JPH07278148A - Imidazopyrazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antiphlogistic sedative agent, an untiulcer agent and an antiallergic agent. CONSTITUTION:This compound is expressed formula I [R1 is a (F-substituted) alkyl, a lower alkenyl, an aralkyl or an aryl; R2 is an aryl or a 5-6 membered heteroaryl containing 1-3 oxygen or sulfur atoms; R3 to R5 each is H], e.g. 6-(4-trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazol. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (X is a halogen, a lower alkanesulfonyloxy or an arylsulfonyloxy; C=Y is carbonyl or acetal) in the presence of a base and treating the resultant compound under an acidic condition.

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 drug having an analgesic / anti-inflammatory action, an anti-ulcer action and an antiallergic action.

[0002]

The conventional analgesic and anti-inflammatory agents have a problem in that they have a side effect of gastrointestinal ulcer formation in a clinical aspect.

The inventors of the present invention proceeded with research aiming at the development of an analgesic anti-inflammatory agent having an ulceration-inhibiting effect, and that the imidazopyrazole derivative represented by the general formula (1) described below has such pharmacological activity. The present invention has been completed and the present invention has been completed.

[0004]

The present invention has the general formula

[0005]

[Chemical 8]

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

In the above formula, R ₁ represents an alkyl group which may be substituted with a fluorine atom, a lower alkenyl group, an aralkyl group or an aryl group, and R ₂ represents an aryl group or a nitrogen, oxygen or sulfur atom. A 5- or 6-membered heteroaryl group containing 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 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert. -Butyl,
Linear or branched chain having 1 to 25 carbon atoms such as n-pentyl, isopentyl, n-hexyl, isohexyl, n-octyl, n-nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, pentacosanyl The alkyl group of can be mentioned.

When R ₁ is “an alkyl group substituted with a fluorine atom”, the substituted alkyl group includes fluoromethyl, trifluoromethyl, 2-fluoroethyl,
An alkyl group having 1 to 3 carbon atoms, which has a fluorine atom as a substituent, such as 2,2,2-trifluoroethyl can be given.

When R ₁ is a "lower alkenyl group", the alkenyl group is allyl, 2-butenyl, 2
Mention may be made of alkenyl groups having 3 to 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. Examples of the aralkyl group having an alkylene moiety having 1 to 3 carbon atoms include methyl, ethyl and n- as substituents on the aromatic ring.
A linear or branched alkyl group having 1 to 3 carbon atoms such as propyl and isopropyl, methoxy,
Mention may be made of a linear 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. However, these substituents may be the same or combined and may be substituted by 1 to 3.

When R ₁ or R ₂ is an “aryl group”, the aryl group may have a phenyl, 1-naphthyl or 2-naphthyl group which may have the same substituent as the above aralkyl group on the aromatic ring. And aryl groups 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"
In the case of, the heteroaryl group may have 1 to 2 substituents identical to the above aralkyl group on the heterocycle, furyl, thienyl, imidazolyl, thiazolyl,
1 to 3 nitrogen atom, oxygen atom or sulfur atom such as oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl and indolyl.
Examples thereof include 5- or 6-membered monocyclic or condensed heteroaryl groups.

As a more preferable substituent in the general formula (1), when R ₁ is a methyl group or an ethyl group, R ₂ is a substituent, and a methyl group, a trifluoromethyl group, a fluorine atom or chlorine is used. Examples thereof include a phenyl group which may have an atom, a bromine atom or a methoxy group, a furyl group or a thienyl group.

Specific examples of the imidazopyrazole derivative having the above 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 method shown below.

Manufacturing method (1)

[0021]

[Chemical 9]

The imidazopyrazole derivative having the formula (wherein R ₁ , R ₂ , R ₄ and R ₅ have the same meanings as described above) has the general formula

[0023]

[Chemical 10]

(Wherein R ₁ and R ₂ have the same meanings as described above), the compound of the general formula

[0025]

[Chemical 11]

(Wherein X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, a> C═Y group represents a carbonyl group or an acetal group, and R ₄ and R ₅ are the same as those described above. And a compound having the same meaning as () are obtained ( first step ) to obtain the compound (4)

[0027]

[Chemical 12]

(Wherein R ₁ , R ₃ , R ₄ , R ₅ and> C
The ═Y group has the same meaning as described above. ) Is closed under acidic conditions ( second step ).

