JPS6248679A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is alkynyl; R is 5-mem bered heterocyclic ring having 1-3 hetero atoms (N, S or O), indolizinyl, imidazo[2,1-a]pyrimidinyl, oxazolonilydene, indolylcarbonyl, etc.] and a salt thereof. EXAMPLE:6-(Thiazol-4-yl)-3,4-dihydrocarbostyril. USE:With positive inotropic action and increasing action on arterial blood stream and useful as a cardiotonic agent for treating cardiopathy, e.g. congestive cardi ac insufficiency, without causing increase in heart rate and further as hypoten sive agent, antimicrobial agent and inhibitor for blood platelet agglutination. PREPARATION:For example, a compound expressed by formula II (X1 is halo gen; R<2> is H or alkyl) is reacted with a compound expressed by formula III (R<3> is alkyl, amino, phenyl or H; Z is S or NH) in a suitable solvent to afford the corresponding compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel carbostyril derivatives and salts thereof.

Disclosure of the Invention The carbostyril M conductor of the present invention is a novel compound disclosed at the end of the literature, and is represented by the following general formula (1).

R1 [wherein R1 is a hydrogen atom or a lower alkynyl group, R has 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, and has a hydroxyl group, an amino group,
a saturated or unsaturated 5-membered hetero ring which may have 1 to 2 substituents selected from the group consisting of a lower alkyl group, an oxo group and a phenyl group, an intridinyl group;
Imidazo[2,1-a]pyrimidinyl group, pyrimidinyl group, imidazo[2,1-b]thiazolidyl, oxalonylidene group which may have a lower alkyl group or oxo group as a substituent on the oxacylone ring, indolyl group represents an indolylcarbonyl group which may have a lower alkyl group as a substituent, or a piperidinyl group which may have an oxo group as a substituent on the piperidinyl base, respectively. ] The compound of the present invention represented by the above general formula (1) has the effect of increasing myocardial contraction (positive degree horn effect)
It has the effect of increasing coronary blood flow and is useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. In particular, the compounds of the present invention are characterized in that they have a strong positive inotropic effect and do not increase heart rate, or the degree of increase is small. Furthermore, the compound of the present invention has a hypotensive effect and is useful as an antihypertensive agent. In general, the compounds of the present invention are characterized in that the above-mentioned pharmacological action lasts for a long time and toxicity is extremely low. In addition, the compounds of the present invention have antibacterial effects and platelet aggregation inhibitory effects, and are useful as antibacterial agents and platelet aggregation inhibitors.

More specifically, each group shown in the above general formula (1) is 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.

a substituent having 1 to 3 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms, and selected from the group consisting of water 11, an amino group, a lower alkyl group, an oxo group, and a phenyl group on the heterocycle; Examples of the saturated or unsaturated 5-negative ring hezorocyclic group which may have 1 to 2 groups include 4-thiazolyl, 2-hydroxy-4-deazolyl, 5-hydroxy-4-deazolyl, 5-deazolyl, 2-deazolyl, 2-amino-4-deazolyl, 2-amino-5-thiazolyl, 2-methyl-4-thiazolyl, 5-ethyl-
4-deazolyl, 4-n-butyl-5-thiazolyl, 4
-hexyl-5-thiazolyl, 3,5-dimethyl-1-
Pyrazolyl, 1-pyrazolyl, 3-methyl-5-71xo-1-pyrazolyl, 3-methyl-5-amino-1-pyrazolyl, 3-amino-5-oxo-1-pyrazolyl,
3-amino-1-pyrazolyl, 3-n-butyl-1-pyrazolyl, 5-hexyl-1-pyrazolyl, 4-imidazolyl, 1-imidazolyl, 5-imidazolyl, 2-phenyl-1-imidazolyl, 2-imidazolyl Rinon-1-
Il, 1. '2.3-thiadiazol-4-yl,5-
Methyl-1,2,3-thiadiazol-4-yl, 4-
Ethyl-1,2,3-thiadiazol-5-yl,]-
Pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, 2-okine-1-gorolidinyl, 2,5-diA'xo-1-pyrrolidinyl, 4-hydroxy-3-pyrrolidinyl, 3-human 11 Ki-2-
pyrrolidinyl, 5(4H)-oxacillon-5-yl,
5(2H)-oxazolon-2-yl, 5-oxasilyl, 2-oxasilyl, 4-A kylyzolyl, 2-methyl-5-oxazolyl, 2-methyl-5(4H)-oxasilon-2-yl, 2 -n-Butyru-5(4H)-oxacillon-2-yl, 2-oxasilinon-1-yl, 4-'')-hexyl-2-okylyzolinon-1-yl, 2,2-dimethyl-3-oxo -tetrahydrofuran-5-yl, 4-propyl-3-oxo-tetrahydrofuran-5-yl, 2,5-dihydrofuran-3-yl, 2-oxo-2,5-dihydrofuran-3-yl, etc. having 1 to 2 groups selected from the group consisting of a hydroxyl group, an amino group, a linear or branched alkyl group having 1 to 6 carbon atoms, an oxo group, and a phenyl group as substituents on the terror ring; a saturated or unsaturated 5-carbon compound having 1 to 3 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms;
Examples include membered heterocyclic groups.

The oxasilinone group that must have a lower alkyl group or oxo group as a substituent on the Δxazolone ring includes:
2-Methyl-5(4H)-oxacylon-4-ylidene, 2-edyl-5(4-1)-A-kylyzolone-4-ylidene, 2-n-butyl 5(4H)-oxacylon-4
1 carbon number on the oxacylon ring such as
5-(4H) substituted with ~6 linear or branched alkyl groups
)-Oxazolonylidene In can be exemplified.

Examples of the indolylcarbonyl group which may have a lower alkyl group as a substituent on the indolyl group include 3-methyl-2-indolylcarbonyl, 4-ethyl-2-indolylcarbonyl pentyl-6-indolylcarbonyl , 6-t-butyl-2-indolylcarbonylpropyl-4-indolylcarbonyl, 3-n-hexyl-7-indolylcarbonyldolylcarbonyl, 5-indolylcarbonyl group, etc., having 1 carbon number as a substituent on the indolyl group. Examples include an indolyl group which may have 6 to 6 linear or branched alkyl groups.

Examples of piperidinyl groups that may have an oxo group as an @ substituent include 1-piperidinyl, 2-piperidinyl
Examples include -oxo-1-piperidinyl, 4-oxo-1-piperidinyl, 3-oxo-1-piperidinyl groups, and the like.

Lower alkynyl groups include ethynyl, propynyl, 2
Examples include straight chain or branched alkynyl groups having 2 to 6 carbon atoms such as -butynyl, 3-butynyl, 2-pentynyl, 2-hexynyl, and 1-butynyl.

Examples of lower alkylidene groups include medilene, ethylidene,
Examples include straight chain or branched alkylidene groups having 1 to 6 carbon atoms such as isopropylidene, pentylidene, hexylidene, and propylidene groups.

The compound of the present invention can be synthesized by various methods, and can be produced, for example, by the methods shown in the following reaction schemes.

[Reaction scheme-1] I in 3 [In the formula, R1 is the same as above. ×1 indicates a halogen atom.

