JPH02229165A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R is H, lower alkyl, lower alkoxy, -NR<3a>R<3b> (R<3a> and R<3b> are H, lower alkyl or R<3a> and R<3b> together with N form 5-6-membered ring)-containing lower alkyl, etc.; A is -CHR<2> (R<2> is OH, lower alkoxy or lower alkanoyloxy), -CH=CH- or -CO-; o is 1 or 2; B is lower alkylene; R<1> is pyridyl, piperidinyl, piperazinyl, etc., which may contain substituted amino group, etc.; l and m are 0 or 1] and a salt thereof. EXAMPLE:8-Methyl-3-[1-hydroxy-1-(2-pyridyl)methyl]carbostyril hydrochloride. USE:An antiarrhythmic agent. PREPARATION:A compound shown by formula II is reacted with a compound shown by formula III in the molar ratio of 1:1-5 in a solvent such as dioxane or benzene at -50-70 deg.C for 0.5-5 hours to give a compound shown by formula IV.

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel carbostyryl derivatives.

DISCLOSURE OF THE INVENTION 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).

General Formula [In the formula, R is a hydrogen atom or a lower alkyl group, and lower is the same or different and represents a hydrogen atom or a lower alkyl group. Further, R3a and R3b may form a 5- to 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom, together with the nitrogen atom to which they are bonded. ) or a halogen atom-substituted lower alkyl group. A represents a group CH- (R2 represents a hydroxyl group, a lower alkoxy group or a lower alkanoyloxy group), a group -CH=CH-1 or a group -C-. 0 indicates 1 or 2. B represents a lower alkylene group. R1 is a pyridyl group or substituent that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and an amino group that may have a lower alkyl group as a substituent; piperidinyl group, pyrazyl group or group which may have a lower alkyl group /R3 -(Co)n-N, (R" and R4 are the same or different and represent a hydrogen atom or a lower alkyl group. Also, R
3 and R4 may form a 5- to 6-membered saturated heterocycle together with the nitrogen atom to which they are bonded, with or without a nitrogen or oxygen atom. The heterocycle may be substituted with a lower alkyl group as a substituent. ) is shown. 4. m and n are each 0
Or indicates 1. However, 10m must not be 0.

Furthermore, when A represents C-, m shall represent 1.

The bond at position 3.4 of the carbostyryl skeleton represents a double bond or a double bond. ] A carbostyryl derivative represented by these and its salt.

The carbostyril derivative represented by the above general formula (1) and its salt have an antiarrhythmic effect.

The above-mentioned compound has the characteristic that it has almost no effect on the contractile force of the myocardium, and suppresses stimulation generation abnormalities that occur during ischemia and the like.

In this specification, each group represented by R5R1, A and B is more specifically as follows.

Examples of the lower alkyl group include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

is, for example, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminobutyl.
Aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2methyl-3-aminopropyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, tert-butyl Aminomethyl, pentylaminomethyl, hexylaminomethyl, dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, diethylaminoethyl, diethylaminoethyl, N-methyl-N-ethylaminomethyl, N-ethyl-N-propylamino Methyl, N-methyl-N-butylaminomethyl, N-methyl-N-hexylaminomethyl, 2-methylaminoethyl, 1-ethylaminoethyl, 3-propylaminopropyl, 4-butylaminobutyl, 1,1- Dimethyl-2pentylaminoethyl, 5-hexylaminopentyl, 6-dimethylaminohexyl, 2-diethylaminoethyl, 1-(N-methyl-N-hexylamino)ethyl, 3-dihexylaminopropyl, 4-dibutylamino Butyl, 2-(N-methyl-N-pentylamino)ethyl, 3-(1-pyrrolidinyl)propyl, (1-piperazinyl)methyl, 2-
Morpholinoethyl, 1-(1-piperidinyl)ethyl,
A hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, such as 4-(1-pyrrolidinyl)butyl, 5-(1-piperazinyl)pentyl, 6(1-pyridinyl)hexyl group, etc. Indicates the group. Further, R3a' and R3b' together with the nitrogen atom to which they are bonded may form a 5- to 6-membered saturated heterocycle such as pyrrolidinyl, piperazinyl, piperidinyl, morpholino, etc., with or without a nitrogen or oxygen atom. ) and a C1-C6 straight or branched alkyl group.

Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert
- C1-C6 straight or branched alkoxy groups such as -butoxy, pentyloxy, hexyloxy groups and the like can be mentioned.

Examples of the lower alkyloxy group include polmyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, t
Examples include straight-chain or branched alkanoyloxy groups having 1 to 6 carbon atoms, such as ert-butylcarbonyloxy and hexanoyloxy groups.

Examples of lower alkylene groups include carbon groups such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2゜2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups. Mention may be made of 1 to 6 linear or branched alkylene groups.

Examples of amino groups that may have a lower alkyl group as a substituent include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, Dipropylamino, dibutylamino, diethylamino, diethylamino, N-methyl-N-ethylamino, N-ethyl-
N-propylamino, N-methyl-N-butylamino, N
-Methyl-N-hexylamino group and other amino groups that may be substituted with one or two straight or branched alkyl groups having 1 to 6 carbon atoms can be mentioned.

As a pyridyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and an amino group that may have a lower alkyl group as a substituent, for example, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 6-dimethylamino-2-pyridyl, 5-methoxy-2-pyridyl, 4-methoxy-2-
Pyridyl, 6-medoxy-2-pyridyl, 3-methyl-
2-pyridyl, 4-methyl-2-pyridyl, 6-methyl-2-pyridyl, 1-methyl-pyridinium, 4-methyl-6-dimethylamino-2-pyridyl, 2-ethyl-
3-pyridyl, 3-propyl-4pyridyl, 4-butyl-2-pyridyl, 3-pentyl-2-pyridyl, 4-hexyl-3-pyridyl, 2-ethoxy-3-pyridyl,
3-propoxy-4-pyridyl, 4-butoxy-2-pyridyl, 3-pentyloxy-2-pyridyl, 4-hexyloxy-3-pyridyl, 4-amino-2-pyridyl, 3-ethylamino-2-pyridyl , 4-propylamino-3-pyridyl, 2-pentylamino-4-pyridyl, 4-hexylamino-2-pyridyl, 6-danitylamino-2-pyridyl, 4-dipentylamino-2-pyridyl, 6-(N- Merti-N-ethylamino)-2-pyridyl, 3゜4-dimethyl-2-pyridyl, 3,4.6
-4-limethyl-2-pyridyl, 3,4.5-)liftoxy-2-pyridyl, 4,6-simethoxy-2-pyridyl, 4-ethyl-6-cypropylamino-2-pyridyl, etc. as a substituent , a straight chain or branched alkyl group having 1 to 6 carbon atoms, a straight chain or branched alkyl group having 1 to 6 carbon atoms, and a straight chain or branched alkyl group having 1 to 6 carbon atoms. Examples include pyridyl groups which may have 1 to 3 groups selected from the group consisting of amino groups which may be substituted with 1 to 2 atoms.

