JPS63230687A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents H, lower alkyl, lower alkenyl or phenyl lower alkyl; R<2> represents formula II (X, Y and Z represent -CH= or N; R<4> and R<5> represent H, lower alkoxy, halogen atom or amino); R<3> represents H, halogen atom, nitro, amino, lower alkanoylamino, lower alkoxy, etc.; bonds at the 3- and 4-positions of carbostyril skeleton are single or double bond] and salt thereof. EXAMPLE:8-Bromo-6-[1H-imidazo-(4,5-c)-pyridin-2-yl]-3,4-dihydrocarbost yril-hy drochloride.monohydrate. USE:A cardiac, hypotensor and antiphlogistic, which has low toxicity and small side-effect. PREPARATION:A compound expressed by formula III is reacted with a com pound expressed by formula IV, as necessary, in the presence of a solvent (example; water, methanol or THF), preferably at room temperature -200 deg.C for 1-10hr.

Description

[Detailed Description of the Invention] 1. Higashijotachi Gogatsu Momme! The present invention relates to novel carbobean chiryl derivatives and salts thereof. The carbostyril derivative of the present invention has the following general formula % R1 [wherein R1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a phenyl lower alkyl group].

are the same or different and represent a group -CH- or a nitrogen atom; R4 and R5 are the same or different and represent a hydrogen atom, a lower alkoxy group, a halogen atom or an amino group, respectively).

R3 is a hydrogen atom, a halogen atom, a nitro group, an amino group,
A lower alkanoylamino group, a lower alkoxy group, a hydroxyl group, a lower alkyl group, a lower alkylthio group, a saturated 5- to 6-membered heterocyclic group that may have a lower alkyl group as a substituent on a heterocyclic group, or a saturated Indicates a lower alkyl group having a 5- to 6-membered heterocyclic group. Further, the 3- and 4-position bonds of the carbostyril skeleton represent a single bond or a double bond. ] The carbostyril derivative represented by the above general formula (1) of the present invention and its salt have the effect of enhancing myocardial contraction (
positive inotropic effect), coronary flow increasing effect, antihypertensive effect, vasoconstriction suppressing effect due to norepinephrine, and anti-inflammatory effect, such as congestive heart failure, mitral valvular heart disease, atrial fibrillation, etc.
It is useful as a cardiotonic agent, antihypertensive agent, and anti-inflammatory agent for the treatment of various heart diseases such as flutter and paroxysmal atrial tachycardia. In particular, carbostyril derivatives represented by the above general formula (1) and their salts have excellent positive inotropic effects, coronary flow increasing effects, and hypotensive effects, but have almost no effect on increasing heart rate. It has characteristics in several respects. In addition, the carbostyril derivative represented by the above general formula (1) and its salts have low toxicity1, and are characterized by having few central side effects such as vomiting, decreased motor function, and tremors. are doing.

In the above general formula (1), specific examples of each group defined are as follows.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of lower alkenyl groups include linear or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl groups. can.

Examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 2-methyl-3-phenylpropyl group.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
6, a straight chain or branched alkoxy group can be exemplified.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of lower alkanoylamino groups include formylamino,
Acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, tert
Examples include straight-chain or branched alkanoylamino groups having 1 to 6 carbon atoms, such as -butylcarbonylamino and hexanoylamino groups.

Lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, te
Examples include straight-chain or branched alkylthio groups having 1 to 6 carbon atoms, such as rt-butylthio, pentylthio, and hexylthio groups.

Examples of the saturated 5- to 6-membered heterocyclic group that may have a lower alkyl group as a substituent on the heterocyclic group include unsubstituted saturated 5- to 6-membered heterocyclic groups such as pyrrolidinyl, piperazinyl, piperidinyl, and morpholino groups. Others, 2-methyl-1-pyrrolidinyl, 3-ethyl-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 3-ethyl-1-piperazinyl,
4-Methyl-1-piperazinyl, 3-ethyl-1-piperidinyl, 3-methylmorpholino, 2-ethylmorpholino, 3-propyl-1-pyrrolidinyl, 4-butyl-1
-piperazinyl, 4-pe,phthyl-1-piperidinyl,
A substituent such as a 3-hexylmorpholino group having 1 or more carbon atoms
5-6 saturated with 6 straight or branched alkyl groups
Examples include membered heterocyclic groups.

Examples of the base alkyl group having a saturated 5- to 6-membered heterocyclic group as a substituent include (1-pyrrolidinyl)methyl, (1-
piperazinyl)methyl, (1-piperidinyl)methyl,
Morpholinomethyl, 2-(pyrrolidinyl)ethyl, 1-
(1-Piperazinyl)ethyl, 3-(1-piperidinyl)propyl, 4-morpholinobutyl, 1,1-dimethyl-2-(1-pyrrolidinyl)ethyl, 5-(1-piperazinyl)pentyl, 6-(1- piperidinyl)hexyl, 2-methyl-3-morpholinopropyl, etc., have a saturated 5- to 6-membered heterocyclic group as a substituent, and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms. A certain group can be exemplified.

The carbostyril derivatives and salts thereof of the present invention can be produced, for example, by the method shown in the reaction formula below.

<Reaction formula-1> [In the formula, R1, R2, R3, X, YlZ and the 3.4-position bond of the carbostyril skeleton are the same as above. ] General formula (2)
The reaction between the compound and the compound of general formula (3) can be carried out in a suitable solvent or without a solvent in the presence of a dehydrating agent. Examples of solvents that can be used here include water, lower alcohols such as methanol, ethanol, and propatool, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, methylene chloride, chloroform, and carbon tetrachloride. Examples include halogenated hydrocarbons such as acetone, dimethylsulfoxide, dimethylformamide, and aprotic polar solvents such as hexamethylphosphoric triamide.

Examples of dehydrating agents include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as thionyl chloride and p-toluenesulfonic acid, methanesulfonic acid-phosphorus pentoxide, phosphorus pentoxide, polyphosphoric acid,
Examples include phosphorus compounds such as phosphorus oxychloride, phosphorus pentachloride, and phosphorus trichloride.

The amount of the compound of general formula (3) to be used is usually approximately equimolar to 5 times the molar amount, preferably equimolar to 2 times the molar amount of the compound of general formula (2). The reaction is generally carried out at a temperature of about 0 to 250°C, preferably room temperature to about 200°C, for about 1 to 10 hours.

In Reaction Formula-1 above, the compound represented by General Formula (2) used as a starting material can be produced, for example, by various methods shown in Reaction Formulas-2 to -7 below.

<Reaction formula-2> (4) (2a) [In the formula, R1 and R3 are the same as above. R6 represents a hydrogen atom or a lower alkyl group. ] The cyclization reaction of the compound of general formula (4) is carried out in a suitable solvent in the presence of a suitable basic compound. Basic compounds used here include, for example, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, sodium bicarbonate, metallic sodium,
Inorganic bases such as metallic potassium, sodium amide, sodium hydride, alcoholades such as sodium ethylate, sodium methylate, potassium tert-butoxide, m bases such as triethylamine, tripropylamine, pyrrolidine, veridine, pyridine, etc. can be exemplified. The use of a darkening basic compound is usually expressed by the general formula (4)
The amount should be at least equimolar, preferably equimolar to twice the molar amount of the compound. Examples of Kyoda solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, impropatol, and t.
Alcohols such as ert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, polar solvents such as N-methylpyrrolidone, dimethylformamide, dimethyl, rusulfoxide, hexamethylphosphoric triamide, acetic anhydride, etc. can be used.

The folding temperature is usually room temperature to about 150°C, preferably room temperature to about 150°C.
The process proceeds at a temperature of about 100°C and is completed in about 1 to 10 hours.

Among the compounds of general formula (2a) obtained by the above reaction, a compound in which R11 represents a lower alkyl group can be hydrolyzed to derive a desired compound in which the corresponding R6 is a hydrogen atom.

The above hydrolysis reaction can be carried out in a suitable solvent in the presence of an acid or basic compound. As the solvent, for example, water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents such as these can be used. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid.
As the chlorinating compound, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. can be used. The above hydrolysis reaction is usually carried out in a room m~1
The process proceeds suitably at about 50°C, preferably about 120°C, and generally ends in about 10 minutes to 15 hours.

(Reaction formula-3> [(5) (2b) [In the formula, R1,
R7 and the 3°4-position bond of the carbostyril skeleton are the same as above. Xl represents a halogen atom. ] The halogenation reaction of the compound of general formula (5) is carried out in a suitable solvent in the presence of a halogenating agent.

Here, the halogenating agent includes various commonly used agents, such as halogen molecules such as bromine and chlorine, iodine chloride,
Sulfuryl chloride, N-bromosuccinimide, N-
Examples include N-halogenated succinimides such as chlorosuccinimide. The secondary halogenating agent is usually used in an amount of approximately 1 to 10 times the molar amount of the compound of general formula (5) used as a raw material, preferably in a range of about 1 to 5 times the molar amount. . Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, alkanoic acids such as acetic acid and propionic acid, and water.

The reaction is usually carried out at about 0 to 100°C, preferably about 0 to 4°C.
The process is completed in about 1 to 15 hours at a temperature around 0°C.

