JPH06306077A - Pyrazolotriazole derivative - Google Patents

Abstract

PURPOSE:To provide a novel compound having antagonistic-action on angiotensin II and useful as a treating agent for hypertension, chronic heart failure, arterial sclerosis, diabetic nephropathy, etc. CONSTITUTION:The compound of formula I [R1 is H, formyl, (esterified) carboxyl; R2 and R3 are H or low alkyl; R4 is H or aralkyl; A<1> ring is (halogen- substituted) benzene, pyridine, benzofuran or indole; A<2> ring is (halogen- substituted) benzene, or pyrrole; L is single bond or carbonyl], e.g. 2,7- diethyl-5-[[3-bromo-2-[2-(N-triphenylmethyltetrazol-5-yl]phenyl]-5-ben zofuranyl]] methyl]-5H-pyrazoro [1,5-b] [1,2,4]triazole. A compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (Y is halogen).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug, and more particularly to a novel pyrazolotriazole derivative or its salt having angiotensin II (hereinafter abbreviated as AII) antagonistic activity.

[0002]

2. Description of the Related Art AII is a physiologically active peptide showing a strong pressor action and has been regarded as a causative agent of hypertension in various mammalian species. There are a few known pathways by which AII is produced in vivo, but the typical pathway is the production of angiotensin I from angiotensinogen by the action of the enzyme renin, which is then converted to angiotensin. The enzyme (ACE) acts to convert it into AII. The compound of the present invention acts on the AII receptor and suppresses the expression of the action of AII.
It is useful as an antagonist.

[0003]

[Problems to be Solved by the Invention] As AII antagonists,
For example, 4-substituted imidazole derivatives having a halogen atom, a nitro group, a cyano group, a substituted alkenyl group or the like at the 4-position of imidazole described in European Patent Application No. 253,310 are known. The present inventors have completed the present invention by recognizing the excellent anti-AII activity of a pyrazolotriazole derivative or a salt thereof having a chemical structure different from that of a known compound.

[0004]

The pyrazolotriazole derivative of the present invention is represented by the following general formula (I).

[Chemical 2]

(The symbols in the formula have the following meanings: R
¹ : a hydrogen atom, a formyl group or an optionally esterified carboxyl group. R ^2, R ^3: same or different and each represents a hydrogen atom or a lower alkyl group. R ^4: a hydrogen atom or an aralkyl group. A ¹ ring: a benzene ring, a pyridine ring, a benzofuran ring or an indole ring which may be substituted with a halogen atom. A ² ring: A benzene ring or a pyrrole ring which may be substituted with a halogen atom. L: a single bond or a carbonyl group. However, if A ¹ ring is a benzene ring optionally substituted by a halogen atom, A ² ring means good pyrrole ring optionally substituted with a halogen atom, A ² ring is optionally substituted with a halogen atom In the case of a benzene ring which may be used, A ¹
The ring is a pyridyl ring optionally substituted with a halogen atom,
It means a benzofuran ring or an indole ring, respectively.
The same applies below. )

The compound (I) of the present invention is described in detail below. The “optionally esterified carboxyl group” in R ¹ is a lower alkyl group or a formula

[Chemical 3] (In the formula, other symbols have the following meanings. R ⁵ : lower alkyl group or cycloalkyl group; L ¹ : lower alkylene group; X: single bond or oxygen atom; same applies hereinafter) Means a converted carboxyl group.

The term "lower" in the definition of the general formula means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. Therefore, as the "lower alkyl group", specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl) group, iso-pentyl group, neo-pentyl group, tert-pentyl group, 1-methylbutyl group, 2-
Methylbutyl group, 1,2-dimethylpropyl group, hexyl group, iso-hexyl group, 1-methylpentyl group, 2
-Methylpentyl group, 3-methylpentyl group, 1,1-
Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2
-Dimethylbutyl group, 1,3-dimethylbutyl group, 2,
3-dimethylbutyl group, 3,3-dimethylbutyl group, 1
-Ethylbutyl group, 2-ethylbutyl group, 1,1,2-
Examples thereof include trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.

Examples of the "cycloalkyl group" of R ^{5 in} the above chemical formula 3 include those having 3 to 7 carbon atoms, specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like. Is mentioned. Further, the “lower alkylene group” of L ^{1 in} the above chemical formula 3 means a straight or branched carbon chain, specifically, methylene group, ethylene group, propylene group, methylmethylene group, dimethylmethylene group, etc. Is mentioned.