R2 represents a hydrogen atom or a lower alkyl group. R3 represents a lower alkyl group, an amino group, a phenyl group or a hydrogen atom. Z represents a sulfur atom or a group=NH. ] The reaction between the compound of general formula (2) and the compound of general formula (3) can be carried out in an appropriate solvent in the presence or absence of a basic compound. Any solvent can be used as long as it does not affect the reaction, such as alcohols such as ethanol, methanol, and isopropanol, and halogenated solvents such as chloroform, dichloromethane, and carbon tetrachloride. Hydrocarbons, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as dioxene, diethylene glycol dimethyl ether, diethyl ether, and tetrahydrofuran, and polar solvents such as dimethylsulfur small oxide and hexamethylphosphoric acid 1-lyamide. I can give an example.

The basic compounds used include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium methoxide, sodium oxide, sodium hydride, sodium metal, Examples include inorganic bases such as metallic potassium and sodium amide, and organic bases such as N,N-dimebuaniline, piperidine, pyridine, triebutylamine, sodium to lithium acetate, and potassium acetate.

- Use of the compound of general formula (3) ω is at least equimolar, preferably equimolar - with respect to the compound of general formula (2).
Should it be 3 times the mole ■? The reaction is usually carried out at room temperature to 15
The process is completed in about 1 to 5 hours at 0°C, preferably around 100'C.

[Reaction Scheme-21 IR1 (1b) [In the formula, X, R' and R2 are the same as above. M indicates total alkali concentration (for example, lithium, potassium, etc.). ] The reaction between the compound of general formula (2) and the compound of general formula (4>) can be carried out under the same conditions as the reaction between the compound of general formula (2) and the compound of general formula (3). .

The reduction reaction of the compound of general formula (5) can be carried out in an appropriate solvent in the presence of an acid. Examples of acids used here include wA acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid. Examples of the solvent used include water, alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents thereof. The reaction is usually carried out at palm temperature to 150'C.
1 Preferably at room temperature to 100'C (1 to 7
It will finish in about an hour.

[Reaction Scheme-3] ■ R1 (2a) (IC) In the U formula, R1 and Xl are the same as above, R4 and R5 are the same -
The reaction between the compound of general formula (2a) and the compound of general formula (6) can be carried out in an appropriate solvent in the presence or absence of a base oil compound. It can be implemented. Any solvent can be used here as long as it does not affect the reaction, but examples include alcohols such as methanol, ethanol, and isopropanol, and alcohols such as benzene, toluene, and xylene. Group hydrocarbons, halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride, geo:
1: Ethers such as Zan, Te1-rahydrofuran, diethyl glycol dimethyl ether, diethyl ether, dimethylformamide, dimethyl sulfoquinite,
Examples include polar solvents such as hequinamedyl phosphate triamide. Further, as the basic compound to be used, any of the basic compounds exemplified in the reaction scheme-1 above can be used. The amount of the compound of general formula (6) to be used is at least equimolar, preferably equimolar to twice the molar amount of the compound of lid formula (2a). The reaction is usually carried out at room temperature to 250°C, preferably about 50 to 200°C.
It took about 10 hours.

[Reaction scheme-4] 1ze1-R' (2a)
(ld) [wherein R1 and x1 are the same as above. R6 does not represent a group. Y is a group -C1-1- or -N
- indicates. In the case of ``W'' and ``N'', ``W'' indicates the base. ] The reaction between the compound of general formula (2a) and the compound of general formula (7) can be carried out in a suitable solvent or in the absence of a basic compound in the presence or absence of a basic compound. As the solvent used here, in addition to the solvents exemplified in Reaction Scheme-3 above, water, mixed solvents thereof, etc. can be used.

As the basic compound, any of the compounds exemplified in Reaction Scheme-1 above can be used. The amount of the compound of general formula (7) to be used is usually equimolar to excess, preferably equimolar to 15 to 8 mol, relative to the compound of general formula (2a).The reaction The reaction is usually completed in about 1 to 15 hours at room temperature to 150°C, preferably around room temperature to 100'C.In the reaction shown in the above reaction scheme-4, the reaction proceeds through the following compound as an intermediate. There is a mouth to do so.

[In the formula ([1 is the same as above. R61 is a group XO [Reaction scheme-51 (1o) (le) [In the formula, R1 is the same as above. R7 represents a hydrogen atom or a lower alkyl group. 1 General formula The reaction between the compound (8) and the compound of general formula (9) can be carried out in a suitable solvent in the presence of an acid or a basic compound.

Examples of solvents used include water, alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and the like. Examples include aprotic polar solvents.

Examples of acids that can be used include mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride; Examples of the basic compound used include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and thorium hydrogen carbonate, and organic bases such as sodium acetate. The amount of the compound of general formula (9) to be used is:
The amount is preferably at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (8). The amount of the acid or basic compound to be used is at least equimolar, preferably equimolar to 5 times the molar amount of the compound of general formula (8). The reaction is usually completed in about 1 to 15 hours at an air temperature to 150'C, preferably around 100'C.

The reaction between the compound of general formula (10) and thionyl chloride (11) can be carried out without a solvent or in the presence of a solvent. As the solvent used here, the reaction scheme -
Any of the d-mediums exemplified in 3) can be used. The use of thionyl chloride (4) is preferably carried out in an amount that is normally 5 times to 20 times the molar excess of the compound of general formula (10). The reaction is usually carried out at O to 100'C, preferably O
It will take about 1 to 10 hours at ~50'C.

[Reaction Scheme-6] R2R2S RI R1 [wherein R1, R2 and M are the same as above. ] The reaction between the compound of general formula (11) and the compound of general formula (12) can be carried out in a suitable solvent. Examples of the solvent used here include water, alcohols such as methanol, ethanol, and isopropanol, and mixed solvents thereof. The reaction is usually carried out at 0 to 100°C, preferably at room temperature to 70'
It will be completed in about 1 to 5 hours near C.

The cyclization reaction of the compound of general formula (13) can be carried out according to a conventionally known cyclization reaction, such as a cyclization method using an acidic substance such as hydrochloric acid, fiA acid, or polyphosphoric acid.

The amount of the acidic substance to be used is preferably an equimolar excess of 5, preferably 10 to 30 times the amount of the compound of general formula (13). The cyclization reaction is usually carried out at air temperature to 150°C.
It completes in about 0.5 to 6 hours.

[Reaction Scheme-7] 8 R9 B I R3-(Ig
) [In the formula, X1 and R1 are the same as above. R8 and R9 are the same.
or differently represents a hydrogen atom, a phenyl group or a lower alkyl group. ×2 represents a group N H or an oxygen atom. ] The reaction between the compound of general formula (22) and the compound of general formula (35) can be carried out in a suitable solvent in the presence of a basic compound. As the solvent used here, any of the solvents exemplified in Reaction Scheme-3 above can be used. As the basic compound used, the reaction scheme -
Any of the basic compounds exemplified in 1 can be used.

The amount of the compound of general formula (35) and the basic compound used is:
The amount is preferably at least equimolar, preferably equimolar - 2 times mole: 17, relative to the compound of general formula (22), respectively. The reaction is usually carried out at 0 to 150°C, preferably at room temperature to io
It ends in about 0.5 to 5 hours near o'c.

The reaction between the compound of general formula (14) and 1,1'-carponyldiimidazole (15) can be carried out in a suitable solvent. As the solvent used here, any solvent can be used as long as it does not affect the reaction, but examples include chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, benzene, 1-toluene, Examples include aromatic hydrocarbons such as xylene, dioxane, diethylene glycol dimedyl ether, diethyl ether, and nitrogen compounds such as tetrahydrofuran. The reaction is usually completed at room temperature to 150'C, preferably around room temperature to 100'C, in about 1 to 10 hours.