The substituent X in the raw material compound having the above general formula (3) is a halogen atom such as chlorine, bromine or iodine, a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy, or benzenesulfonyloxy. Examples of the arylsulfonyloxy group such as paratoluenesulfonyloxy and an acetal group having a> C═Y group include di-lower alkyl acetal groups such as dimethyl acetal and diethyl acetal.

In carrying out the reaction of the first step of this method, as the solvent, halogenated hydrocarbons such as methylene chloride and chloroform, benzene, toluene,
Aromatic hydrocarbons such as xylene, acetonitrile,
Dimethylformamide or the like is used. As the base, sodium hydride and triethylamine are preferably used. The reaction is carried out by heating at a reaction temperature of 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 can be poured into water, treated by a conventional method, and optionally purified by column chromatography.

The ring-closing reaction of the obtained compound (4) in the second step is carried out in an organic solvent which does not participate 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 at room temperature The heating is performed near the boiling point of the solvent used. After completion of the reaction, the reaction mixture is poured into ice water, made alkaline with ammonia or sodium bicarbonate, extracted with an organic solvent and treated by a conventional method to obtain the target compound (1a). It can be purified by column chromatography, a recrystallization method or the like.

The intermediate compound (4) can also be heated with PPA (polyphosphoric acid) to obtain (1a).

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

[0034]

[Chemical 13]

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

[0036]

[Chemical 14]

(Wherein R ₄ and R ₅ have the same meanings as described above) ( the first step)
Floor ), the obtained compound (4)

[0038]

[Chemical 15]

The compound of interest (1) was obtained by reacting and purifying the compound under the same conditions as in the reaction of the second step of the production method (1) .
a) can be obtained.

In carrying out the reaction of the first step , as a solvent, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene are used. Examples thereof include acetonitrile, acetonitrile and dimethylformamide. The reaction is carried out by heating at a reaction temperature of 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 can be distilled off from the reaction mixture, and the residue can be purified by a recrystallization method or column chromatography, if necessary.

Compound (2) as a starting material was synthesized according to the method of Takamizawa et al. (Pharmaceutical Journal 84 , 1113 (1964)).

[0042]

INDUSTRIAL APPLICABILITY The imidazopyrazole derivative (1) and salts thereof of the present invention have been shown by pharmacological tests to show excellent analgesic, anti-inflammatory, anti-ulcer and 5-lipoxygenase inhibitory effects. Next, their analgesic, anti-inflammatory action, acute toxicity, antiulcer action and 5-lipoxygenase inhibitory action will be exemplified.

[0043]

[Table 4]

Each drug was orally administered.

[Anti-inflammatory effect (carrageenan edema method)] Tests were carried out by the carrageenin edema method using Wistar rats. (CA Winter, E .;
A. Risley, G .; W. Nuss: J. Pharn
acol, Exp. Therap. , 141 , 369
(1963)). The edema suppression rate (%) was calculated.

[Anti-inflammatory action (reverse passive Arthus reaction)] S
Using prague-Dawley rats, fasting is performed for 17 hours, the back is hair-removed with clippers, and 0.1 ml / site of anti-rat IgG rabbit serum is intradermally injected 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, carbon dioxide gas was killed, the skin was peeled off, and pigmentation of blue spots was performed. For the extraction, the skin was cut into strips and extracted with 5 ml of the extract at room temperature for 2 days, and the centrifugal supernatant was measured with a spectrophotometer and an absorption wavelength of 605 nm. The inhibition rate of the drug administration group with respect to the control group was calculated. In the case of oral administration, the drug was administered immediately before inflammation.

[Analgesic action] Wistar
The rats were tested by the Randall-Serit method. (L.O. 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, and observed for 7 days.

[Inhibitory action on gastric juice secretion] Shay method [H. S
Hay; Gastroenterology, Volume 5, 4
3 (1945)], the following was performed.
A group of 5 SD male rats weighing about 180 g was used. Before the experiment, they were fasted for 24 hours and had free access to water. The abdomen was opened under ether anesthesia, the pyloric region was ligated, and the test compound suspended in 0.5% carboxymethylcellulose solution was administered into the duodenum. After 4 hours, kill the rat with carbon dioxide,
The stomach was removed and the amount of gastric juice was measured.

