JPH0156067B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel tetrazole derivatives, and more particularly to tetrazole derivatives represented by the following general formula () and salts thereof. [In the formula, A is a lower alkylene group, R ¹ is a lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, phenyl group or phenyl lower alkyl group, R ² is the formula

【formula】

【formula】

In the group represented by the formula, R ³ and R ⁴ are the same or different and represent a hydrogen atom or a lower alkyl group, and R ⁵ represents a lower alkanoyl group. It has anti-ulcer effect, cardiotonic effect (positive myocardial inotropic effect), anti-inflammatory effect and antihypertensive effect, and is a prophylactic and therapeutic agent for thrombosis.
It is useful as a phosphodiesterase inhibitor, anti-ulcer agent, cardiotonic agent, anti-inflammatory agent, antihypertensive agent, etc. In this specification, each group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A can specifically include the following. That is, examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups; examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 1-phenylethyl, and 3-phenylethyl. -Fnylpropyl,
4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylxyl, 2-methyl-3-phenylpropyl group, etc.; cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group Lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoid groups, etc.; cycloalkyllower alkyl groups include cyclopropylmethyl, 4-
Cyclohexylbutyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, cyclopentylmethyl, 2-cyclohexylethyl, 2
-Cyclohexylpropyl, 2-cycloheptylethyl, 3-cyclobutylpropyl, 1,1-dimethyl-2-cyclohexylethyl, 1-methyl-2-cyclopentylethyl, 5-cyclohexylpentyl, 6-cyclohexylhexyl group, etc.; lower alkylene Examples of the group include methylene, ethylene, methylmethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethyltrimethylene, 1-methyltrimethylene, etc. can be mentioned. Among the compounds of the present invention, typical ones are listed below. 2-[3-(1-cyclohexyltrazole-
5-yl)propoxy]naphthalene 1-[4-(1-phenyltrazol-5-yl)butoxy]naphthalene 2-[3-(1-benzyltetrazol-5-
yl)propoxy]naphthalene 1-[4-(1-cyclohexylmethyl-5-
yl)butoxy]naphthalene 4-(3-(1-cyclohexyltetrazol-5-yl)propoxy)acetanilide 3-[4-(1-phenyltetrazol-5-
yl)butoxy]propionylanilide 2-[3-(1-benzyltetrazole-5-
yl)propoxy]acetanilide 4-(4-(1-cyclohexylmethyltetrazol-5-yl)butoxy]butyrylanilide 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]benzimidazole 4-[4-(1) -Phenyltetrazole-5-
yl)butoxy]benzimidazole 5-[3-(1-benzyltetrazole-5-
yl)propoxy]benzimidazole 4-[4-(1-cyclohexylmethyltetrazol-5-yl)butoxy]benzimidazole 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-3.3-dimethyl-2
-Oxindole 4-[4-(1-phenyltrazol-5-yl)butoxy]-3,3-dimethyl-2-oxindole 5-[3-(1-benzyltetrazole-5-
yl)propoxy]-3,3-dimethyl-2-oxindole 4-[4-1-cyclohexylmethyltetrazol-5-yl)butoxy]-3,3-dimethyl-2-oxindole 5-[3-(1 -cyclohexyltetrazol-5-yl)propoxy]-1,3-dihydro-
2H-benzimidazol-2-one 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1-methyl-1,3
-dihydro-2H-benzimidazol-2-one 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1,3-dimethyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1-ethyl-1,3
