JPH0318634B2 - - 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 is a hydrogen atom or the following group shows. In the above group, R ³ , R ⁴ and R ⁵ represent a lower alkyl group, and A represents a lower alkylene group. R ¹
is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, 2
-tetrahydropyranyloxy group or the following group (R ³ , R ⁴ , R ⁵ and A are the same as above). R ² is a hydrogen atom, a lower alkyl group, or the following group (R ³ , R ⁴ , R ⁵ and A are the same as above). However, only one of R, R ¹ and R ² must be the above group. shall be shown. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] The carbostyril derivative represented by the above general formula (1) has excellent platelet aggregation inhibiting action, calcium antagonist action (Ca-Antagonist) action, antihypertensive action, and phosphodiesterase inhibitory action, and can be used as a prophylactic or therapeutic agent for thrombosis, for example. It is useful as a coronary circulation improving agent such as a coronary vasodilator, an antihypertensive agent, a phosphodiesterase inhibitor, and the like. In particular, the compounds of the present invention are particularly useful as preventive or therapeutic agents for heart diseases in which platelet aggregation is enhanced, such as angina pectoris and myocardial infarction, and as antihypertensive agents. In this specification, the lower alkyl group is
Examples include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups. Examples of lower alkoxy groups include methoxy,
Examples include alkoxy groups having 1 to 6 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, ttert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower alkenyloxy groups include vinyloxy, allyloxy, 2-butenyloxy,
3-butenyloxy, 1-methylallyloxy,
Examples include alkenyloxy groups having 2 to 6 carbon atoms such as 2-pentenyloxy and 2-hexenyloxy groups. Examples of lower alkynyloxy groups include ethynyloxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 1-methyl-2
-propynyloxy, 2-pentynyloxy, 2
-C2-C6 alkynyloxy groups such as -hexynyloxy group can be mentioned. Examples of lower alkylene groups include methylene,
Ethylene, methylmethylene, trimethylene, 2-
Examples include alkylene groups having 1 to 6 carbon atoms such as methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethyltrimethylene, and 1-methyltrimethylene. The compound of the present invention can be produced by various methods, and one preferred example thereof is the method shown below. [In the formula, R ¹ , R ³ , R ⁴ , R ⁵ , A and the carbon-carbon bonds between the 3- and 4-positions of the carbostyril skeleton are the same as above. R ¹ ′ is a hydrogen atom, a hydroxyl group, a lower alkoxy group,
It represents a lower alkenyloxy group, a lower alkynyloxy group, or a 2-tetrahydropyranyloxy group. R ² ' represents a hydrogen atom or a lower alkyl group.
X represents a halogen atom. ] That is, the compound of the present invention is obtained by reacting a hydroxycarbostyryl derivative represented by general formula (2) with a compound represented by general formula (3) under dehydrohalogenation reaction conditions. This pure hydrogen halide reaction is carried out using a basic compound as a dehydrohalogenating 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, sodium methylate, sodium ethyl Alcoholates such as latkes,
Examples include organic bases such as triethylamine, pyridine, and N,N-dimethylaniline. The reaction can be advantageously carried out in the presence of a solvent, and any inert solvent that does not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol, dimethyl ether, and tetrahydrofuran. , ethers such as dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, N,N-dimethylformamide, dimethyl Examples include aprotic polar solvents such as sulfoxide and hexamethylphosphoric triamide. The reaction also involves sodium iodide,
It can also be carried out in the presence of a metal iodide such as potassium iodide. The ratio of compound (3) to compound (2) in the above method is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in a molar range of 1 to 5 times the former, preferably 5 times the molar ratio of the latter. It is desirable to use it in a molar to 2 times molar amount. Further, the reaction temperature is not particularly limited, but is usually room temperature to
It is carried out at 200°C, preferably 50-160°C. The reaction time is usually 1 to 30 hours, preferably 2 to 10 hours. Thus, in the compound represented by general formula (1), R
is the basis A compound (compound of general formula (1a)) can be obtained. In the compound represented by general formula (1), R ¹ or R ² is a group Similarly, a compound showing the above reaction scheme - can also be used as a raw material for the compound represented by the corresponding general formula (2)
It can be manufactured according to 1. [In the formula, R ¹ ', R ² ', R ³ , R ⁴ , R ⁵ , A, X and the carbon-carbon bonds between the 3- and 4-positions of the carbostyril skeleton are the same as above. ] In the reaction between the hydroxycarbostyryl derivative (2) and the compound (4) in the above reaction scheme-2, the same reaction conditions as for the reaction between the compound (2) and the compound (3) in the above-mentioned reaction scheme-1 are used. can be adopted. In the reaction between compound (5) and compound (6), usual esterification reaction conditions can be employed.
This reaction is usually carried out in the presence of a catalyst, and as the catalyst used in this case, a wide variety of catalysts that are used in ordinary esterification reactions can be used. Typical examples include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, and p-tosylic acid. ,