Examples of the piperidinyl group that may have a lower alkyl group as a substituent include 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-methyl-2-piperidinyl, 1-ethyl-2-piperidinyl, 1-propyl-2
-piperidinyl, 1-butyl-2-piperidinyl, 1-
Pentyl-2-piperidinyl, 6-methyl-2-piperidinyl, 5-methyl-2-piperidinyl, 1-hexyl-2-piperidinyl, 2-methyl-3-piperidinyl,
3-Methyl-4-piperidinyl, 1-ethyl-3-piperidinyl, 1-butyl-4-piperidinyl, 1,6-cymethyl-2-piperidinyl, 1.3.4-trimethyl-
Examples include (23- or 4-)piperidinyl groups, such as 2-piperidinyl groups, which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents.

A 5-membered or 6-membered compound formed with the nitrogen atom to which R3 and R4 are bonded, with or without a nitrogen atom or an oxygen atom.
Examples of the member saturated heterocyclic group include a piperazinyl group, a piperidinyl group, a morpholino group, and a pyrrolidinyl group.

Examples of the above heterocyclic group substituted with a lower alkyl group include 4-methyl-1-piperidinyl, 2methyl-1-morpholino, 2-methyl-1-pyrrolidinyl, 4-ethyl-
1-piperazinyl, 3propyl-1-morpholino, 4-
Isopropyl 1-piperidinyl, 3-butyl-1-pyrrolidinyl, 4-tert-butyl-1-piperazinyl,
4pentyl-1-piperidinyl, 3-hexyl-1morpholino, 3,4-dimethyl-1-piperazinyl, 2,4
-dimethyl-1-piperazinyl, 2゜6-cymethyl-1
-Piperidinyl, 3,4.5-trimethyl-1-piperazinyl, and other heterocyclic groups substituted with 1 to 3 straight or branched alkyl groups having 1 to 6 carbon atoms.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, chloromethyl,
Bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2.
2.2-trifluoroethyl, 2,2.2-trichloroethyl, 3chloropropyl, 2,3-dichloropropyl, 4゜4.4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms and having 1 to 3 halogen atoms, such as -2-methylpropyl, 5-bromohexyl, and 5,6-dichlorohexyl.

The carbostyryl derivative represented by the above-mentioned (1) can be produced by various methods, and for example, it can be easily produced according to the method shown in the following reaction formula.

[Reaction formula-1] H (1a) [In the formula, R, R', B, m and 3 of the carbostyril skeleton
, the bond at position 4 is the same as above. M is lithium or MgX
(X represents a halogen atom).

] The reaction between the compound of general formula (2) and the compound of general formula (3) is carried out in a suitable solvent. Examples of the solvent used here include dioxane, tetrahydrofuran,
Examples include ethers such as diethyl ether, aromatic hydrocarbons such as benzene and toluene, saturated hydrocarbons such as pentane, hexane, heptane, and cyclohexane, and mixed solvents thereof. Compound (3) is usually used in an amount of at least equimolar, preferably equimolar to 5 times the molar amount of compound (2). The above reaction is usually -50 to 1
The process progresses suitably at 00°C, preferably around -50°C to 70°C, and is generally completed in about 0.5 to 5 hours.

[Reaction formula-2] [In the formula, R, R3, R4 and 3 of the carbostyryl skeleton,
The bond at position 4 is the same as above. X represents a halogen atom. ] Examples of the halogen atom include chlorine, bromine, iodine, and fluorine atoms.

The reaction between compound (2) and compound (4) is carried out in a suitable solvent in the presence of a basic compound.

The basic compounds used here include inorganic bases such as sodium metal, potassium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate;
Metal alcoholades such as sodium methylate, sodium ethylate, potassium t-butoxide, alkyl and aryl lithium or lithium amides such as methyllithium, n-butyllithium, phenyllithium, lithium diisopropylamide, pyridine, piperidine, quinoline, triethylamine, Examples include organic bases such as N,N-dimethylaniline. Any solvent can be used as long as it does not affect the reaction, but examples include alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme, and benzene. , aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as hexane, heptane and cyclohexane, amines such as pyridine, N,N-dimethylaniline, N,N-dimethylformamide, dimethylsulfoxide, hexamethyl Examples include polar solvents such as phosphoric acid triamide. The reaction temperature is usually around 100°C, preferably around 0-80°C. The reaction is completed in about 0.5 to 5 hours. The amount of compound (4) used is the same as that of compound (2).
The amount is usually 1 to 10 times, preferably 1 to 6 times, by mole.

The reaction between compound (5) and compound (6) is carried out in a suitable solvent or in the absence, preferably in a solvent and in the presence of a basic compound. Examples of the solvent used here include, for example,
Ethers such as dioxane, tetrahydrofuran, and ethylene glycol dimethyl ethers, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphorus. Examples include aprotic polar solvents such as acid triamides. As the basic compound, the compound (6) can be used in excess, but for example, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium amide, triethylamine, etc. , tripropylamine, pyridine, quinoline, and other organic bases.

The reaction is usually carried out at room temperature to 200°C, preferably room temperature to 12
The process is carried out at a temperature around 0°C and usually takes about 1 to 24 hours to complete.

The amount of compound (6) to be used is usually at least equimolar, preferably equimolar - large excess to compound (5).

[Reaction formula-3] H (IC) (1d) (1a) OR" (1f) (1e) [In the formula, RSR', B, m, X and the bond at position 3.4 of the carbostyril skeleton are as described above Same. R5 represents a lower alkanoyl group. R6 represents a lower alkoxy group.] The reaction between compound (1a) and compound (7a) or (7b) can be carried out without a solvent or in a suitable solvent in the presence of a basic compound. It is carried out in the presence or absence, preferably in the presence.

Suitable solvents for the above reaction include, for example, the aromatic hydrocarbons mentioned above, lower alcohols such as methanol, ethanol and propatool, dimethylformamide and dimethyl sulfoxide, as well as halogenated hydrocarbons such as chloroform and methylene chloride. , acetone, pyridine, etc. can be used. Examples of the basic compound include tertiary amines such as triethylamine and pyridine, sodium hydroxide, potassium hydroxide, and sodium hydride. The above reaction can also be carried out in a solvent such as acetic acid in the presence of a mineral acid such as sulfuric acid.

The usage ratio of compound (7a) or (7b) is
It is sufficient to use an equimolar amount or more, preferably about an equimolar to 10 times the molar amount of a), and the reaction is usually carried out at a temperature of about 0 to 200°C, preferably about 0 to 150°C. ~
It will be completed in about 15 hours.

The reaction of leading compound (IC) to compound (1d) is carried out by reducing compound (IC) using a catalytic reduction catalyst in a suitable solvent. Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol; hydrocarbons such as hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether; ethyl acetate; Esters such as methyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide. The catalytic reduction catalyst used is
Examples include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The catalyst is generally 0.02
It is best to use about 1 times the amount. The reaction temperature is usually -20
The temperature is preferably around 150°C, preferably around 0-100°C, the hydrogen pressure is usually 1-10 atm, and the reaction is generally completed in about 0.5-10 hours.

