 53.26 4.15 13.31 11.23 18.05 Found: 53.18 4.21 13.32 11.28 18.00

[0070]

Example 27 7- (4-Methylphenyl) -6-methyl-1H-imi
Mixture of Dazo [1,2-b] pyrazole 2- (4-methylphenyl) -3-oxobutyronitrile (1.7 g), ethanol (20 ml), 2,2-diethoxyethylhydrazine (1.5 g) After the solution was refluxed for 7 hours, 4N-dioxane hydrochloride (30 ml) was added to the reaction solution, the mixture was refluxed for 30 minutes, and the reaction solution was cooled.
Crystals precipitate when ether is added. The crystals are collected by filtration and separated with ethyl acetate and dilute aqueous ammonia. The organic layer is washed with water, dried over magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from a mixed solution of ethyl acetate and hexane to give colorless scales. 1.5 g of a target product in the form of crystals were obtained. (Physical properties consistent in Example 35 compound) mp 231 to 233 ° C. Elemental analysis: C H N calcd _{C 13 H 13 N 3: 73.91} 6.20 19.89 Found: 74.21 6.47 20.02 The following compounds were synthesized as in Example 27.

[0071]

[Table 9]

[0072]

[Formulation Example 1] (Tablet) One tablet of the above formulation was prepared by ordinary formulation operation.
mg tablets.

[0073]

[Formulation Example 2] (Capsule) After mixing the powder having the above formulation and passing through a 20-mesh sieve, 340 mg of this powder was placed in a No. 2 gelatin capsule to prepare a capsule.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yoshio Iizuka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kazuo Hasegawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Keiichi Tabata 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References Special Table Sho 62-501035 (JP, A) (58) Fields surveyed (Int .Cl. ⁶ , DB name) C07D 487/04 A61K 31/415 A61K 31/44 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (Wherein, R ₁ is an alkyl group optionally substituted with a fluorine atom,
A lower alkenyl group, an aralkyl group or an aryl group; R ₂ represents an aryl group or a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms; R ₃ , R ₄ and R ₅ Represents a hydrogen atom. ) Or a salt thereof. 2. A compound of the general formula (Wherein, R ₁ is an alkyl group optionally substituted with a fluorine atom,
R ₂ represents a lower alkenyl group, an aralkyl group or an aryl group, and R ₂ represents a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. ) Is converted to a compound having the general formula: (Wherein, R ₄ and R ₅ represent a hydrogen atom, X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, and> C ＝ Y represents a carbonyl group or an acetal group. Wherein the compound having the general formula (1) is reacted in the presence of a base, and the resulting compound is treated under acidic conditions. (Wherein, R ₁ , R ₂ , R ₄ and R ₅ have the same meanings as described above). 3. A compound of the general formula (Wherein, R ₁ is an alkyl group optionally substituted with a fluorine atom,
R ₂ represents a lower alkenyl group, an aralkyl group or an aryl group, and R ₂ represents a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. ) Having the general formula: (Wherein R ₄ and R ₅ represent a hydrogen atom, and> CＣY represents a carbonyl group or an acetal group), and treating the resulting compound under acidic conditions. Characteristic general formula (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as described above). 4. An analgesic and anti-inflammatory agent comprising the imidazopyrazole derivative or a salt thereof according to claim 1 as an active ingredient. 5. An anti-ulcer agent comprising the imidazopyrazole derivative according to claim 1 or a salt thereof as an active ingredient. 6. An antiallergic agent comprising the imidazopyrazole derivative according to claim 1 or a salt thereof as an active ingredient.