Therefore, as the group represented by the above chemical formula 3, for example, acetoxymethyl group, 1-acetoxyethyl group, 2
-Acetoxyethyl group, pivaloyloxymethyl group,
2,2-dimethylpropanoyloxymethyl group, 1-
(Pivaloyloxy) ethyl group, 1- (pivaloyloxy) propyl group, 2- (pivaloyloxy) ethyl group,
2- (pivaloyloxy) propyl group, (pivaloyloxy) propan-2-yl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) ethyl group, 2- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, 2- (ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group,
1- (propoxycarbonyloxy) ethyl group, 2-
Examples thereof include (propoxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group and 2- (cyclohexyloxycarbonyloxy) ethyl group.

The lower alkyl group in R ² , R ³ and R ⁵ has the same meaning as the above lower alkyl group. Also, R
Examples of the “aralkyl group” in ⁴ include triphenylmethyl group, benzyl group, phenethyl group, 1-phenylethyl group and the like. Specific examples of the “halogen atom” include iodine atom, bromine atom, chlorine atom, fluorine atom and the like.

The compound (I) of the present invention forms salts with acids and bases. Examples of salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid,
Acid addition with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid Mention may be made of salt. Examples of salts with bases include inorganic bases such as lithium, sodium, potassium, magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine and ethanolamine, lysine,
Examples thereof include salts with basic amino acids such as ornithine and ammonium salts. It may also contain an asymmetric carbon atom depending on the kind of the substituent. Therefore, in the compound (I) of the present invention,
It includes a mixture of various isomers such as geometrical isomers, tautomers, and optical isomers, as well as isolated ones. Further, the compound (I) of the present invention includes all hydrates, solvates, polymorphs and the like.

Representative compounds among the compounds of the present invention will be exemplified below.

[Chemical 4]

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

1) Tri: trityl group

[Chemical 5]

These compounds can be synthesized by a method similar to the synthetic route described in the following process charts and examples.

(Production Method) The compound (I) of the present invention can be produced by applying various production methods, and representative production methods thereof will be described below.

(First manufacturing method)

[Chemical 6]

(The symbols in the formula have the following meanings: Y:
Halogen atom. The same applies below. The compound (I) of the present invention is produced by reacting a pyrazolotriazole compound represented by the general formula (II) with a halide represented by the general formula (III).

In this reaction, the compound (II) and a corresponding amount of the compound (III) are reacted in an inert solvent at room temperature or under heating with stirring. A base is preferably added to accelerate this reaction. Examples of the inert solvent include tetrahydrofuran, benzene, chloroform, methylene chloride, water, N, N-dimethylformamide, N, N-
Examples thereof include dimethylacetamide and toluene. As the base, potassium butoxide, potassium carbonate, sodium hydroxide, sodium hydride, metallic sodium, sodium methoxide, pyridine, triethylamine, picoline, lutidine, N, N-dimethylamine and the like are used.

If desired, the compound (Ia) having a tetrazolyl group which is not substituted with an aralkyl group can be produced by dearalkylation. The compound (Ia) can be obtained by subjecting the compound (I) to a reduction reaction such as catalytic reduction, liquid reduction or treatment with an acid. As the acid, for example, acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid-acetic acid, etc. are used. This reaction is usually carried out in an organic solvent such as methanol, ethanol or acetone or in water at room temperature or under heating (under reflux).

(Second manufacturing method)

[Chemical 7]

In the compound (I) of the present invention, the compound having a tetrazolyl group represented by the general formula (Ib) is represented by the general formula (IV)
It is also possible to synthesize from a compound having a cyano (CN) group represented by This reaction is carried out, for example, with compound (IV)
Can be carried out by stirring in dimethylformamide in the presence of sodium azide and ammonium chloride at room temperature to reflux conditions for several hours to several days. It can also be synthesized by reacting compound (IV) in the presence of trialkyltin or triaryltin in an inert solvent such as benzene or toluene at room temperature to reflux conditions for several days to several hours. .

(Third manufacturing method)

[Chemical 8]

(The symbols in the formula have the following meanings: Y
¹ , Y ² : one is a halogen atom and the other is -B
(OH) ₂ . The same applies below. )

In the compound (I) of the present invention, the compound represented by the general formula (Ic) includes a compound represented by the general formula (V) and a reaction-activator of the compound represented by the general formula (VI) in an amount corresponding to the reaction. And are stirred in an inert solvent under ice cooling to room temperature. In carrying out this method, it is preferable to interpose a zero-valent palladium catalyst as a reaction promoting substance. It is also preferable that a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate be present. Examples of the inert solvent in this production method include tetrahydrofuran, hexane, benzene, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, water, methanol, ethanol and the like.