Incidentally, during the above reaction, a metal such as iron powder or a salt thereof may be added to the reaction system as required.

General formula (2b
) Among the compounds represented by R6, a compound in which R6 represents a lower alkyl group may be subjected to a hydrolysis reaction in the same manner as the hydrolysis reaction of the compound of general formula (2a) obtained by the method shown in Reaction Formula-2 above. Accordingly, a desired compound in which the corresponding R6 is a hydrogen atom can be derived.

<Reaction formula-4> (6) (2G> [R3 in the formula,
R6, Xl and the 3,4-position bonds of the carbostyryl skeleton are the same as above. Rla represents the R1 group other than a hydrogen atom. ] The reaction between the compound of general formula (6) and the compound of general formula <7) can be carried out in a suitable solvent in the presence of a basic compound. Examples of the basic compound used here include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium C hydride, metallic sodium, metallic potassium, sodium amide, potassium amide, and the like. In addition, as a solvent, ethers such as dioxane, tetrahydrofuran, and ethylene glycol 2-methyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, etc. can be used. .

The ratio of the compound of general formula (6) and the compound of general formula (7) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is at least equimolar to the former; Preferably equimolar! It is preferable to set the amount to about 3 to 3 times the molar amount. The reaction normally proceeds at a temperature of about 0 to 100°C, preferably about 0 to 70°C, and generally about 0.5 to about 70°C.
It will take about 12 hours.

Among the compounds of the general formula (2C) obtained by the method shown above, the compound in which R8 represents a lower alkyl group is the compound of the general formula (2a) obtained by the method shown in the reaction formula-2.
) A desired compound in which R8 is a hydrogen atom can be derived by performing a hydrolysis reaction in the same manner as in the hydrolysis reaction of the compound (2).

Furthermore, in the reaction shown in Reaction Formula-4 above, general formula (6
) as a compound of R1! When a hydrogen atom (carboxylic acid) is used, the carboxyl group of the carboxylic acid may also be esterified at the same time, but the compound thus obtained can be easily separated from within the reaction system, and such The compound can be easily converted into a carboxylic acid compound by the above hydrolysis reaction.

Reaction formula-5〉%Formula%(14 [In the formula, R', X+ and 3゜4-
The position bond is the same as above. R7 represents a lower alkyl group. X
2 represents a halogen atom. ] The reaction between the compound of general formula (8) and the compound of general formula (9) is carried out in the presence of a suitable basic compound. Examples of basic compounds include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, silver carbonate, and sodium hydride, and alkalis such as metallic sodium and metallic potassium. metal, sodium ethylate, sodium methylate, potassium-ter
Alcoholades such as t-butoxide, triethylamine, tripropylamine, pyrrolidine, piperidine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo(4,3,0) Nonene-5 (DBN>, 1°8-
Diazabicyclo(5,4,O)undecene-7 (DBU
), 1,4-diazabicyclo(2,2゜2]octane (
Examples include organic bases such as DABCO). The above reaction can be carried out without a solvent or with a solvent. The solvents used include various inert solvents that do not adversely affect the reaction, such as water, alcohols such as methanol, ethanol, propatool, butanol, and ethylene glycol, and ethers such as dimethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme. , acetone, ketones such as methyl ethyl ketone, benzene,
Aromatic hydrocarbons such as toluene and xylene, esters such as methyl acetate and ethyl acetate, dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethyl phosphoric acid triamide, and mixed solutions Is thereof.

The above reaction can also be carried out in the presence of metal iodides such as, for example, sodium iodide, potassium iodide, etc., and it is generally advantageous to use such iodides.

Compound of general formula (8) and general formula (9) in the above reaction
The proportion of the compound to be used is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in about an equimolar to 7 times the molar amount of the former, preferably about an equimolar to 4 times the molar amount of the latter. It is desirable to use it in moderation. The reaction temperature is not particularly limited, but is usually around room temperature to about 200°C,
Preferably, the temperature is selected from the range of about room temperature to about 150°C, and the reaction time is about 1 to 70 hours, preferably about 1 to 70 hours.

The reaction to obtain the compound of general formula (11) from the compound of general formula (10) obtained by the above reaction is generally called Claisen rearrangement, and for example, the compound of general formula (10) is heated in a suitable solvent. It is implemented by Examples of the solvent used here include high boiling point solvents such as N,N-dimethylaniline, dimethylformamide, and tetralin. The heating temperature is usually 1.
The temperature is about 00 to 250°C, preferably about 150 to 250°C, and the reaction is completed in about 1 to 20 hours.

The compound of the general formula (11) thus obtained and the compound of the general formula (
The reaction with the compound of formula (12) can be carried out under the same conditions as the reaction between the compound of general formula (8) and the compound of general formula (9).

Further, the reaction for converting the compound of general formula (13) into the compound of general formula (14) can be carried out in a suitable solvent in the presence of a suitable acid or basic compound. As the acid, for example, inorganic acids such as phosphoric acid and perchloric acid, organic acids such as p-toluenesulfonic acid, acetic acid, and acetic anhydride, and mixed acids such as these can be used. Examples of the basic compound include alkali metal salts such as potassium tert-butoxide and n-butyllithium. These acidic or basic compounds are usually used in an amount of at least equimolar amount, preferably approximately m-2 times the molar amount of the compound of general formula (13).

Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, and polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction is typically O~150
It takes about 10 minutes to about 5 hours at a temperature of about 0.degree. C., preferably from room temperature to about 100.degree.

The compound of general formula (14) obtained above can be induced into a desired compound of general formula -(2d) by subjecting it to an oxidation reaction. This oxidation reaction is carried out in a suitable solvent.
It can be carried out in the presence of an oxidizing agent or by conventional ozonolysis, with particular preference being given to the process carried out in the presence of the abovementioned oxidizing agents.

In this method, the oxidizing agents used include various usual ones, such as permanganates such as potassium permanganate and sodium permanganate, periodates such as sodium periodate, and the above-mentioned permanganate. Mixtures of salts and periodates, chromic acid and its salts such as chromic acid, potassium dichromate, sodium dichromate,
Examples include ruthenium tetrachloride. It is desirable that the oxidizing agent is used in an amount ranging from about the same molar amount to a large excess amount, preferably about an equimolar amount to about 7 times the molar amount, relative to the compound of general formula (14). Further, as the solvent, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, water, ketones such as acetone, or a mixed solvent thereof can be advantageously used. The reaction is usually carried out at a temperature of about 0 to 100°C, preferably about 0 to 70°C, for about 1 to 10 hours. The above oxidation reaction can also be carried out in the presence of a basic compound such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc., and the use of such basic compounds According to the method, the reaction proceeds more favorably.

Reaction formula-6〉 (2e) (2f) [In the formula, R1
, RB, R7, ×2 and carbostyryl skeleton 3,4-
The position bond is the same as above. ] The reaction between the compound of general formula (2e) and the compound of general formula (12) is the same as the reaction between the compound of general formula (11) and the compound of general formula (12) shown in reaction formula-5 above. It can be carried out under the following conditions.

In addition, in the above reaction, when using a compound of general formula (2e) in which R6 is a hydrogen atom (carboxylic acid) and/or R1 is a hydrogen atom, esterification of the carboxyl group of the carboxylic acid and/or R1 Although alkylation of each group may occur simultaneously, the ester thus obtained can be easily separated from within the reaction system, and can be obtained by the general formula (
A carboxylic acid can be derived by a hydrolysis reaction similar to the hydrolysis reaction of the compound in 2a).

Further, the reaction for inducing the compound of general formula (2f) into the compound of general formula (2e) can be carried out in an appropriate solvent in the presence of a catalytic reduction catalyst. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents such as acetic acid, and examples of the catalytic reduction catalyst include, for example, palladium- Conventional catalytic reduction catalysts such as carbon and palladium black can be used, respectively. The reaction is
It can be carried out under conditions of a temperature of about 0 to 100° C. and a hydrogen pressure of about 1 to 10 atm, usually taking about 0.5 to 3 hours.

The reaction for converting the compound of the general formula (2f) into the compound of the general formula (2e) can also be carried out using a Lewis acid such as aluminum chloride, nium chloride, boron tribromide, boron trifluoride, etc. Acids such as hydrochloric acid and water, chloroform, dichloromethane,
In a halogenated hydrocarbon such as carbon tetrachloride, an alcohol such as methanol, ethanol, isopropanol, or a mixture thereof, at a temperature of about room temperature to about 150°C, preferably room temperature to about 120°C, about It can also be carried out by reacting for 1 to 10 hours.

In addition, in the above reduction reaction, when using a compound of the general formula (2f) in which R6 represents a lower alkyl group, the C0OR' group of the compound may also be converted to a C0OH group,
This material can be easily separated.

(2Q) (wherein R1, R3, ×1 and carbostyril skeleton 3
, the 4-position bond is the same as above. R8 represents an aromatic amine. ) The reaction between the compound of general formula (15) and the compound of general formula (16) (aromatic amine) is carried out in a suitable solvent or without solvent. As the solvent, any inert solvent that does not adversely affect the reaction can be used, examples of which include chloroform, methylene chloride, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, alcohols such as methanol, ethanol, isopropanol, butanol, esters such as methyl acetate, ethyl acetate, aprotons such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc. Examples include polar solvents and acetonitrile.

