JPS6254308B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel carbostyryl derivative, and more particularly to a carbostyril derivative represented by the following general formula () and a salt thereof.

[In the formula, R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group, or a lower alkylthio group, R ₂ is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group, A is a lower alkylene group,
B and Z each represent an oxygen atom or a sulfur atom. In addition, the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond.] The carbostyril derivative represented by the above general formula () has excellent platelet aggregation inhibitory activity, phosphodiesterase inhibitory activity, and anti-ulcer activity. It has cardiotonic effect (positive myocardial inotropic effect), anti-inflammatory effect, anti-hypertensive effect, and central nervous system depressant effect, preventive and therapeutic agent for thrombosis, phosphodiesterase inhibitor, anti-ulcer agent, cardiotonic agent, anti-inflammatory agent, anti-hypertensive agent. It is useful as a tranquilizer, etc.

In this specification, each group represented by R ₁ , R ₂ and A can be more specifically exemplified by the following groups.

Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
Cycloalkyl groups such as pentyl and hexyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups; phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, and 3-phenylpropyl. , 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl group, etc.
Examples of lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups; examples of lower alkenyl groups include vinyl, allyl, 2-butenyl, 3-butenyl, 1
- Lower alkylene groups such as methylallyl, 2-pentenyl, 2-hexenyl groups include methylene, ethylene, methylmethylene, trimethylene,
Examples thereof include 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethyltrimethylene, and 1-methyltrimethylene groups.

Representative compounds of the present invention are listed below.