(Fourth manufacturing method)

[Chemical 9]

(The symbols in the formula have the following meanings: R
^a : a lower alkyl group. The same applies below. In the compound (I) of the present invention, the carboxylic acid ester compound of the general formula (Ie) is an aldehyde compound represented by the general formula (Id), manganese dioxide and sodium or potassium cyanide in an alcohol such as methanol or ethanol at room temperature to It can be produced by reacting under heating. At this time, it is preferable to add an acid or the like to promote the reaction. As the acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid-acetic acid or the like is used.

In the compound (I) of the present invention, the compound of the general formula (I-
The carboxylic acid compound represented by f) is produced by hydrolyzing the carboxylic acid ester compound (Ie). The hydrolysis reaction of the ester compound may be carried out by a conventional method. Specifically, the ester compound in an inert solvent adjusted to be basic with sodium hydroxide, potassium hydroxide or the like is added, and the mixture is stirred at room temperature or under heating or It is carried out by refluxing. The method of esterification or O-alkylation reaction of carboxylic acid to obtain compound (Ie) from compound (If) can be easily understood by those skilled in the art, including the necessity of protection and deprotection by the reaction.

(Fifth manufacturing method)

[Chemical 10]

(The symbols in the formula have the following meanings: R
^b : an aralkyl group. The same applies below. In the compound (I) of the present invention, the compound (Ig) having a tetrazolyl group substituted with an aralkyl group is a compound represented by the general formula (Ia) and an amount of an aralkyl halide corresponding to the reaction, in an inert solvent and cooled with ice. It can be produced by reacting at below to room temperature. Examples of the insoluble solvent include tetrahydrofuran, dimethoxyethane, water, N, N-dimethylformamide, N, N-dimethylacetamide and the like. In addition, it is preferable to add a base such as sodium hydride or sodium hydroxide in order to accelerate the reaction. Further, the compound (Ia) can be produced by subjecting this compound (Ig) to dearalkylation. This method is similar to the dearalkylation of the first production method.

Isolation and purification of the target substance from the reaction solution
It is carried out by a conventional method by appropriately combining extraction with an organic solvent, chromatography, crystallization and the like.

[0031]

The compound of the present invention is angiotensin II.
(AII) Since it has an antagonistic effect, various diseases caused by physiological effects of AII (hypertension, chronic heart failure, cardiac hypertrophy, arteriosclerosis (vascular wall thickening), diabetic nephropathy, diabetic retinopathy, chronic thread) Treatment of glomerulonephritis, proliferative glomerulonephritis, glaucoma, amnesia, anxiety, benign prostatic hypertrophy and accompanying dysuria, peripheral circulatory failure, concomitant and secondary hyperaldosteronism, cerebrovascular disorder, etc.) Useful for. Further, the compound of the present invention is produced by AII produced without mediating renin or ACE.
Since it also shows an antagonistic action against ACE, a broader hypotensive spectrum can be expected compared with ACE inhibitors and renin antagonists. A preparation containing one or more kinds of the compound (I) of the present invention or a salt thereof as an active ingredient is prepared by using a carrier, an excipient and other additives usually used for preparation. The carrier or excipient for the preparation may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. Other commonly used ones can be mentioned. It is administered orally by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous injection and intramuscular injection, suppositories,
Any form of parenteral administration such as transdermal administration may be used. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex, etc., however, in the case of oral administration, it is usually 10 to 1000 mg per day for an adult, and once or twice Dosage is divided into 4 doses.

[0032]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention. In addition, since the raw material compound of the present invention is a novel compound,
The compound is shown as a reference example.

Reference Example 1 2,7-Diethyl-5- [4- [4-bromo-2-cyano-1-pyrrolyl] benzyl] -5H-pyrazolo [1,
5-b] [1,2,4] triazole

2,7-diethyl-1H-pyrazolo [1,
1.40 g of 5-b] [1,2,4] triazole are dissolved in 25 ml of methylene chloride. 4- (4-bromo-2-cyano-1-pyrrolyl) benzyl bromide 3.0
4 g, tetrabutylammonium bromide 1.10 g,
Add 1.07 g of sodium hydrogen carbonate and 25 ml of water and stir vigorously at room temperature overnight. The methylene chloride layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The title compound was obtained by purifying the obtained residue by silica gel column chromatography. Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.30 (3H, t), 1.39 (3
H, t), 2.66 (2H, q), 2.78 (2H,
q), 5.33 (2H, s), 6.97 (1H, d),
7.06 (2H, t), 7.43 (4H, s) (2) Mass spectrum (FAB): 425 MH ⁺

