JPS648623B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril derivatives. The carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R ¹ represents a lower alkyl group, R ² represents a cycloalkyl group or a pyridyl group, and A represents a lower alkylene group. Also, 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position represents a single bond or a double bond. ] The carbostyril derivative represented by the above general formula (1) has excellent platelet aggregation inhibiting action, phosphodiesterase inhibiting action, antiulcer action, inotropic action (positive myocardial inotropic action), anti-inflammatory action, and antihypertensive action,
It is useful as a prophylactic and therapeutic agent for thrombosis, a phosphodiesterase inhibitor, an antiulcer agent, a cardiotonic agent, an antiinflammatory agent, an antihypertensive agent, and the like. More specifically, the groups represented by R ¹ , R ² and A in this specification include the following. Lower alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc. Lower alkylene group: methylene, ethylene, methylmethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2
-ethyltrimethylene, 1-methyltrimethylene group, etc. Representative compounds of the present invention are listed below. Γ 6-[3-[N-methyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl, 6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]-3,
4-dihydrocarbostyryl (these are collectively referred to as "6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl and its 3- and 4-position hydrogen bodies"). The same applies to the following compounds. ) Γ 6-[3-(N-methyl-N-cyclooctylcarbonylamino)propoxy]carbostyryl and its 3,4-position hydrogen product Γ 6-[3-(N-methyl-N-cyclopropylcarbonylamino)propoxy ] Carbostyril and its 3,4-position hydrogen product Γ 6-{3-[N-methyl-N-(2-pyridylcarbonyl)amino]propoxy} Carbostyril and its 3-,4-position hydrogen product Γ 6-{3- [N-methyl-N-(3-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3,4-position hydrogen product Γ 6-{3-[N-methyl-N-(4-pyridylcarbonyl)amino]propoxy} Carbostyryl and its 3,4-position hydrogen product Γ 6-[3-[N-ethyl-N-cyclohexylcarbonylamino)propoxy] Carbostyril and its 3-,4-position hydrogen product Γ 6-{3-[N-ethyl- N-(2-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3,4-position hydrogen product Γ 6-{3-[N-ethyl-N-(3-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3 , 4-position hydrogen product Γ 6-[3-[N-ethyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl and its 3- and 4-position hydrogen product Γ 6-{3-[N-propyl-N-(3- pyridylcarbonyl)amino]propoxy}carbostyryl and its 3,4-position hydrogen product Γ 6-[3-[N-heptyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl and its 3-,4-position hydrogen product Γ 6-{ 3-[N-t-butyl-N-(2-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3,4-position hydrogen product Γ 6-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy] Carbostyryl and its 3,4-position hydrogen product Γ 6-{4-[N-methyl-N-(3-pyridylcarbonyl)amino]butoxy} Carbostyril and its 3-,4-position hydrogen product Γ 6-[4-[ N-ethyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl and its 3,4-position hydrogen product Γ 6-{4-[N-ethyl-N-(3-pyridylcarbonyl)amino]butoxy}carbostyryl and its 3 , 4-position hydrogen product Γ 6-[4-[N-butyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl and its 3- and 4-position hydrogen product Γ 6-{4-[N-t-butyl-N-( 6-[6-(N-methyl-N-cyclohexylcarbonylamino)hexyloxy]carbostyryl and its 3,4-hydrogen product Γ 5-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl and its 3,4-position hydrogen product Γ 5-[4-(N-ethyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl and Its 3- and 4-position hydrogen product Γ 5-{3-[N-ethyl-N-(3-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3- and 4-position hydrogen product Γ 5-[6-(N-hexyl -N-cyclohexylcarbonylamino)hexyloxy]carbostyryl and its 3,4-hydrogen product Γ 7-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl and its 3,4-hydrogen product Γ 7-{3-[N-methyl-N-(3-pyridylcarbonyl)amino]propoxy}carbostyryl and its 3,4-position hydrogen product Γ 7-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy ] Carbostyril and its 3,4-position hydrogen product Γ 8-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy] Carbostyril and its 3,4-position hydrogen product Γ 8-{4-[N-methyl -N-(3-pyridylcarbonyl)amino]butoxy}carbostyryl and its 3,4-position hydrogen compound The compound of the present invention can be produced by various methods, but a preferred example thereof is the following reaction scheme-1. Manufactured by the method shown below. [In the formula, X ¹ and X ² represent a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group.