Examples include organic acids such as benzenesulfonic acid and ethanesulfonic acid, trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as the catalyst. The amount of these catalysts to be used is not particularly limited, and is used within the range used in ordinary esterification reactions. The above reaction proceeds either without a solvent or in a solvent. As the solvent used at this time, solvents used in ordinary esterification reactions can be effectively used, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane, chloroform, and tetrachloride. halogenated hydrocarbons such as carbon,
Examples include ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. In the above reaction, the ratio of compound (5) and compound (6) to be used may be appropriately selected over a wide range, but in order to improve the production rate of the target product of the present invention, solvent-free is usually used. The latter is used in large excess over the former, and when a solvent is used, the latter is used in an equimolar amount to the former.
It is preferable to use 5 times the molar amount, particularly preferably equimolar to 2 times the molar amount. In addition, when carrying out the above reaction, it is also possible to further increase the production rate by removing the produced water from the reaction system using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, or phosphorus pentoxide. be. The reaction temperature in this reaction may be selected as appropriate and is not particularly limited, but it is usually carried out in the range of about -20 to 200°C, particularly preferably about 0 to 150°C. Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in about 10 minutes to 20 hours. A compound of general formula (1a) is thus obtained. In the compound represented by general formula (1), R ¹ or R ² is a group Similarly, a compound showing the above reaction scheme -
It can be manufactured according to 2. [In the formula, R ¹ ′, R ² ′, R ⁴ , R ⁵ , A and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] The reaction between compound (5) and compound (7) in the above reaction formula is carried out in an appropriate solvent in the presence of a catalyst.
Examples of the catalyst include organic bases such as triethylamine, pyridine, and N,N-dimethylaniline, basic compounds such as inorganic bases such as sodium acetate and potassium carbonate, sulfonic acids such as p-toluenesulfonic acid, boron trifluoride, etc. Acidic compounds such as Lewis acid and the like can be mentioned. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, esters such as methyl acetate and ethyl acetate, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane, ether, and tetrahydrofuran. , ethers such as dioxane, monoglyme, and diglyme, ketones such as acetone and methyl ethyl ketone, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, and N-methylpyrrolidone. Can be done. The usage ratio of compound (5) and compound (7) is as follows:
Generally, the latter may be used in at least an equimolar amount, preferably 1 to 2 times the molar amount of the former. The amount of the catalyst to be used is not particularly limited, but it is usually about 1/100 to 10 times the mole of compound (5). The reaction is usually −20 to
Generally at 200℃, preferably around -20~100℃
It takes about 10 minutes to 20 hours to complete. Then, the reaction between the obtained compound (8) and compound (9) is also carried out in a suitable solvent in the presence of a catalyst. Examples of the solvent include methanol, ethanol,
Alcohols such as propanol, butanol, and ethylene glycol; ethers such as ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; and methylene chloride, chloroform, and 1,2-dichloroethane. halogenated hydrocarbons, N,N-dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethylphosphoric triamide, carboxylic acids such as acetic acid and propionic acid, and pyridine. Examples of catalysts include pyridine, piperidine, triethylamine, diethylamine, and DBU. Organic bases, metal alcoholates such as sodium ethylate and sodium methylate, inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium acetate, mineral acids such as hydrochloric acid and sulfuric acid, and carboxylic acids such as acetic acid and propionic acid. , Lewis acids such as boron trifluoride, and the like. The ratio of compound (8) and compound (9) to be used is usually at least an equimolar amount of the latter to the former, preferably about an equimolar to twice the molar amount. In addition, the amount of catalyst used is as follows:
The amount of catalyst may be the same as in the reaction between (5) and compound (7). The reaction is generally completed at about -20 to 200°C, preferably about -20 to 150°C, in about 10 minutes to 50 hours. The reaction between compound (10) and compound (11) can be advantageously carried out in the presence of a solvent. All inert solvents that do not adversely affect the reaction can be used as solvents, such as ketones such as acetone, halogenated hydrocarbons such as chloroform, alcohols such as methanol, ethanol, propanol, and ethylene glycol, diethyl ether, tetrahydrofuran,
Ethers such as dioxane, monoglyme and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, carboxylic acids such as acetic acid and propionic acid, organic bases such as pyridine, N, Examples include aprotic polar solvents such as N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The ratio of compound (10) and compound (11) to be used is usually about 1 to 10 times the mole of the former, preferably about 1 to 2 times the mole of the former. The reaction is generally completed at about -20 to 200°C, preferably about 50 to 150°C, in about 10 minutes to 20 hours. Thus, in the compound represented by general formula (1), R is a group A compound (compound of general formula (1b)) in which R ³ represents a methyl group can be obtained. In the compound represented by general formula (1), R ¹ or R ² is a group A compound in which R ³ is a methyl group can also be produced in the same manner according to the above reaction scheme-3 using the corresponding compound represented by general formula (5) as a raw material. [In the formula, R ² ′, R ³ , R ⁴ .R ⁵ , A, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. R ⁶ is a lower alkyl group, a lower alkenyl group,