Using the corresponding starting materials, the compounds of Reference Examples 2 and 3 were obtained in the same manner as in Reference Example 1. Reference Example 2 2,7-diethyl-5-[[2-bromopyridyl-5-
Il] methyl] -5H-pyrazolo [1,5-b] [1,
2,4] Triazole Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t), 1.36 (3
H, t), 2.66 (2H, q), 2.81 (2H,
q), 5.18 (2H, s), 6.94 (1H, d),
7.46-7.48 (2H, m), 8.30-8.39
(1H, m) (2) Mass spectrum value (FAB): 334 M ⁺

Reference Example 3 2,7-Diethyl-5- [5- [1- (2-cyanobenzoyl) indole] methyl] -5H-pyrazolo [1,
5-b] [1,2,4] triazole Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t), 1.40 (3
H, t), 2.63 (2H, q), 2.89 (2H,
q), 5.37 (2H, s), 6.64 (1H, d),
6.98 (1H, s), 7.06 (1H, d), 7.3
5 (1H, dd), 7.53 (1H, d), 7.69-
7.80 (2H, m), 7.87 (1H, d), 8.4
1 (1H, d) (2) Mass spectrum (FAB): 423 M ⁺

Example 1 2,7-Diethyl-5-[[3-bromo-2- [2-
(N-Triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -5H-pyrazolo [1,5-b] [1,2,4] triazole

2,7-Diethyl-1H-pyrazolo [1,
500 mg of 5-b] [1,2,4] triazole was dissolved in 30 ml of a mixed solution of methylene chloride-water (1: 1). To this mixed solution under ice cooling, sodium hydrogen carbonate 385 m
g, tetrabutylammonium 400 mg, 5- [2-
2.1 g of [3-bromo-5- (bromomethyl) -2-benzofuranyl] phenyl] -N- (triphenylmethyl) tetrazole were sequentially added. After stirring the reaction solution overnight, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with methylene chloride and combined with the previous organic layer. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 2,7-diethyl-5-.
[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -5H-pyrazolo [1,5-b] [1,
450 mg of 2,4] triazole was obtained as an oily substance.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.02 (3H, t), 1.15 (3
H, t), 2.18 (2H, q), 2.52 (2H,
q), 5.31 (2H, s), 6.88-9.78 (2
3H, m) (2) Mass spectrum (FAB): 761 MH ⁺

Example 2 was obtained in the same manner as in Example 1. Example 2 2,7-Diethyl-5- [4- [4,5-dibromo-2
-[2- (N-triphenylmethyltetrazole-5-
Yl) -1-pyrrolyl] benzyl] -5H-pyrazolo [1,5-b] [1,2,4] triazole

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.23 (3H, t), 1.38 (3
H, t), 2.55 (2H, q), 2.84 (2H,
q), 5.15 (2H, s), 6.74-7.36 (2
1H, m) (2) Mass spectrum (FAB): 788 MH ⁺

Example 3 5-[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [1,5-b] [1,2,4] triazole-6-carbaldehyde

2,7-diethyl-1H-pyrazolo [1,
To 320 ml of a DMF solution of 4.0 g of 5-b] [1,2,4] triazole-6-carbaldehyde, potassium t-
2.48 g of butoxide was added, and the mixture was stirred at room temperature for 10 minutes. The solution was ice-cooled and 5- [2- [3-bromo-5- (bromomethyl) -2-benzofuranyl] phenyl] -N-
15.52 g of (triphenylmethyl) tetrazole was added, and the mixture was stirred overnight. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 50 ml of ethyl acetate and washed twice with 50 ml of water. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and further crystallized from methanol to give 5-[[3- Bromo-2-
[2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,
7-diethyl-5H-pyrazolo [1,5-b] [1,
2,4] Triazole-6-carbaldehyde 5.20
g was obtained as white crystals.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.34 (3H, t), 1.42 (3)
H, t), 2.89 (2H, q), 2.91 (2H,
q), 5.90 (2H, s), 6.78-8.21 (2
3H, m), 9.99 (1H, s) (2) Mass spectrum (FAB): 788 MH ⁺

Example 4 5-[[2,3-Dibromo-1- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -1H
-Indol-4-yl] methyl] -2,7-diethyl-5H-pyrazolo [1,5-b] [1,2,4] triazole