R ¹ , R ² , A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] That is, the compound of the present invention represented by general formula (1) can be obtained by reacting a known carbostyryl derivative represented by general formula (2) with a known compound represented by general formula (3), and then producing the general formula A general formula produced by reacting a carbostyril derivative represented by (4) with a known alkylamine represented by general formula (5)
It is produced by reacting the carbostyryl derivative represented by (6) with a known acid chloride represented by general formula (7). The reaction between the compound of general formula (2) and the compound of general formula (3) can be carried out without a solvent or in a common inert solvent at room temperature to
Under a temperature condition of about 200℃, preferably 60 to 120℃,
It will be completed within a few hours to 24 hours. Examples of inert solvents include dioxane, tetrahydrofuran,
Ethers such as ethylene glycol and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, and acetonitrile. can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine,
Examples include tertiary amines such as quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and is appropriately selected within a wide range, but the latter is usually equal to the former. The amount is preferably about 1 molar to about 3 times the molar amount. The reaction between the compound of general formula (4) and the compound of general formula (5) may be carried out in the same manner as the reaction between the compound of general formula (2) and the compound of general formula (3). The usual Schotten-Baumann reaction can be applied to the reaction between the compound of general formula (6) and the compound of general formula (7). The Schotten-Baumann reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]nonene-5( DBN), 1,
5-diazabicyclo[5,4,0]undecene-
5 (DBU), 1,4-diazabicyclo[2,2,
2] Organic bases such as octane (DABCO) and 4-dimethylaminopyridine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. Specific examples of solvents used include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane;
Aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, methyl acetate,
Examples include esters such as ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is carried out at about -20 to 150°C, preferably 0 to 50°C, and the reaction time is generally about 5 minutes to 10 hours. The ratio of the compound of general formula (6) and the compound of general formula (7) to be used is not particularly limited and is appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably It is preferable to use equimolar to 1.5 times the molar amount. In the reaction scheme-1, the lower alkanesulfonyloxy groups represented by X ¹ and X ² are specifically methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy,
Examples of the arylsulfonyloxy group include propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy groups, and specific examples of the arylsulfonyloxy group include phenylsulfonyloxy,
Substitution of 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy group, or Examples of unsubstituted arylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, and 2-phenylbutylsulfonyloxy. -Methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy. Further, the compound of the present invention represented by the general formula (1) can be produced by the method shown in the following reaction scheme-2. [In the formula, R ¹ , R ² , A, X ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] In the reaction scheme-2, the reaction between the compound of general formula (2) and the compound of general formula (8) involves the reaction between the compound of general formula (2) and the compound of general formula (3) above. Similar reaction conditions can be employed. The compound of general formula (8) is a new compound, and is produced, for example, according to the method shown in the following reaction scheme-3. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above. ] The reaction between the compound of general formula (3) and the compound of general formula (5) in reaction scheme-3 involves the reaction between the compound of general formula (2) and the compound of general formula (3) above. Similar reaction conditions can be used, and the reaction between the compound of general formula (9) and the compound of general formula (7) is similar to that of the reaction between the compound of general formula (6) and the compound of general formula (7). The same reaction conditions as in the case can be adopted. In addition, in the compound of the present invention, the reaction scheme -
As shown in 4, a compound (1a) in which the carbon-carbon bond at the 3- and 4-positions of the carbostyryl skeleton is a double bond, and a compound (1b) in which the carbon-carbon bond is a single bond.