- The reaction between the compound of installation (1a) and the compound of general formula (8) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of inert solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether, lower alcohols such as methanol, ethanol, isopropanol, and butanol, heptane, Examples include aliphatic hydrocarbons such as hexane and cyclohexane, acetic acid, ethyl acetate, acetonitrile, dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoric acid triamide, and mixed solvents thereof. Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium, and sodium amide. , metal alcohols such as sodium methylate and sodium ethylate, alkyl and aryl lithium or lithium amides such as methyllithium, n-butyllithium, phenyllithium, lithium diisopropylamide, pyridine, dimethylaminopyridine, triethylamine, 1,
5-Diazabicyclo[4,3,O] nonene-5 (DB
N), 1,8-diazabicyclo[5,4,0]undecene7 (DBU), 1,4-diazabicyclo[2゜2
．． 2] Organic bases such as octane (DABCO), etc., or mixtures thereof of 2s or more can be mentioned. - The usage ratio of the compound of installation (1a) and the compound of general formula (8) is not particularly limited and may be appropriately selected within a wide range,
It is preferable to use the latter in at least an equimolar amount to the former, preferably in an equimolar to about 5 times the molar amount. The reaction is usually carried out at about 50 to 120°C, preferably about -40 to 100°C.
The process is carried out at a temperature of about °C and generally takes about 30 minutes to 50 hours to complete.

The reaction for converting compound (1a) into compound (1f) is carried out in a suitable solvent or in the absence of a solvent in the presence of an oxidizing agent. Examples of the oxidizing agent used include acetic anhydride-dimethyl sulfoxide, phosphorus pentoxide-dimethyl sulfoxide, dicyclohexylcarbodiimide-dimethyl sulfoxide,
Chromates such as oxalyl chloride, chromic acid, chromic acid-pyridinium salt, chromic acid-2-pyridinium salt,
Examples include manganese dioxide. Further, when oxalyl chloride is used as the oxidizing agent, it is preferable to add the same basic compound as used in compound (2) and compound (4) of Reaction Formula-2 above.

The solvents used here include the aforementioned aromatic hydrocarbons, lower alcohols, halogenated hydrocarbons, ethers, dimethyl sulfoxide, dimethylformamide,
Examples include polar solvents such as hesamethyl phosphoric triamide. The reaction is usually carried out at 0 to 150°C, preferably at room temperature to 1
It is carried out at a temperature around 00°C and is completed in about 1 to 30 hours.

The amount of the oxidizing agent to be used is usually equivalent to 20 times the amount of compound (1a), preferably equivalent to 10 times the amount.

[Reaction formula-4] H (1 g) [In the formula, R, R3, R', ASB, l! , m and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above.

However, the number of carbon atoms in the group -(B)m-CH2- shall not exceed 6. ] In the above-mentioned reduction reaction, a reduction method using a hydrogenation reducing agent is suitably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane, etc., and the amount used is at least equimolar to the raw material compound, preferably in the range of equimolar to 15 times the molar amount. be.

This reduction reaction is usually carried out using an appropriate solvent, such as water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, and diglyme, and mixed solvents thereof. It is carried out at -60 to 150°C, preferably -30 to 100°C, for about 10 minutes to 5 hours.

In addition, when lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, or the like.

[Reaction formula-5] 0H (1i) (1j) [In the formula, R, R', B, m and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] The reaction for leading compound (11) to compound (1j) can be carried out in the presence or absence of a solvent, and in the presence of an acid or a basic compound.

Examples of the solvent used here include pyridine, diacetone alcohol, uridine, dimethylformamide,
Polar solvents such as dimethyl sulfoxide, ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzenesulfonic acid, benzene, xylene, lower alkanoic anhydrides such as acetic anhydride, lower alkanoic acids such as acetic acid, methanol, ethanol, etc. Examples include lower alcohols.

Examples of acids include hydrochloric acid, sulfuric acid, hydrobromic acid, boric acid, N-bromoacetamide-sulfur dioxide, Florisil brand name, powdered magnesia (silica)-iodine, mesityl chloride-
Sulfur dioxide, methylchlorosulfide, naphthalene-β
-Sulfonic acid, oxalic acid, phosphoryl chloride, phthalic anhydride, thionyl chloride, p-toluenesulfonic acid, p
Examples include -1 luenesulfonyl chloride, phosphorus pentoxide, and potassium hydrogen sulfate.

Examples of the basic compound include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine.

The acid or basic compound is preferably used in a large equimolar excess relative to compound (11). The reaction is generally carried out at room temperature
1 to 1 at -200℃, preferably around room temperature to 150℃
It ends in about 0 hours.

[Reaction formula-6] Indicates an amino lower alkyl group that may be

R7 and R8 are the same or different and represent a hydrogen atom or a lower alkyl group. ] The reaction between compound (1k) and compound (9) is expressed by the above reaction formula -
The reaction is carried out under the same conditions as the reaction of compound (1a) and compound (8) in 3. Further, the reaction proceeds advantageously by adding an alkali metal iodide such as sodium iodide or potassium iodide.

The above starting material compound (2) can be produced, for example, according to the following reaction formula.

[In the formula, R', A, B, lSm and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. Ra represents a lower alkyl group having one halogen atom. Rb has a lower alkyl group as a substituent [Reaction formula-7(2a)] [wherein R is the same as above]. R9 represents a lower alkoxy group. ] Compound (10) and compound (11) can be reacted by a conventional amide bond forming reaction. Conditions for known amino bond forming reactions can be easily applied to the amide bond forming reaction. For example, (a) mixed acid anhydride method, i.e., a method in which carboxylic acid (11) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with amine (10), (b) active ester method, i.e. carboxylic acid (11) as p-nitrophenyl ester,
Active esters such as N-hydroxysuccinimide ester and 1-hydroxybenzotriazole ester,
A method in which amine (10) is reacted with this, (iii) carbodiimide method, that is, amine (10) is reacted with carboxylic acid (11).
(2) Another method is to convert carboxylic acid (11) into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride. A method of reacting an amine (10) with an ester of a carboxylic acid (11) and a lower alcohol under high pressure and high temperature. Examples include a method of reacting the amine (10) with a ride.

The mixed acid anhydride used in the mixed acid anhydride method (a) is obtained by the usual Schotten-Baumann reaction, and is usually reacted with the amine (10) without isolation to form the compound of general formula (12). A compound is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, Schotten-
Compounds customary for the Baumann reaction are used, for example triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,03nonene-5 (DBN), 1,8-diazabicyclo[5, 4,0) Undecene-7 (DBU),
1.4-diazabicyclo[2,2,2]octane (DA
Examples include organic bases such as BCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is usually carried out at -20 to 100°C
Preferably, the reaction is carried out at about 0 to 50°C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine (10) is usually carried out at about -20 to 150°C, preferably at about 10 to 1
The reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate, ethyl acetate, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc. or a mixed solvent such as these.

Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like.

In this method, the proportions of carboxylic acid (11), alkylhalocarboxylic acid, and amine (10) to be used are usually equal moles. ) are respectively 1 to 1.
It can be used within a range of about 5 times the molar amount.