A) 2.00 g of 4-methylindole is dissolved in 20 ml of dimethyl sulfoxide, 0.68 g of sodium hydride having a content of about 60% in a paraffin solution is added, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and 2-fluorobenzonitrile 2. in 2 ml dimethylsulfoxide.
04 g is added dropwise. The reaction mixture was stirred overnight at room temperature, ice water was added, and the precipitated solid was collected by filtration to give 1
-(2-Cyanophenyl) -4-methylindole 3.
50 g was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 2.60 (3H, s), 6.78 (1)
H, d), 7.01 (1H, d), 7.13-7.19.
(2H, m), 7.40 (1H, d), 7.48 (1
H, t), 7.61 (1H, d), 7.73 (1H,
t), 7.84 (1H, d) (2) Mass spectrum (EI): 232 M ⁺

B) A mixture of 3.45 g of 1- (2-cyanophenyl) -4-methylindole, 70 ml of toluene and 9.90 g of tributyltin azide is heated under reflux overnight. After allowing to cool, 50 ml of ether and 50 ml of 1N aqueous sodium hydroxide solution are added and the mixture is stirred for 1 hour. The aqueous layer is further washed with ether, adjusted to pH 4 with hydrochloric acid and extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the resulting residue was mixed with 70 ml of dimethylformamide,
Triethylamine (4.1 ml) and triphenylmethyl chloride (4.96 g) are added, and the mixture is stirred at room temperature overnight. The organic solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with ethyl acetate.
[2- (4-Methyl-1H-indol-1-yl) phenyl] -N-triphenylmethyltetrazole 6.8
3 g was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 2.45 (3H, s), 6.27 (1)
H, d), 6.74 (6H, d), 7.16 (6H,
t) (2) Mass spectrum (FAB): 517 M ⁺

C) A mixture of 0.27 g of 5- (2- (4-methyl-1H-indol-1-yl) phenyl] -N-triphenylmethyltetrazole, 15 ml of carbon tetrachloride and 0.30 g of N-bromosuccinimide. The mixture is stirred at room temperature for 2 hours, washed with multi-layered water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residue is subjected to silica gel column chromatography and ethyl acetate-n-hexane (1: 9, v / v). 5- [2-
(2.3-Dibromo-4-methyl-1H-indole-
1-yl) phenyl] -N-triphenylmethyltetrazole 0.10 g was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 2.67 (3H, s), 6.62 (1)
H, d), 6.78 (6H, d), 6.91 (1H,
t), 7.17 (6H, t) (2) Mass spectrum (FAB): 676 MH ⁺

D) 5- (2- (2,3-dibromo-4-)
Methyl-1H-indol-1-yl) phenyl] -N
A mixture of 0.66 g of triphenylmethyltetrazole, 20 ml of carbon tetrachloride, 0.19 g of N-bromosuccinimide and 0.02 g of dibenzoyl peroxide is heated under reflux for 15 minutes under irradiation with a tungsten lamp. After cooling, the insoluble matter is filtered off, the organic layer is washed with multi-layered water, and then concentrated under reduced pressure. 6 ml of methylene chloride and 5 of water were added to the resulting residue.
ml, sodium hydrogen carbonate 0.12 g, tributylammonium bromide 0.15 g and 2,7-diethyl-1H-pyrazolo [1,5-b] [1,2,4] triazole are added, and the mixture is stirred at room temperature overnight. . The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained is subjected to silica gel column chromatography, and ethyl acetate-n-hexane (1:
1, v / v) to elute 5-[[2.3-
Dibromo-1- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -1H-indole-4
-Yl] methyl] -2,7-diethyl-5H-pyrazolo [1,5-b] [1,2,4] triazole 0.24 g
Got

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.19 (3H, t), 1.42 (3)
H, t), 2.49 (2H, q), 2.89 (2H,
q), 5.56 (1H, d), 5.83 (1H, d),
6.69 (1H, s) (2) Mass spectrum (FAB): 838 MH ⁺

Example 5 2,7-Diethyl-5-[[3-bromo-2- [2-
(Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -5H-pyrazolo [1,5-b]
[1,2,4] triazole

2,7-diethyl-5-[[3-bromo-
2- [2- (N-triphenylmethyltetrazole-5
-Yl) phenyl] -5-benzofuranyl] methyl]-
A 5% acetic acid-ethanol solution containing 450 mg of 5H-pyrazolo [1,5-b] [1,2,4] triazole was heated under reflux for 5 hours, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the mixture was evaporated under reduced pressure twice. The residue was subjected to silica gel column chromatography (chloroform: methanol: acetic acid = 200: 10: 0.5).
2,7-diethyl-5-[[3-bromo-2- [2-
(Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -5H-pyrazolo [1,5-b]
160 mg of [1,2,4] triazole was obtained as white crystals.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.02 (3H, t), 1.15 (3
H, t), 2.18 (2H, q), 2.52 (2H,
q), 5.31 (2H, s), 6.93 (1H, s),
7.15-7.35 (2H, m), 7.65-7.66
(3H, m), 7.83 (1H, d), 8.10 (1
H, d) (2) Mass spectrum (FAB): 517 M ⁺