[Reaction scheme-8] /l' 2 R2 [
In the formula, M, R1 and R2 are the same as above. RID represents a lower alkanoyl group and RT + represents a lower alkyl group. ×3 indicates a halogen atom. ] The reaction between the compound of general formula (2) and the compound of general formula (36) can be carried out in a suitable solvent. As the solvent used here, any of the solvents exemplified in Reaction Scheme-3 above can be used. The amount of the compound of general formula (36) to be used is at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (2). The reaction is usually O
~150'C1 preferably at around air temperature ~100''C,
It completes in about 0.5 to 5 hours.

The reaction between the compound of the general formula (16) and the compound of the general formula (17) is generally carried out by the Rifomatsky reaction (Rcforma
tzky reaction), and can be carried out in a suitable solvent in the presence of a metal such as zinc or magnesium. Examples of the solvent used here include aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, tetrahydrofuran, diethyl glycol dimedyl ether, and dioxane. The compound of general formula (17) may be used in an amount at least equimolar, preferably equivalent to 5 times the molar amount of the compound of general formula (16).

The amount of the metal to be used is equivalent to -10 times the amount of the compound of general formula (16), however, it is preferably equivalent to -5 times the amount of the compound.

Incidentally, the intermediate obtained by the reaction between the compound of general formula (16) and the compound of general formula (17) can be subjected to the next cyclization reaction without being taken out. The cyclization reaction can be carried out in the same manner as in the cyclization reaction of the compound of general formula (13) shown in Reaction Scheme-6 above.

[Reaction Scheme-9] B IB 1 (18) (li)
[In the formula, R1 and x3 are the same as above. ] The reaction between the compound of general formula (18) and the compound of general formula (19) can be carried out in a suitable solvent in the presence or absence of a basic compound. Examples of solvents used here include alcohols such as methanol, ethanol, isopropanol, chloroform, dichloromethane,
Halogenated hydrocarbons such as carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as dioxane, diethylene glycol dimethyl ether, diethyl needle, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoric acid 1 -A polar layer rs such as lyamide can be exemplified. The basic compounds used include inorganic salt bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium thulium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium, metallic potassium, and sodium amide. , piperidine, pyridine, triethylamine, and other organic bases. The amount of the compound of general formula (19) to be used is at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (18). The reaction is usually O~150'C1, preferably 50~
It ends in about 1 to 7 hours at around 100'C.

[Reaction Scheme-10] [In the formula, R1 is the same as above. R+2 represents a hydrogen atom or a lower alkyl group. ] The reaction between the compound of general formula (18) and the compound of general formula (20) can be carried out in a suitable solvent in the presence or absence of an acid, preferably in the absence. Examples of the solvent used here include water, methanol, ethanol,
Alcohols such as isopropanol, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride,
Aromatic hydrocarbons such as benzene, 1-toluene, and xylene, ethers such as dioxane, diethylene glycol dimethyl ether, diethyl needle, and tetrahydrofuran, polar solvents such as dimethylformamide, dimethyl sulfoxide, hexyrimedyl phosphate triamide, and acetonitrile, acetic acid, and propionic acid. Examples include lower alkanoic acids such as, and mixed solvents thereof. Examples of acids used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and PtA acids such as acetic acid and pt-luenesulfonic acid. Use of the compound of the general formula (20) 0 means the use of the compound of the general formula (1
The amount is preferably at least equimolar, preferably equimolar to twice the molar amount of the compound 8). The reaction is usually O~
150'C1 Preferably, the process is completed in about 5 minutes to 5 hours at a temperature of seedlings to around 100°C.

[Reaction Scheme-11] [In the formula, R1 is the same as above. R+3 represents a cyano group or a lower alkanoyl group, and R14 represents a lower alkanoyl group or a lower alkoxycarbonyl group, respectively. R+5 represents a hydrogen atom, an amino group or a lower alkyl group, and Ree represents a hydrogen atom, an oxo group or a lower alkyl group, respectively. The 4 and 5 positions of the pyrazole ring in general formula (1k) represent a single bond when RIB represents an oxo group and represent a double bond when RIB represents a hydrogen atom or a lower alkyl group.

] The reaction between the compound of general formula (18) and the compound of general formula (21) can be carried out in a suitable solvent in the presence or absence of an acid or basic compound.

Examples of solvents used here include alcohols such as methanol, ethanol, and isopropanol; aromatic hydrocarbons such as benzene, toluene, and xylene; []Tonic polar solvents and the like can be mentioned. Examples of the acids used include mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and acids such as p-toluenesulfonic acid and acetic acid. Basic compounds used include, for example, sodium hydroxide, potassium hydroxide, mono-lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, mono-lithium hydride, metals. Inorganic bases such as sodium, metallic potassium, sodium amide, piperidine, pyridine,
Examples include organic bases such as triethylamine. The amount of the compound of general formula (21) to be used is at least equimolar, preferably equimolar to 2 times the molar amount of the compound of general formula (18). The reaction is usually completed at about 0 to 150°C, preferably from air temperature to around 100°C, in about 1 to 15 hours.

[Reaction Scheme-121 [In the formula, R1 is the same as above. RI7 and RI8 each simultaneously represent a lower alkoxy group or an oxo group. R+9
and R20 simultaneously represent a hydrogen atom or an oxo group. The bonds at the 2.3-position and 4-5 position of the pyrrole ring in general formula (1Q) are single bonds when RI9 and R20 are oxo groups,
When R+9 and R20 are hydrogen atoms, it indicates a double bond. ] The reaction between the compound of general formula (22) and the compound of general formula (23) can be carried out in a solvent or in the absence of a solvent, in the presence or absence of an acid. The solvent used here is
Alcohols such as Metasil, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, and diethylene glycol dimethyl ether, lower alkanoic acids such as acetic acid and propionic acid, and chloroform. , dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. Examples of acids used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as p-toluenesulfonic acid and acetic acid. The amount of the compound of general formula (23) to be used is:
The amount is preferably at least equimolar, preferably equimolar to 2 times the molar amount of the compound of general formula (22). The reaction is usually completed at about 50 to 250'C1, preferably about 50 to 200C, in about 0.5 to 5 hours.

[Reaction scheme-131 IR1 (24) (1m) [In the formula R
1 and x3 are the same as above. A represents a tetramethylene group which may be substituted with a lower alkyl group, an oxo group or a phenyl group, or a pentamethylene group which may have an oxo group. ] The cyclization reaction of the compound of general formula (24) can be carried out in a suitable solvent in the presence of a basic compound. Solvents used here include alcohols such as methanol, ethanol, isopropanol, benzene,
Aromatic hydrocarbons such as toluene and xylene, erthyl compounds such as diethyl ether, dioxane, tetrahydrofuran, and diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric acid. Examples include triamide. As the basic compound used here, the reaction scheme -
Any of the basic compounds exemplified in No. 11 can be used. The reaction is usually carried out at 0 to 150°C, preferably at room temperature to 10°C.
It will be completed in about 1 to 15 hours near 0'Ci''.

General used as a starting material in Reaction Scheme-13.

The compound of formula (24) can be prepared, for example, by the following reaction scheme-14.
It can be manufactured according to the method of

[Reaction scheme-14] /? I
R1(22> (24)[
In the formula, R', X3 and A are the same as above. X4 represents a halogen atom. ] The reaction between the compound of general formula (22) and the compound of general formula (25) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent.