As the aromatic amine (16), for example, pyridine, quinoline, etc. can be used. The amount of the secondary aromatic amine to be used is usually small (about an equimolar amount, preferably a large excess amount) relative to the compound of general formula (15). This is carried out at a temperature of about 200°C, preferably about 70 to 150°C, for about 1 to 10 hours.

The hydrolysis reaction of the compound of general formula (17) obtained by the above reaction is carried out in water at room temperature to about 150°C in the presence of an inorganic basic compound such as sodium hydroxide or potassium hydroxide.
It can be carried out for about 1 to 10 hours at a certain temperature,
Through this hydrolysis reaction, the desired compound of general formula (2g) can be produced.

In addition, in the method shown in the above reaction formula-7, the compound of general formula (15) used as a raw material can be produced, for example, by the method shown in the following reaction formula-8.

Reaction formula-8> [In the formula, R1, R3, x1, X2 and the 3,4-position bonds of the carbostyryl skeleton are the same as above. ] The reaction between the compound of the general formula (18) and the compound of the general formula (19) or the compound of the general formula (20) is generally called a Friedel-Crach reaction, and is a reaction of a Lewis acid in a suitable solvent. It can be done in the presence of As the solvent, any of the various solvents commonly used in this type of reaction can be used. For example,
For example, carbon disulfide, nitrobenzene, chlorobenzene,
dichloromethane, dichloroethane, trichloroethane,
Examples include carbon tetrachloride.

All commonly used Lewis acids can be used. Examples include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, and concentrated sulfur. The amount of Lewis acid to be used can be determined as appropriate, and is usually about 2 to
It is suitable that the amount is about 6 times the molar amount, preferably about 3 to 4 times the molar amount. Compound of general formula (19) or general formula (2
The amount of the compound 0) to be used is usually at least an equimolar amount, preferably an equimolar amount to about 4 times the molar amount of the compound of general formula (18). The reaction is usually carried out at room temperature to about 1
The reaction is carried out at a temperature of about 20°C, preferably room temperature to about 70°C, and is completed in about 30 minutes to 24 hours depending on the raw material compound, catalyst (Lewis acid), reaction temperature, etc. used.

The carbostyryl derivatives and salts thereof of the present invention can also be produced by the methods shown in Reaction Formulas -9 and -10 below.

Reaction formula-9> [In the formula, R2, R3, Rla, x1 and the 3,4-position bond of the carbostyryl skeleton are the same as above. ] Compound of general formula (1a) and general formula (7) according to the method shown in Reaction-9 above
The reaction with the compound is expressed by the general formula (
The reaction can be carried out in the same manner as the reaction between the compound of formula (6) and the compound of general formula (7).

Reaction formula-10> [In the formula, R1, R2 and R3 are the same as above. ] The dehydrogenation reaction of the compound of general formula (1G) according to the method shown in Reaction Formula-10 above is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include 2,3-dichloro-5,6-dicyazbenzoquinone, chloranil (2,3
, 5゜6-titrachloropenzoquinone), halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide, bromine, selenium dioxide, palladium-carbon, palladium black, palladium oxide, Raney nickel, etc. Hydrogenation catalysts and the like can be mentioned. The amount of the halogenating agent to be used is not particularly limited and may be appropriately selected within a wide range, but it is usually about equimolar to 5 times the molar amount, preferably equimolar to 5 times the molar amount of the compound of general formula (1C).
It is preferable to make it about twice the molar amount. In addition, when using a hydrogenation catalyst, normal contact ts! It is better to set it to l. Examples of solvents include ethers such as dioxane, tetrahydrofuran, methoxyethanol, and dimethoxymethane, aromatic hydrocarbons such as benzene, toluene, xylene, and cumene, dichloromethane, dichloroethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, butanol 1,
Examples include alcohols such as amyl alcohol and hexanol, polar protic solvents such as acetic acid, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is usually carried out at room temperature to about 300'C, preferably at very low temperature to 200'C.
The test is generally completed in about 1 to 40 questions.

Further, the reduction reaction of the compound of general formula (1d) can be carried out under normal catalytic reduction conditions.

Examples of the catalyst used here include metal catalysts such as palladium, palladium-carbon, platinum, and Raney nickel, and such metal catalysts are preferably used in normal catalytic amounts. Further, as the solvent, for example, methanol, ethanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane, cyclohexane, acetic acid, ethyl acetate, etc. can be used. The above-mentioned catalytic reduction reaction can be carried out either under normal pressure or under increased pressure, but usually from normal pressure to about 20 kD/cm2, preferably from normal pressure to about 20 kD/cm2.
It is best to do this at around 10 kg/cm2. The reaction temperature is usually about 0 to 150°C, preferably room temperature to
It is desirable to adopt a temperature of about 100°C.

The carbostyryl derivative represented by the general formula (1) of the present invention can be produced by the methods shown in the above reaction formulas.

Furthermore, among the compounds of the present invention represented by general formula (1),
R1 is a hydrogen atom and the carbostyryl skeleton is 3.4
The compound whose -position bond is a double bond is the following reaction formula-11.
As shown in Figure 3, lactam-lactim can be tautomeric.

Reaction formula-11> ■ (1e) (1f) [In the formula, R
2 and R3 are the same as above. ] Further, the compound of the present invention represented by the general formula (1) can also be produced by various methods shown below depending on the type of R3 group it has.

Among the compounds of general formula (1), the compound in which R3 is a hydroxyl group can be prepared by a reaction similar to the reaction between the compound of general formula (2e) shown in reaction formula-6 and the compound of general formula (12).
This can lead to a compound in which 3 is a lower alkoxy group.

Among the compounds of general formula (1), the compound in which R3 is a lower alkoxy group can be prepared by a reaction similar to the reduction reaction that leads to the compound of general formula (2f) shown in reaction formula-6 to the compound of general formula (2e). , can lead to a compound in which R3 is a hydroxyl group.

Among the compounds of general formula (1), a compound in which R3 is an amino group can be converted into a compound in which R3 is a lower alkanoylamino group by reacting it with a suitable acylating agent.

In this acylation reaction, as the acylating agent, for example, lower alkanoic acids such as acetic acid, lower alkanoic anhydrides such as acetic anhydride, lower alkanoic acid halides such as acetyl chloride, etc. can be used. When a lower alkanoic anhydride or a lower alkanoic acid halide is used as the acylating agent, the above acylation reaction is carried out in the presence of a basic compound. Examples of basic compounds include hydroxides, carbonates, bicarbonates, and pyridine of alkali metals such as sodium metal and potassium metal, and secondary alkali metals;
Aromatic amine compounds such as piperidine can be used. The reaction proceeds either in the absence of a solvent or in a solvent, but it is usually preferable to carry out the reaction in a suitable solvent. As a solvent,
For example, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, and water can be used. The acylating agent is used in an approximately equimolar to large excess amount relative to the raw material compound, but generally about 5 to 1 molar excess.
It is preferable to use 0 times the molar amount. The reaction proceeds at about 0 to 70°C, but it is generally preferable to carry out the reaction at about 0 to 70°C. In addition, when lower alkanoic anhydride or lower alkanoic acid is used as the acylating agent, mineral acids such as sulfuric acid and hydrochloric acid, p-toluenesulfonic acid,
The acylation reaction proceeds advantageously by adding a sulfonic acid such as benzenesulfonic acid or ethanesulfonic acid and preferably maintaining the reaction temperature at about 50 to 120''C.

Among the compounds of general formula (1), the compound in which R3 is a lower alkanoylamino group can be prepared by a hydrolysis reaction similar to the ester hydrolysis reaction detailed in the section of reaction formula-2 above.
This can lead to compounds in which R3 is an amino group.

Among the compounds of general formula (1), a compound in which R3 is an amino group can also be easily produced by subjecting a compound in which R3 is a nitro group to a reduction reaction.
” This reduction reaction can be carried out according to conventional methods for reducing aromatic nitro groups to aromatic amino groups.

More specifically, conventional methods such as a method using a reducing agent such as sodium nitrite or sulfur dioxide gas, and a catalytic reduction method using a reduction catalyst such as palladium-carbon can be followed.

Among the compounds of general formula (1), the compound in which R3 is a lower alkylthio group is a compound of general formula (1) in which R3 is a hydroxyl group, and the compound in which R3 is a hydroxyl group has the general formula '>N-C-Xt (21>R theory R9 and Rlo represent lower alkyl groups.

×1 is the same as above. ] It can be obtained by reacting the compound represented by the following and then heating the resulting intermediate without a solvent, usually at about 150-250'C, preferably at about 200-250'C.

In addition, in this method, this can be expressed by the general formula (
Similarly, by applying to the compound of 2e),
The hydroxyl group of the compound of general formula (2e) can also be converted to a lower alkylthio group.