Indicates a lower alkynyl group or a 2-tetrahydropyranyl group. OTHP represents 2-tetrahydropyranyloxy group. ] According to the reaction scheme-4 above, R in the compound represented by general formula (1) is a group. and R ¹ is a 2-tetrahydropyranyloxy group (a compound of the general formula (1c)) to obtain a compound in which the corresponding R ¹ is a hydroxyl group (a compound of the general formula (1d)) Further, by reacting the compound (1d) with the compound (12), the corresponding R ¹ is a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, or a 2-
Compound (1) showing a tetrahydropyranyloxy group
compounds of general formula (1e)). In the above, hydrolysis of compound (1c) is carried out without a solvent or in an appropriate solvent by the action of an acid. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, acetic acid, and mixed solvents thereof. Examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, and carboxylic acids such as p-toluenesulfonic acid, pyridine P-toluenesulfonate, acetic acid, and propionic acid. The amount of such acid to be used is preferably at least equimolar or more, usually in large excess, relative to compound (1c). The reaction temperature is usually -20~
The temperature is preferably 200°C, preferably about -20 to 50°C, and the reaction is generally completed in about 0.5 to 5 hours. The reaction between compound (1d) thus obtained and compound (12) is carried out under normal alkylation reaction conditions, for example in the presence of a basic compound. The basic compounds used in this case include, for example, alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, bicarbonates, or alcoholates of these alkali metals, and aromatic amine compounds such as pyridine and piperidine. Examples include organic bases such as triethylamine and 1,8-diazabicycloundecene-7. The reaction is
The process is advantageously carried out in a suitable solvent, and the solvents used at this time include water, lower alcohols such as methanol, ethanol, isopropanol, and n-butanol, ketones such as acetone and methyl ethyl ketone, and halogens such as chloroform and dichloroethane. Examples include carbonated hydrocarbons, aromatic hydrocarbons such as benzene, toluene, and xylene, and aprotic polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. The ratio of compound (1d) and compound (12) to be used is usually at least equal mole of the latter to the former, preferably equimolar to 2.
It is best to use about twice the molar amount. The reaction temperature is generally -20 to 200°C, preferably 0 to 100°C.
It is generally completed in about 10 minutes to 20 hours. In the compound represented by general formula (1), R ² is a group Compounds in which R ¹ represents a hydroxyl group, compounds in which R ¹ represents a lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, or 2-tetrahydropyranyloxy group also include compounds in which R ¹ represents a 2-tetrahydropyranyl group. From compounds exhibiting a hydroxyl group,
It is converted in the same manner according to the above reaction scheme-4. In the reaction scheme-1, the compound of general formula (3) as a starting material is, for example, the following reaction scheme-5.
It can be easily manufactured by the method shown below. [In the formula, R ³ , R ⁴ , R ⁵ , A and X are the same as above. ] In the above reaction formula, compound (9) and compound (13)
The reaction with the compound in the above reaction scheme-3
The same reaction conditions as for the reaction between (8) and compound (9) can be employed. Further, the reaction between compound (14) and compound (11) can be carried out under the same reaction conditions as the reaction between compound (10) and compound (11) in the reaction scheme-3 above. Among the compounds represented by the general formula (1) thus obtained, those having a basic group can form salts with pharmacologically acceptable acids. Specific examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid. 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 can be appropriately selected from a wide range, but in order to achieve the desired effect, it is preferably 0.06 to 10 mg per kg of body weight per day. Also, the active ingredient may be contained in the dosage unit form from 1 to 1.
It is recommended to contain 500 mg. In the present invention, oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. 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. Syrups or elixirs contain the compounds of the present invention, sweeteners such as sucrose, and methyl-
and preservatives and colorants such as propylparabens,
Manufactured by mixing with seasonings, etc. Moreover, parenteral preparations are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline.
Solutions having the desired clarity, stability and suitability for parenteral use are prepared by dissolving about 1 to 500 mg of the active ingredient in water and organic solvents and in polyethylene glycol having a molecular weight of 200 to 5000. .
Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol. Furthermore, in the above solvent, disinfectants and fungicides such as benzyl alcohol, phenol, and thimerosal are added, and if necessary, sucrose,
Isotonic agents such as sodium chloride, local anesthetics, stabilizers, buffers, and the like may also be included. To further increase stability, parenterally administered drugs can be frozen after filling and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use. Preparation of tablets 5 mg each of 5-{2-[2,6-dimethyl-
1000 tablets for oral use containing 5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropridine-3-carboxy]ethoxy}carbostyril are prepared according to the following formulation.