Examples of inert solvents that can be used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, impropatol, and butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and hexane. Examples include methylphosphoric triamide. Examples of basic condensing agents include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide; and metals such as sodium methylate and sodium ethoxide. Examples include tertiary amines such as alcoholade, pyridine, and triethylamine. The ratio of the compound of general formula (22) and the compound of general formula (25) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually at least equimolar to the former, preferably It is preferable to use equimolar to 5 times the molar amount. The reaction is usually carried out at a temperature of about 40 to 120°C, preferably 50 to 100°C, and is generally completed in about 1 to 15 hours.

[Reaction Scheme-15] [In the formula, R1 is the same as above. R22 represents a lower alkyl group. ] The reaction between the compound of general formula (26) and the compound of general formula (27) can be carried out in a suitable solvent in the presence of a basic compound. Examples of solvents used here include halogenated hydrocarbons such as chloroborm, dichloromethane, dichloroethane, and carbon tetrachloride, alcohols such as methanol, ethanol, and isopropanol, and aromatic carbonates such as benzene, toluene, and xylene. Hydrogens, dioxin 4
Examples include ethers such as non-fluoride, diethylene glycol dimethyl ether, diethyl ether, and tetrahydrofuran, and polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetic anhydride, acetonitrile, dimethylsulfoxide, and hexamethylphosphoric triamide.

The basic compounds used here include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium ethoxide, sodium ethoxide, sodium hydride, sodium metal, metal Inorganic bases such as potassium and sodium amide, N,N-dimethylaniline, piperidine, pyridine, triethylamine, sodium acetate,
Examples include organic bases such as potassium acetate.

The amount of the compound of general formula (27) to be used is at least equimolar, preferably equimolar to the compound of general formula (26).
It is better to use twice the molar amount. The reaction is usually carried out at air temperature to 200 ℃
'C1 preferably around 50-150'C, 1-5
It will finish in about an hour.

[Reaction Scheme-16] HI R1 [wherein R1 is the same as above. R23 represents a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. ] The reaction between the compound of general formula (26) and the compound of general formula (28) can be carried out in a suitable solvent in the presence of a basic compound. As the solvent used here, any solvent can be used as long as it does not affect the reaction, and any of the solvents exemplified in Reaction Scheme-15 above can be used.

As the basic compound used here, any of the basic compounds exemplified in Reaction Scheme-15 above can be used. The amount of the compound of general formula (28) to be used is
) The amount should be at least equimolar, preferably equimolar to twice the molar amount of the compound. The reaction is carried out at O°~150
'C, preferably at room temperature to around 100°C, 0.5 to 5
It will finish in about an hour.

[Reaction scheme-171 R1R1 (29) (ip) [R1 in the formula
Same as above. R24 and R25 are the same or different and represent a hydrogen atom or a lower alkyl group. ] The cyclization reaction of the compound of general formula (29) can be carried out in the presence of an acid in a suitable solvent. As the solvent used here, any solvent or medium that does not affect the reaction can be used, and any of the solvents exemplified in Reaction Scheme-15 above can be used. Examples of acids used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as p-toluenesulfonic acid. The reaction is usually carried out at room temperature to 150'C, preferably around room temperature to 100'C,
It completes in about 10 to 60 hours.

[Reaction Scheme-18] 1R1 (30) (1q) [In the formula, R1 and R2 are the same as above. ] The reaction between the compound of general formula (30) and formamide (31) can be carried out without a solvent or in a solvent. As the solvent used here, any solvent can be used as long as it does not affect the reaction, but the solvent used in the reaction scheme-1
Any of those exemplified in No. 5 can be used. The amount of formamide (31) to be used is usually a large excess (2), preferably 10 to 20 times m, relative to the compound of general formula (30). The reaction is usually completed at 50 to 250°C, preferably 100 to 200°C, in about 1 to 10 hours.

General formula (
Compound 29) can be obtained, for example, according to the method shown in Reaction Scheme-19 below.

[Reaction Scheme-191 B I B L [In the formula, R1, R24 and R25 are the same as above. ] General formula (26
) and the compound of general formula (32) 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 the solvents and basic compounds exemplified in Reaction Scheme-15 above can be used. The amount of the compound of general formula (32) to be used is at least equimolar to the compound of general formula (26), preferably about equimolar to twice the molar amount.

The reaction is usually carried out at -20 to 100°C, preferably from 0° to 5
The process is completed in about 1 to 20 hours at around 0°C.

Compound (30) used as a starting material in Reaction Scheme-18 can be obtained, for example, by the method shown in Reaction Scheme-20 below.

[Reaction Scheme-20] R3-R'J- [In the formula, R1, R2, x1 and M are the same as above. ] The reaction between the compound of general formula ('2) and the compound of general formula (33) can be carried out in a suitable solvent. As the solvent used here, any of the solvents exemplified in Reaction Scheme-15 above can be used. General formula (33) may be used in an amount of at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (2).

The reaction is usually carried out at a temperature of 0 to 150°C, preferably room temperature to 100°C.
It will finish in about 0.5 to 5 hours in the vicinity.

[Reaction Scheme-21] (lr) (IS) [In the formula, R is the same as above. R1' represents a lower alkynyl group. ×5 indicates a halogen atom. ] The compound represented by the general formula (1r) is reacted with a basic compound such as an alkali metal such as sodium hydride, potassium hydride, sodium amide, potassium cumamide, metallic sodium, metallic potassium, etc. to form a carbostyril skeleton. The position of the nitrogen atom at position 1 is guided to the alkali metal salt. The reaction is carried out in a suitable solvent, such as aromatic solvents such as benzene, toluene, xylene, n-
Saturated hydrocarbon solvents such as hexane and cyclohexane, ether solvents such as diethyl ether, diethylene glycol dimethyl ether, 1,2-dimethoxyethane, and dioxane, aprotons such as dimethylformamide, hexamethylphosphoric acid 1-lyamide, and dimethyl sulfoxide. The reaction is carried out in a polar solvent, preferably a non-polar solvent. The reaction temperature was 0 to 200'C.

It is preferably carried out at room temperature to 50°C. The alkali metal salt of compound (1r) thus obtained is reacted with a halogen compound represented by the general formula (34) by a conventional method.The reaction is usually carried out in the appropriate solvent used to form the alkali metal salt. The process is suitably carried out by heating in air at a temperature of about 0 to 70°C, preferably from 0 to 70°C.The amount of the basic compound to be used is usually 1 to 5 times the mole of compound (1r), preferably 1 to 3 times the mole. level, and halogen compounds (34
) is about 1 to 5 times the mole, preferably about 1 to 3 times the mole. The reaction usually ends in about 0.5 to 15 hours.

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid.

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

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative Mat chromatography.

Incidentally, 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 contains commonly used fillers, extenders,
It is prepared using diluents or excipients such as 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, tablets, powders, liquids, suspensions,
Examples include emulsions, granules, capsules, suppositories, 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,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose cellulose, potassium phosphate, polyvinylpyrrolidone, etc. binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitacone fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, disintegration inhibitors such as stearin, cocoa butter, and hydrogenated oils;
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, purified talc, stearate, and boric acid powder. Examples include lubricants such as polyethylene glycol and the like. Furthermore, the tablets can be made into tablets with conventional coatings as required, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a rough shape, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, powdered gum arabic, etc. , tragacanth powder, gelatin, binders such as ethanol, laminaran,
Examples include disintegrants such as agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter,
Examples include higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions, and suspensions,
All diluents commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can. In this case, sufficient salt, glucose, or glycerin to prepare a temporary solution may be included in the above preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary.