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

The inhibition rate (R) relative to the control group was calculated by the following formula.

R = (1-B / A) × 100 A: Gastric acid excretion in control group (μEq / h) B: Gastric acid excretion in sample administration group (μEq / h) Table 2 Test compound (Example number) Dose (mg / kg) Suppression rate (%) 4 10 67 30 100 Cimetidine 10 62 30 58 [5-Riboxygenase inhibitory action] Preparation of white blood cells
Barra's method [Sbarra A .; J. and K
arnovsky, M .; L. : J. Biol. Che
m. 234, was carried out in 1355-1362 (1959)]. A 2% casein solution was intraperitoneally administered to a male guinea pig (Hartley system) weighing 400 to 500 g, and 1
After 4 to 16 hours, polymorphonuclear leukocytes were obtained from the abdominal cavity.

The enzyme was prepared by the method of Yoshimoto et al. [Yoshimoto, T. et al. , Furukawa,
M. , Yamamoto, S .; , Horie, T .; an
d Watanabe-Kohno, S .; : Bioch
em. Biophys. Commun. 116, 612
-618 (1983)]. The extracted polymorphonuclear leukocytes were treated with 10% ethylene glycol and 1 mM EDT.
1 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, 10,0
The mixture was centrifuged at 00 × g for 10 minutes, and the supernatant was stored as an enzyme fraction at −80 ° C.

The enzyme assay is carried out by the method of Ochi et al. [Oc
hi, K.K. , Yoshimoto, T .; , Yamamo
to, S. Taniguchi, K .; and Myy
amoto, T .; : J. Biol. Chem. 258 ,
5754-5758 (1983)] with some modifications. 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), test compound (dissolved in 4 μl DMSO) and enzyme (200 μg as protein amount) in 50 mM phosphate buffer (pH 7. In 4), the total volume was 200 μl. The test compound and the enzyme were pretreated at 30 ° C. for 5 minutes, and after reacting with arachidonic acid, they were reacted at 30 ° C. for 30 minutes. Then 50 μl
0.2 N citric acid 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
cossatraenoic acid (5-HET
E) The fraction was identified with a radio active scanner and the radioactivity was measured. The inhibitory activity of the test compound was determined by the rate of inhibition of control 5-HETE production.

[0055] As is clear from the results of the above-mentioned pharmacological tests, the compound having the general formula (1) has anti-inflammatory action, analgesic action, and antipyretic action. For example, rheumatoid arthritis, osteoarthritis, lumbago, shoulder It is useful as a therapeutic agent for improving periarthritis, cervical-shoulder-arm syndrome, upper airway inflammation and the like, and also has gastric juice secretion inhibitory action and ulcer formation inhibitory action, and 5-lipoxygenase inhibitory action and antiallergic action.

When the compound (1) is used as such a medicine, it may be used alone or in admixture with a pharmacologically acceptable carrier, excipient or diluent to prepare a powder, granules, tablets, capsules or injections. , Suppositories, ointments, patches and the like can be safely administered orally or parenterally. Although the dose varies depending on the target disease, symptom, administration subject, administration method, etc., for example, when administered orally to an adult, a single dose of 0.025 to 0.5 g is administered 1 to 3 times a day. Is preferred.

Next, the present invention will be described more specifically with reference to examples and formulation examples.

[0058]