[Table] 5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3-carboxy]ethoxy}
Thoroughly mix carbostyril, lactose, corn starch and crystalline cellulose, and add 5 ml of methylcellulose.
% aqueous solution, pass through a 200 mesh sieve and carefully dry. The dried granules are passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets. Preparation of capsules 10 mg each of 6-{2-[2,6-dimethyl-
1000 two-piece hard gelatin capsules for oral use containing 5-methoxycarbonyl-4-(3-nitrophenyl)1,4-dihydropyridine-3-carboxy]ethoxy}carbostyril were prepared according to the following formulation: be done.

[Table] The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having the desired dimensions. Preparation of Injection A sterile aqueous solution suitable for parenteral administration is prepared according to the following recipe.

【table】

[Table] The above parabens, sodium metabisulfite and sodium chloride were dissolved in about half the amount of distilled water above at 80°C with stirring. The resulting solution was cooled to 40°C, and 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3-carboxy]propoxy}-8-hydroxy-3,4-dihydrocarbostyryl and polyoxyethylene sorbitan monooleate were dissolved in the solution. The solution was then adjusted to the final volume by adding distilled water for injection and sterilized by passing through a suitable filter paper. Preparation of capsules 10 mg each of 5-{3-[2,6-dimethyl-
5-Methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxy]propoxy}-8-propoxy-3,4-
1000 two-piece hard gelatin capsules for oral use containing dihydrocarbostyril are prepared according to the following formulation.