The number of compounds of general formula (1) to be contained in the preparation of the present invention is not particularly limited and can be selected from a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight of the total composition. be.

There are no particular restrictions on the method of administering the preparation of the present invention, and administration may be carried out in a manner 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. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and when necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

The dosage of the 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 the amount of the compound of general formula (1), which is the active ingredient, is usually determined per body weight per day. It is preferable to set the amount to about 0.1.about.10q per K'j.

Further, it is preferable that the dosage unit form contains 2 to 200 mg of the active ingredient.

Example Reference examples and examples are listed below.

Reference Example 1 A mixture of 5 g of 6-α-chloroacedel-3,4-dihydrocarbostyryl, 2.17 g of potassium thiocyanide and 50 d of methanol is heated under reflux for 2 hours. After the reaction is completed, the precipitated crystals are collected and separated and purified by silica gel column chromatography to obtain 5.169 6-α-diocyanatoacediyl-3.4-dihydrocarbostyryl.

Reference example 2 6-propionyl-3,4-dihydrocarbosuril 5g
was dissolved in 200 d of methanol, and 4.12 Sj of semicarbazide hydrochloride and 6.05 g of sodium acetate were added to this solution.
A 40% solution of water was added at 50°C. Then at room temperature,
- Set up at night to dissipate precipitated crystals. Recrystallization from methanol yields 3.949 6-(1-semicarbazinopropyl)-3,4-dihydrocarbostyryl.

Colorless powder reference example 3 Dissolve 6 g of potassium hydroxide in 20 d of methanol, divide into 2 equal parts, saturate one half with hydrogen sulfide, and add the other half.
Warm to 0°C. Add chloroform 49 to this and react violently. After the reaction is completed, the mixture is cooled and the generated potassium chloride is eliminated to obtain a methanol solution of potassium dithioformate. Next, 2 g of 6-α-aminoacetyl-3,4-dihydrocarbostyryl monohydrochloride was dissolved in 20 parts of water, and the potassium dithioformate solution was added first. At room temperature,
After stirring for 2 hours and taking out the precipitated product, it was 1.95! ? 6
-α-Thioformylaminoacetyl-3,4-dihydrocarbostyryl Reference Example 4 8 6-amino-3,4-dihydrocarbostyryl, 5.2 ni of ethylene bromohydrin, 7 n of sodium carbonate,
89 and ethanol 150mf! Heat to reflux for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is extracted with chloroform-ethanol and hot water. After distillation under reduced pressure, the residue was purified by silica gel column chromatography to obtain 2.5 g of 6-hydroxyethylamino-3,4-dihydrocarbostyryl.

N, M, R, δ(DMSO-ds>:2.
20-2.50 (m, 2H) 2 , 55-2. 85 (m, 2 t1)2.97 (t, 2H, J=5f-iz)3,
47 t't, 2 t(, J=5H1)6
．． 23-6.66 (m, 3H) 9.67 (brs, IH) Reference Example 5 6-chloroacetyl-3,4-dihydrocarbostyryl 109 and sodium acetate 5.5g were dissolved in dimethylformamide 80d, Heat the reaction at ℃ for 2 hours. After the reaction is complete, pour the reaction solution into water, count the amount of precipitate, wash with water, and dry.

Recrystallization from ethanol yields 9.0 g of 6-acetoxyacetyl-3,4-dihydrocarbostyryl.

N, M, R, δ (DMSOds >: 2.10 (s, 3H) 2, 31~2.57 (m, 2) 2, 75~3.02 (m, 2)
1) 5, 30 (S, 2 1)
)6, 90 (d, IH, J=9 tf
Z) 7.68-7.85 (m, 2t-f) Reference Example 6 Lowformyl-3,4-dihydrocarbostyryl 3.5
g, 1-acetyl isopropanol and 50 m of ethanol at 0°C.
．． Add 69 g of 151 dl ethanol solution. After stirring at the same temperature for 5 hours, the mixture was stirred at room temperature overnight. Next, the reaction solution is adjusted to pH 4 to 5 with concentrated hydrochloric acid, and the solvent is distilled off. 1
The resulting residue was purified by silica gel column chromatography and then recrystallized from ethanol to obtain 2.3 g of 6-
(4-hydroxy-4,4-dimethyl-3-oxo-1
-butenyl)-3,4-dihydrocarbostyryl is obtained.

ml), 204-207°C Colorless prismatic reference example 7 10 g of lochloroacetyl-3,4-dihydrocarbostyryl and potassium formate were mixed with 80 d of dimethylformamide.
and heat reaction at 60'C for 3 hours. After the reaction is complete, pour the reaction solution into water and count the amount of precipitate. washing with water,
After drying, dry with dimethylformamide to give 6.5g
6-formyloxyazetyl-3,4-dihydrocarbostyryl is obtained.

N, M, R, δ(DMSOds >: 2.40-2.68 (m, 2H) 2.80-3.10 (m, 2H) 5.51 (s, 2l-1) 6.98 (d , IH, J=9Hz) 7, 76 (dd, 1 F+, J
=9H2°1.5Hz) 7.84 (s, 1H) 8.41 (S, 1H) 10.49 (brs, IH) Example 1 6-α-chloroacetyl-3,4-dihydrocarbostyryl 13. 8g, 7.5g thioformamide and 1407g ethanol! Heat to reflux for 3 hours. After the reaction is completed, the precipitated amount is removed, the mother liquor is concentrated to dryness, ethanol is added to the obtained residue, and the precipitated amount is calculated as i. This was separated and purified using silica gel column chroma 1 to graphie, and the obtained crude crystals were recrystallized from isopropanol.
-(thiazol-4-yl)-3,4-dihydrocarbostyryl is obtained.

mp, 200-201°C Colorless needle crystals Example 2 5 g of 6-α-chloroacetyl-3,4-dihydrocarbostyryl, 2.559 thiourea and 40 rr of ethanol
11 was heated under reflux for 2 hours, and the precipitated product was counted. The crude crystals are recrystallized from 70% aqueous ethanol to obtain 4.82 g of 6-(2-aminothiazol-4-yl)-3,4-dihydroluposdiryl monohydrochloride 1/2 hydrate.

mp, colorless needle crystals on 300"Ca Example 3 5 g of 6-α-chloroacetyl-3,4-dihydrocarbostyryl, 2.52 g of thioacetamide and 40 rIJl of ethanol were heated under reflux for 2 hours, and the precipitated product was collected in t. The crude crystals are recrystallized from water to obtain 1.71 g of 6-(2-methylthiazol-4-yl)-3,4-dihydrocarbostyryl.

mp, 183.5-185°C Colorless flocculent Example 4 4.2 g of benzamidine hydrochloride is dissolved in 3 d of ION sodium hydroxide and 20 ml of water, and the benzamidine is extracted with chloroform. After drying the chloroform layer with calcium chloride, 5 g of 6-α-chloroacetyl-3,4-dihydrocarbostyryl was added to the chloroform layer.
Heat to reflux for an hour.