-dihydro-2H-benzimidazol-2-one 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1,3-diethyl-
1,3-dihydro-2H-benzimidazole-
2-one 4-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-1-methyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 5-[3-(1 -cyclohexyltetrazol-5-yl)propoxy]-1-propyl-1,
3-dihydro-2H-benzimidazole-2-
On 4-[3-(1-cyclohexylterazol-
5-yl)propoxy]-1,3-dipropyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-1-butyl-1,3-
Dihydro-2H-benzimidazol-2-one 4-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1,3-dibutyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1-methyl-3-butyl-1,3-dihydro-2H-benzimidazol-2-one 5-[4-(1 -cyclohexyltetrazol-5-yl)butoxy]-1-methyl-3-propyl-1,3-dihydro-2H-benzimidazol-2-one 4-[3-(1-cyclohexyltetrazol-5-yl)propoxy] -1-Propyl-3-
Butyl-1,3-dihydro-2H-benzimidazol-2-one 5-[3-(1-phenyltetrazol-5-
yl)propoxy]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 5-[3-(1-phenyltetrazol-5-
propoxy]-1,3-dimethyl-1,3
-dihydro-2H-benzimidazol-2-one 5-[3-(1-phenyltetrazol-5-
propoxy]-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one 4-[4-(1-phenyltetrazol-5-
yl)butoxy]-1-butyl-1,3-dihydro-2H-benzimidazol-2-one 4-[4-(1-phenyltetrazol-5-
yl)butoxy]-1-propyl-3-butyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[3-(1-benzyltetrazole-5-
propoxy]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 5-[3-(1-benzyltetrazol-5-
propoxy]-1,3-diethyl-1,3
-dihydro-2H-benzimidazol-2-one 6-[4-(1-benzyltetrazol-5-
yl)butoxy]-1-propyl-1,3-dihydro-2H-benzimidazol-2-one 5-[4-(1-benzyltetrazol-5-
yl)butoxy]-1-methyl-3-propyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[3-(1-cyclohexylmethyltetrazol-5-yl)propoxy]-1-methyl-
1,3-dihydro-2H-benzimidazole-
2-one 4-[4-(1-cyclohexacylmethyltetrazol-5-yl)butoxy]-1-ethyl-
1,3-dihydro-2H-benzimidazole-
2-one 5-[3-(1-cyclohexylmethyltetrazol-5-yl)propoxy]-1,3-dipropyl-1,3-dihydro-2H-benzimidazol-2-one 4-[4-(1- cyclohexylmethyltetrazol-5-yl)butoxy]-1-methyl-3
-Butyl-2H-benzimidazol-2-one 5-[(1-cyclohexylmethyltetrazol-5-yl)methoxy]-1-methyl-1,3
-Dihydro-2H-benzimidazol-2-one The compound of the present invention can be produced by various methods, for example, by the method shown in the reaction formula below. reaction formula [In the formula, A, R ¹ and R ² are the same as above. X represents a halogen atom] The method represented by the reaction formula - is carried out by subjecting a hydroxy compound of the general formula () and a tetrazole derivative of the general formula () to a dehydrohalogenation reaction in a conventional manner. In the hydroxy compound represented by the general formula (), R ² is

All compounds other than those of the formula are known compounds. R ² is

A compound having the formula, i.e., a hydroxy-1,3-dihydro-2H-benzimidazole derivative, is a known or unknown compound, whereas an unknown compound is a compound having the formula [In the formula, R means lower alkyl] It can be produced by dealkylating a compound represented by the following by heating in the presence of a dealkylating agent in an appropriate solvent or non-solvent. .
