JPH01180878A - Condensed pyrazole compound - Google Patents

Abstract

NEW MATERIAL:A condensed pyrazole of formula I [X is CH, N; R<1> is H, alkyl, (substituted) phenyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl: R<2> is H, alkyl, halogen, alkoxy; R<3> is isopropyl, tert.-butyl; where R<3> is isopropyl, when X is N]. EXAMPLE:3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-1H-indazole. USE:The compound inhibits both cyclooxygenase and 5-riboxygenase and has excellent anti-inflammatory, antipyretic, analgesic and antiallergic actions. Thus, it is used as an antiarthritic, antirheumatic, and antiplatelet agent. PREPARATION:The reaction of a compound of formula II (X<1> is halogen) with a compound of formula III gives the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to fused pyrazole compounds that are novel and useful as pharmaceuticals.

[Conventional technology]

JP-A-58-148858 discloses 3,5-di-tert-butyl-4-hydroxyphenyl-substituted pyrazoles having anti-inflammatory, antipyretic and analgesic effects.

[Problem to be solved by the invention]

The present inventors have discovered excellent pharmaceuticals, especially anti-inflammatory agents, analgesic antipyretic agents, antiallergic agents, antiarthritic agents, antirheumatic agents,
We have been conducting intensive research to develop compounds that are useful as platelet aggregation inhibitors.

[Means to solve the problem]

The present inventors have discovered that a new condensed pyrazole compound has these excellent effects, and have completed the present invention.

That is, the present invention is based on the general formula R3 R’ (I) This invention relates to a fused pyrazole compound represented by:

In the above formula, X is -CH- or a nitrogen atom, R1 is hydrogen, alkyl, phenyl, substituted phenyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl,
R2 is hydrogen, alkyl, norogen, alkoxy, R
3 represents isopropyl or tertiary butyl. However, when X is a nitrogen atom, R3 represents isopropyl.

In the above definition and this specification, alkyl has 1 to 4 carbon atoms.
straight or branched alkyl, methyl,
Examples include ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl. Substituted phenyl refers to halogen (chlorine, bromine, fluorine, iodine), amino, nitro, hydroxyl group, alkyl, alkoxy (carbon number 1 to 4 linear or branched alkoxy, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary
Class butoxy is mentioned. ), represents phenyl substituted with at least one substituent selected from trifluoromethyl, and hydroxyalkyl is a straight or branched alkyl in which the alkyl moiety has 1 to 4 carbon atoms, such as ,
Hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxyethyl, 1-hydroxy-2-propyl, 2-hydroxypropyl, 2.3-dihydroxypropyl, 1.3-
Dihydroxy-2-propyl is mentioned, and alkoxyalkyl is a linear or branched chain in which both the alkoxy and alkyl moieties have 1 to 4 carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, and isopropoxy. Methyl, butoxymethyl, isobutoxymethyl, tertiary butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2
-Butoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-butoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4
-propoxybutyl, 4-butoxybutyl, and acyloxyalkyl is an alkanoyl in which the acyl moiety has 2 to 5 carbon atoms, and a linear or branched alkyl in which the alkyl moiety has 1 to 4 carbon atoms. , acetoxymethyl,
2-acetoxyethyl, 3-acetoxypropyl, 4-
Acetoxybutyl, propionyloxymethyl, 2-propionyloxyethyl, 3-propionyloxypropyl, 4-propionyloxybutyl, isobutyryloxymethyl, 2-isobutyryloxyethyl, 4-isobutyryloxybutyl, butyryl Oxymethyl, 2-butyryloxyethyl, 4-butyryloxybutyl, valeryloxymethyl, 2-valeryloxyethyl, 4-valeryloxybutyl, pivaloyloxymethyl, 2-pivaloyloxyethyl, Examples include 4-pivaloyloxybutyl, halogen refers to the above-mentioned chlorine, bromine, fluorine, and iodine, and alkoxy refers to the above-mentioned linear or branched alkoxy having 1 to 4 carbon atoms. .

- When the compound (I) has an asymmetric carbon, both its optical isomer and racemate are included in the present invention.

The compound (1) of the present invention is, for example, a compound represented by the formula (II) (wherein, Xl represents a halogen, and other symbol numbers have the same meanings as above) and the general formula It can be produced by reacting a compound represented by ([1) (wherein R1 has the same meaning as above) or a hydrate thereof.

The reaction is usually carried out in an inert solvent (methanol, ethanol,
base (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium amide, etc.)
The reaction proceeds for 1 to 24 hours at a temperature from room temperature to the boiling point of the solvent used, in the presence or absence of .

It can also be produced by isolating a hydrazone compound represented by -sacrifice (in the formula, each symbol has the same meaning as above) as an intermediate during the reaction, and then subjecting it to a ring-closing reaction in the presence of the base described above. be done.