[Table] The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having the desired dimensions. The results of pharmacological tests on the compounds of the present invention are listed below. <Pharmacological test 1> The platelet aggregation inhibitory effect was measured using the Platolett aggregation tracer model according to the method of Kimura et al.
PAT-6M (Platelet Aggregation Tracer
Model PAT-6M; manufactured by Niko Bioscience)
Measured using
See Nature 927-929 (1962)]. That is, a blood sample was collected from a rabbit, and was a mixture of 3.8% sodium citrate solution ("Citrate", manufactured by Midori Juji Co., Ltd.) and whole blood at a mixing ratio of 1:9 (volume ratio). The sample was centrifuged at 1000 rpm (200 x g) for 10 minutes to collect platelet rich serum.
plasma (PRP)]. The resulting PRP is separated and the remaining blood sample is further centrifuged at 3000 rpm (200×g) for 15 minutes to obtain platelet poor plasma (PPP). The number of platelets contained in the PRP was determined using the Brecher-Cronkite method.
Method) and dilute PRP with PPP.
A PRP sample containing 600000/μ platelets was prepared. 0.2 ml of the PRP sample prepared above was added to 2 μ of a solution containing the compound to be tested at a predetermined concentration, and the mixture was placed in a constant temperature bath at a temperature of 37° C. for 1 minute.
Then add 20μ of ADP or collagen solution to the mixture.
added. The permeability of this mixture was measured, and the change in permeability was measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. In this test, the ADP solution was prepared to a concentration of 7.5×10 ⁻⁵ M using Oren-Veronal buffer (PH7.35).
In addition, collagen solution is collagen (ollagen,
reagent Hovm; manufactured by Hovm) in physiological saline.
The concentration was adjusted to 200 μg/ml. The platelet aggregation inhibitory effect is measured as the inhibition rate (%) relative to the control aggregation rate. The aggregation rate is calculated according to the formula below. Aggregation rate = 3-a/b-a x 100 where a: Transparency of PRP b: Transparency of PPP c: Transparency of PRP containing the test compound and aggregation inducing agent At this time, the aggregation rate of the control is A, the test When the aggregation rate of the compound is B, the inhibition rate (%) of the test compound is expressed by the following formula. Inhibition rate (%) = AB/A x 100 Table 1 shows the inhibitory effect on rabbit platelet aggregation induced by collagen, and Table 2 shows the inhibitory effect on rabbit platelet aggregation induced by ADP.
The test compounds are as follows. Test compound No. 1 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-8-propenyloxy-3,4-dihydrocarbostyryl 2 5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1 ，
4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl 3 6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl 4 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-3,4-dihydrocarbostyryl 5 6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-3,4-dihydrocarbostyryl6 7-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-3,4-dihydrocarbostyryl 7 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-8-hydroxy3,4-dihydrocarbostyryl 8 6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}carbostyryl 9 8-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-3,4-dihydrocarbostyryl 10 6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]ethoxy}carbostyryl 11 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-8-propoxy-3,4-dihydrocarbostyryl 12 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}-8(2-propynyloxy)-3,4
-dihydrocarbostyryl 13 8-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl 14 7-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl 15 6-{4-[2,6-dimethyl-5-methoxycarbonyl]-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]butoxy}carbostyryl 16 6-{4-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]butoxy}-3,4-dihydrocarbostyryl 17 5-{4-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]butoxy}-3,4-dihydrocarbostyryl 18 5-{4-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]butoxy}carbostyryl 19 5-{4-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyrezine-3-carboxy]butoxy}-8-allyloxy-3,4-dihydrocarbostyryl20 6-{{2-[2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl) −
1,4-dihydropyridine-3-carboxy]
ethoxy}carbostyryl 21 6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl22 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3-carboxy]propoxy}carbostyryl

【table】

【table】

[Table] <Pharmacology test 2> Coronary blood flow and blood pressure were measured using the method of Yagura et al.
57, pp. 380-391 (1961) and the flat method [Clin.
exd.pharmacol.physiol., Vol. 6, pp. 301-316 (1976)]. Specifically, an adult male and female mixed breed dog weighing 8 to 13 kg was anesthetized by intravenous administration of 30 mg/Kg of pentobarbital sodium salt, fixed in a dorsal position, thoracotomy was performed under artificial respiration, and heparin treatment (500 U/Kg) was performed. Kg, additional administration of 100 U/Kg every hour), then perform the following experiment. 1. Intra-arterial administration Insert a glass cannula from the right carotid artery into the left coronary artery orifice to create an extracorporeal circulation path between it and the femoral artery. Coronary blood flow was measured using an electromagnetic blood flow meter with an invasive blood flow probe attached to the extracorporeal circuit. The test compound was administered using a microsyringe through a branch similarly created in the extracorporeal circuit, and the amount of increase in coronary blood flow was determined. Similarly, adenosine 30μg or 100μg
The amount of increase in coronary blood flow resulting from administration of the test compound was determined, and the larger value was set as 100%, and the coronary blood flow increasing effect (%) of the test compound was calculated. The results are shown in Table 3. 2. Intravenous administration: Insert the Morabitsu cannula into the coronary sinus from the right atrial appendage, return the outflowing venous blood to the right jugular vein, and measure the blood flow using an electromagnetic blood flow meter using an invasive blood flow probe attached midway. was measured. A cardiac contractile force pick-up was attached to the anterior wall of the left ventricle to measure cardiac contractile force, blood pressure from the femoral artery, and heart rate from the pulse wave. The test compound was administered through a cannula inserted into the femoral vein. Table 4 shows the increase in coronary blood flow due to administration of the test compound, and Table 5 shows the change in blood pressure.
Each is shown in the table. In Tables 3 to 5, the test compounds are the test compound No. in <Pharmacological Test 1> above.
Indicated by