Similar to Example 5, Example 6 and Example 7
Got Example 6 2,7-Diethyl-5- [4- [4,5-dibromo-2
-(Tetrazol-5-yl) -1-pyrrolyl] benzyl] -5H-pyrazolo [1,5-b] [1,2,4] triazole

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 0.97 (3H, t), 1.27 (3
H, t), 2.29 (2H, q), 2.77 (2H,
q), 5.32 (2H, s), 6.97 (1H, s),
7.12 (1H, s), 7.28 (2H, d), 7.3
7 (2H, d) (2) Mass spectrum (FAB): 546 MH ⁺

Example 7 5-[[3-Bromo-2- [2- (tetrazole-5-
Iyl) phenyl] -5-benzofuranyl] methyl]-
2,7-Diethyl-5H-pyrazolo [1,5-b]
[1,2,4] triazole-6-carbaldehyde

Physicochemical properties (1) Nuclear magnetic resonance spectrum (DMSO, TMS) δ (ppm): 1.28 (3H, t), 1.31 (3
H, t), 2.77 (2H, q), 2.97 (2H,
q), 5.86 (2H, s), 7.25 (1H, t),
7.26-7.49 (2H, m), 7.80-7.95
(2H, m), 10.13 (1H, s) (2) Mass spectrum (FAB): 547 MH ⁺

Example 8 Ethyl 5-[[3-Bromo-2- [2- (tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [1,5 −
b] [1,2,4] triazole-6-carboxylate

5-[[3-Bromo-2- [2- (tetrazol-5-yl) phenyl] -5-benzofuranyl]
Methyl] -2,7-diethyl-5H-pyrazolo [1,5
-B] [1,2,4] Triazole-6-carbaldehyde 2.38 g of ethanol solution 250 ml of ethanol were sequentially added with sodium cyanide 1.08 g, manganese dioxide 8.81 g, and acetic acid 0.36 ml, and stirred at room temperature for 3 days. did. The insoluble material was removed by filtration through Celite, and the filtrate was evaporated under reduced pressure. Chloroform (100 ml) was added to the obtained residue, the insoluble material was filtered off, and the filtrate was again distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol: acetic acid = 100: 1: 0.1), and ethyl 5-[[3-bromo-2- [2- (tetrazole-5
-Yl) phenyl] -5-benzofuranyl] methyl]-
2,7-Diethyl-5H-pyrazolo [1,5-b]
1.96 g of [1,2,4] triazole-6-carboxylate was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.00 (3H, t), 1.09 (3
H, t), 1.39 (3H, t), 2.38 (2H,
q), 2.63 (2H, q), 4.41 (2H, q),
5.86 (2H, s), 7.13-7.26 (3H,
m), 7.64-7.67 (2H, m), 7.82 (1
H, dd), 8.08 (1H, dd) (2) Mass spectrum (FAB): 591 MH ⁺

Example 9 5-[[3-Bromo-2- [2- (tetrazole-5-
Iyl) phenyl] -5-benzofuranyl] methyl]-
2,7-Diethyl-5H-pyrazolo [1,5-b]
[1,2,4] triazole-6-carboxylic acid

Ethyl 5-[[3-bromo-2- [2-
(Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [1,5-b] [1,2,4] triazole-6-carboxylate 1.96 g of 1N under ethanol cooling in ethanol solution
10.0 ml of sodium hydroxide was added, the mixture was returned to room temperature and stirred overnight. After the reaction solution was distilled off under reduced pressure, the residue was replaced with 20 ml of water.
Dissolved in. The pH was adjusted to 2 with 1N hydrochloric acid, and the mixture was extracted twice with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in hot ethyl acetate. The solution was cooled to 5 ° C., and the precipitated crystals were collected by filtration to give 5-[[3-bromo-2- [2- (tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-. Diethyl-5H-pyrazolo [1,5-
b] [1,2,4] triazole-6-carboxylic acid 1.
85 g was obtained as white crystals.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (DMSO, TMS) δ (ppm): 1.21 (3H, t), 1.37 (3
H, t), 2.74 (2H, q), 2.89 (2H,
q), 5.85 (2H, s), 7.21 to 7.24 (1
H, m), 7.40 (1H, s), 7.49 (1H,
d), 7.76-7.81 (2H, m), 7.87-
7.95 (2H, m) (2) Mass spectrum (FAB): 563 MH ⁺