In the general formula (1), a compound in which R1 represents a substituent other than hydrogen is, for example, a compound in which R1 is hydrogen in -Sakura (1), that is, -Sakura (where each symbol has the same meaning as above). ) and the general formula % () [wherein R1 is a group other than hydrogen, X2 is a reactive atom or group (halogen or methanesulfonyloxy, benzenesulfonyloxy, p- toluenesulfonyloxy, etc.). ] is produced by reacting with a compound represented by:

The reaction is usually carried out using an inert solvent (methanol, ethanol, Hensen, toluene, acetone, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidone). or a mixed solvent thereof), preferably a base (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium amide, etc.). In the presence of
Proceed for 1 to 24 hours at room temperature or under heat.

In addition, the compound in which R1 is acyloxyalkyl in -Sacrifice (I) is a compound in which R1 is hydroxyalkyl in -Saccharide (I), that is, the compound in which R1 is hydroxyalkyl (in the formula, RM represents hydroxyalkyl in R1, Other symbols have the same meanings as above.) It is produced by reacting a compound represented by the following with an acid halide (acid chloride, acid bromide, etc.), an acid anhydride, or a mixed acid anhydride.

- The reaction of the compound (■) with an acid halide, acid anhydride or mixed acid anhydride is usually carried out using an inert solvent (such as chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, Hensen, toluene, etc.), or 1 to 2 hours at 0 to 150°C, preferably in the presence of a base (triethylamine, N-methylmorpholine, N-ethylmorpholine, pyridine, etc.)
It will proceed in 4 hours.

The compound of general formula (1) of the present invention thus obtained can be extracted from the reaction mixture, concentrated, neutralized, filtered, recrystallized,
It can be isolated and purified using conventional separation and purification means such as column chromatography and thin layer chromatography.

- Among the compounds of killing (1), compounds with asymmetric carbon are usually produced as racemates, but these are optically active acids (such as optically active mandelic acid, tartaric acid, dibenzoyltartaric acid, 1o-camphorsulfonic acid, etc.) or optically active bases (cinchonidine, cinchonidine, quinine, quinidine,
Each optical isomer can be derived by forming a salt with α-methylhensylamine, dehydroabiethylamine, etc.) or by separating by a conventional method such as chromatography or fractional recrystallization. It can also be produced by using optical isomers as raw materials.

The compound of the general formula (III), which is the raw material compound of the present invention, is, for example, a compound represented by the following formula (wherein, X3 represents a halogen, and the other symbols are as defined above) and the general formula (in the formula, , R3 has the same meaning as above.) A compound represented by
That is, it is produced by reaction in an inert solvent (dichloroethane, tetrachloroethane, carbon disulfide, nitrobenzene, etc.) in the presence of a catalyst (aluminum chloride, ferric chloride, tin chloride, zinc chloride, etc.). Ru.

[Action and effect of the invention]

The fused pyrazole compound represented by the general formula (1) of the present invention inhibits both cyclooxygenase and 5-riboxygenase, and has excellent anti-inflammatory and analgesic effects.
It has antipyretic, antiallergic, antiarthritic, antirheumatic, and platelet aggregation inhibitory effects, and is an anti-inflammatory agent.
It is useful as a medicine such as analgesic, antipyretic, antiallergic, antiarthritic, antirheumatic, and platelet aggregation inhibitor.

When the compound of the present invention is used as a medicine, it can be prepared by itself or mixed with pharmaceutically acceptable carriers, excipients, diluents, etc. to form powders, granules, tablets (including film-coated tablets and sugar-coated tablets), capsules, and injections. It can be administered orally or parenterally to patients in need of treatment in the form of pharmaceutical compositions such as drops, suppositories, ointments, drops, and eye drops. The dosage may vary depending on the target disease, its symptoms, the age of the patient, the administration method, etc., but in the case of oral administration, it is usually
1~11000rr per day, preferably 50~50rr
0■ is administered once or in divided doses.

〔Example〕

The present invention will be described in more detail below with reference to Reference Examples and Examples, but it goes without saying that the present invention is not limited thereto.