After the reaction is completed, the reaction solution is concentrated to dryness, and the resulting residue is extracted hot with dilute hydrochloric acid. After cooling, the precipitated crystals are collected and separated and purified by silica gel column chromatography. Recrystallization from isopropanol gives 0.111 of 6-(2-phenylimidazol-4-yl)-3,4-dihydrocarbostyryl.

ff1.208.5-210°C Colorless powder Example 5 6-α-thiocyanatoacetyl-3,4-dihydrocarbostyryl 4! iFS! 80 m of hydrochloric acid and 40 m of water
React for 4 hours at ~90°C. After the reaction, the precipitate was separated and purified by silica gel column chromatography, and recrystallized from dimethylformamide-water to give 3.4 g of 6-(2-hydroxythiazol-4-yl). 3.4-dihydrocarbostyryl is obtained.

mp, 300°C or higher Colorless powder Example 6 A mixture of 5 g of 6-α-chloroacetyl-3,4-dihydrocarbostyryl, 3.02 g of 0-amino-acetophenone and 50 parts of dimethylformamide was heated to 140 to 150 g.
Heat to reflux at ℃ for 5 hours.

After the reaction is completed, the solvent is distilled off, and the residue is extracted with chloroform, water, and 1N aqueous sodium hydroxide solution. The chloroform layer is washed with saturated saline and dried. The solvent was distilled off, and the resulting residue was recrystallized from chloroborum-methanol to obtain 2.41 of 6-(3-methyl-2-indolylcarbonyl)-3,4-dihydrocarbostyryl.

mp, 266.5-268°C Colorless powder Example 7 5 g of 6-α-chloroacetyl-3,71-dihydrocarbostyryl and 20 rIif of α-pyurin! 85~9
Stir at 0°C for 2 hours. The reaction solution was cooled, ether was added thereto, the precipitated crystals were collected for i months, washed with ether, the precipitated crystals were dissolved in 100 ml of water, and 6 ml of sodium bicarbonate was added.
g and stirred at 85-90°C for 1 hour. After the reaction is completed, the reaction solution is cooled with ice water, and the precipitated product is taken out and washed with water. Recrystallized from methanol to obtain 2.96 g of 6-(pyrrolo[
1,2-a]pyridin-2-yl)-3,4-dididrocarbostyryl is obtained.

mo, 298-301°C (decomposition) Colorless needle crystals Example 8 5 g of 6-α-chloroacetyl-3,4-dihydrocarbostyryl, 6.72 y of 2-aminothiazole and 20 ml of ethanol are heated under reflux for 6 hours. The reaction solution was cooled with ice water, the amount of precipitation was t, and 25 m of ethanol, 20 d of water, and 5 d of 1ON sodium hydroxide aqueous solution were added to the amount of precipitation.
Heat the reaction at 90°C for 1 hour. Concentrate the reaction solution, add water, and adjust the pH to about 1 by adding concentrated hydrochloric acid. Calculate the amount of precipitation by the number of households,
After washing with water, it is recrystallized from water and 6-(imidazo[2,1-
b] 2.95 tJ of thiazol-6-yl)-3,4-dihydrocarbostyryl hydrochloride 1/2 hydrate is obtained.

mp, 301-303.5°C (decomposed) Colorless flocculent Example 9 6-α-chloroacetyl-3,4-dihydrocarbostyryl 59. 6.38 g of 2-aminopyrimidine and 20 d of ethanol are heated under reflux for 10 hours. . After the reaction is complete, count the amount of precipitate and suspend it in water. Add concentrated hydrochloric acid, p
The amount of precipitation is determined by approximately 1 J'I. Recrystallize from water to obtain 6-(imidazo[1,2-a]pyrimidine-
2-yl)-3,4-dihydrocarbostyryl hydrochloride.
3.00 g of 1/2 permanent product is obtained.

mp, 300-303°C (decomposed) Pale yellow needle crystals Example 10 Thionyl chloride 12d is cooled with ice water, and 3 g of 6-(1-semicarbazinopropyl)-3,4-dihydrocarbosryl is added thereto. React for 3 hours at 0~5° and 4 hours at room temperature, and excess thionyl chloride is distilled off. To the obtained residue,
Extract by adding chloroform and 1N sodium hydroxide,
Wash the chloroform layer with water and dry. Chloroform is distilled off, and the resulting residue is separated and purified using silica gel chromatography. Recrystallized from methanol to give 0.78 g of 6-(5-methyl-1,2,3-thiadiazole-4-
yl)-3,4-dihydrocarbostyryl is obtained.

rTlp, 119.5-121°C (decomposed) colorless needle crystals Example 11 1.959 of 6-α-thioformylaminoacetyl-3,4-dihydrocarbostyryl was gradually added to 2d of concentrated sulfuric acid, Time reacts.

Pour the reaction mixture onto ice and neutralize with 1ON aqueous sodium hydroxide solution. The amount of precipitate is counted, dried, and separated and purified using silica gel column chromatography. Recrystallized from methanol to give 6-(thiazol-5-yl)-3,4-
1.77 g of dihydrocarbostyril are obtained.

mp, 207.5-208.5°C Colorless needles Example 12 0.69 of 6-(2-aminoethyl)amino-3,4-dihydrocarbostyryl and 1.29 of N,N'-carbonyldiimidazole The mixture of Te1 to Lahydrofuran 20d is heated under reflux for 3 hours. After the reaction, tetrahydrofuran was distilled off, the resulting residue was separated and purified by silica gel column chromatography, and then recrystallized from methanol to give 0.33 of 6-(2-imidazolinon-1-yl)-
3,4-dihydrosuburyl is obtained.

mp, 269-271°C Colorless prismatic Example 13 1.5 g of 6-hydroxyethylamino-3,4-dihydrocarbostyryl, 2.4 g of N,N'-carbonyldiimidazole and 50 rnl of tetrahydroquinoline were added to 8
Heat to reflux for an hour. After the reaction is complete, let it cool and collect the precipitated product. Recrystallize from dimethylformamide to obtain 1.2
g of 6-(2-oxasilinon-3-yl)-3,4-
1q of dihydrocarbostyril.

mp, 274-276°C Colorless prismatic Example 14 3.79 6-acedoxyacetyl-3,4-dihydrocarbostyryl and 1.57 f of zinc were dispersed in 50 d of benzene, and ethyl bromoacetate was dissolved under a nitrogen flow rate. 2.
A solution of 87d in benzene 25d is added dropwise over 1 hour.

After 30 minutes of reaction, 1.969 g of zinc was added to the colander, and under reflux,
Ethyl bromoacetate 3.3rIdl benzene 30
Add m1 solution dropwise over 1 hour. 1 change of 30 minute reaction,
Allow to cool, add a mixture of 20 rnl of concentrated sulfuric acid and 20 ml of water, and stir at room temperature for 5 hours. After the reaction is completed, the precipitate, the residue obtained by distilling off the BenU layer, and the aqueous layer extracted with chloroform are combined and separated and purified using silica gel column chromatography. Recrystallize from chloroform-methanol to obtain 0.6 g of 6-(2-oxo-2,5-dihydrofuran-4-yl)-3,4-dihydrocarbostyryl.

mp, 280-284°C (min wl) Colorless needle crystals Example 15 6-hydrazino-3,4-dihydrocarbostyryl 2 g
, 1.05 g of epichlorohydrin and 20 m of methanol
The mixture was heated to reflux for 4 hours.