Furthermore, among the other methods (d) above, when adopting a method of reacting the amine (10) with the carboxylic acid halide,
The reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound used, a wide variety of known ones can be used. For example, in addition to the basic compounds used in the Schotten-Baumann reaction, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. can be mentioned. Examples of solvents include, for example, in addition to the solvents used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, and pyridine. , acetone, etc. The ratio of the amine (10) to the carboxylic acid halide is not particularly limited and may be appropriately selected within a wide range, but usually the latter is smaller than the former (about equimolar amounts, preferably equimolar). -5
It is preferable to use about twice the molar amount. The reaction is usually -20~
It is carried out at about 180°C, preferably about 0 to 150°C, and is generally completed in about 5 minutes to 30 hours.

The amide bond formation reaction involves carboxylic acid (11) and amine (
10) and triphenylphosphine, diphenylphosphinyl chloride, phenyl-N phenylphosphoramide chloridate, diethyl trichlorophosphate, diethylcyanophosphonate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc. It can also be carried out by a method of reacting a phosphorus compound in the presence of a condensing agent.

The reaction is carried out in the presence of the solvent and basic compound used in the method of reacting the carboxylic acid halide with the amine (10), usually at about -20 to 150°C, preferably at 0 to 150°C.
The process is carried out at around 100°C and generally takes about 5 minutes to 30 hours to complete. The amounts of the condensing agent and the carboxylic acid (11) to be used are at least equimolar, preferably equimolar to twice the molar amount of the amine (10).

The reaction of cyclizing compound (12) to lead to compound (2a) is carried out in the presence of an acid without a solvent or in an appropriate solvent.

Examples of the acids used include organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, inorganic acids such as polyphosphoric acid, p-toluenesulfonic acid, ethanesulfonic acid, and trifluoroacetic acid.

Any solvent can be used as long as it does not adversely affect the reaction, such as water, methanol, ethanol, propatool, butanol, and 3-methoxy-1.
-Alcohols such as butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, etc., halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, Examples include ethers such as dimethoxyethane and diphenyl ether, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphate triamide, or mixed solvents thereof. . The reaction is usually -20 to 150
It is carried out at about °C, preferably about 0 to 150 °C,
Generally, it takes about 5 minutes to 30 hours to complete.

[Reaction formula-8] )(H (13) (14) (2b)
[In the formula, R is the same as above. ] In the above reaction formula, compound (13) is ring-closed to form compound (1
The reaction leading to 4) is carried out in the presence of an N,N-substituted formamide and an acid catalyst (commonly referred to as Willsmeier reagent) in a suitable solvent or in the absence of a solvent. The N,N-substituted formamide used here includes N,
Examples include N-dimethylformamide, N,N-diethylformamide, N-ethyl-N-methylformamide, and N-methylN-phenylformamide. Examples of acid catalysts include phosphorus oxychloride, thionyl chloride, and phosgene. Solvents used include chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, and 1,2-dichloroethylene, chlorobenzene, 1,
Examples include aromatic hydrocarbons such as 2-dichlorobenzene. N.

The amounts of N-substituted formamide and acid catalyst used are as follows:
3), the former is usually in large excess, preferably 2 to
The amount is preferably 5 times the molar amount, and the latter is preferably 5 to 10 times the molar amount. The reaction temperature is usually 0 to 150°C, preferably 50 to 100°C.
It is best to do this at around °C. The reaction takes about 3 to 24 hours to complete.

Moreover, the reaction to obtain compound (2b) from compound (14) is
Compound (14) can be used, for example, with hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, sodium carbonate, potassium carbonate, and carbonic acid. In the presence of an inorganic alkali compound such as potassium hydrogen, or an organic acid such as acetic acid,
At 0 to 150°C, preferably 70 to 120°C, 0.5
This is done by heating for about 24 hours.

[Reaction formula-9] [In the formula, R and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as above. RIG represents a hydrogen atom or a lower alkyl group. ] The reduction reaction of compound (15) is usually carried out using a hydrogenation reducing agent. Examples of the hydrogenation reducing agent include sodium borohydride, lithium aluminum hydride, siborane, etc., and the amount used is usually determined by the amount of the compound (15
), preferably at least equimolar to
The range is 3 times the mole. This reduction reaction is usually carried out using a suitable solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, ethyl ether and diglyme, and preferably at a temperature of about -60 to 50°C. The heating is carried out at 0° C. to room temperature for about 10 minutes to 5 hours. In addition, when lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether, tetrahydrofuran, or diglyme.

Further, the above reduction reaction is also carried out by catalytic reduction in the presence of a suitable reduction catalyst. Examples of the reduction catalyst used include ordinary catalysts for catalytic reduction such as platinum, platinum oxide, palladium black, palladium carbon, and Raney nickel, and the amount used is usually 0.2 to 0. The range is .5 times the weight. This catalytic reduction is carried out in a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl ether, etc. under a hydrogen atmosphere of 1 to 10 atm, preferably 1 to 3 atm, from -30°C to the temperature of the solvent. Boiling point temperature, preferably 0°C ~
This is done by shaking well at around room temperature.

[Reaction formula-10] (1m) (1n) [In the formula, R, R1, A, B1, l and m are the same as above] The reaction of dehydrogenating the above compound (1m) to lead to compound (1n) is , carried out in a suitable solvent and in the presence of a dehydrogenating agent. As a dehydrogenating agent, for example, 2゜3-dichloro-5,
Benzoquinones such as 6-dicyazbenzoquinone, 2,3,5,6-tetrachloropenzoquinone (-ship name Chloranil), halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide, bromine, and carbon dioxide. Examples include dehydrogenation catalysts such as selenium, palladium on carbon, palladium black, palladium oxide, and Raney nickel. The amount of the dehydrogenating agent used is not particularly limited, but in the case of a halogenating agent,
Usually, the amount is preferably 1 to 5 times, preferably 1 to 2 times the mole of the compound (1m), and in the case of a dehydrogenation catalyst, it is generally good to use an excess amount. Other dehydrogenating agents are also usually used in equimolar to excess amounts. Examples of solvents include ethers such as dioxane, tetrahydrofuran, methoxyethanol, and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, and cumene; halogenated hydrocarbons such as dichloromethane, dichloromethane, chloroform, and carbon tetrachloride; Examples include alcohols such as butanol, 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 300°C, preferably room temperature to 200°C, and is generally completed for about 1 to 40 hours.

Further, by reducing compound (1n), compound (1m) can be obtained. This reduction reaction is carried out under the usual conditions for catalytic reduction, for example, in the presence of a metal catalyst in a suitable solvent. Examples of the catalyst include metal catalysts such as palladium, palladium on carbon, platinum, and Raney nickel, which are used in normal catalytic amounts. Examples of solvents used include water, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane,
Examples include cyclohexane, ethyl acetate, and mixed solvents thereof. The reaction can be carried out either at normal pressure or under increased pressure, but usually at normal pressure to 20 kg/cm2, preferably at normal pressure to 10 kg/cm2, at 0 to 150°C, preferably at room temperature to 100°C. It will be done.

Among the compounds (1) of the present invention, compounds in which the bond between the 3rd and 4th positions of the carbostyryl skeleton is a double bond have tautomerism of the lactam lactim type, as shown by the formula below. can be taken.