Example 1 6- (4-trifluoromethylphenyl) -1H-imi
Dazo [1,2-b] pyrazole 3-amino-5- (trifluoromethylphenyl) pyrazole (1.0 g), N, N-dimethylformamide (5 ml) (hereinafter abbreviated as DMF) was added to sodium hydride (0 0.15 g) at room temperature in a suspension of DMF (15 ml),
The mixture was slowly added dropwise with stirring, and after stirring for 1 hour, 2,2-
Dimethoxyethyl bromide (1.06 g) is added dropwise at room temperature with stirring, and the mixture is stirred at 70 to 80 ° C for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the ethyl acetate layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give 3-amino-2 which is the target 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) for 30 minutes at 100 ° C., 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 mixed solution of ethyl acetate and hexane to give 6- (4-trifluoromethylphenyl).
0.3 g of light brown needle crystals of -1H-imidazo [1,2-b] pyrazole were obtained. Melting point 134-135 ° C. Elemental analysis value: C H N F as C ₁₂ H ₈ N ₃ F ₃ Calculated value: 57.37 3.21 16.73 22.69 Measured value: 57.80 3.35 16.79 22 .14 The following compounds were synthesized in the same manner 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), DMF (10 ml) in a suspension of sodium hydride (0.3 g) and DMF (20 ml) at room temperature and stirring The mixture is slowly added dropwise under agitation and stirred for 1 hour, 2,2-dimethoxyethyl bromide (2.1 g) is added dropwise at room temperature with stirring, and the mixture is stirred at 80 to 90 ° C for 3 hours.
The reaction mixture was partitioned with ethyl acetate and water, the ethyl acetate layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated to give 3-amino-2 which is the target intermediate.
-Dimethoxyethyl-5- (4-fluorophenyl) pyrazole (1.2g) was obtained as an oil. After refluxing a mixture of the intermediate (1.2 g), 4N-dioxane hydrochloric acid (10 ml) and ethanol (5 ml) for 30 minutes,
The solvent of the mixture was evaporated, the residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was washed with brine and dried over magnesium sulfate, and the solvent was evaporated to give crude crystals of the desired product. To get The crude crystals were isolated by silica gel chromatography and recrystallized from a mixed solution of ethyl acetate and hexane to give 6- (4-fluorophenyl)-.
0.5 g of pale purple needle crystals of 1H-imidazo [1,2-b] pyrazole were obtained. Mp 225 to 227 ° C. Elemental analysis: C ₁₁ H ₈ N ₃ F as C H N F Calculated: 65.67 4.01 20.88 9.44 Found: 65.97 4.25 20.99 9. 22 The following compounds were synthesized in the same manner 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) 55%
Sodium hydride (0.26g), DMF (15ml)
Was slowly added dropwise to the suspension of 1. at room temperature with stirring, and after stirring for 1 hour, 2,2-dimethoxyethyl bromide (1.3
g) was added, and the mixture was reacted at 50 to 600 ° C. for 3 hours, then partitioned with 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 target intermediate was obtained as an oil. After refluxing a mixed solution of the intermediate (0.9 g), 4N-dioxane hydrochloric acid (5 ml) and ethanol (3 ml) for 10 minutes, the reaction solution was poured into ice water, made basic with ammonia water, and then with ethyl acetate. Extraction, the extract was washed with brine, dried over magnesium sulfate, the solvent was distilled off, the residue was purified by silica gel chromatography, ethyl acetate-
Recrystallization from hexane gives colorless target crystals 0.3
5 g was obtained. Melting point 199 to 203 ° C. Elemental analysis value: C ₉ H ₇ N ₃ S CH N S calculated value: 57.12 3.73 22.21 16.94 Measured value: 57.09 3.69 22.08 17. 05

[0064]

Example 21 7-Methyl-6- (2-thienyl) -1H-imidazo
[1,2-b] pyrazole

[0065]

[Chemical 16]

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) and DMF.
After slowly adding dropwise to a suspension of (10 ml) at room temperature under stirring and stirring 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, then, The mixture was partitioned with 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 target intermediate as an oil. After refluxing a mixed solution of the intermediate (0.4 g), 4N-dioxane hydrochloric acid (4 ml) and ethanol (1.5 ml) for 10 minutes, the reaction solution was poured into ice water and 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 desired product as light brown needle crystals. Melting point 205 to 208 ° C. Elemental analysis value: C ₁₀ H ₇ N ₃ S CH N S calculated value: 59.09 4.46 20.67 15.77 Actual value: 59.12 4.49 20.52 16. 06

[0067]