Example 10 5-[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [1,5-b] [1,2,4] triazole-6-carboxylic acid

5-[[3-Bromo-2- [2- (tetrazol-5-yl) phenyl] -5-benzofuranyl]
Methyl] -2,7-diethyl-5H-pyrazolo [1,5
-B] [1,2,4] triazole-6-carboxylic acid 1.75 g in DMF solution 20 ml under ice cooling triethylamine 350 mg triphenylmethyl chloride 960 mg
Were sequentially added. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 50 ml of chloroform, washed with 50 ml of water, and the organic layer was dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 5-[[3-bromo-2-
[2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,
7-diethyl-5H-pyrazolo [1,5-b] [1,
2.10 g of 2,4] triazole-6-carboxylic acid was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.21 (3H, t), 1.37 (3
H, t), 2.74 (2H, q), 2.89 (2H,
q), 5.85 (2H, s), 6.75-8.20 (2
2H, m) (2) Mass spectrum (FAB): 803 M ⁺

Example 11 1-Ethoxycarbonyloxyethyl 5-[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7 -Diethyl-5H-pyrazolo [1,5-
b] [1,2,4] triazole-6-carboxylate

5-[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl]]
-5-Benzofuranyl] methyl] -2,7-diethyl-
Ethanol solution 10 of 2.10 g of 5H-pyrazolo [1,5-b] [1,2,4] triazole-6-carboxylic acid
To 0 ml, 27.4 ml of 0.1 M ethanolic potassium hydroxide solution was added under ice cooling, and the mixture was stirred for 15 minutes. After the solvent was distilled off under reduced pressure, the residue was dissolved in 75 ml of acetone. 15 ml of an acetone solution of 1-iodoethyl ethyl carbonate prepared from a mixture of 1-chloroethyl ethyl carbonate 1.20 g, sodium iodide 3.54 g, and acetonitrile 30 ml was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
-Ethoxycarbonyloxyethyl 5-[[3-Bromo-2- [2- (N-triphenylmethyltetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [ 1,5-
b] [1,2,4] triazole-6-carboxylate 1.09 g was obtained.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.16-1.48 (9H, m), 1.
68 (3H, d), 2.74-3.10 (4H, m),
4.24 (2H, q), 5.86 (2H, s), 6.7
6-8.28 (23H, m) (2) Mass spectrum (FAB): 921 MH ⁺

Example 12 was obtained in the same manner as in Example 5. Example 12 1-Ethoxycarbonyloxyethyl 5-[[3-Bromo-2- [2- (tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2,7-diethyl-5H-pyrazolo [1 , 5-b] [1,2,4] Triazole-6-carboxylate

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.04 (3H, t), 1.11 (3
H, t), 1.28 (3H, t), 1.64 (3H,
d), 2.43 (2H, q), 2.63-2.75 (2
H, m), 4.16-4.24 (2H, m), 5.85.
(2H, dd), 7.00 (1H, dd), 7.16-
7.21 (2H, m), 7.31 (1H, s), 7.6
3-7.67 (2H, m), 7.80-7.83 (1
H, m), 8.07-8.09 (1H, m) (2) Mass spectrum (FAB): 679 MH ⁺

Example 13 2,7-Diethyl-5- [4- [4-bromo-2- (tetrazol-5-yl) -1-pyrrolyl] benzyl]-
5H-pyrazolo [1,5-b] [1,2,4] triazole

2,7-diethyl-5- [4- [4-bromo-2-cyano-1-pyrrolyl] benzyl] -5H-pyrazolo [1,5-b] [1,2,4] triazole 2.
After adding 7.10 g of tributyltin azide to 40 ml of a 26 g toluene solution, the reaction solution was heated under reflux for 5 hours.
Then, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl ether 1
It was dissolved in 00 ml and 100 ml of 1N sodium hydroxide aqueous solution, and stirred at room temperature for 15 minutes. After the liquid separation operation, the aqueous layer was adjusted to pH 4.0 with concentrated hydrochloric acid under ice cooling, and the insoluble matter was extracted with chloroform. The chloroform layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol: acetic acid = 200: 10: 0.5), and then crystallized from ethyl acetate. 2,7-diethyl-5-
[4- [4-bromo-2- (tetrazol-5-yl)
-1-Pyrrolyl] benzyl] -5H-pyrazolo [1,5
600 mg of -b] [1,2,4] triazole was obtained as white crystals.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TM
S) δ (ppm): 1.22 (6H, t), 2.54 (2
H, q), 2.64 (H, q), 5.47 (2H,
s), 6.96 (2H, d), 7.29 (4H, q),
7.50 (1H, d), 7.72 (1H, s) (2) Mass spectrum (FAB): 468 MH ⁺