[In the formula, R,, R', A, B5-5 and m are the same as above. ] Among the compounds of general formula (1), compounds in which R1 is a pyridyl group that may have a lower alkyl group are treated in the same manner as in the reaction for converting compound (1C) to compound (1d) in Reaction Formula-3 above. By catalytic reduction under these conditions, a compound in which R1 is a piperidinyl group which may have a lower alkyl group can be obtained. The reaction proceeds advantageously by adding an acid such as hydrochloric acid.

The carbostyril derivative represented by the general formula (1) of the present invention can be easily formed into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of nucleic acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid;
Organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid can be mentioned.

The carbostyryl derivative represented by the general formula (1) of the present invention can easily form a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like. Also, methyl iodide,
A quaternary salt can be formed by reacting with an alkyl halide such as ethyl chloride.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation method include solvent extraction method, dilution method, recrystallization method,
Examples include Column Chroma I and GraphE Preparative Thin Layer Chromatography.

Note that the present invention naturally also includes optical isomers.

The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. 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 representative examples include tablets, gunpowder, powder, liquid, suspension, and
Examples include emulsions, granules, capsules, skewers, injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran Sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Disintegrants such as sulfur/lium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases, and sodium lauryl sulfate;
Humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid;
Examples include purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When molding into the form of gunpowder, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose, starch,
Excipients such as cocoa butter, hydrogenated vegetable oil, kaolin, and talc,
Binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminalan agar can be used. When forming into a skewer, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood stasis, and when formed into the form of solutions, emulsions and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated instearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. Furthermore, if necessary, the pharmaceutical preparation may contain coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceuticals.

The amount of the compound of general formula (1) to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected from a wide range, but is usually 1 to 70% by weight, preferably 1 to 70% by weight based on the total composition.
The polymerization rate is 30%.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the method is determined depending on the various preparation forms, age, sex and other conditions of the patient, the severity of the disease, and the like. For example, tablets, gunpowder, liquid,
Suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid containing glucose, amino acids, etc., and if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. If it is partially opened, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the compound of general formula (1), which is the active ingredient, is 1 kg of body weight per day. It is preferable to administer about 0.1 to 10 mg per dose. It is also possible to contain two or more active ingredients in a dosage unit form.
It is preferable to contain up to 200 mg.

Examples Reference examples, working examples, pharmacological test examples, and formulation examples are listed below.

Reference Example 1 To a suspension of 2.0 g of 60% sodium hydride in 50 m2 of dimethylformamide, 1 g of trimethylsulfoxonium iodide was added little by little, and the mixture was stirred at room temperature for 30 minutes.

4.7 g of 8-methyl-3-formylcarbostyryl was added little by little, and after stirring at 10°C for 1 hour, the reaction solution was poured into 200 ml of ice water. After adding ethyl acetate to this, insoluble matter was filtered out, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 1.0 g of 8-methyl 3-oxiranylcarbostyryl. Obtained.

NMR(CDCf3)δ; 2-49 (3H, s) 2, 71 (IH, dd, J=2.5Hz.

6.0Hz) 3.22 (IH, dd, J=4.0Hz.

6.0Hz) 4.20 (IH, dd, J=2.5Hz.

4.0Hz) 7.14 (IH, t, J=7.5Hz)'l 34
(IH, d, J=7,5H, z) 7.42 (IH, d
, J=7.5Hz) 7.67 (IH, s) 9.36 (IH, brs) Reference Example 2 3.22 g of 2-(4-chlorobutyryl)aniline and 1. 71+rM2 was dissolved in 80 parts of diethyl ether, and a solution of 4.38 g of 60% 3-methoxyacrylyl chloride in 20 parts of diethyl ether was added dropwise while stirring while cooling with water. The mixture was further stirred at room temperature all day and night. Ice water was added to the reaction solution, the crystals were collected, washed with water, washed with cold ethanol, and dried to give 4.82 g of N-(3-ethoxyacrylyl)-2.
-(4chlorobutyryl)aniline was obtained.

NMR (CDCf3) δ; 1.37 (3H, t, J=7.0Hz) 2.15-2
．． 28 (2H, m) 3.25 (2H, t, J=7.0Hz) 3.71 (
2H, t, J=7.0Hz) 3.97 (2H,' q
, J=7.0Hz) 5.40 (IH, d, J=12.
0Hz) 7.09 (IH, d-t, J=1.5Hz7
．． 0Hz) 7.55 (IH, d-'t, J=1.5Hz7, QH
z)'l 67 (IH, d, J=12°0Hz)7,
94 (IH, dd, J=1.5Hz7,
0Hz) 8.83 (IH, dd, J=1.5Hz7
, 0Hz) 11, 57 (IH, brs) Reference Example 3 N-(3-ethoxyacrylyl)- to 48 g of polyphosphoric acid
Add 2-(4-chlorobutyryl)aniline and heat to 70°C.
The mixture was heated and stirred for 30 minutes. The reaction solution was poured into ice water, and the precipitated crystals were collected, washed with water, dried, and purified by silica gel column chromatography (eluent: chloroform:ethyl acetate-3=2). propyl)
2.29 g of -3-formylcarbostyril was obtained.

NMR (CDCJ3) δ; 2, 03 ~ 2.22 (2H, m) 3.51 (2H, t, J = 7.0Hz) 3.78 (
2H, t, J=7.0Hz) 7, 28~7.48
(2H, m)7.65 (IH, t, J=7.
5Hz) 8, 02 (LH, d, J=7.5
Hz) 10, 03 (LH, 5) 12, 07 (IH, brs) Example 1 15% n was added to a solution of 10 g of 2-bromopyridine in 50 g of diethyl ether under cooling and stirring at -30 to -20°C. −
Butyllithium n-hexane solution 41 times was added dropwise. After stirring at the same temperature for 30 minutes, the solution was cooled at -30°C while stirring, 8-methyl-3-formylcarbostyryl 4.0
The mixture was added dropwise to a suspension of 50 g of tetrahydrofuran. After stirring at the same temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Add dichloromethane to the resulting residue to remove insoluble matter. After going door to door, I washed it with water. The residue obtained by drying over magnesium sulfate and concentrating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: dichloromethane:methanol-20=1).

Recrystallization from ethanol-water gave 2.1 g of 8-methyl-3-[1-hydroxy-1-(2-pyridyl)methyl]carbostyryl hydrochloride.

mp 250-270°C (decomposition) Pale brown powder NMR (DMSO-d6) δ; 2,43 (3H,s) 6.11 (IH,s) 7.16 (IH,t, J=6.8Hz )7.39 (
LH, d, J = 6.8Hz) 7.64 (IH, d, J
= 6.8Hz) 7.94 (2H, m) 8.20 (IH, s) 8.42 (IH, t, J = 7.6Hz) 8.79 (
IH, d, J = 6.0 Hz) 11.09 (IH, s) Example 2 A few drops of dibromobutane were added to a suspension of 0.76 g of metallic magnesium in 1 g of tetrahydrofuran, and 3. 8 g of tetrahydrofuran 10111i2 solution was added dropwise. After further stirring at room temperature for 30 minutes, this solution was added dropwise to a suspension of 2.0 g of 8-methyl-3-formylcarbostyryl in tetrahydrofuran while stirring and cooling with water. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is used as fumarate,
Recrystallized from ethanol-water to give 1.6 g of 8-methyl-
3-(1-hydroxy-4-dimethylaminobutyl)carbostyryl fumarate was obtained.

mp 205-207°C Colorless needles Example 3 15% n-butyllithium n was added to a 10% solution of diisopropylamine in tetrahydrofuran at 10°C or below.
- Add 15 drops of hexane solution.