are mutually convertible by reduction reaction and dehydrogenation reaction. [In the formula, R ¹ , R ² and A are the same as above. ] Normal catalytic reduction conditions are applied to the reduction of the compound of general formula (1a). Examples of the catalysts used include metals such as palladium, palladium-carbon, platinum, and Raney nickel, and it is preferable to use such metals in normal catalytic amounts. Examples of solvents that can be used include methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane, cyclohexane, and ethyl acetate. The reduction reaction can be carried out either at normal pressure or under elevated pressure, but it is usually carried out at normal pressure to 30 kg/cm ² , preferably at normal pressure to 3 kg/cm ² . In addition, the reaction temperature is usually 0 to 100
The temperature is preferably about .degree. C., preferably room temperature to 70.degree. Further, the dehydrogenation reaction of the compound of general formula (1b) is carried out using an oxidizing agent in a suitable solvent. The oxidizing agent used is, for example, 2,3-dichloro-
5,6-dicyanobenzoquinone, chloranil (2,3,5,6-tetrachlorobenzoquinone)
Brominating agents such as benzoquinones such as N-bromosuccinimide and bromine can be mentioned. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually used in an amount of 1 to 5 times, preferably 1 to 2 times, by molar amount relative to the compound of general formula (1b). It is better. In addition, as a solvent, ethers such as dioxane, tetrahydrofuran, methoxyethanol, dimethoxyethane, etc.
Aromatic hydrocarbons such as benzene, toluene, xylene, and cumene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; alcohols such as butanol, amyl alcohol, and hexanol; dimethylformamide, dimethyl sulfoxide, and hexane. Examples include polar aprotic solvents such as methylphosphoric triamide. The reaction is usually carried out at room temperature to 300°C, preferably at 50°C.
The reaction is carried out at ~200°C and generally completes in about 1 to 40 hours. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation methods, extraction methods, recrystallization methods, column chromatography, preparative thin layer chromatography, and the like. The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers.
The dosage unit form is not particularly limited and can be appropriately selected and used as required. Examples of such dosage unit forms include tablets, granules, oral preparations such as oral solutions, and parenteral preparations such as injections. The amount of the active ingredient to be administered is not particularly limited and is appropriately selected from a wide range, but in order to achieve the desired effect, it should be 0.1 to 30 mg per kg of body weight per day.
It is best to administer in divided doses. Further, it is preferable that the dosage unit form contains 1 to 500 mg of the active ingredient. In the present invention, oral preparations such as tablets, capsules, and oral solutions 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 prepared 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, and the like. In addition, parenteral preparations such as injections are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving or suspending the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline. Production examples of raw material compounds for synthesizing the compounds of the present invention are listed below as reference examples, and production examples of the compounds of the present invention are listed below as examples. Reference Example 1 4.5 g of 5-(2-chloroethoxy)-3,4-dihydrocarbostyryl was dissolved in 50 ml of ethanol, 14.6 g of tert-butylamine was added, and the mixture was refluxed for 12 hours. The reaction solution was concentrated under reduced pressure, and concentrated hydrochloric acid was added to the residue to precipitate it. 5-(2-chloroethoxy)-
Leave 3,4-dihydrocarbostyryl. The liquid is concentrated to dryness under reduced pressure. The concentrated residue is dissolved in water and extracted with ethyl acetate, the aqueous layer is made alkaline with diluted sodium hydroxide solution, and then extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, ethyl acetate is distilled off, the residue is dissolved in itpropanol, a dioxane solution saturated with hydrochloric acid gas is added, and the precipitated crystals are collected. The crystals are recrystallized from ethanol to obtain 0.2 g of 5-(2-tert-butylaminoethoxy)-3,4-dihydrocarbostyryl hydrochloride in the form of colorless scales. Melting point: 280°C (decomposed) Reference Example 2 4.5 g of 5-(2-chloroethoxy)-3,4-dihydrocarbostyryl was dissolved in 50 ml of ethanol, 11.8 g of isopropylamine was added, and the mixture was refluxed for 15 hours. The reaction solution is concentrated under reduced pressure, and concentrated hydrochloric acid is added to remove the precipitate. This solution is concentrated under reduced pressure, and the residue is dissolved in water and made alkaline with dilute sodium hydroxide solution. Collect precipitated crystals, dissolve in isopropanol, add hydrochloric acid gas saturated methanol solution, and collect precipitated crystals. The crystals are recrystallized from ethanol to obtain 0.8 g of colorless needle-like 5-(2-isopropylaminoethoxy)-3,4-dihydrocarbostyryl hydrochloride. Melting point 228-231℃ Reference example 3 Dissolve 48g of 6-hydroxy-3,4-dihydrocarbostyryl in 500ml of dimethylformamide,
Add 55g of potassium carbonate and heat at approximately 40℃ for 1 to 3 minutes while stirring.
-Drop dibromopropane. After stirring for 4 hours,
The potassium carbonate is removed and the liquid is concentrated to dryness. Add water to the residue to crystallize it, wash with water, and give 36g.