In these methods, the raw material compound and the above general formula (21)
The reaction with the compound can be carried out in a suitable solvent in the presence of a basic compound. As the solvent and basic compound used here, any of those exemplified in the reaction of the compound of general formula (8) and the compound of general formula (9) in Reaction Formula-5 above can be used. The amount of the compound of general formula (21) to be used is:
It is appropriate that the amount is usually at least equimolar, preferably equimolar to about twice the molar amount of the starting compound.

The reaction is usually carried out at about 0 to 100°C, preferably about 0 to 70°C.
It takes about 1 to 7 hours to carry out the process at a temperature around .degree.

Among the carbostyril derivatives represented by the general formula (1) of the present invention, compounds having a basic group can be easily converted into pharmaceutically acceptable acid addition salts by reacting with an appropriate acid. can.

Examples of nucleic acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; and acidic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. .

Furthermore, among the carbostyril derivatives represented by the general formula (1) of the present invention, compounds having an acidic group can easily form pharmaceutically acceptable salts by reacting with an appropriate basic compound. be able to. Examples of the basic compound include sodium oxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The target compound and the compound of the present invention obtained in each step thus obtained can be easily isolated and purified by conventional separation means. Examples of such separation methods include solvent extraction, dilution, recrystallization, column chromatography, and pre-variety thin layer chromatography.

Incidentally, the present invention naturally includes optical isomers and stereoisomers.

The compounds of the present invention and their salts are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and these are representative.

Examples include compressed tablets, emulsions, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.). When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pylori, binder such as ton, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, boron , lyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin,
Disintegration inhibitors such as cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose,
Adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. If necessary, the tablets may be coated with a conventional coating, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into an emulsion, carriers such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, laminaran, A disintegrant such as agar can be used. When forming into a suppository, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsules are usually prepared by mixing the compound of the present invention or a salt thereof with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to a conventional method.

When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when molded into these forms, diluents such as water, water, etc.
Ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to adjust the isotonicity of the solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. In addition, coloring agents, preservatives, fragrances,
Flavoring agents, sweeteners, etc. and other pharmaceutical agents may also be included in the pharmaceutical formulation.

The amount of the compound of the present invention or its salt to be contained in the above pharmaceutical formulation is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1% by weight in the pharmaceutical formulation.
It is preferable to set the amount to 30%.

The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, intramuscularly or intramuscularly alone.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally.The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, the patient's age, sex and other conditions, the severity of the disease, etc., but usually the active ingredient, the compound of the present invention or The amount of salt is preferably about 0.01 to 10 mQ per 1 ka of body weight per day. In addition, the amount of active ingredient in the dosage unit form is 0.1 to 200%.
It is preferable to contain 111J.

! --5111 Reference examples, examples, pharmacological test results, and formulation examples are listed below.

Reference example 1 2-(1-pyrrolidinyl)-N-(2-formyl-4-
In a solution of 5 g of ethoxycarbonylphenyl)acetamide in absolute ethanol 2001 + IQ, 420 mQ of sodium
And sodium ethoxide prepared from 20% of absolute ethanol was added. After heating under reflux for 1 hour, ethanol was distilled off, water was added to the resulting residue, extracted with chloroform, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 700 mg of 6-nitoxycarbonyl-3-(1-pyrrolidinyl)carbostyryl.

NMR (CD093) δ: 1.41 (3H, t, J-7, 12Hz>1.98
(4H, m> , 3.62 (4H, m> 4.4 (2
H, q, J-7, 12Hz>6.53 (1H,s) 7.09 (1H,d, J-8,42Hz>7.85
(IH, dd, J-8, 42Hz) 8.11 (1H,
d), 9.7 (1H, brs) Reference Example 2 Iron powder 5001110 was added to a solution of 6-nitoxycarbonyl-3,4-dihydrocarbostyryl 20Q in chloroform 350ITIQ, and bromine 5.
A solution of 2111Q in chloroform was gradually added dropwise. Thereafter, the temperature was returned to room temperature, and the mixture was stirred overnight.

After chloroform was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 2.
6g of 8-promo-6-nitoxycarbonyl-3.4-
Dihydrocarbostyril was obtained.

NMR (CDC9G) δ: 1.35 (3H, t, J-7, 1Hz>2.64-2
゜71 (2H, m> 3.02-3.69 (2H, m> 4.36 (2H, q, J-7, 1Hz>7.92 (
1H, d, J-1,8 Hz>8.10 (IH, brs) 8.11 (1H, d, J-1,8 Hz>Reference example 3 1.3 Q of sodium hydroxide, 20 tablespoons of water and 2 tablespoons of methanol
8-bromo-6-ethoxycarbonyl-tyryl 2. OQ was added, and the mixture was heated and stirred at 50 to 60°C for 30 minutes. Thereafter, the solvent was distilled off, and the resulting residue was dissolved in water and acidified with concentrated hydrochloric acid. The precipitated crystals were collected, washed with water, and then recrystallized from chloroform-methanol.
1.10 of 8-bromo-6-carboxy-3,4-dihydrocarbostyryl was obtained.

NMR (DMSO-da) δ: 2,46-2.70 (2H,m>2,85-3.20 (2H.m) 7,88 (IH,d,J-1.5Hz>7,91 (
1H, d. J-1.5Hz>9,40゛(IH,brs
) In the same manner as in Reference Example 3 above, using appropriate starting materials,
The following compounds were obtained.

06-Carboxy-3-(1-pyrrolidinyl)carbostyryl NMR (DMSO-ds) δ: 1,63 (4H,m), 3.46 (4H,m>6
,647 (1H,s) 7,16 (1H,d.J-8.6Hz>7,72 (
IH, d, J - 8.6Hz>8,00 (1H,s) 1 1,60 (1H,brs) 06-carboxy-3-(4-methyl-1-piperazinyl)carbostyryl NMR (DMSO-ds) δ: 2, 29 (3H, s) 2, 57 (4H, brs) 3, 23 (4H, brs) 7, 25 (IH, s) 7, 30 (1H, d, J-8.6) 1z) 7, 85
(IH, dd, J-8.6Hz.

1,7Hz) 8,18 (1H, d, J=1.7Hz) 12,1
(1H, brs) 06-carboxy-3-(1-pyrrolidinylmethyl)carbostyryl NMR (DMSO ds) δ: 1,
95 (4H, brs)3, 31 (
4H, brs) 4, 25 (2H, s) 7, 45 (IH, d, J-8. 6
Hz>8, 10 (1H, dd, J-8
．． 6Hz.

1, 8Hz) 8, 28 (11-1, d, J=1.
8Hz>8, 40 (1)-f. s>12
, 48 (1H.brs)01-(2-phenethyl)-6-carboxy-3.

4-dihydrocarbostyryl NMR (DMSO-ds) δ: 4,65-4.72 (2H,m) 4,66-5.01 (4H,m>4,22 (2H,t,J-7.4Hz) >7,10 (
1H, d. J=8.6Hz)7,26 (5H,m>'7.94 (1H.d,J-1.8Hz)8,03
(IH, dd, J-1.8Hz.

8,6Hz) 01-isopropyl-6-carboxy-3.4-dihydrocarbostyryl NMR (CDCQ3) δ: 1,55 (6H,d,J=7.0Hz>2,58-2
．． 65 (2H, m> 2, 88-2.93 (2H, m> 4, 72 (IH, septet, J-7.
0Hz>7, 20 (IH.d,J=8.6Hz>7,
92 (1H,s) 8,00 (1f-1.6,J-8.6Hz>01-benzyl-6-carpoxycarpostyryl, NMR (D
MSO d6 CDCQ3 ) δ:5.57 (2
H, S) 6.82 (1H, d, J=9.5Hz>7.22-7
．． 35 (6H, m> 7.80 (1H, d, J=9.5Hz>8.07 (
1H, d, J-9Hz> 8.29 (1H, 5) Ql-benzyl-6-carpoxy 7-methoxy 3,
4-dihydrocarbostyryl Melting point 154-158°C Properties Colorless needle crystals (recrystallized from methanol-water) Ql-
Benzyl-6-carpoxy-7-ethoxy Melting point 14
0-141.5℃ Properties Colorless needle crystals (recrystallized from methanol-water) 01-
benzyl-6-carpoxy-7-n-propoxy-3,
4-dihydrocarbostyryl melting point 155-156.5
°C Properties Colorless needle crystals (recrystallized from methanol-water) o6-
Carpoxy 7-ethoxy 3.4-dihydrocarbostyryl Melting point 246-249°C (decomposed) Properties White powder (recrystallized from methanol-water) o6-
Carpoxy 7-n-propoxy-3,4-dihydrocarbostyryl Melting point 242-246°C (decomposed) Properties Colorless scaly crystals (recrystallized from ethyl acetate-methanol) 06-Carpoxy 7-methyl-3,4-dihydrocarbostyryl Melting point 300 ``C or higher (decomposed) Properties Pale yellow powder (recrystallized from dimethylformamide-methanol) 06-carpoxy-7-chloro-3,4-dihydrocarbostyryl Melting point 310°C or higher (decomposed) Properties Pale yellow powder (recrystallized from dimethylformamide-water) Recrystallization) 06-carpoxy 7-methoxy 1-methyl-3, 4
-dihydrocarbostyril Melting point 202.5-206.5℃ Properties Colorless prismatic crystals (recrystallized from methanol) 06
-Carpoxy 7-methylthiohydrocarbostyryl Melting point 300-307°C (decomposed) Properties Pale yellow needle crystals (recrystallized from dimethylformamide-methanol) Reference example 4 2-(4-methyl-1-piperazinyl)-N- (2-formyl-4-ethoxycarbonylphenyl)acetamide 5.470 is dissolved in tert-butanol 10011112 and potassium tert-butoxide 2.1
g was added thereto, and the mixture was heated and stirred at 70°C for 1 hour. Then ter
t-Butanol was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform.