Reference Example 2 - 52.8 g of chloronicotinic acid chloride and 2.
Dissolve 64 g of 6-diituprobylphenol in 300 ml of dichloroethane, cool on ice, and add 44 g of anhydrous aluminum chloride in three portions while stirring. After adding the entire amount, react at 80°C for 5 hours, then pour the reaction mixture into ice water and stir for a while. After separating the organic layer, it is washed with water, dried and concentrated. When the obtained residual aroma is recrystallized from isopropyl alcohol, 4-(2-chloronicotinoyl)-2,6-
546 g of diituprobyl phenol are obtained as yellow-brown crystals. Melting point: 159-163 DEG C. Example 1 6.6 g of 3.5-ditertiary phthyl-4-hydroxy-2'-fluorohensiphenone was dissolved in 40 ml of pyridine, 3 g of hydrazine elongate was added, and the mixture was refluxed for 24 hours. After pyridine is distilled off, ethyl acetate is added, and the mixture is washed successively with water, diluted hydrochloric acid, and water, dried, and then concentrated. When the residual aroma was purified by silica gel column chromatography (eluted with chloroform) and recrystallized from ethanol-water, 2.6 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-indazole became pale yellow. Obtained as crystals. Melting point 144-145°C Example 2 3.5-di-tert-butyl-4-hydroxyphenyl-2
' - 6.6 g of fluorohensyphenone and 40 g of pyridine
To m1? Dissolve, add 2.3 g of methylhydrazine and add 15
Reflux for an hour. After the reaction is complete, pour into ice water, collect the precipitated crystals by filtration, and wash with water. When the crude crystals are recrystallized from ethanol, 5.3 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-IH-indazole is obtained as white crystals. Melting point 142-14
4°C Example 3 React in the same manner as in Example 2 using 15.9 g of 4-(2-chloronicotinoyl)-2,6-diitupropylphenol, 7.6 g of 2-hydrazinoethanol and 80 ml of pyridine. When the resulting crude crystals are recrystallized from ethanol, 3-(3,5-diisopropyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)-
12.5 g of 1H-pyrazolo[3,4-b)pyridine are obtained as pale yellow crystals. Melting point 165-167°C Example 4 Dissolve 5 g of 3-(3,5-diisopropyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)=1H-pyrazolo(3,4-b)pyridine in 20 ml of toluene. Then, add 3.3 g of acetic anhydride and stir at 90°C for 4 hours. After cooling with water, wash with water, dry, and concentrate. When the residual aroma is recrystallized from toluene, 1-(2-acetoxyethyl)-3-
(3,5-diisopropyl-4-hydroxyphenyl)
4.2 g of -LH-pyrazolo(3,4-b)pyridine are obtained as white crystals. Melting point: 136-138°C Example 5 Using 32.8 g of 3.5-di-tert-butyl-4-hydroxy-2'-fluorohensiphenone, 15.2 g of 2-human raditethanol and 165 ml of pyridine. ,
When the reaction and treatment were carried out in the same manner as in Example 2, and the obtained crude crystals were recrystallized from methanol, 3-(3,5-ditertiary-butyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)- 30 g of 1H-indazole are obtained as white crystals. Melting point: 144-145°C Example 6 3.7 g of 3-(3,5-ditertiary-butyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-indazole, 1.2 g of l-ethylamine , 2 g of acetic anhydride and 20 ml of dichloroethane were reacted and treated in the same manner as in Example 4, and the resulting crude product was recrystallized from hexane to give 1-(2-acetoxyethyl)-3-(
3,5-ditertiarybutyl-4-hydroxyphenyl)-
3.5 g of 1H-indazole are obtained as white crystals. Melting point 88-89°C Example 7 6.4 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-indazole and 5.5 g of 4-toluenesulfonic acid 2-methoxyethyl ester were added in 1.5 g. Dissolve in 40 ml of 3-dimethyl-2-imidazolidinone, add 2.8 g of potassium carbonate, and stir at 80°C for 4 hours. Pour the reaction solution into ice water and extract with ethyl acetate.

Wash with water, dry and concentrate. The residual aroma was purified by silica gel column chromatography (eluted with chloroform) and recrystallized from hexane to yield 3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(2-methoxyethyl)-1H- 3.8 g of indazole are obtained as pale yellow crystals. Melting point 103-107°C Example 8 23 g of 3.5-di-tert-butyl-4-hydroxy-2'-fluorobenzophenone and 8 phenylhydrazine
．． 3 g was dissolved in 140 ml of pyridine and refluxed for 20 hours. Condensed water from which pyridine has been distilled off is added, and the precipitated crystals are collected by filtration. When the crude crystals are recrystallized from ethanol, the melting point is 1.
22 g of the phenylhydrazone compound of the starting ketone is obtained as yellowish brown crystals of 64-166 c.

10.5g of the above phenylhydrazone compound to 50ml of hexamethylphosphoric triamide? Add 5 g of potassium carbonate and stir at 80° C. for 6 hours. Pour the reaction solution into ice water, extract with ethyl acetate, wash with water, dry and concentrate.

When the residual aroma is recrystallized from ethanol-hexane, l(3
,5-ditertiarybutyl-4-hydroxyphenyl)-1
6.1 g of -phenyl-IH-indazole are obtained as light brown crystals. Melting point: 162-163°C Example 9 Using 9 g of 3.5-di-tert-butyl-4-hydroxy-2'-iodo-5'-methylbenzophenone, 2.8 g of methylhydrazine, and 45 ml of pyridine, Example 2
When the crude product obtained by the reaction and treatment was recrystallized from hexane, 3.2 g of 3-(3,5-ditertiary-butyl-4-hydroxyphenyl)-1,5-dimethyl-IH-indazole was obtained. is obtained as pale yellow crystals. Melting point 14
5-147°C Example 10 Same as Example 2 using 8.6 g of 3.5-di-tert-butyl-4-hydroxy-2'-iodo-5''-chlorobenzophenone, 4.2 g of methylhydrazine and 43 ml of pyridine. When the crude product obtained after reaction and treatment is recrystallized from hexane, 5-chloro-3-(3,5-di-tertiary
butyl-4-hydroxyphenyl)-1-methyl-I
3 g of H-intersol are obtained as pale yellow crystals. Melting point 135-136℃

Claims (1)

[Claims] (1) A fused pyrazole compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. In the above formula,
R^3 represents isopropyl or tertiary butyl. However, when X is a nitrogen atom, R^3 represents isopropyl.