Colorless needle-like crystals of 6-(3-bromopropoxy)-
3,4-dihydrocarbostyryl is obtained. Melting point: 121-124°C Compounds of Reference Examples 4-6 are obtained in the same manner as in Reference Example 2. Reference example 4 6-[3-(N-methylamino)propoxy]
Carbostyril Yellow prismatic crystals, melting point 160-161.5℃ Reference example 5 6-[4-(N-methylamino)butoxy]carbostyril Colorless needle crystals, melting point 210-213℃ Reference example 6 6-[4-(N-) methylamino)butoxy〕―
3,4-dihydrocarbostyryl Colorless needle crystals, melting point 182-183.5°C Example 1 6-[3-(N-methylamino)propoxy]
-2 grams of carbostyril and 50 grams of dimethylformamide
ml, add 20 ml of water and 1.65 g of potassium carbonate, and add cyclohexanecarboxylic acid chloride under external ice cooling.
Add 1.75 g dropwise and stir at room temperature for 1.5 hours. Extract with chloroform and wash thoroughly with saturated saline, followed by dilute hydrochloric acid and water. After concentration, it is purified by silica gel column chromatography (chloroform:methanol=30:1). Chloroform-recrystallized from petroleum ether to form colorless needle-like crystals of 6-[3-
(N-methyl-N-cyclohexylcarbonylamino)propoxy] carbostyril 1.5g (50.8
%). Melting point: 162-163.5°C Compounds of Examples 2-6 are obtained in the same manner as in Example 1 using appropriate starting materials. Example 2 6-{3-[N-methyl-N-(3-pyridylcarbonyl)amino]propoxy}carbostyryl Colorless needle crystals, melting point 164-166.5°C Example 3 6-[3-(N-methyl-) N-cyclohexylcarbonylamino)propoxy}-3,4-dihydrocarbostyryl Colorless prismatic crystals, melting point 87-89°C Example 4 6-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl Colorless needle Crystals, melting point 118.5-120°C Example 5 6-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy]-3,4-dihydrocarbostyryl Colorless prismatic crystals, melting point 89.5-91°C Example 6 5 -[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]-3,4-dihydrocarbostyryl Colorless needle crystals, melting point 76-79°C Example 7 6-[4-(N-methyl)butoxy] 20 ml of dimethylformamide and 0.98 ml of triethylamine are added to 3.6 g of carbostyril, and after cooling on ice, 0.5 g of cyclohexanecarboxylic acid chloride is added dropwise.
Stir at room temperature for 2 hours. The reaction solution is extracted with chloroform. The chloroform layer is thoroughly washed with saturated brine, followed by dilute sodium bicarbonate solution, dilute hydrochloric acid, and water, and then dried over sodium sulfate. After concentrating the solvent, it was purified by silica gel column chromatography (AcOEt→AcOEt:MeOH=10:1) to obtain colorless needle crystals of 6-[4-(N-methyl-N-cyclohexylcarbonylamino)butoxy]carbostyryl. Obtain 0.7g. Melting point 118.5-120℃ Example 8 6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl
Add 100 ml of methanol and 0.2 g of 10% Pd-C to 0.7 g for catalytic reduction. Hydrogenation is carried out at 60-70°C and 2-3 atmospheres of hydrogen for 6 hours. After removing the catalyst and concentrating, it was recrystallized from ethyl acetate-isopropyl ether to give colorless prismatic crystals of 6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]-
0.5 g of 3,4-dihydrocarbostyryl is obtained. Melting point: 87-88°C Compounds of Examples 9-10 are obtained in the same manner as in Example 8 using appropriate starting materials. Example 9 6-[3-(N-methyl-N-cyclohexylcarbonylamino)butoxy]-3,4-dihydrocarbostyryl Colorless prismatic crystals, melting point 89.5-91°C Example 10 6-[4-(N-propyl) -N-cyclohexylcarbonylamino)butoxy]-3,4-dihydrocarbostyryl Colorless needle crystals, melting point 109-111.5°C Pharmacological test 1 Platelet aggregation inhibition according to the method described in Nature, pp. 927-929 (1962) The effect was investigated. In other words, the platelet aggregation inhibiting effect was measured using an AG-type aggregometer (Bryston Manufacturing Company).