【table】

【table】

[Table] Reference Example 1 Dissolve 4.2 g of potassium hydroxide in 200 ml of methanol, add 10 g of 5-hydroxy-3,4-dihydrocarbostyryl, and dropwise add 10 g of 2-bromoethanol under reflux. After completion of the dropwise addition, the mixture was refluxed for 4 hours, and after concentration, water was added to the residue to remove insoluble matter.
Recrystallized from water-washed methanol to form colorless needle-shaped 5-
2.1 g of (2-hydroxyethoxy)-3,4-dihydrocarbostyryl are obtained. mp176-178°C The following compound is obtained in the same manner as above. 5-(3-hydroxypropoxy)-8-propenyloxy-3,4-dihydrocarbostyryl Colorless needle crystals (chloroform-hexane) mp80-81.5℃ 6-(2-hydroxyethoxy)-3,4-dihydrocarbostyryl Colorless needle crystals (hydrated methanol) mp183-155℃ Reference example 2 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyryl 2g and triethylamine 2
ml is added to 50 ml of chloroform, and 1 g of diketene is added dropwise to this. After stirring at room temperature for 2 days, insoluble materials were removed, the liquid was concentrated, and the residue was purified by silica gel column chromatography (eluent, chloroform). After concentration, recrystallization from chloroform-ether gave colorless needle-like crystals of 5- (2-acetoacetoxyethoxy)-
1.5 g of 3,4-dihydrocarbostyryl are obtained. mp134.5-135.5°C 5-(3-acetoxypropoxy)-8-propenyloxy-3,4-dihydrocarbostyryl is obtained in the same manner as above. Colorless powder crystal (chloroform-hexane) mp66-67℃ Reference example 3 6-(2-acetoacetoxy) in 30ml of ethanol
-3,4-dihydrocarbostyryl 2g and 3-
Add 1 g of nitrobenzaldehyde, add 0.1 ml of piperidine under external ice cooling, and stir at room temperature for 3 days. After concentration, add ether to remove the precipitate.
Crystallized from chloroform-ether to give 6-{2-
1.3 g of [2-(3-nitrobenzylidene)acetoacetoxy]ethoxy}-3,4-dihydrocarbostyryl are obtained. Pale yellow powder crystal NMR: δ (CDCl ₃ ) = 2.45 (3H, s), 2.46 ~
2.70 (2H, m), 2.75~3.00 (2H, m),
4.00~4.27 (2H, m), 4.47~4.65 (2H,
m), 6.50-6.70 (3H, m), 7.25-7.70
(3H, m), 7.95-8.30 (3H, m) ppm Reference example 4 10 g of 3-nitrobenzaldehyde and 11 g of 2-chloroethyl acetoacetate were added to 100 ml of toluene.
Dissolve the solution in water and blow in hydrochloric acid gas for 2 hours while cooling on ice.
After being left at room temperature for 2 days, it was concentrated, and the residue was extracted with chloroform. After washing with saturated saline and saturated sodium bicarbonate, dry over magnesium sulfate. Chloroform was distilled off and the residue was recrystallized from isopropanol to give colorless needle-like crystals of 2-chloroethyl 2-(3-
10 g of nitrobenzylidene acetoacetate are obtained. mp~95~97℃ Reference Example 5 25 g of 3-chloropropyl 2-(3-nitrobenzylidene) acetoacetate and 10 g of methyl 3-aminocronate obtained in the same manner as in Reference Example 3 above.
was added to 100 ml of methanol, refluxed for 4 hours, and left to cool overnight. The deposited precipitate was collected and recrystallized from isopropanol to give yellow prismatic crystals of 3-chloropropylmethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5.
-22.7 g of dicarboxylate are obtained. mp144-145°C Example 1 1.6 g of 8-hydroxy-3,4-dihydrocarbostyryl and 1.5 g of potassium carbonate were added to 30 ml of DMF and heated to 80-90°C, and 3-iodopropylmethyl 1,4-dihydro- 2,6-dimethyl-4
A solution of 5 g of -(3-nitrophenyl)pyridine-3,5-dicarboxylate in 30 ml of DMF is added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 5 hours, concentrated, and the residue was extracted with chloroform, washed with water, 0.5N aqueous sodium hydroxide, 5% aqueous hydrochloric acid, and saturated brine, and dried over magnesium sulfate. After concentration, it is purified by silica gel column chromatography (eluent: chloroform-methanol = 100:1). Recrystallization from aqueous methanol yields 8-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxy]propoxy}-3,4-dihydro Obtain 2.9 g of carbostyril. Yellow plate crystals mp167-167.5°C Examples 2-33 Compounds of Examples Nos. 2-33 listed in Table 6 below are obtained in the same manner as in Example 1 above.