6-[3-(1,3,4-oxadiazole-
5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated form, 6-[3-(2-methyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3, 4-position hydrogen saturated product, 6-[3-(2-ethyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-[3-( 2-propyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-isopropyl-1,3,4-)
Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-butyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated form, 6-[3-(2-t-butyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated form, 6-[3-(2-hexyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-methylthio-1, 3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-propylthio-1,3,4-)
Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-hexylthio-1,3,4-
Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-cyclohexyl-1,3,4
-Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-cyclopropyl-1,3,4
-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-cyclooctyl-1,3,4
-Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)propoxy]carbo Styryl and its saturated hydrogen at 3,4 positions, 6-[3-(2-benzyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its saturated hydrogen at 3,4 positions, 6 -{3-(2-(1-phenylethyl)-
1,3,4-oxadiazol-5-yl]propoxy}carbostyryl and its 3,4-position hydrogen saturated product, 6-{3-(2-(2-phenylethyl)-
1,3,4-oxadiazol-5-yl]propoxy}carbostyryl and its 3,4-position hydrogen saturated product, 6-{3-[2-(6-phenylhexyl)-
1,3,4-oxadiazol-5-yl]propoxy}carbostyryl and its 3,4-position hydrogen saturated product, 6-[4-(2-methyl-1,3,4-oxadiazole-5-) yl)propoxy]carbostyryl and its 3,4-hydrogen saturated form, 6-[6-(2-methyl-1,3,4-oxadiazol-5-yl)hexyloxy]carbostyryl and its 3,4-hydrogen saturated form 6-[(2-cyclohexyl-1,3,4-oxadiazol-5-yl)methoxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-[6-(2-cyclohexyl) -1,3,4
-Oxadiazol-5-yl)hexyloxy]carbostyryl and its 3,4-hydrogen saturated product, 5-[3-(2-methyl-1,3,4-oxadiazol-5-yl)propoxy] carbostyril and its 3,4-position hydrogen saturated form, 8-[3-(2-methyl-1,3,4-oxadiazol-5-yl)propoxy] carbostyril and its 3,4-position hydrogen saturated form, 7-[3-(2-ethyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 5-[4-(2-propyl-1, 3,4-oxadiazol-5-yl)butoxy]carbostyryl and its 3,4-position hydrogen saturated product, 5-[3-(2-cyclohexyl-1,3,4
-Oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 5-[3-(2-methylthio-1,3,4-oxadiazol-5-yl)propoxy]carbo Styryl and its hydrogen saturated product at 3,4 positions, 5-[2(2-phenyl-1,3,4-oxadiazol-5-yl)methoxy]carbostyryl and its hydrogen saturated product at 3,4 positions, 5- [6-(2-benzyl-1,3,4-oxadiazol-5-yl)hexyloxy]carbostyryl and its 3,4-position hydrogen saturated product, 7-{3-[2-(1-phenylethyl) ―
1,3,4-oxadiazol-5-yl]propoxy}carbostyryl and its 3,4-position hydrogen saturated product, 1-allyl-6-[3-(2-cyclohexyl-1,3,4-oxadiyl) azol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 1-benzyl-6-[3-(2-methyl-1,
3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 1-methyl-6-[3-(2-phenyl-1,
3,4-oxadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 1-allyl-5-[3-(2-cyclohexyl-1,3,4-oxadiazole-) 5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-[3-(2-methyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product Hydrogen saturated product, 6-[3-(2-hexyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyril and its 3,4-position hydrogen saturated product, 6-[3-(2-methylthio- 1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-[3-(2-hexylthio-1,3,4-
thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-cyclohexyl-1,3,4
-thiodiazol-5-yl)propoxy]carbostyryl and its 3,4-hydrogen saturated product, 6-[3-(2-cyclooctyl-1,3,4
6-[3-(2-phenyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3-, 4-hydrogen-saturated product, , 4-position hydrogen saturated product, 6-[3-(2-benzyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-{3-(2 -(6-phenylhexyl)-
1,3,4-thiadiazol-5-yl)propoxy}carbostyryl and its 3,4-position hydrogen saturated product, 6-[4-(2-methyl-1,3,4-thiadiazol-5-yl)propoxy] Carbostyryl and its 3,4-position hydrogen saturated product, 1-allyl-8-[3-(2-cyclohexyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated product body, 1-benzyl-5-[4-(2-methylthio-
1,3,4-thiadiazol-5-yl)butoxy]carbostyryl and its 3,4-position hydrogen saturated product, 5-[3-(2-methyl-1,3,4-thiadiazol-5-yl)propoxy] Carbostyril and its 3,4-position hydrogen saturated form, 8-[3-(2-methyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl and its 3,4-position hydrogen saturated form, 7- [6-(2-hexyl-1,3,4-thiadiazol-5-yl)hexyloxy]carbostyryl and its 3,4-position hydrogen saturated product, 6-[3-(2-methyl-1,3,4 -thiadiazol-5-yl)propoxy]-thiocarbostyryl and its 3,4-position hydrogen saturated product, 6-[3-(2-ethyl-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbo Styryl and its 3,4-position hydrogen saturated product, 6-[3-(2-hexyl-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbostyryl and its 3,4-position hydrogen saturated product, 6 -[3-(2-methylthio-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbostyryl and its hydrogen saturated product at the 3,4 positions, 6-[3-(2-cyclohexyl-1,3) ,4
-thiadiazol-5-yl)propoxy]-thiocarbostyryl and its 3,4-hydrogen-saturated form, 6-[3-(2-phenyl-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbo Styryl and its saturated hydrogen at 3,4 positions, 5-[4-(2-methyl-1,3,4-thiadiazol-5-yl)butoxy]-thiocarbostyryl and its saturated hydrogen at 3,4 positions, 8 -[3-(2-methylthio-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbostyryl and its 3,4-position hydrogen saturated product, 7-[3-(2-cyclohexyl-1,3) ,4
-thiadiazol-5-yl)propoxy]-thiocarbostyryl and its 3,4-hydrogen saturated form.

The compound of the present invention can be produced by various methods, for example, by the method shown in the reaction formula below.