After the reaction is complete, leave the reaction solution at room temperature and collect the precipitated product. The crude crystals were separated and purified using silica gel column chromatography, and then recrystallized from isopropanol.
1 q of 0.1 g of 6-(1-pyrazolyl)-3,4-dihydrocarbostyryl is taken.

mD, 188-188.5°C Colorless columnar crystal Example 16 Rhohydrazino 3.4-dihydrocarbostyryl 3 g
, 1-methyl-1 in a solution of 15 ml of acetic acid and 15 ml of water.
Add 1.49 -amino-2-cyanoethylene at room temperature. Next, heat and stir at 90'C for 15 minutes. After the reaction is completed, the reaction solution is concentrated to dryness, and the residue is extracted with chloroborum, water, and a 1N aqueous sodium hydroxide solution. Wash the chloroborum layer with water and dry.

Chloroform is distilled off, and acetone and concentrated hydrochloric acid are added to the residue to adjust the pH to about 1. The precipitated crystals were recrystallized from water to give 6-(3-methyl-5-amino-1-pyrazolyl)-3,4-dihydrocarbostyryl mp. 309 - 311.5°C (decomposed) colorless needle crystals Example 17 Rhohydrazino 3,4-dihydrocarbostyryl 2 g
, acetylacetone 1.13! l? and methanol 20
Stir m for 9 hours at room temperature. After the reaction is completed, the precipitated product is separated and dissolved in hot methanol to eliminate insoluble matter.

The solution was concentrated to dryness, and the residue was subjected to silica gel column chromatography to prepare Separation M, and then recrystallized from isopropanol to obtain 6-(3.5-dimethyl-1-pyrazolyl).
0.27 g of -3,4-dihydrocarbostyryl is obtained.

rnp. 206.5 - 207.5°C Colorless needle-like product Example 18 6-hydrazino-3.4-dihydrocarbostyryl 2 g
, ethyl acetoacetate 1.479 and methanol 20ml
Heat to reflux for 2 hours. After the reaction is completed, insoluble matter is removed and the two-part solution is concentrated to dryness. The obtained residue was separated and purified by silica gel column chromatography, and then recrystallized from methanol to obtain 6-(3-methyl-5-pyrazolone-
1-yl)-3,4-dihydrocarbostyryl 0.49
! ? get.

mp, 176-179°C Colorless powder Example 19 6-hydrazino-3,4-dihydrocarbostyryl 5 in a solution of 1.309 parts sodium metal and 50 parts ethanol
g and ethyl cyan acetate 3.20!7, add 1
Heat to reflux for 11 hours. After the reaction is complete, the solvent is distilled off, water is added, and the mixture is treated with activated carbon. Add 3.24 ml of acetic acid to the solution, dissipate the precipitate, and purify with silica gel column chromatography, then adjust to about 1 l-1 with methanol, chloroform, and concentrated hydrochloric acid. The solvent was distilled off and 1q of the residue was recrystallized from water to give 0.439 6-(3-amino-5-pyrazolon-1-yl)-3,4-dihydrocarbostyryl mp. 263.5 - 265°C (decomposed) colorless & monomorphic crystals Example 20 6-amino-3,4-dihydrocarbostyryl 2g, 2
A mixture of 1,77 g of ,5-dimethoxytetrahydrofuran and 20 rdt of acetic acid is heated under reflux for 1 hour. After the reaction is completed, the reaction solution is concentrated to dryness, and 1 q of residue is separated and purified by silica gel column chromatography. Recrystallized from ethanol to obtain 1.51 g of 6-(1-pyrrolyl)-
3.4-dihydrocarbostyryl mp. 185-186.5°C Colorless needle crystals Example 21 5 g of 6-amino-3,4-dihydrocarbostyryl and 4.6 g of succinic anhydride are melted at 190-200°C for 1 hour. Add methanol to the reactant and disperse it. After purification by silica gel column chromatography, it was recrystallized from ethanol and 6.5 g of 6-(2
．． 5-Dioxo-1-pyrrolidinyl)-3,4-dihydrocarbostyryl is obtained.

ml), 231-233°C Colorless needle crystals Example 22 6-amino-3,4-dihydrocarbostyryl 29,2
After heating and refluxing 2.86 g of -hydroxy-1,4-dibromobutane and ethanol for 2.5 hours, 654 mg of sodium carbonate was added to the mixture, and further 11.5 g of sodium carbonate was added.
Heat to reflux for an hour. The reaction solution was filtered while hot to eliminate insoluble matter, the solution was allowed to cool, and the precipitated product was recrystallized from methanol several times to obtain 0.553 6-(3-hydroxy-1-
pyrrolidinyl)-3,4-dihydrocarbostyryl is obtained.

mD. 212.5-214°C Colorless needle crystals Example 23 3.0 g of 6-formyl, 3.0 g of acetylglycine and 1.5 g of sodium acetate were added to anhydrous vinegar! Dissolve in 10d and heat at 110'C for 2 hours. After the reaction is completed, 10 d of water is added to the reaction solution to dissipate the precipitate. After purification by silica gel column chromatography, it was recrystallized from chloroform-methanol and 1.0 g of 6-(2-methyl-5 (4H)-oxazolone-4-ylidene)-3.4-dihydrocarbostyryl 1/ A tetrahydrate is obtained.

mp. -278°C (decomposed) Colorless powder Example 24 1.5 g of 4-chlorobutyrylamine, no-3,4-dihydrocarbostyryl, is dispersed in 15 d of dimethylformamide, and 510 ml of sodium hydride is added at once. Upon completion, stir at room temperature for 3 hours.

After the reaction is completed, the reaction solution is poured into water and extracted with chloroform. After washing with water and drying with magnesium sulfate, chloroform is distilled off and the residue is washed with diethyl ether. Recrystallization from methanol yields 1 culm of 1.2 g of 6-(2-oxo-1-pyrrolidinyl)-3,4-dihydrocarbostyryl.

mp, 228-230°C Colorless prismatic Example 25 The following compound is obtained in the same manner as in Example 24 using appropriate starting materials.

6-(2-oxo-1-piperidinyl)-3,4-dihydrocarbostyryl mp, 179-181°C Colorless prismatic (recrystallized from impropatul) Example
26 Disperse 1.75 g of low formil, potassium carbonate and 2.1 g of p-tosylmethyl isocyanide in 60 m of methanol,
Heat to reflux for an hour. After the reaction is completed, methanol is distilled off under reduced pressure, and water is added to the residue to dissipate the precipitate. After drying, purification by silica gel column chromatography and recrystallization from methanol-chloroform yielded 1.5 g of 6-(5-
oxacylyl)-3,4-dihydrocarbostyryl is obtained.

mp. 225 to 230°C Colorless prismatic example 27 6-(4-hydroxy-4,4-dimethyl-3-oxo-1-butenyl)-3,4-dihydrocarbostyryl 2
．． A solution of 2 g and a catalytic amount of p-toluenesulfonic acid in 80 ml of dichloroethane is heated under reflux for 50 hours. After the reaction is complete, add coloform to the reaction solution and wash with saturated aqueous sodium hydrogen carbonate solution. After distilling off the solvent and washing the resulting residue with silica gel column chromatography,
Recrystallized from ethanol to give 6-(2,2-dimethyl-
3-oxote 1-rahydrofuran-5-yl)-3,
4-dihydrocarbostyryl.

mp. 179-182°C Colorless flake crystals Example 28 6-formyloxydiacejiru 3. , 2.3 g of 4-dihydrocarbostyryl was added to 4 ml of formamide, and the mixture was heated and reacted at 180 to 190° C. for 5 hours.