【table】

[Table] In Table 1, the base is expressed as a side chain. Further, DMF means dimethylformamide, and -O-THP means 2-tetrahydropyranyloxy group. Example 34 5-(2-hydroxyethyl)-3,4-dihydrocarbostyryl 2.0 g, 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carvone 3.3 g of acid and 2.1 g of dicyclohexylcarbodiimide
Add g to 50 ml of DMF and heat to 80-90°C for 5 hours.
After cooling, remove the precipitate, concentrate, and extract the residue with chloroform. After washing with 1N sodium hydroxide and saturated saline, drying and concentration over magnesium sulfate, purification with silica gel column chromatography (eluent, 50:1 chloroform-methanol), and recrystallization from chloroform-isopropyl ether gave yellow powdery crystals. 5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxy]ethoxy}
0.5 g of 3,4-dihydrocarbostyryl is obtained. mp262-263.5°C Example 35 In the same manner as in Example 34, Example No. 2,
Compounds 4-8, 11-14, 16.24, 26-29, 32 and 33 are obtained. Example 36 1.3 g of 6-{2-[2-(3-nitrobenzylidene)acetoacetoxy]ethoxy}-3,4-dihydrocarbostyryl and 0.5 g of methyl 3-aminocrotonate are added to 10 ml of pyridine and refluxed for 8 hours. . After concentration, the residue is extracted with chloroform, washed with saturated potassium hydrogen sulfate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol = 100:1), and then recrystallized from chloroform-ether to give 6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-( 0.92 g of 3-nitrophenyl)-1,4-dihydropyridine-3-carboxy]ethoxy}-3,4-dihydrocarbostyryl is obtained. Pale yellow powder crystals mp172.5-174°C Example 37 Compounds of Example Nos. 24 and 25 were obtained in the same manner as in Example 36. Example 38 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3-carboxy]propoxy}-8-(2-tetrahydropyranoxy)-3,
Add 15 g of 4-dihydrocarbostyril to a mixture of 100 ml of tetrahydrofuran and 30 ml of water, and add 10% hydrochloric acid 2.
ml and stir overnight at room temperature. After concentration, the mixture is extracted with chloroform, washed with saturated brine and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated. Ether was added to the residue to remove insoluble matter, and recrystallization from aqueous methanol gave yellow columnar crystals of 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4 -dihydropyridine-3
-carboxy]propoxy}-8-hydroxy-
8.9 g of 3,4-dihydrocarbostyryl are obtained. mp193.5-194℃ Example 39 5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-
2.7 g of dihydropyridine-3-carboxy]propoxy}-8-hydroxy-3,4-dihydrocarbostyryl, 0.7 g of potassium carbonate and 0.74 g of propyl bromide were added to 30 ml of acetone and refluxed for 3 hours. After concentration, the residue is extracted with chloroform and shaken with a 1N aqueous sodium hydroxide solution to remove the formed precipitate. The organic layer is washed with saturated brine and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent; chloroform-methanol =
After concentration, the residue was recrystallized from methanol to give 5-{3-[2,6-dimethyl-5
0.8 g of -methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxy]propoxy}-8-propoxy-3,4-dihydrocarbostyryl is obtained. Pale yellow prismatic crystals mp150.5-152.0°C Example 40 In the same manner as in Example 39, the above Example Nos. 3, 9,
Compounds 15 and 24 are obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom or the following group shows. In the above group, R ³ , R ⁴ and R ⁵ represent a lower alkylene group, and A represents a lower alkylene group.
R ¹ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a 2-tetrahydropyranyloxy group, or the following group (R ³ , R ⁴ , R ⁵ and A are the same as above). R ² is a hydrogen atom, a lower alkyl group, or the following group (R ³ , R ⁴ , R ⁵ and A are the same as above). However, only one of R, R ¹ and R ² must be the above group. shall be shown. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] Carbostyryl derivative represented by.