Example 22 6- (2-furyl) -1H-imidazo [1,2-b] pyr
Razole 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) at room temperature with stirring, and after stirring for 1 hour, 2,
2-dimethoxyethyl bromide (2.7 g) was added,
After reacting at 60 to 70 ° C for 4 hours, the mixture was partitioned with ethyl acetate and water, 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 target intermediate as an oil. Intermediate (1.2 g), 4N-dioxane-hydrochloric acid (10 ml),
After refluxing the mixed solution of ethanol (4 ml) for 20 minutes,
The reaction solution was poured into ice water and made basic with ammonia water,
Extract with ethyl acetate, wash the extract with brine, dry over magnesium sulfate, evaporate the solvent, purify the residue by silica gel chromatography, and recrystallize with ethyl acetate-hexane to give pale brown needle crystals. 0.44 g of the target product of 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) with sodium hydride (76 mg), DMF
The suspension of (10 ml) was slowly added dropwise at room temperature under stirring, and the mixture was stirred for 30 minutes. Ethyl bromide was added dropwise under cooling with ice water, and then the mixture was stirred for 30 minutes at room temperature. The reaction mixture was partitioned with ethyl acetate and water, the ethyl acetate layer was washed with water,
The extract was washed with brine and dried over magnesium sulfate, the solvent was evaporated, and the product was isolated by silica gel chromatography to obtain the target oily substance. This oily substance was made into hydrochloride with 4N-dioxane hydrochloric acid and recrystallized from a mixed solution of acetone and ether to give 1-ethyl-6- (3-trifluoromethylphenyl) -1H-imidazo [1,2- b] 750 mg of pale brown prismatic crystals of pyrazole-hydrochloride were obtained. Melting point 135-141 ° C. Elemental analysis value: C ₁₄ H ₁₃ N ₃ ClF ₃ CH N Cl F calculated value: 53.26 4.15 13.31 11.23 18.05 Actual value: 53.18 4.21 13.32 11.28 18.00

[0070]

Example 27 7- (4-Methylphenyl) -6-methyl-1H-imi
Dazo [1,2-b] pyrazole 2- (4-methylphenyl) -3-oxobutyronitrile (1.7 g), ethanol (20 ml), 2,2-diethoxyethylhydrazine (1.5 g) mixed The solution was refluxed for 7 hours, 4N-dioxane hydrochloric acid (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 were collected by filtration, and then separated with ethyl acetate and diluted ammonia water, the organic layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized with a mixed solution of ethyl acetate and hexane to give colorless scales. 1.5 g of the target compound in the form of crystals was obtained. (Physical properties are the same as those of the compound of Example 35) Melting point 231 to 233 ° C Elemental analysis value: C ₁₃ H ₁₃ N ₃ CHN calculated value: 73.91 6.20 19.89 Actual value: 74.21 6.47 20.02 The following compounds were synthesized as in Example 27.

[0071]

[Table 9]

[0072]

[Formulation Example 1] (Tablets) One tablet of the above-mentioned prescription is 200
mg tablets.

[0073]

[Formulation Example 2] (Capsule) The powders of the above formulation were mixed, passed through a 20-mesh sieve, and 340 mg of this powder was put into a No. 2 gelatin capsule to give a capsule.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoshio Iizuka 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kazuo Hasegawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Keiichi Tabata 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (6)

[Claims] 1. A general formula: (In the formula, 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, and R ₃ , R ₄ and R ₅ Represents a hydrogen atom. And an imidazopyrazole derivative or a salt thereof. 2. A general formula: (In the formula, R ₁ is an alkyl group optionally substituted with a fluorine atom,
A lower alkenyl group, an aralkyl group or an aryl group is shown, and R ₂ is an aryl group or a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. A compound having the general formula: (In the formula, R ₄ and R ₅ represent a hydrogen atom, X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, and a> C═Y group represents a carbonyl group or an acetal group. 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), and a method for producing an imidazopyrazole derivative. 3. A general formula: (In the formula, R ₁ is an alkyl group optionally substituted with a fluorine atom,
A lower alkenyl group, an aralkyl group or an aryl group is shown, and R ₂ is an aryl group or a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. A compound having the general formula: (Wherein R ₄ and R ₅ represent a hydrogen atom, and a> C═Y group represents a carbonyl group or an acetal group), and the resulting compound is treated 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), and a method for producing an imidazopyrazole derivative. 4. An analgesic and anti-inflammatory agent comprising the imidazopyrazole derivative or the salt thereof according to claim 1 as an active ingredient. 5. An anti-ulcer agent containing the imidazopyrazole derivative or the salt thereof according to claim 1 as an active ingredient. 6. An anti-allergic agent comprising the imidazopyrazole derivative or the salt thereof according to claim 1 as an active ingredient.