Examples of the solvent used include acetic acid, benzene, nitrobenzene, dichloromethane, and pyridine. Dealkylating agents used include hydrobromic acid, aluminum chloride, aluminum bromide,
Examples include boron trichloride. The amount of dealkylating agent used is usually in large excess relative to compound (). The reaction temperature is usually 35~
The reaction is completed in 30 minutes to 5 hours at 250°C. Examples of the halogen atom of group X in formula () include bromine, chlorine, and iodine. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenation agent. A wide range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alkalis such as sodium and potassium. metals, alcoholates such as sodium methylate, sodium ethylate,
Triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,
3,0] nonene-5 (DBN), 1,5-diazabicyclo[5,4,0] undecene-5 (DBU),
Examples include organic bases such as 1,4-diazabicyclo[2,2,2]octane (DABCO) and 4-dimethylaminopyridine. The reaction may be carried out without a solvent or in the presence of a solvent. As a solvent, any inert solvent that does not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and ethylene glycol, and ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme. , ketones such as acetone and methyl ole ketone, aromatic hydrocarbons such as benzene, toluene, and xylene, esters such as methyl acetate and ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxade, and hexamethylphosphoric triamide. Further, the reaction is advantageously carried out in the presence of metal iodide such as sodium iodide or potassium iodide. The ratio of the hydroxy compound () and the tetrazole derivative () used in the above method is not particularly limited, and is appropriately selected from a wide range;
Usually, it is desirable to use the latter in an amount of equimolar to 5 times the mole, preferably equimolar to twice the molar amount of the former. Further, the reaction temperature is not particularly limited, but it is usually carried out at room temperature to 200°C, preferably 50 to 150°C. The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours. Hydroxycarbostyryl (), one of the starting materials used in the above method, is a known compound, but the other starting material, tetrazole derivative (), is an unknown compound. Manufactured. Reaction formula: [In the formula, X represents a halogen atom such as chlorine, bromine and iodine, and R ¹ and A are the same as above]. That is, a haloamide represented by the general formula (), which is known or produced by a method similar to the known method, is reacted with PCl ₅ to form a haloimine derivative (), and this is converted into hydrazoic acid (HN ₃ ) without isolation. Tetrazole derivative () by reacting
get. The reaction of haloamide () with PCl ₅ is carried out in a solvent according to the general formula. All inert solvents that do not adversely affect the reaction are used, such as aromatic hydrocarbons such as benzene, xylene and toluene, halogenated aromatic hydrocarbons such as chlorobenzene and bromobenzene, Ethers such as diethyl ether and dioxane, n-
Examples include hydrocarbons such as hexane and n-heptane. The ratio of haloamide () and PCl ₅ to be used is usually from 1 to 2 times the mole of the former, preferably from 1 to 1.2 times the mole of the former. The reaction temperature is usually -20°C to 50°C, preferably 0 to 25°C, and the reaction time is 30 minutes to 50°C.
time, preferably 1 to 3 hours. The haloimine derivative () obtained as described above is reacted with HN ₃ (usually used as a solution in benzene, xylene, diethyl ether, n-hexane, etc.) without being isolated. The usage ratio of haloimine derivative () and HN ₃ is
Usually, the latter is selected from the range of equimolar to 5 times the mole, preferably equimolar to 3 times the mole of the former. Further, the reaction temperature is 0 to 150°C, and the reaction time is 3 hours to 2 days. The compounds of the present invention can be administered to animals and humans neat or with conventional pharmaceutical carriers. As the administration form, usual forms are employed, such as oral preparations such as tablets, granules, and oral solutions, and parenteral preparations such as injections. The amount of the active ingredient to be administered is appropriately selected from a wide range, but in order to achieve the desired effect, it is recommended to administer 0.1 to 30 mg/Kg per day at once or divided into several doses. . Further, it is preferable that the dosage unit form contains 1 to 500 mg of the active ingredient. Oral preparations such as tablets, capsules, and oral solutions according to the present invention are manufactured according to conventional methods. For example, tablets are formed by mixing the compound of the invention with conventional pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum acacia, and the like. Capsules are produced by mixing the compound of the present invention with an inert pharmaceutical filler or diluent and filling the mixture into hard gelatin capsules, soft capsules, or the like. Parenteral preparations such as injections are also prepared according to conventional methods, for example, by dissolving or suspending the compound of the present invention in a liquid carrier such as sterilized water or physiological saline. Raw material compounds for producing the compound of the present invention and production examples of the compound of the present invention are listed below as Reference Examples and Examples. Reference example 1 Add 30.6 g of N-(3-chlorobutyryl)cyclohexylamine to 200 ml of dry benzene, and add 36 g of PCl ₅ while cooling the outside with ice and keeping the internal temperature below 20°C.
Add under stirring. After stirring this mixture at room temperature for 2 hours, the reaction solution was heated to 50°C using an evaporator.
Concentrate to about half the volume at temperatures below ℃. Add 10 to the concentrated liquid.
140 ml of benzene containing % HN ₃ was heated to an internal temperature under stirring.