After washing with saturated saline and drying with magnesium sulfate,
Chloroform was distilled off. 3. Crystallization from diethyl ether; OQ 6-nitoxycarbonyl-3-(4
-Methyl-1-piperazinyl) carbostyryl NMR (CDCQ3) δ: 1,42 (3H,t,J-7.1Hz>2,40 (
3H,s), 2.70 (4H,m>3, 35 (4
1-1,m>4,40 (2f-1,q,J-7.1Hz>7,28
(1H, d.J-8.5Hz) 8, 01 (1H, d.
d, J-1.8Hz.

8,5Hz) 8,23 (1H,d,J-1.8Hz>1 1,07
(1H, brs) In the same manner as in Reference Example 4 above, using appropriate starting materials,
The following compounds were obtained.

06-Nitoxycarbonyl-3-(1-pyrrolidinylmethyl)carbostyryl NMR (CDCQa) δ: 1.4243 (3H, t, J-7, 12Hz) 1.6
7 (4H, m), 2.71 (4H, m>3.75
(2H, s) 4.41 (2H, q, J-7, 12Hz) 7.38
(1H, d, J-8, 55Hz) 7.98 (IH, s
) 8.13 (IH, dd, J-1, 84Hz.

8.55Hz> 8.32 (1H, d, J-1, 84Hz) 11.60
(IH, brs) Reference Example 5 6-nitoxycarbonyl-3,4. - A solution of 5 g of dihydrocarbostyryl, 4.5 g of potassium hydroxide, and 50 g of β-bromoethylbenzene in dimethyl sulfoxide was stirred at room temperature for 8 hours. Thereafter, the reaction mixture was poured into water, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The residue obtained by distilling off ethyl acetate was purified by silica gel column chromatography (eluent: dichloromethane).
6, OQ of 1-(2-phenethyl)-6-nitoxycarbonyl-3,4-dihydrocarbostyryl was obtained.

NMR (CDCi2a) δ: 1.40 (3H, t, J-7, 1Hz) 2.61-2
．． 65 (2H, m> 2.65-2.98 (4H, m> 4.20 (2H, t, J-8,0Hz>4.38 (
2H, q, J-7, 1Hz>7.06 (1H, d, J
-8,6Hz>7.21-7.34 (5H,m>7.66 (1H,d,J-2,0Hz>7.95 (
1st, dd, J-8, 6Hz.

2.0H2) In the same manner as in Reference Example 5 above, using appropriate starting materials,
The following compounds were obtained.

01-Isofuropyru-6-nidoxycarbonyl-3.4
-dihydrocarbostyryl NMR (CDCQa) δ: 1.39 (3H,t, J-7,1Hz>1.53 (
6H, d, J-7,0Hz>2.54-2.62 (2
H, m> 2.84-2.91 (2H, m> 4.37 (2H, Q, J-7, 1Hz>4, 70 (
I H,5eptet, J-7,0Hz>7.16
(1H,d, J-8,5Hz>7.65 (1H,d,
J-2,1Hz) 7.81 (1H,dd, J-2,1
Hz.

8.5H2) ol-benzyl-6-carpoxy-7-hydroxy-3
, 4-dihydrocarbostyryl Melting point 212-216°C (decomposed) Properties Colorless needle crystals (recrystallized from methanol-ethanol) 01-Methyl-6-medoxycarbonyl-7-methoxy-3,4-dihydrocarbostyryl Melting point 154. 5~
156.5°C Properties Colorless acicular crystals (recrystallized from methanol) 06-carpoxy-7-methoxy-1-methyl-3,4-dihydrocarbostyryl Melting point 202.5-206.5°C Properties Colorless prismatic crystals (recrystallized from methanol) ) Reference Example 6 5-hydroxy-3,4-dihydrocarbostyryl 15
Potassium carbonate (19C) was added to 150ml of dimethylformamide solution of Q, and allyl bromide (12mQ) was added to this under water cooling.
A dimethylformamide 20111G solution of was added dropwise.

After the dropwise addition was completed, the mixture was stirred at room temperature overnight, and the reaction mixture was soaked in ice water for 1 hour.
The precipitated crystals were collected, washed with water, and then recrystallized from methanol to obtain 12.9 g of 5-7lyloxy-3,4-dihydrocarbostyryl.

Melting point 140-148°C Properties Pale yellow platelet crystals Reference example 7 5-allyloxy-3,4-dihydrocarpos-)l,
J Le 17 (j dimethylformamide 70mG solution,
The reaction mixture was heated to reflux for 5 hours under a nitrogen stream, allowed to cool, and the reaction mixture was ice-cooled and poured into dilute hydrochloric acid containing 50 mQ of concentrated hydrochloric acid and 1Q of water. The precipitated crystals were collected, washed with water, and then recrystallized from methanol. , 11.10 of 5-hydroxy-6-allyl-3,4-dihydrocarbostyryl was obtained.

Melting point: 108-116°C (decomposed).

Properties Colorless needle crystals Reference example 8 5-hydroxy-6-allyl-3,4-dihydrocarbostyryl 4.1 g of dimethylformamide 40111Q
5.5 g of potassium carbonate was added to the solution, and then 2.511 Q of methyl iodide was added dropwise while cooling with water. After the addition was completed, the mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 2.5 hours. The reaction mixture was poured into 50ml of ice water, and the precipitated crystals were collected.

After washing this with water, it was recrystallized from methanol-water and 3.6
1 g of 5-methoxy-6-allyl-3,4-dihydrolupostyryl.

Melting point: 170-172°C Properties: Colorless needle crystals Using appropriate starting materials in the same manner as in Reference Example 8 above,
The following compounds were obtained.

o5-jl-Propoxy-6-allyl-3,4-dihydrocarbostyryl Melting point 131-132°C Properties Colorless needle crystals (recrystallized from methanol-water) 01-
Benzyl-6-carpoxy-7-methoxy-3,4-dihydrocarbostyryl Melting point 154-158°C Properties Colorless needle crystals (recrystallized from methanol-water) Reference example 9 5-methoxy-6-allyl-3,4-dihydrocarbo To a solution of 3.3 g of styryl in 30 mQ of dimethyl sulfoxide was added 2.6 q of potassium tert-butoxide at room temperature, and the mixture was stirred at 50°C for 30 minutes.

The reaction mixture was poured into ice water and acidified with hydrochloric acid. The precipitated crystals were collected, washed with water, and recrystallized from methanol to give 2.
．． 8 g of 5-methoxy-6-(1-propenyl)-3,
4-dihydrocarbostyryl was obtained.

Melting point: 199-207°C Properties: Colorless schistose crystals Using appropriate starting materials in the same manner as in Reference Example 9 above,
The following compounds were obtained.

05-n-propoxy-6-(1-propenyl)-3,
4-dihydrocarbostyryl Melting point 155-159°C Properties Pale yellow plate crystals (recrystallized from methanol) Reference example 1
0 5-Methoxy-6-(1-propenyl)-3゜4-dihydrocarbostyryl 1. 0.80 g of sodium bicarbonate was added to a suspension of 200 ml of Nasetone, and then 4.1 g of potassium permanganate was added while cooling with water, and 1 g of potassium permanganate was added at the same temperature.
The mixture was stirred for 1 hour and further stirred at room temperature for 3 hours. Add a small amount of methanol to the reaction mixture to decompose excess potassium permanganate, then concentrate to about half the volume under reduced pressure, remove insoluble matter, pour this into 200 mQ of 5% aqueous sodium carbonate solution, and stir for 1 hour. did. After removing insoluble matter with Celite, the furnace solution was acidified with concentrated hydrochloric acid, the precipitated crystals were collected, and subjected to silica gel column chromatography (eluent; chloroform:methanol:acetic acid -7,0:10:1~ 50:10:
1), recrystallized from dimethylformamide-water to give 0.17CI of 5-methoxy-6-carboxy-
3゜Stop taking 4-dihydrocarbostyril.

Melting point: 263-265°C (decomposed) Properties: Colorless needle crystals The following compound was obtained in the same manner as in Reference Example 10 above using appropriate starting materials.

o5-jl-Propoxy-6-carboxy-3,4-dihydrocarbostyryl Melting point 258-263°C (decomposition) Properties Colorless needle crystals (recrystallized from methanol) Reference example 11 6-chloroacetyl-7-hydroxy-3, 43.4 g of 4-dihydrocarbostyryl and 350 mg of pyridine were heated and stirred at 80-790°C for 1 hour. After cooling, the precipitated crystals were collected and washed with ethanol. The obtained 6-pyricinium acetyl-7-hydroxy-3,4
- Dihydrocarbostyryl chloride was added to a solution of 40 g of sodium hydroxide in 500 mO of water at 80-90'C.
The mixture was heated and stirred for 1 hour. After cooling, acidify with concentrated hydrochloric acid, take off the precipitated product, wash with water, dry, and prepare 30.40-6.
-, carboxy-7-hydroxy-3,4-dihydrocal, bostyril was obtained.