Example 14 was obtained in the same manner as in Example 13. Example 14 2,7-Diethyl-5- [5- [1- [2- (tetrazole) benzoyl] indole] methyl] -5H-pyrazolo [1,5-b] [1,2,4] triazole

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.27 (3H, t), 1.40 (3
H, t), 2.63 (2H, q), 2.89 (2H,
q), 5.54 (2H, s), 6.64 (1H, d),
6.98 (1H, s), 7.06 (1H, d), 7.3
5 (1H, dd), 7.53 (1H, d), 7.69-
7.80 (2H, m), 7.87 (1H, d), 8.4
1 (1H, d) (2) Mass spectrum (FAB): 466 MH ⁺

Example 15 2,7-Diethyl-5-[[4- [2- [2- (tetrazol-5-yl) phenyl] pyridinyl] methyl]-
5H-pyrazolo [1,5-b] [1,2,4] triazole

To 25 ml of a dimethoxyethane solution of 1.85 g of 2- (N-trimethylphenyltetrazol-5-yl) phenylboronic acid, 110 ml of 8% aqueous potassium carbonate solution was added dropwise at room temperature, and then 2,7-diethyl-5-.
[[2-Bromopyridyl-5-yl] methyl] -5H-
25 ml of dimethoxyethane solution of 1.30 g of pyrazolo [1,5-b] [1,2,4] triazole, tetrakis (triphenylphosphine) -palladium (0) 30
mg was added sequentially. The reaction solution was heated under reflux for 3 hours and then returned to room temperature. 100 ml of ethyl acetate and 10 parts of water in the reaction solution.
After adding 0 ml and performing liquid separation operation, the aqueous layer was adjusted to pH 3.0 with 1N hydrochloric acid. Water layer is chloroform 100ml
After being extracted twice with, the organic layer was dried over magnesium sulfate. The solution was evaporated under reduced pressure, and the obtained residue was crystallized from hot ethyl acetate to give 2,7-diethyl-5-[[4- [2-
[2- (tetrazol-5-yl) phenyl] pyridinyl] methyl] -5H-pyrazolo [1,5-b] [1,
500 mg of 2,4] triazole was obtained as white crystals.

Physicochemical properties (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS) δ (ppm): 1.29 (3H, t), 1.36 (3
H, t), 2.63 (2H, q), 2.82 (2H,
q), 5.33 (2H, s), 7.04 (1H, s),
7.51-7.56 (2H, m), 7.63 (2H, d
d), 7.78 (1H, dd), 8.25 (1H, d
d), 8.70 (1H, d) (2) Mass spectrum (FAB): 400 MH ⁺

Example 16 was obtained in the same manner as in Example 5. Example 16 5-[[2,3-Dibromo-1- [2- (tetrazol-5-yl) phenyl] -1H-indol-4-yl] methyl] -2,7-diethyl-5H-pyrazolo [1 , 5-b] [1,2,4] triazole

Physicochemical properties (1) Melting point 192-195 ° C. (decomposition) (2) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TM
S) δ (ppm): 1.23 (6H, t), 2.56 (2
H, q), 2.67 (2H, q), 5.91 (1H,
d), 6.02 (1H, d), 6.61 (1H, d),
6.80 (1H, d), 7.03 (1H, t), 7.4
3 (1H, s) (3) Mass spectrum (FAB): 596 MH ⁺

Claims (1)

[Claims] 1. The following general formula (I): (The symbols in the formulas have the following meanings: R ¹ : hydrogen atom,
Formyl group or optionally esterified carboxyl group. R ^2, R ^3: same or different and each represents a hydrogen atom or a lower alkyl group. R ^4: a hydrogen atom or an aralkyl group. A ¹
Ring: a benzene ring optionally substituted with a halogen atom,
Pyridine ring, benzofuran ring or indole ring. A ²
Ring: A benzene ring or a pyrrole ring which may be substituted with a halogen atom. L: a single bond or a carbonyl group. However, A
¹ when the ring is a benzene ring which may be substituted by a halogen atom, A ² ring means good pyrrole ring optionally substituted with a halogen atom, A ² rings may be substituted by a halogen atom In the case of a benzene ring, A ¹ ring means a pyridine ring optionally substituted with a halogen atom, a benzofuran ring or an indole ring. ] The pyrazolotriazole derivative shown by these, or its salt.