It takes 90 minutes to drip while keeping the temperature below 15℃. After the addition, the reaction solution is left at room temperature overnight. The mixture was refluxed for 3 hours with stirring and then concentrated. Add 200 ml of chloroform to the obtained concentrate for extraction.
The chloroform layer is washed with 5% aqueous sodium bicarbonate and water, and dried over sodium sulfate.
After removing the drying agent, the mother liquor is concentrated and the residue is recrystallized from aqueous isopropanol to obtain 28 g of 1-cyclohexyl-5-(3-chloropropyl)tetrazole in the form of colorless needles. Melting point: 82-8°C Reference Example 2 11.5 g of sodium iodide is added to 11 g of 1-cyclohexyl-5-(3-chloropropyl)tetrazole, followed by 60 ml of acetone and refluxed for 5 hours. After concentrating the reaction solution, it is extracted with chloroform, and the extract is dried over magnesium sulfate and concentrated to obtain 13.5 g of 1-cyclohexyl-5-(3-iodopropyl)tetrazole as a yellow solid. Reference example 3 47 to 7.3g of 1-ethyl-6-methoxy-1,3-dihydro-2H-benzimidazol-2-one
% bromic acid and refluxed for 2 hours in an argon atmosphere.
Concentrate to dryness. Activated carbon treatment in 80% ethanol;
After concentration, recrystallization from dilute ethanol yields 5.6 g (83
%). Melting point: 196-199℃ Example 1 2-naphthol in 50ml of isopropyl alcohol
3.0 g and DBU 3 g were added, and 150 ml of an isopropyl alcohol solution containing 8.3 g of 1-cyclohexyl-5-(3-iodopropyl)tetrazole was added dropwise thereto over 2 hours while refluxing. The mixture is refluxed for 3 hours, concentrated, and extracted with chloroform. The chloroform layer is washed with 10% hydrochloric acid, 1N aqueous sodium hydroxide solution and water, and dried over magnesium sulfate. After concentrating this, the target substance was separated by silica gel column chromatography (solvent: chloroform) and recrystallized from ethyl acetate-n-hexane, resulting in colorless needle crystals of 2-[3-(1
3.2 g (46%) of -cyclohexyltetrazol-5-yl)propoxy]naphthalene are obtained. melting point
96.3-97.0°C Example 2 The following compound was obtained in the same manner as in Example 1. 4-[3-(1-cyclohexyltetrazol-5-yl)propoxy]acetanilide, colorless needle crystals, melting point 150.5-151.5°C Example 3 Add 2 g of 5-hydroxybenzimidazole and 2.6 ml of DBU to 100 ml of isopropyl alcohol and reflux. While stirring, add 1-cyclohexyl-
150 ml of isopropyl alcohol solution containing 6.1 g of 5-(3-iodopropyl)tetrazole was added dropwise over 100 minutes. After the addition, the mixture is refluxed for 4 hours with stirring and then concentrated. The resulting residue was extracted with chloroform, the chloroform layer was washed with dilute aqueous sodium hydroxide solution and water in that order, dried over sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (chloroform:methanol = 20:1). )
Refine with. The concentrated residue is acidified with methanol-hydrochloric acid and recrystallized from methanol-isopropyl alcohol to yield a yellow powder of 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy].
Obtain 1.3 g (24%) of benzimidazole hydrochloride.
Melting point: 243-245.5°C (decomposed) Example 4 0.33 g of 3.3-dimethyl-5-hydroxy-2-oxindole in 20 ml of isopropyl alcohol
and 0.4 g of DBU were added and the mixture was refluxed.