Properties Brown powder Reference Example 12 In the same manner as Reference Example 8 above, using appropriate starting materials,
The following compounds were obtained.

01-Benzyl-6-carpoxy 7-ethoxy Melting point 140-141.5°C Properties Colorless needle crystals (recrystallized from methanol-water) 01-
benzyl-6-carpoxy-7-n-propoxy-3,
4-dihydrocarbostyryl melting point 155-156.5
°C Properties Colorless needle crystals (recrystallized from methanol-water) 'o5
-Methoxycarbonyl-7 Nitoxy-3.

4-dihydrocarbostyryl melting point 19i. 5-193.0℃ Properties Pale yellow needle crystals (recrystallized from methanol-water) 06
-Medoxycarbonyl-7-n-propoxy-3.4-
Dihydrocarbostyril Melting point 166.5-168.0°C Properties Colorless needle crystals (recrystallized from ethyl acetate-〇-hexane) o6-carpoxy7-ethoxy3.4-dihydrocarbostyril Melting point 246-249°C (decomposed) Properties White powder (recrystallized from methanol-water) 06-
Carpoxy 7-n-propoxy-3,4-dihydrocarbostyryl Melting point 242-246°C (decomposed) Properties Colorless scaly crystals (recrystallized from ethyl acetate-methanol) Reference example 13 Suspension of aluminum chloride 6,69 in dichloromethane for 20 minutes A 5 ml solution of 2-chloroacetyl chloride in dichloromethane was added dropwise to the solution under water cooling.

After stirring at room temperature for 40 minutes and then at 65°C for 20 minutes, cooling on ice again, 7-methyl-3,4-dihydrocarbostyryl 2. OQ was added and stirred at room temperature for 2 hours.

The reaction mixture was poured into ice water, the precipitated crystals were collected,
After washing with water, recrystallization from dimethylformamide-methanol yielded 2.2 g of 6-(α-chloroacetyl)-7-methyl-3.

4-dihydrocarbostyryl was obtained.

Melting point: 201-203°C Properties: Colorless needle crystals In the same manner as in Reference Example 13 above, using appropriate starting materials, the following compound was obtained.

06-(α-chloroacetyl)-7-chloro-3.

4-dihydrocarbostyril Melting point 207-214°C (decomposed) Properties Pale brown needle crystals (recrystallized from dimethylformamide-methanol) Reference example 14 6-Medoxycarbonyl-7-hydroxy-4-dihydrocarbostyril 14 g dimethylformamide 200
11112 suspension, add 2.8 ml of sodium hydride under water cooling.
g, stirred at room temperature for 20 minutes, and then heated at 40"C for 20 minutes.
Stirred for 0 minutes. Next, after cooling with water again, dimethylthiocarbamoyl chloride 11,7CI was added and kept at the same temperature for 1 hour.
Each mixture was further stirred at room temperature for 2 hours. Thereafter, 4 g of dimethylthiocarbamoyl chloride was further added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, the precipitated crystals were collected, and after washing with water, the crude crystals were added to an approximately 10% aqueous sodium hydroxide solution, and after stirring at room temperature for 20 minutes, the crystals were collected again. After thorough washing with water, it was recrystallized from methanol-chloroform to obtain 9.69 6-medoxycarbonyl-7-dimethylthiocarbamoyloxytyryl.

Melting point: 219-220°C, Properties: Colorless needle crystals Reference Example 15 6-Medoxycarbonyl-7-dimethylthioca, Sibamoyloxy-3,4-dihydrocarbostyryl9.
6g was heated at 220-230°C for 2 hours under nitrogen atmosphere. After cooling, methanol was added to the reaction mixture to dissolve the lumps, and the resulting residue was purified by silica gel column chromatography (eluent: methanol: dichloromethane - 1:100). Recrystallization from chloroborum gave 0.5 g of 6-medoxycarbonyl-7-methylthiostyryl.

Melting point 212-216°C Properties Pale yellow needle crystals Example 1 0.49 CI of 8-bromo-6-carboxy-3,4-dihydrocarbostyryldiaminopyridine was added to a solution of 20 q of methanesulfonic acid and 2 q of phosphorus pentoxide. Ta. After stirring at room temperature for 2 hours, at 50-60'C for 1 hour, then at 100°C.
The mixture was heated and stirred for 2 hours. Thereafter, the reaction mixture was poured into water and made slightly alkaline with a 50% aqueous sodium hydroxide solution, and the precipitated crystals were collected and washed with water, and the resulting crystals were subjected to silica gel column chromatography (eluent: dichloromethane:methanol = 10 After purification in step 1), it was made into a hydrochloride with ethanol-concentrated hydrochloric acid. It was then recrystallized from ethanol-water to give 8-bromo-6-(it-1-imidazo(4.5-c)-pyridin-2-yl)-3.4-dihydrocarbostyryl of 0.8(J).・Hydrochloride monohydrate was obtained.

Melting point: 300°C or higher Properties: White powder NMR (DMSO-dB) δ: 2, 51-2.65 (2) 1. m>3,00-3.20 (2H,m>8,08 (IH,d,J-6.48Hz>8,16
(1 day.s), 8.38 (1H.s) 8, 52 (1
H. d,J-6.48Hz>9,34 (1H,s>,
9.56 (IH,s) Example 2 0.3G of 7-medoxy6-carboxy-3,4-dihydrocarbostyryl and 0.3G of 3,4-diaminopyridine.
16 (J is phosphorus pentoxide-methanesulfonic acid (1:10
) was added to 7 g of the mixture and stirred at 100°C for 2 hours.

The reaction mixture was poured into ice water and made weakly alkaline with a 10% aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution, and the precipitated crystals were collected, washed with water, and dried. After purification by silica gel column chromatography (eluent; methanol:chloroform = 1:20 to 1:15), the hydrochloride was prepared with ethanol-concentrated hydrochloric acid, recrystallized from water-ethanol, and 0.29 g of 7- Medoxie 6-
(1H-imidazo(4,5-c)-pyridin-2-yl)-3°4-dihydrocarbostyryl hydrochloride monohydrate was obtained.

Melting point 240-263°C (decomposed) Properties White powder NMR (DMSO-66) δ: 2.47-2.57 (2H, m> 2.89-2.99 (2H, m) 4.02 (3H, s), 6.79 (1)-1, s)
8.1"l'('1 day, d, J-6,0Hz)8.
17 (IH,s) 8.51 (IH,d,J-6,0Hz>9.25 (
IH, 5) 1o, 40 (1H, s) Examples 3 to 41 In the same manner as in Examples 1 and 2, each compound shown in Table 1 below was obtained using appropriate starting materials.

Further, the morphology, crystal form, and melting point (and NMR analysis results in some cases) of each compound obtained are shown in Table 2.