Manufacturing Co.)]. The blood sample collected from the rabbit was a mixture of 3.8% sodium citrate aqueous solution and whole blood, and the mixing ratio was 1:9 (volume ratio). The sample was rotated at 1000 rpm (200 rpm
×g) for 10 minutes to obtain a supernatant portion, platelet rich plasma (hereinafter referred to as “PRP-1”). Obtained PRP-1
and the remaining blood sample at 3000 rpm (1500 x g)
After further centrifugation for 15 minutes at
plasma) (hereinafter referred to as ``PPP''). The number of platelets contained in the PRP-1 was determined using the Bretscher-Cronkhite method.
Clonkite Method, J.Appl.Physiol., 3 , 365~
375 (1950)). For adenosine diphosphate (ADP)-induced aggregation inhibition test, PRP-1 was diluted with PPP to prepare a sample containing 300000/ ^mm3 platelets (hereinafter referred to as "PRP-2"), and collagen-induced aggregation inhibition test was conducted. For the aggregation inhibition test, PRP-1 was diluted with PPP to 450,000/
A sample containing platelets of mm ³ (hereinafter referred to as "PRP-3") was prepared. (1) ADP-induced aggregation inhibition test A solution containing a predetermined concentration of the compound to be tested in a platelet aggregation measurement cell containing a rotor (0.01%)
ml and 0.6 ml of PRP-2 prepared above were added, and the 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, 0.07ml of 7.5×10 ^-5 MADP solution
and the change in light transmittance was recorded. The 7.5×10 ⁻⁵ MADP solution used in the above test was prepared by adding ADP powder (manufactured by Sigma) to Oren-Veronal buffer (PH=7.35). 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 where a ₁ : Light transmittance of PRP-2 b ₁ : Light transmittance of PPP c ₁ : Platelet aggregation caused by the above method , light transmittance when platelet aggregation reaches maximum The platelet aggregation inhibiting effect of the test compound was determined as follows. A solvent in which the test compound was dissolved was added instead of the test compound solution, platelets were agglomerated in the same manner as above, and the aggregation rate was determined, and this 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 The results obtained are shown in Table 1. (2) Collagen-induced aggregation inhibition test A solution containing a predetermined concentration of the compound to be tested in a platelet aggregation measurement cell containing a rotator (0.01%)
ml and 0.6 ml of PRP-3 prepared above were added, and the 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, 7.5×10 ^-5 M collagen solution
0.07 ml was added and the change in light transmission was recorded.
The 7.5×10 ^-5 M collagen solution used in the above test was Oren Veronal buffer (PH = 7.35).
It was prepared by adding 100 mg of collagen to 5 ml 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 where a ₂ : Light transmittance of PRP-3 b ₂ : Light transmittance of PPP c ₂ : Platelet aggregation caused by the above method , light transmittance when platelet aggregation reaches maximum The platelet aggregation inhibiting effect of the test compound was determined as follows. A solvent in which the test compound was dissolved was added instead of the test compound solution, platelets were agglomerated in the same manner as above, and the aggregation rate was determined, and this was used as the control aggregation rate. Inhibition rate (%) = A ₂ −B ₂ /A ₂ ×100 A ₂ : Aggregation rate of control B ₂ : Aggregation rate of test compound The results obtained are shown in Table 2. The test compounds for this test are as follows. No.1 6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]carbostyryl (compound of the present invention, Example 1) No.2 6-{3-[N-methyl-N-(3- pyridylcarbonyl)amino]propoxy}carbostyryl (compound of the present invention, Example 2) No. 3 6-[3-(N-methyl-N-cyclohexylcarbonylamino)propoxy]-
3,4-dihydrocarbostyryl (compound of the present invention, Example 3) No. 4 6-(3-propionylamino)propoxy-3,4-dihydrocarbostyryl (Example described in JP-A-54-30184) No. 5 6-[3-(imidazolin-2-ylamino)propoxy]-3,4-dihydrocarbostyryl (compound of Example 4 described in JP-A-54-30184)

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a lower alkyl group, R ² represents a cycloalkyl group or a pyridyl group, and A represents a lower alkylene group. Also, 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position represents a single bond or a double bond. ] Carbostyryl derivative represented by.