40 ml of an isopropyl alcohol solution containing 0.9 g of 1-cyclohexyl-5-(3-iodopropyl)tetrazole was added dropwise to this over 1 hour. The mixture was refluxed for 6 hours, concentrated, and extracted with chloroform. The chloroform layer is washed successively with 1N aqueous sodium hydroxide solution, water, 10% hydrochloric acid, water, and saturated saline, and dried over sodium sulfate. After concentration, it was purified by Silica gel column chromatography (chloroform:methanol = 20:1) and recrystallized from ethyl acetate to give colorless needle-like crystals of 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]. ―
3,3-dimethyl-2-oxindole 0.16g
(23%). Melting point: 195-197°C Example 5 3.0 g of 1,3-dihydro-5-hydroxy-2H-benzimidazol-2-one and 3.3 g of DBU are added to 150 ml of isopropyl alcohol, and the mixture is refluxed for 1 hour. To this, 1-cyclohexyl-5-(3
150 ml of isopropyl alcohol solution containing 7.4 g of -iodopropyl)tetrazole is added dropwise over 2 hours. The mixture was refluxed for 8 hours, concentrated, and then extracted with chloroform. The chloroform layer is washed with 20% potassium carbonate aqueous solution, 10% hydrochloric acid, and water, and concentrated.
Add 2N sodium hydroxide solution to the resulting residue.
ml, stir for 1 hour, and filter. Add concentrated hydrochloric acid to the solution to adjust the pH to 1, cool on ice, and remove the precipitated lees. After washing this precipitate with water, it is dissolved in 80% ethanol, treated with activated carbon, and concentrated. Then, when this is recrystallized from acetone, colorless plate-like crystals of 5-[3
0.9 g (13%) of -(1-cyclohexyltetrazol-5-yl)propoxy]-1,3-dihydro-2H-benzimidazol-2-one is obtained.
Melting point: 205-206°C Example 6 In 50 ml of isopropyl alcohol, 1.55 g of 5-hydroxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 2.9 g of DBU
was added, refluxed for a while, and 4.6 g of 1-cyclohexyl-5-(3-iodopropyl)tetrazole was added to the solution.
A solution of isopropyl alcohol containing is added dropwise over 15 hours. After refluxing this mixture for 3 hours, it was concentrated.
Extract with chloroform. This extract was washed with 10% hydrochloric acid and water, concentrated, and subjected to silica gel column chromatography (chloroform: methanol = 30:
After separation in step 1), treatment with activated carbon, and recrystallization from ethanol-water, colorless plate-like crystals of 5-[3-
(1-cyclohexyltetrazol-5-yl)
propoxy]-1-methyl-1,3-dihydro-
2H-benzimidazole-2-one 1.38g (41%)
get. Melting point: 191.5-193.5°C Examples 7-12 The following compounds were obtained in the same manner as in Example 6. (7) 5-[3-(1-phenyltetrazole-5
-yl)propoxy]-1-methyl-1,3-
Dihydro-2H-benzimidazol-2-one, melting point 161.5-164.5℃ (8) 5-[3-(1-benzyltetrazole-5
-yl)propoxy]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one,
Melting point 140.5-143.5℃ (9) 5-[3-(1-cyclohexylmethyltetrazol-5-yl)propoxy]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, melting point 165.5-168 ℃ (10) 5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one, melting point 113-115℃ ( 11) 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-1-ethyl-
1,3-dihydro-2H-benzimidazol-2-one, melting point 157-158℃ (12) 6-[3-(1-ethyltetrazol-5-
propoxy]-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
Melting point 122-125℃ Pharmacological test Test compound: 1.5-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-3,3-dimethyl-2-oxindole (compound of Example 4) 2.6-[3 -(1-cyclohexyltetrazol-5-yl)propoxy]-1-ethyl-1,
3-dihydro-2H-benzimidazole-2-
(Compound of Example 6 (11)) Test Method: A pharmacological test was conducted according to the method described in Nature, pages 927-929, 1962. The platelet aggregation inhibiting effect is measured using an AG-type aggregometer [Bryston Manufacturing Company (Bryston
Manufacturing Co.)]. 3.8% sodium citrate aqueous solution to blood collected from a rabbit [The mixing ratio of 3.8% sodium citrate aqueous solution and blood is 1:9 (volume ratio)]
The blood sample to which PRP is added is centrifuged at 1000 rpm (200xg) for 10 minutes to separate the supernatant, platelet rich plasma (hereinafter the separated blood is referred to as PRP-1). omitted). The remaining blood sample after separation of PRP-1 was further
Centrifuge at 3000 rpm (1500xg) for 15 minutes and collect the supernatant to obtain platelet poor plasma (hereinafter the separated plasma will be abbreviated as PPP). The number of platelets contained in the PRP-1 was determined by the Bretscher-Krokaint method.