After the reaction is completed, water is added to the reaction solution, made alkaline with ammonium hydroxide, and the precipitated product is washed several times with water and dried.

After separation and purification using silica gel column chromatography,
Recrystallized from ethanol-n-hexane to give 6-(5-
1.5 g of (imidazolyl)-3,4-dihydroquinoline are obtained.

mp. 258-260°C (decomposition) Colorless powder Example 29 In the same manner as in Example 8 above, using an appropriate starting material 1, the following compound is obtained.

1-propargyl-6-(imidazo[2.1-b]thiazol-6-yl)-3.4-dihydrocarbostyryl monohydrochloride mp. 229.5 ~ 232°C (decomposition) Colorless cotton-like product (
Dilute hydrochloric acid J: recondensation) Example 30 5-(imidazo[2.1-b]thiazol-6-yl)
-3.4-Dihydrocarbostyryl 2, 76g in dimethylformamide 1007! Add thorium hydride (50% oil base > 600 my) and stir at room temperature for 2 hours. Then add 1.46 g of propargyl bromide and react at room temperature for 3 hours. The reaction solution is concentrated to dryness, chloroform and 5N sodium hydroxide is added and extracted. The chloroform layer is washed with water, dried, and then distilled off. The residue is filtered onto silica.

The oil obtained by purification with a gel column is made into a hydrochloride by adding hydrochloric acid in acetone. The precipitate was dissipated and recrystallized from dilute hydrochloric acid to give 1-propargyl-6-(imidazo[2,1-
b] 1 q of 1.59 thiazol-6-yl)-3,4-dihydrocarbostyryl monohydrochloride. .

Colorless flocculent crystals Melting point: 229.5-232°C (decomposition) Below, examples of pharmacological tests conducted on the compounds of the present invention are listed.

Pharmacological Test> Bendoparbital sodium salt was intravenously administered at a rate of 30 ml/Kg to an adult dog of the 1st breed weighing 8 to 13 ffg and anesthetized. Heparin sodium salt 1
After intravenous administration at a rate of 000 U/Kg, the animals were bled to death and the heart was removed. The specimen consists mainly of papillary muscles and the ventricular septum, and is perfused with blood drawn from a donor via a cannula inserted into the anterior septal artery at a constant pressure of 100 m to 1 g. Donor dogs were anesthetized in advance by intravenously administering 30 my/'J of bendoparbital sodium salt at a weight of 18 to 27.
Heparin sodium salt 1000 tJ/Kff was administered intravenously. Using bipolar electrodes, voltage 1.5 times the threshold (0,5-3V), stimulation width of 5 m5ec, 120 pulses per minute.
Stimulate the papillary muscles with a square wave with a stimulation frequency of 1. The resting tension of the papillary muscles is 1.59, and the generated tension of the papillary muscles is measured via a force displacement exchanger. Blood flow in the anterior septal artery is measured using electromagnetic flow. The generated tension and blood flow rate are recorded on the ink writing record d. The details of this method have already been reported by Endo and Hashimoto (Am, J., Physio.
l, 218. 1459-1463, 1970).

The test compound is administered intraarterially in a volume of 10-30 μQ over 4 seconds. The inotropic effect of the test compound is expressed as a % change in the tension generated before drug administration. The effect on coronary blood flow is expressed as the change in absolute value (m/m1n) from before administration. The results are shown in Table 1 below.

Test compound N.

1.6-(2-oxasilinon-3-yl)-3,4-
Dihydrocarbostyryl 2,6- (2-oxo-2,5-dihydrofuran-4
-yl)-3,4-dihydrocarbostyryl 3,6-(5-oxyzolyl)-3,4-dihydrocarbostyryl 4,6-(imidazo[1.2-a]pyrimidin-2-yl)- 3.4-dihydrocallevosti hydrochloride acid 1◆1/
2-elongated product 5,6- (2-hydroxythiazol-4-yl)-
3,4-dihydrocarbostyryl 6,6- (2--aminodeazol-4-yl)-3
, 4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 7,6-(3.5-dimethyl-1-pyrazolyl)-3
,4-dihydrocarbostyryl 8,6-(deazol-4-yl)-3,4-dihydrocarbostyryl9,6-(1-pyrrolyl)-3,4-dihydrocarbostyryl10,6-(1-pyrazolyl) )-3.4-dihydrocarbostyryl 11, 6-(2-oxo-1-pyrrolidinyl)-3
, 4-dihydrocarbostyryl 12, 6- (2-methylthiazol-4-yl)-
3,4-dihydrocarbostyryl 13,5-(thiazol-5-yl)-3,4-dihydrocarbostyryl 14, 6-(5-methyl-1.2.3-thiadiazol-4-yl)- 3,4-dihydrocarbostyryl 15.6-(imidazo[2,1-b]thiazole-6-
yl)-3,/4-dihydrocarbostyryl hydrochloride 1
/Dihydrate Examples of formulations using the compounds of the present invention are listed below.

Formulation example 1 6-(5-deazolyl)-3,4 monodihydrocarbostyryl 5my starch 132mg magnesium stearate 18mFl lactose
A total of 45 mg and a total of 200 mg were prepared into tablets of the above composition in one tablet using a conventional method.

Formulation Example 2 6-(5-methyl-1,2,3-thiazol-4-yl)-3,4-dihydrocarbostyryl starch 127my magnesium stearate 18m3 lactose 45my total 200mg The above composition in one tablet by a conventional method Manufacture tablets.

Formulation example 3 6-(5-thiazolyl)-3.4 dihydrocarbostyryl 500 mg□ Polyethylene glycol (molecule base: 4000> 0.3 g Solutonium to Lium chloride 0.9 g Polyoxyethylene sorbitan monooleate 1 to 0.4 g Sodium metabisulfite 0.1g Methyl-paraben 0.189 Propyl-paraben
0.02g distilled water for injection
100d The above parabens, sulfur metabisulfite and sodium chloride are dissolved in the above distilled water at 80'C with stirring. The resulting solution was cooled to 40°C, and the compound of the present invention, then polyethylene glycol rice and polyoxyethylene sorbitan monooleate were dissolved in the solution. Next, the solution is adjusted to the final volume by adding distilled water for injection, sterilized by filtration using a suitable filter paper, and dispensed into LD ampoules to prepare an injection.

Formulation example 4 6-(4-thiazolyl)-3.4 monodihydrocarbosdidyl 5mtj starch 132mymagnesium stearate l~18m3 lactose
45m total
200 mg Tablets of the above composition were packed into one tablet using a conventional method.

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Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom or a lower alkynyl group, R is 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom and a saturated or unsaturated 5-membered hetero ring which may have 1 to 2 substituents selected from the group consisting of a hydroxyl group, an amino group, a lower alkyl group, an oxo group, and a phenyl group on the hetero ring Cyclic group, indolizinyl group, imidazo[2,1-a]pyrimidinyl group, pyrimidinyl group, imidazo[2,1-b]thiazolyl group, oxazolone which may have a lower alkyl group or oxo group as a substituent on the ring A zolonylidene group, an indolylcarbonyl group that may have a lower alkyl group as a substituent on an indolyl group, or a piperidinyl group that may have an oxo group as a substituent on a piperidinyl group, respectively. ] A carbostyryl derivative represented by these and its salt.