Table 1 (x1) NMR (DMSO-da) 6:2.40
-2.80 (2H, m> 2.85-3.20 (2H, m> 7.08 (1H, d, J-9Hz> 7.48 (11-1, dd, J-8Hz, 5Hz>8
．． 10-8.40 (3H, m> 8.48 (IH, d, J-5Hz) 10.50 ('IH, brs) (yg2) NMR (DMSOds) δ near, 20-
8.40 (7H, m) 9.21 (IH, s) ('3) NMR (DMSOds) δ: 2.43-
2.75 (2H, m> 2.90-3.20 (2H, m> 3.48 (1H, brs) 7.10-7.30 (1H, m> 7.85-8.40 (4H, m> 9.49 (IH, brs) ('X4) NMR (DMSO-da) δ: 2.40
-2.75 (2H, m) 2.90-3.20 (2H, m> 7.06 (IH, d, J-9Hz> 7.85 (1H, d, J-6Hz) 8.10 (IH , d, J-9Hz> 8.20 (IH, s) 8.45 (IH, d, J-6Hz> 9.20 (1H, 5) 10.55 (1H, brs) ('5) NMR (DMSOds +020) δ:1.
20 (3) (,t, J-7,5Hz>2.50-2.
80 (2H, m> 2.80-3.20 (2H, m> 3.90 (2H, q, J-7,5Hz) 7.32 (
IH, d, J-8Hz) 7.90-8.30 (3H, m> 8.50 (1H, m> 9.10 (1H, brs) (yA6 > NMR (DMSOda) δ: 4.60
(2H, m> 4.95-5.30 (2) (, m> 5.60-6.20 (1H, m> 7.28 (1H, d, J-9H2) 8.05-8.35 (3 days, m > 8.60 (IH, d, J-7Hz) β 9.36 (1H, s) ('7) NMR (DMSO-ds) δ: 5.56
(2H, s) 6.83 (IH, d, J-9, 4Hz) 7, 18-7
．． 27 (5H, m> 7.62 (IH, d, J-8,9Hz) 8,08 (
1) f, d, J-6,5)-fz)8.13 (1
H, d, J-9, 4Hz>8.40 (1H, d, J-8
,9Hz>8.52 (1H,d,J-6,5Hz)(
"8) NMR (DMSO-ds) δ: 1.75-
2.05 (4H,m> 2.40-2.60 (4)1.m> 6.69 (1H,s) 7.40 (1)-1,d, J-8,6)-1z) 8.
10-8.20 (2H, m) 8.45 (1H, S) 8.58 (IH, d, J-6, 4H2) 9.39 (
1H, 5) 12.09 (IH, s) (''9) NMR (DMSOds) δ: 2.82 (
3H, s) 3.10-3.80 (6H, m) 3.90-4.10 (2H, m> 7.34 (IH, S) 7.48 (IH, d, J-8, 5Hz> 8.10 (
IH, d, J-6, 45Hz>8.30 (IH, d,
J-8, 5th Z) 8.56 (IH, d, J-6, 45
Hz>8.65 (1H,s>, 9.37 (IH,s
)11.14 (IH, brs) 12.28 (IH, s) (' 10) NMR (DMSO-ds) δ: 2.00
(4H, m> , 3.50 (4H, m> 4.34
(2H,s) 7.60 (1H,d,J-8,79Hz>8.10
(1H, d, J-6, 45Hz) 8.45-8.65
(3H, m) 8.76 (IH, s), 9.38 (IH, 5) 10
．． 60 (1H, brs) 12.58 (1H, s) (' 11) NMR (DMSOds) δ: 2.60-
2.80 (2H, m> 3.10-3.35 (2H, m> 8.14 (1H, d, J-6, 43Hz>8.58
(2H, m> 8.94 (1H, d, J-1,8Hz>9.43 (
IH,s) (”12) NMR (DMSO-ds) δ: 2.50-
2.70 (2H, m> 2.90-3.10 (2H, m> 7, 43 (1H, s), 7.53 (1H, s> 8.
00 (IH, d, J-5, 0Hz>8.50 (1H,
d, J-5,0Hz) 9.30 (1H,s), 9.65
(1H,s)(”13)NMR(DMSOds)δ
: 2.50-2.60 (2H, m>"2.99-3.09 (2H, m> 3, 7.8 (3) f, s) 8.91 (IH, d, J-8, 6)-fz)8.12
(IH, d, J-6, 4Hz>8.14 (1H, d
, J-8,6Hz>8.54 (1H,d, J-6,4
Hz>9.33 (IH, s>, 10.55 (IH,
s) ('14) NMR (DMSOds) δ: 0.8
7 (3H, t, J-7,0Hz) 1.69 (2H,
5ixt, J-7,0Hz>2.50-2.60 (2
H, m> 2.98-3.08 (2H, m> 3.71 (2H, t, J-7,0Hz>6.89
(1H, d, J-8, 5Hz>7.97 (1H, d,
J-8,5Hz>8.09 (1H,d, J-6,5H
z>8.56 (1H, d, J-6,5Hz>9.40
(IH, brs) 10.54 (1H, s) (' 15) NMR (DMSOds) δ: 1.46
(3H, t, J-7,0Hz) 2.48-2.58
(2H, m> 2.89-2.99 (2H, m> 4.35 (2H, Q, J-7, 0H2) 6.81
(11-1,s) 8.09 (1H,d, J-6,4Hz>8.13 (
1H,s) 8.50 (IH,d,J-6,4Hz>9.26 (
IH, 5) 10.38 (1H,S) ('' 1B) NMR (DMSOds) δ: 0.95
(3H, t, J-7, 2H2) 1.90 (2H, 5i
xt, J-7, 2Hz>7.46-7.56 (2)i
, m> 2.89-2.99 (2H, m> 4.24 (2H, t, J-7, 2Hz>6.82 (
1H,s) 8.13 (1H,d,J-6,4Hz>8.14 (
IH,s) 8.53 (1H,d, J-6,4Hz>9.30 (
1H,s), 10.38 (IH,s)(” 17)
NMR (D20) δ: 2.45-2.55 (2H, m> 2.82-2.92 (2H, m> 6.57 (1H, S), 7.93 (IH, s) 8.
00 (1H, d, J-6, 3Hz>8.38 (1H
, d, J-6,3Hz>9.04 (IH,s) (US 1B>NMR (DMSO-ds) δ:2.50-
2.60 (2H, m> 2.95-3.05 (2H, m) 7.14 (IH, s), 7.91 (1H, s) 8
．． 16 (1H, d, J-6, 4Hz>8.60 (1
H, d, J = 6.4 Hz > 9.47 (1t-f, s)
, 10.55 (if-1,s) (" 19) NMR (
DMSO-ds) δ: 2.45-2.55 (2H,
m> 2.59 (3H, s) 2.86-2.96 (2H, m> , 6.86 (1H, s), 7.79 (IH, s) 7
．． 99 (1H, d, J-6, 2Hz>7.47 (1
H, d, J-6, 2Hz>9.26 (IH, s), 1
0.29 (IH, s>(1″20) NMR (trifluoroacetic acid-d) δ: 1.43 (3H, d, J-8H
z) 2.90-3.65 (3H, m> 7.25-7.55 (2H, m> 7.80-9.30 (4H, m>('21) NMR (DMSOds) δ: 1. 32 (
3H, d, J-7Hz> 2.20-3.40 (3H, m) 7.12 (1H, d, J-8Hz) 8.10-8.33 (3H, m) 8.60 (1H, d, J-7Hz>9.34 (1H,s) ('22) NMR (DMSO-da +D20) δ:2
．． 31 (3H, s) 2.45-2.80 (2H, m> 2.80-3.25 (2 days, m> 7.80 (2H, m> 7.90-8.20 (1H, m ), 8.40-8.60 (1H, m) 9.15(1)-1,S) (''23) NMR (D20) δ: 6.30 (1H, d, J-8Hz> 6.45 -7.10 (3H, m> 7.30 (1H, d, J-7Hz) 7.88 (1H, s) 7.85 (1H, d, J-7Hz> 8.30 (IH, s) ( *24) NMR (DMSO-ds) δ: 2.45-
2.55 (2H, m> 2.95-2.05 (2H, m> 7.45 (IH, d, J-8,0Hz>7.83 (I
H,s) 7.90 (1H,dd, J-1,8Hz.

8.0H2) 8.11 (1H, d, J-6,5Hz>8.56
(IH, d, J-6, 5Hz>9.41 (1) f,
s), 10.46 (IH, s) ('25) NMR (D
MSOda) δ: 2.55-2.65 (2H, m> 3.00-3.10 (2H, m) 7.22 (1 day, t, J-7, 6Hz>7.51
(1H, d, J-7, 6Hz) 8.17 (1H, d,
J-6,4Hz) 8.21 (IH,d, J-7,6
Hz＞, 8.62 (11-1, d, J-6, 4
Hz>9.54 (18,s), 11.58 (11-
i,s)('26)NMR(DMSOds)δ:2
．． 46-2.56 (2H, m) 2.93-3.03 (2) f, m> 3.79 (3H, s) 6.80 (1H, dd, J-2,4Hz.

8.8H2) 6.96 (1H, d, J-8, 2Hz>6.90-7
．． 00 (1H,brs)7.43 (IH,d,J-
8,8Hz>7.90 (1H,d,J-8,2tlz
)7.94 (IH,s>, 10.31 (1H,s
>12.58 (1H, brs) (”27) NMR (CDC93) δ: 2.60-2
．． 70 (2)-f, m>2.98-3.08 (2H
,m) 3.93 (6)-1,s) 6.89 (1H,d,J-8,3Hz>6.97 (
IH, brs) 7.28 (IH, brs) 7.84 (1H, d, J-8, 3Hz>7.97 (
1H, 5) 11.30 (1H, brs) ('2B>NMR(DMSO-ds) δ: 2.5
0-2.59 (21-i, m) 2.99-3.05
(21-1, m>7.06 (IH, d, J-8, 2H
z>8.10-8.20 (2H, m> 9.0-9.4 (2H, brs) 10.50 (IH, s) (*29) NMR (DMSOds) δ: 2.56-2
．． 66 (2H, m>- 2,90-3,00 (2H, m) 3.37 (3H, S), 4.15 (3H, s) 6.
92 (IH,s) 8.12 (1H,d, J-6,4Hz>8.22 (
1st, S) 8.53 (IH, d, J-6, 4Hz) 9.29 (
1H, brs) (30) NMR (DMSO-ds) δ: 2.43
<38. s) 2.50-2.60 (2H, m) 2.90-3.00 (2H, m> 7.05 (IH, s), 7.90 (IH, s) 8.
10 (11-1, d, J-6, 4Hz>8.56 (
1H, d, J-6, 4Hz>9.41 (1H, s),
10.40 (IH,s)31) NMR (DMSOd
s) δ: 2.50-2.60 (2 days, m) 2.90-3.10 (2H, m> 3.35 (2H, brs) 6.90-7.10 (3H, m) 7 .49 (1H, d, J-8,8Hz) 7.95 (
11-1, d, J-8, 8Hz>8.01 (1H, 5
) 10.52 (1H,brs) Example 42 0.40 of 8-amino-6-(IH-imidazo(4,5-〇)-pyridin-2-yl)-3,4-dihydrocarbostyryl in anhydrous vinegar M! 20 mQ, 1 drop of concentrated sulfuric acid was added, and the mixture was heated and stirred at 80-90°C for 7 hours. Thereafter, the reaction mixture was poured into water, the pH was adjusted to 7 to 8 with a 50% aqueous sodium hydroxide solution, and the water was distilled off under reduced pressure. The obtained residue was extracted with chloroform-ethanol, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent dichloromethane: methanol-10
After purification in step 1), the obtained crystals were added to 30 ml of a 5% aqueous potassium carbonate solution and stirred at heather temperature for 2 hours. filter,
After washing with water, the hydrochloride was prepared with ethanol-concentrated hydrochloric acid, recrystallized with ethanol-water, and 0.2 g of 8-acetylamino-6-(IH-imidazo(4,5-C)-pyridine-2)
-yl)-3,4-dihydrocarbostyryl was obtained.