Clonkite Method) [J.APPl.Physiol.3, 365~
375 (1950)]. In order to perform the adenosine diphosphate-induced aggregation inhibition test (hereinafter abbreviated as ADP-induced aggregation inhibition test), PRP-1 was diluted with PPP.
A sample containing 300000/mm ² platelets was prepared (the sample prepared here will be abbreviated as PRP-2 below). In addition, for collagen-induced aggregation inhibition test,
PRP-1 was diluted with PPP to prepare a sample containing 450000/mm ² platelets (the sample prepared here will be abbreviated as PRP-3 below). ADP-induced aggregation inhibition test: A clot containing a predetermined concentration of the compound to be tested is placed in a platelet aggregation measurement cell containing a rotor.
Add 0.01 ml and 0.6 ml of PRP-2 prepared above, place the cell in the cell chamber of a platelet aggregometer kept at 37°C (rotation speed is adjusted to 1100 rpm), and after 1 minute. , 7.5 x 10 _- 0.07 ml of ⁵ M ADP solution
was added and the change in light transmittance was recorded. The 7.5×10 ^-5 M ADP solution used in the above test is
ADP powder (manufactured by Sigma) was added to Oren-Veronor buffer (PH = 7.35) for adjustment. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate (%) = c ₁ - _{a 1} / b ₁ - _{a 1} × 100 a ₁ : Light transmittance of PRP-2 b ₁ : Light transmittance of PPP c ₁ : Platelet aggregation is caused by the above method. Transmittance of light when platelet aggregation reached maximum The platelet aggregation inhibiting effect of the test compound was determined as follows. Instead of the test compound solution, a solvent in which the test compound was dissolved was added to cause platelet aggregation in the same manner, and the aggregation rate was determined, which was used as the control aggregation rate. Inhibition rate (%) = A ₁ - B ₁ / A ₁ × 100 A ₁ : Aggregation rate of control B ₁ : Aggregation rate of test compound Collagen-induced aggregation inhibition test: Test in a platelet aggregation measurement cell containing a rotor. A solution containing the desired compound at a predetermined concentration of 0.01
ml and PRP-3 prepared above, add 0.6 ml,
This cell was placed in the cell chamber of a platelet aggregometer kept at 37°C (the rotation speed of the rotor was adjusted to 1100 rpm), and after 1 minute, 0.07 ml of 7.5 × 10 ^-5 M collagen solution was added. , the change in light transmission was recorded. The collagen solution used in the above test was prepared by grinding and adding 100 mg of collagen to 5 ml of Oren-Veronal buffer (PH = 7.35) and separating the resulting supernatant. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate (%) = c ₂ - _{a 2} / b ₂ - _{a 2} × 100 a ₂ : Light transmittance of PRP-3 b ₂ : Light transmittance of PPP c ₂ : Platelet aggregation caused by the above method Transmittance of light when platelet plate aggregation reached the maximum The calculated effect of the test compound on inhibiting platelet aggregation was determined as follows. Instead of the test compound solution, a solvent in which the test compound was dissolved was added to cause platelet aggregation in the same manner, and the aggregation rate was determined, which was used as the control aggregation rate. Rejection rate (%) = A ₂ - B ₂ /A ₂ ×100 A ₂ : Aggregation rate of control B ₂ : Aggregation rate of test compound Results: The above test results are shown in the following table.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, A is a lower alkylene group, R ¹ is a lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, phenyl group or phenyl lower alkyl group, R ² is the formula [formula] [formula] or [formula] A tetrazole derivative and a salt thereof represented by the following group, R ³ and R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group, and R ⁵ is a lower alkanoyl group.