After stirring for 30 minutes under water cooling, this was cooled to -50 to -60°C, and dimethylacetamide 2nd grade was added dropwise. After stirring at the same temperature for 1 hour, this solution was added dropwise to a suspension of 1.8 g of 8-methyl-3-formylcarbostyryl in 10 geese of tetrahydrofuran while cooling and stirring at -50°C, and the temperature was gradually raised to room temperature. The mixture was stirred for 2 hours while stirring. Pour the reaction solution into ice water.
The mixture was poured into ethyl acetate to remove insoluble matter. The insoluble matter was further washed with ethyl acetate, combined with the above-mentioned furnace solution, and dried over magnesium sulfate. Concentrate the solvent under reduced pressure to obtain 1.24g
8-methyl-3-(1-hydroxy-2-dimethylaminocarbonylethyl)carbostyryl was obtained.

NMR (DMSO-ds) δ; 2.48 (3H, s) 2.40-2. 60 (IH, m)2.82 (
IH, dci, J=2.5Hz15, 0Hz) 2.69 (3H,s) 3, 04 (3H,s) 5, 14 (2H,d, J=7,0Hz) 5.41
(LH, brs) 7.14 (IH, t, J=7.5Hz) 7.36
(IH, d, J=7.5Hz) 7-59 (IH
, d, J=7.5Hz) 7, 99 (LH, 5
) ICL 98 (IH, brs) Examples 4 to 34 In Table 2 below, the number written in front of each group indicates the substitution position of that group.

The following compounds were obtained in the same manner as in Examples 1 to 3 using appropriate starting materials.

6 1) NMR (CDCf3) δ; (Furi-integrated NM
R) 3.16 (IH, dd, J=8.38Hz.

J=14.8Hz) 3.52 (LH, J = 3.04Hz.

J=14.8Hz) 3.91 (3H,s) 3.94 (3H,s) 5.35 (IH,m) 6.21 (IH,s) 6.78 (IH,s) 6.94 ( IH, s) 7.20 (2H, dd, J=7~8HzJ=1~2
Hz) 7.59 (LH, dt, J=1~2HzJ=7~3
Hz) 7.87 (IH, s) 8, 54 (IH, m) 11, 36 (LH, s) 2) NMR (DMSO-ds) δ; 1, 26
(6H, t, J=6.5Hz) 1.80~2
．． 18 (2H, m)2, 92-3. 52
(9H, m)3, 57-3.80 (IH, m)5
．． 49-5. 56 (IH, m)7, 29 (
IH,t, J=7. 0Hz) 7.42 (IH
, d, J=7. 0Hz) 7, 56 (IH,
t, J='7.0Hz)7.89~8. 12
(3H, m)8, 5:3 (IH,t, J=7
．． 0Hz) 8.84 (IH, d, J=5°
0Hz) 10, 50 (LH, brs) 12, 10 (LH, brs) 3) NMR (DMSO-ds) δ; 1, 35
(9H, s) 1, 81-2. 17 (2H, m)2, 89-
3.44 (6H, m)3. 52-3. 90
(IH, m)5, 30-5. 71 (IH, m)
7, 30 (IH, t, J=7.5Hz)7.
41 (LH, d, J=7.5Hz)7, 5
9 (IH, t, J=7.5Hz)7, 73
~8. 29 (3H, m)8, 39-8. 51
(IH, m) 8, 55-8. 99 (2H,
m, ) 12, 12 (IH, brs) 4) NMR (DMSO-ds) δ; 2.4B
(3H2s) 6, 11 (IH,s) 7, 16 (IH,t, J=6.8Hz)7.
39 (IH, d, J=6.8Hz)7.64
(LH, d, J=6.8Hz)7, 91 (
2H, m) 8, 20 (IH, s) 8.42 (IH, t, J=7° 6Hz)8.
79 (IH, d, J=6.0Hz) 11.09
(IH,s) 5) NMR (DMSO-ds)6;2.47 (
3H, s) 3.25 (LH, dd, Ja=8.4J b=
15Hz) 3.68 (IH, dd, J-3,0Hz.

J-15Hz) 4.48 (3H, s) 5, 10-5. 20 (IH, m)5.90
(IH, d, J ~3~4Hz) 7, 16 (IH
,t, J=6Hz)7, 39 (LH,d,
J=6Hz)7, 62 (IH,d, J=6
Hz) 7, 90-8. 10 (3H, m)8,
52 (IH, t, J=6Hz)9.02 (
IH, d, J=6Hz) 11, 15 (IH,
s) 6) NMR (CDCI!, a) δ; (Free NMR) 1, 11 (9H, s) 2, 46 (3H, s) 2, 68 (IH, dd, J=8.4Hz.

J=15Hz) 3-16 (IH, dd, J=3Hz.

J=15Hz) 4, 83 (IH, m) 7, 13 (IH, t, J=7.6Hz) 7,
31 (IH, d, J=7.6Hz)7.4
7 (IH, d, J=7.6Hz) 7, 94
(IH, s) 7) NMR (CDCJa) δ;
MR) 2, 31 (3H,s) 2, 30-2. 65 (9H, m)2, 7C1
-3,0 (IH, broad s ) 3.01 (L
H, dd, J=3Hz.

J=15Hz) 4, 24 (IH, s) 5.01 (LH, dd, J-3Hz.

J=8Hz) 7, 12 (IH, t, J=7.6Hz)7.
31 (IH, d, J=7.6Hz) 7.45 (
IH, d, J=7.6Hz) 8.01 (IH,
s) 9.62 (1'H, s) 8) NMR (DMS O-d6); δ2.48 (
3H, s) 2.40-2.60 (LH, m) 2.82 (IH, dd, J=2.5Hz.

J=15. 0Hz) 2, 69 (3H, s) 3, 04 (3H, s) 5.14 (2H, d, J=7.0Hz) 5.41
(IH, brs) 7.14 (IH, t, J=7.5Hz) 7.36
(IH, d, J=7.5Hz) 7.59 (LH,
d, J=7.5Hz) 7.99 (IH, 5) 10.98 (LH, brs) 9) NMR (CDCJ3) δ; 1.80-2°29 (2H, m) 2.79-3. 11 (2H, m) 3.39 (IH, dd, J=6.0Hz.

J-13゜5Hz) 52~3.79 (3H, m) 5.36~5.60 (IH, m) 5.97 (IH, d, J=10.0Hz) 6.97-
7.38 (3H, m) 7.39-7.67 (3H, m) Otsu 79 (IH, d, J=8.0Hz) 8, 56
(IH, d, J=4.0Hz) 12, 8
(IH, brs) Example 35 4.0 g of 8-methyl-3-[1-hydroxy-2-(2-pyridyl)ethyl]carbostyryl in 40 m of dichloromethane! Add methyl iodide 5w2 to the solution and add 90% methyl iodide in a sealed tube.
The mixture was heated and stirred at ~100°C for 5 hours. After the reaction was completed, the precipitated crystals were collected, washed with dichloromethane, and dried. Recrystallize from ethanol and water to obtain 4.7 g of 2-
[2-Hydroxy-2-(8-methylcarbostyryl-
3-yl)ethyl]-1-methylpyridinium iodide was obtained.

mp　265-275°C (decomposition) yellow prismatic NMR (DMSO-66)δ 2.47 (3H, s) 3, 25 (IH, dd, J = 8.4Hz.