Melting point 284-286°C (decomposed) Properties Yellow prismatic Example 43 6-(1H-imidazo(4,5-C)pyridin-2-yl)-7-nitoxy-3,4-dihydrocarbostyryl at -37°C 1.0 g of boron tribromide was added dropwise at ~-40°C. Thereafter, the mixture was stirred overnight at air temperature, and then heated and stirred at 45° C. for 6 hours. Thereafter, the mixture was cooled to −40° C., methanol was added dropwise to decompose excess boron tribromide, and the reaction mixture was poured into ice water and made basic with a saturated aqueous sodium hydrogen carbonate solution.

The precipitated crystals were taken out by centrifugation, dried, and then subjected to silica gel column chromatography (eluent: chloroform:methanol:ammonium hydroxide-50:1).
0:1). The hydrochloride was prepared from concentrated hydrochloric acid and recrystallized from water to give 58 ma of 6-(1H-imidazo(4,5-c)pyridin-2-yl]-7-hydroxy-3,4-dihydrocarbostyryl hydrochloride. I got it.

Properties Slight yellow powder Melting point 290°C or higher (decomposed) NMR (D20) δ: 2,45-2.55 (2H,m) 2,82-2.92 (28,m) 6,57 (1 , s), 7.
93 (11-1, s>8,00 (IH,
d, J-6.31-1z) 8, 38 (IH, d, J-
6.3Hz>9,04 (IH,s) Formulation Example 1 6-(benzimidazol-2-yl)-3,4-dihydrocarbostyryl 5ma Starch 132mg Magnesium Stearate 18mO乎
45℃ meter, 200ml
One tablet of the above composition was manufactured by a conventional method.

Formulation example 2 7-Medoxy 6-(IH-imi Dazo(4.5-C)pyridine-2 monoyl)-3,4-dihydrocal Bostiril 500m.

Polyethylene glycol 0.3q (molecular weight:
4000) Sodium chloride 0.9q Polyoxyethylene Rubitan 0.4g Sodium monooleate metabisulfite 0.1q Methyl-paraben 0.11 Propyl-paraben
0.02g00m12 - Dissolve the above parabens, sodium metabisulfite and sodium chloride in the above distilled water at 80°C with stirring. The obtained solution was cooled to 40°C, and the compound of the present invention,
Polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, then the solution is adjusted to the final volume by adding distilled water for injection, and sterilized by sterile filtration using a suitable filter paper. Dispense each into ampoules and give the injection as m@.

Blood perfusion excised papillary muscle specimen> Anesthetized an adult male and female mixed breed dog weighing 8 to 13 kg by intravenously administering bendoparbital sodium salt at a rate of 30*Mka. 1000tJ/heparin sodium salt
After intravenous administration, the animals were bled to death and the hearts were removed. The specimen mainly consists of papillary muscles and cardiac septum, and is perfused with blood from a donor dog at a constant pressure of 100 mmHg through a cannula inserted into the anterior septal artery. Donor dog weighs 1
Bendoparbital sodium salt 30111111/kQ was administered intravenously in advance at 8 to 27 kO for anesthesia, and heparin sodium salt 1000 LJ/ka was intravenously administered. Using bipolar electrodes, a voltage of 1.5 times the threshold (0
, 5 to 3 V), a stimulation width of 5 m 5 ec, and a stimulation frequency of 120 times per minute to stimulate the papillary muscles with a square wave. The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. The generated tension and blood flow were recorded with an ink recorder. The details of this method have already been reported by Tori and Hashimoto (A11.
459-1463°1970>.

The test compound was intra-arterially administered in a volume of 10-30 μQ for 4 seconds. The inotropic effect of the test compound was expressed as a % change in the tension developed before drug administration. The effect on coronary blood flow was expressed as the change in absolute value from before administration (7 minutes before administration).

The results using each of the following compounds as test compounds are shown in Table 3 below.

<Test compound> 1.8-amino-6-(1H-imidazo(4,5-C)
pyridin-2-yl)-3,4-dihydrocarbostyryl 2,. 6-(6-chloro-1 day-penzimidazole-
2-yl)-3,4-dihydrocarbostyryl monohydrate 3.8-promo 6-(1H-imidazo[4,5-C)
pyridin-2-yl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate 4,8-methoxy-6-(IH
-imidazo(4゜5-C)pyridin-2-yl)-3,
4-dihydrocarbostyryl 5.7-medoxy6-(1H-imidazo[4゜5-C
[Pyridin-2-yl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate 6.6-(5-methoxy-1
7.6-(IH-imidazo(4,5-b)pyrimidine-
2-yl)-3,4-dihydrocarbostyryl hydrochloride 372 effluent 8.7-methyl-6-(IH-imidazo[4,5-C)
pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride 2/3 hydrate 9.1-Methyl-7-medoxy6-(1H-imidazo(4,5-C)pyridine-2
-yl)-3,4-dihydrocarbostyryl hydrochloride
4/3 hydrate 10.6-(5-amino-1 day-penzimidazole-
2-yl)-3,4-dihydrocarbostyryl 11.7-hydroxyl 6-(1H-imidazo(4,5
-C) Pyridin-2-yl]-3゜4-dihydrocarbostyryl hydrochloride 12.7-chloro-6-(IH-imidazo[4゜5-C
[Pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride salt monohydrate 13.4-methyl-6-(I
H-imidazo(4゜5-C)pyridin-2-yl)-3
,4-dihydrocarbostyryl hydrochloride monohydrate 14
．． 8-Methyl-6-(1H-imida[4,5-c)pyridin-2-yl)-3,4-dihydrocarbostyryl.
Hydrochloride 1/2 hydrate 15.6-(1H''-i'midazo(4,5-c)pyridin-2-yl)-3,4-dihydrocarbostyryl 1/2 sulfate 3/ Dihydrate 16.
6-(1H-imidazo(4,5-b)pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride 1
/dihydrate 17.1-allyl-6-(1H-imidazo(4°5-C
]Pyridin-2-yl)-3,4-dihydrocarbostyryl-18,1-ethyl-6-(1H-i.midazo[4.

5-C]pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride 19,5-n-propoxy-6-(IH-imida(4.
5-C) pyridin-2-yl)-3.

4-dihydrocarbostyryl Φ hydrochloride 1/2 hydrate 20,1-(2-7enethyl)-6-(IH-imidazo(4.5-c)pyridin-2-yl2-3,4-dihydrocarbo Styryl hydrochloride dihydrate 21,1-benzyl-6-(IH-imidazo[4.

5-C]pyridin-2-yl]carbostyryl 22,8-nitro6-(1H-imidazo[4.

5-C]pyridin-2-yl)-3,4-dihydrocarbostyryl23,8-acetylamino-6-(1H-imidazo(4
．． 5-c) pyridin-2-yl)-3.

4-dihydrocarbostyryl 24,5-methoxy-6-(1H-imidazo(4.

5-C]Pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride monohydrate 25,3-methyl-6-
(IH-imidazo (4.

5-C) Pyridin-2-yl)-3,4-dihydrocarbostyryl hydrochloride monohydrate 26,6-(1H-pensimidazol-2-yl)-3,4-dihydrocarbostyryl Table 3

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a phenyl lower alkyl group. R^2 is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X, Y and Z are the same or different and represent the group -CH= or a nitrogen atom, and R^4 and R^5 are the same or different and represent hydrogen. atom, lower alkoxy group, halogen atom, or amino group). R^3 is a hydrogen atom, a halogen atom, a nitro group, an amino group, a lower alkanoylamino group, a lower alkoxy group, a hydroxyl group, a lower alkyl group, a lower alkylthio group, or a heterocyclic group having a lower alkyl group as a substituent. It represents a certain saturated 5- to 6-membered heterocyclic group or a lower alkyl group having a saturated 5- to 6-membered heterocyclic group as a substituent. Further, the 3- and 4-position bonds of the carbostyril skeleton represent a single bond or a double bond. ] A carbostyryl derivative represented by these and its salt.