J=15Hz) 3, 68 (IH, dd, J-3,0Hz.

J=15Hz) 4.48 (3H, s) 5, 10~5.20 (LH, m') 5.90
(IH, d, J=3~4Hz)7, 16 (I
H, t, J=6Hz) 7.39 (IH, d,
J=6Hz)7, 62 (IH,d, J=6
Hz) 7, 90-8. 10 (3H, m)8,
52 (IH, t, J=6Hz)9.02 (
IH, d, J = 6Hz) 11, 15 (IH, s
) Example 36 8-methyl-3-oxiranylcarbostyryl 0.50
The solution was dissolved in 20 g of acetonitrile, 5 g of butylamine was added thereto, and the mixture was heated under reflux for 8 hours.

Water was added to the reaction solution, and the mixture was extracted with dichloromethane.

After washing with water and drying magnesium sulfate, the solvent was concentrated under reduced pressure. Dichloromethane-diethyl ether was added to the resulting residue, and the precipitated crystals were collected, washed with dichloromethane-diethyl ether, and dried.

After converting it into a hydrochloride, it was recrystallized from ethanol-diethyl ether to obtain 0.20 g of 8-methyl-(1-hydroxy-2-t-butylaminoethyl)carbostyryl hydrochloride.

mp 255-262°C (decomposition) White powder Preparation of Examples 18, 21 and 22 in the same manner as Example 36
The compound was obtained.

Example 37 1.25 g of 8-methyl-3(1-hydroxy-2-dimethylaminocarbonylethyl)carbostyryl was added to a suspension of 0.30 g of lithium aluminum hydride in 20 yoke of tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. Under water cooling,
Saturated sodium sulfate was added to the reaction solution, and after stirring at room temperature for 1 hour, it was filtered through Hyfloth-Parcel, and the precipitate was washed with tetrahydrofuran and dried over magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was converted into a fumarate salt, which was recrystallized from ethanol-water to give 0.26 g.
8-methyl-3-(1-hydroxy-3-dimethylaminopropyl)carbostyryl 1/2 fumarate was obtained.

mp 212-214°C Pale yellow powder Compounds of Examples 18, 20 and 21 were obtained in the same manner as in Example 37 using appropriate starting materials.

Example 38 0.5 g of 8-methyl-3-[1-hydroxy-2-(2pyridyl)ethyl]carbostyryl was dissolved in pyridine, 0°84Tnf2 of acetic anhydride was added, and the mixture was heated and stirred at 70°C for 1 hour. . Pour the reaction solution into ice water and fold the folded crystals into
One portion was taken, washed with water, and dried.

The oxalate was recrystallized from ethanol-n-hexane to obtain 0.427 g of 8-methyl-3-[1acetyloxy-2-(2-pyridyl)ethyl]carbostyryl oxalate.

mp 137-141°C (decomposition) yellow powder NMR (DMSO-ds); δ 2.02 (3H, s) 2.45 (3H, s) 3.19 (IH, dd, J=8.5Hz.

J=14.0Hz) 3.44 (IH, dd, J=4.0Hz.

J=14-0Hz) 6.32 (IH, dd, J=4.0Hz.

J=8.5Hz) 7.12 (LH, t, J=7.5Hz)7.20~7
．． 42 (3H, m) 7.55 (LH, d, J=7.5Hz) 7, 75
(IH, t, J=7.5Hz) 7, 84
(IH, s) 8, 51 (LH, d, J=4.0Hz) 1
1, 10 (IH, brs) Three Examples 8-
Methyl-3-[1-acetyloxy2-(2-pyridyl)ethyl]carbostyryl oxalate 0.63. g was added thereto, and hydrogenation was carried out at 50°C under a hydrogen pressure of 1 atm. After the catalyst was separated from the furnace, the seven door liquid was concentrated under reduced pressure. The resulting residue was converted into a hydrochloride and recrystallized from ethanol diethyl ether to give 8-
0.38 g of methyl:3-[:2-(2-pyridyl)ethyl]carbostyryl hydrochloride was obtained.

mp 205-209°C (decomposition) Free integral NMR (CDCf3) of colorless acicular compound (CDCf3); δ 2.49 (3H, s) 3.05-3.30 (4H, m) 7.05-7 .40 (5H, m) 7.60 (2H, m) 8.56 (IH, d, J='6~7Hz) 9.73
(LH, brs) Example 40 0.143 g of 60% sodium hydride was suspended in 25 yoke of tetrahydrofuran, and 8-
1.0 g of methyl-3-[1-hydroxy 2-(2-pyridyl)ethylcocarbostyryl was added, and the mixture was stirred at room temperature for 30 minutes. This was cooled to -40°C and 1.54Mn-
Butyllithium n-hexane solution 2. After dropping 32n of methyl iodide and stirring at the same temperature for 30 minutes,
8 g of tetrahydrofuran solution was added dropwise, the temperature was gradually raised, and the mixture was stirred at o'c for 48 hours. A saturated aqueous ammonium chloride solution was added, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: carbon tetrachloride diacetonitrile-5=1). The fumarate was recrystallized from ethanol-n-hexane to obtain 0.505 g of 8methyl-3-[1-methoxy-2-(2-pyridyl)ethyl]carbostyryl fumarate.

mp 182-184°C (decomposition) Colorless needle Example 41 Dissolve 1.0 g of 8-methyl-3-[1-hydroxy-2-(2pyridyl)ethyl]carbostyryl in 5 fibers of dimethyl sulfoxide, and dissolve 2 acetic anhydride. Add it dropwise and let it stand for 20 minutes at room temperature.
Stir for hours. The reaction solution was poured into ice water, and the precipitated crystals were collected, washed with water, and dried. This was made into a hydrochloride salt, recrystallized from ethanol, and 0.35 g of 8-methyl-3-[2'
-(2pyridyl)acetyl]carbostyryl hydrochloride was obtained.

mp 260-263°C (decomposition) Yellow powder Example 42 0.4 g of 8-methyl-3-[1-hydroxy 2-(5
-methoxy-2-pyridyl)ethyl]carbostyryl and 49% hydrobromic acid 5m! ] A heating reaction was carried out at 00°C for 3 hours. After cooling the reaction solution, the precipitate was collected and recrystallized from methanol to give 0.3 g of 8-methyl-3-[2-
(5-methoxy-2-pyridyl)-1-vinyl]carbostyryl was obtained.

mp 215-223°C Yellow prismatic NMR (CDCJ:a): δ 2.48 (3H, s) 3.88 (3H, s) 7.10-7.50 (5H, m) 7, 74 (2H , ABq, J=20Hz)7
, 92 (IH, s) 8, 32 (LH, d, J=2~3Hz) 9,
05 (IH,s) Example 43 0.1 g of platinum oxide was suspended in 70 m2 of methanol, and 8-
Methyl-3-[1-hydroxy-2-(2-pyridyl)
ethyl]carbostyril 1.0g and concentrated hydrochloric acid 0. 59
m! was added, and catalytic reduction was carried out at 50°C and 4 atmospheres of hydrogen pressure.

After hydrogen absorption had stopped, the catalyst was filtered, and the furnace liquid was concentrated to dryness under reduced pressure. Water was added to the residue, the pH was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After distilling off the solvent,
The residue was subjected to silica gel column chromatography (eluent;
Methylene chloride: methanol - 10 = 1 → methylene chloride:
Methanol:ammonia-10:1:0.1). This was converted into a hydrochloride, recrystallized from ethanol-diethyl ether, and 8methyl-3-[1-hydroxy-2-(2-piperidinyl)ethyl]carbostyryl.
0.32 g of hydrochloride was obtained.

mp 256.0-256.5°C (decomposition) White powder Example 44 Platinum oxide 0. ], g was suspended in 100 fibers of methanol, 2
'-[2-(8-methylcarbostyryl-3yl)-2
-Hydroxyethylio1-methylpyridinium iodide (1.0 g) was added, and catalytic reduction was carried out at 50°C and 4 atmospheres of hydrogen pressure. After hydrogen absorption had stopped, the catalyst was filtered, and the furnace liquid was concentrated to dryness under reduced pressure. Water was added to the residue, the pH was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After distilling off the solvent, it was converted into a hydrochloride salt and recrystallized from ethanol diethyl ether to give 0.34 g of 8-methyl-3-
[2-(1-methyl-2-piperidinyl)-1,-hydroxyethyl]carbostyryl hydrochloride was obtained.

mp 254.5-255°C (decomposition) White powder Example 45 Dissolve 1.0 g of 4-(3-chloropropyl)-3-[1-hydroxy-2-(pyridyl)ethyl]carbostyryl in acetonitrile 20T119. , 0.60 g of diethylamine, 0.44 g of sodium iodide and 0.44 g of potassium carbonate were added.

The mixture was heated under reflux for 10 hours. The reaction solution was concentrated under reduced pressure, water was added, and extraction was performed with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent; methylene chloride:methanol-20=1-methylene chloride:methanol:ammonia-10:1:0.1). As hydrochloride,
Recrystallized from ethanol-diethyl ether to give 0.7
6 g of 4-(3-diethylaminopropyl)-3[1-
Hydroxy-2-(2-pyridyl)ethyl]carbostyryl dihydrochloride was obtained.

mp 1.44-148°C (decomposed) Pale yellow powder Compounds of Examples 14 and 15 were obtained in the same manner as in Example 45 using appropriate starting materials.

Pharmacology test examples and effort [C1rc, Res, Vol. 48, No. 51
0518 (1980)] used for canine ventricular myocardium.

That is, a cat (weight 1.5-5 kg) was administered ketamine 30 μ/
kg intramuscular injection and bendoparbital 20 mg/kg
After being anesthetized by intraperitoneal administration of
5.9 mmol, glucose 5.5 mmol, MgCl
21.0 mmol, NaH2PO40.42 mmol,
KCffi 2.7 mmol and CaCl 21.8 mmol]. The papillary muscle of the right ventricle was removed according to a conventional method and suspended in a Magnus device filled with Tyrode's solution. The Tyrode solution was aerated with a gas mixture of 95% oxygen and 5% carbon dioxide and maintained at a temperature of 37°C.

The rest tension was adjusted to 0.5 kg. The specimen was stabilized for approximately 30 minutes while applying electrical stimulation at a frequency of 0.5 Hz. Stimulation was stopped and Tyrode's solution was replaced with free Tyrode's solution. After 30 minutes, it was replaced with K- and Ca-free Tyrode's solution, and after another 30 minutes, it was replaced with K-free and Ca-free Tyrode's solution.
3.6 mmol) of Tyrode's solution. After 1.0 minutes, train stimulation was applied 10 times at a stimulation interval of 320 m5ec every 5 minutes, and after-contraction was observed after the stimulation stopped in about half of the cases. After the electrical stimulation-induced contractions and after-contractions became constant, the test compound was administered cumulatively at 20-minute intervals, and the 10th contraction (indicated as "LCx" in Table 2) and the 1st after-contraction (the second The effect on rA-1''J in the table was investigated.

The following compounds were used as test compounds. The results obtained are shown in Table 2.

Test compound> 1.8-Methyl-3-[1-hydroxy-2(2-pyridyl)ethyl]carbostyril Table 2 5 mg Formulation example 1 3-[2-(2-pyridyl)-1 hydroxyethyl] -8-Methylcarbostyryl starch Magnesium stearate Lactose 32 mg 8 mg 5 mg Total 200 mg Tablets of the above composition in one tablet were manufactured by a conventional method.

Formulation example 2 3-[2-(2-pyridyl)-1500mg hydroxyethyl]-8-methylcarbostyryl polyethylene glycol 0.3g (molecular weight:
4000) Sodium chloride 0.9g Polyoxyethylene sorbitan 0.4g Sodium metabisulfite 0.1g Methyl-paraben 0. 18g Propyl-paraben 0.02g Distilled water for injection
100% addition of the above parabens, sodium metabisulfite and thorium chloride at 80°C with stirring.
Dissolved in distilled water. The resulting solution was cooled to 40°C and the compound of the invention, followed by polyethylene glycol and oxyethylene sorbitan monooleate, were dissolved into the solution. Next, add distilled water for injection to the solution to make it to the final volume, and sterilize it using a suitable filter paper. The mixture was sterilized by filtration and dispensed into ampoules one by one to prepare an injection.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a hydrogen atom, lower alkyl group, lower alkoxy group, group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^3^
a and R^3^b are the same or different and represent a hydrogen atom or a lower alkyl group. Further, R^3^a and R^3^b may form a 5- to 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom, together with the nitrogen atom to which they are bonded. ) or a halogen atom-substituted lower alkyl group. A is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^2 is a hydroxyl group,
Indicates a lower alkoxy group or a lower alkanoyloxy group. ), the group -CH=CH-, or the group ▲Mathematical formulas, chemical formulas, tables, etc. are available▼. O represents 1 or 2. B represents a lower alkylene group. R^1 is a pyridyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and an amino group that may have a lower alkyl group as a substituent; Piperidinyl group, pyrazyl group, or group that may have a lower alkyl group as a substituent ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R^3 and R^4
are the same or different and represent a hydrogen atom or a lower alkyl group. Further, R^3 and R^4 may form a 5- to 6-membered saturated heterocycle together with the nitrogen atom to which they are bonded, with or without a nitrogen or oxygen atom. The heterocycle may be substituted with a lower alkyl group as a substituent. ) is shown. l, m and n
indicates 0 or 1, respectively. However, l+m must not be 0. Furthermore, when A indicates ▲There are mathematical formulas, chemical formulas, tables, etc.▼, m is 1
shall be shown. The bonds at the 3rd and 4th positions of the carbostyryl skeleton represent a single bond or a double bond. ] A carbostyryl derivative represented by these and its salt.