[In the formula, R ¹ , R ² , A, B, Z and the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above, R ³ is the group -COR ¹ or -CSR ¹ (R ¹ is the same as above) The method shown in the reaction formula is a method in which a carboxyalkoxycarbostyryl derivative represented by the general formula () and a hydrazine derivative represented by the general formula () are reacted in a normal amide bond forming reaction. be. In the present invention, a compound whose carboxy group is activated may be used instead of the compound of general formula (). As the amide bond forming reaction, known amide bond forming reaction conditions can be easily applied. For example, (a) mixed acid anhydride method, that is, a method in which a carboxylic acid () is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with a hydrazine derivative (), (b) an active ester method, i.e. A method in which carboxylic acid () is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and a hydrazine derivative () is reacted with this, (c) carbodiimide method, i.e. A method in which a hydrazine derivative () is condensed with a carboxylic acid () in the presence of an activating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; Method of reacting acid anhydride with hydrazine derivative (), carboxylic acid ()
Examples include a method in which a hydrazine derivative () is reacted with an ester of a carboxylic acid () and a lower alcohol under high temperature and high pressure, and a method in which an acid halide of a carboxylic acid (), that is, a carboxylic acid hydride, is reacted with a hydrazine derivative (). Among these, the mixed acid anhydride method is preferred. 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. Mixed acid anhydrides can be obtained by the usual Schotten-Baumann reaction, which is usually not isolated and converted into hydrazine derivatives ().
The compound of the present invention is produced by reacting with. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N
-Methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), 1,4
-Diazabicyclo [2.2.2] Octane (DABCO)
Examples include organic bases such as potassium carbonate, inorganic bases such as potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The Schotten-Baumann reaction is carried out at -20 DEG to 100 DEG C., preferably 0 DEG to 50 DEG C., and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and hydrazine derivative () is −20 to
carried out at 150°C, preferably 10 to 50°C,
The reaction time is selected from the range of 5 minutes to 10 hours, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used.
Specifically, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, methyl acetate,
Examples include esters such as ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of carboxylic acid (), alkylhalocarboxylic acid, and hydrazine derivative () used in this method is usually equivalent molar, but the ratio of alkylhalocarboxylic acid and amine () to carboxylic acid () is 1 to 1.5 times. Molar amounts may be used.

The cyclization reaction of the compound of general formula () can be carried out according to various conventionally known cyclization reactions. For example, heating, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, acetyl chloride, p-toluenesulfonic acid, benzenesulfonic acid, thionyl chloride, concentrated sulfuric acid, hydrochloric acid, acetic anhydride, polyphosphoric acid, and other dehydrating agents are used. An example is the conversion method. When a cyclization method by heating is employed, a solvent such as high-boiling hydrocarbons and high-boiling ethers, such as phenyl ether, diethylene glycol dimethyl ether, decalin, tetralin, toluene, xylene, mesitylene, chlorobenzene, and bromobenzene, is used. , usually 100-250℃, preferably 150-200℃
Heating conditions of ℃ can be adopted. In addition, when using an oxidation method using an acidic substance, it is better to use polyphosphoric acid as a dehydrating agent, and polyphosphoric acid is added in an equimolar amount to a large excess amount relative to the compound (), preferably in a large excess amount.
What is necessary is to use 10 to 20 times the amount and allow the reaction to occur usually at 100 to 250°C for 5 minutes to 6 hours.

The starting material carboxylic acid ( ) used in the above reaction formula is a known compound, and some of the hydrazine derivatives ( ) are known compounds, but they also include new compounds, and these new compounds are similar to known ones. For example, the following reaction formula -
Manufactured by the method shown in

[In the formula, R ³ is the same as above] In the reaction formula -, the reaction between the carboxylic acid () and hydrazine hydrate (a) is carried out under the same conditions as the reaction of the compound () and the compound () in the above reaction formula -. It can be done with

The compound of general formula () can also be produced by the method of reaction formula -.

[In the formula, R ¹ , R ² and A are the same as above, R ³ ' is a group -
COR ¹ ] In the reaction formula -, the reaction between compound (a) and phosphorus pentasulfide is carried out without a solvent or in a solvent. As the solvent used, aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene, halogenated hydrocarbons such as chlorobenzene and bromobenzene, and ethers such as dimethoxyethane and diphenyl ether can be used.
The reaction temperature is usually 80-300℃, preferably 100-210℃
℃, and the reaction time is about 5 minutes to 20 hours. The amount of phosphorus pentasulfide to be used is usually at least the same mole, preferably from the same mole to twice the mole of the compound ().

The compound of general formula () can be further reacted with the following reaction -
It can also be manufactured by the following method.

[In the formula, R ² , A and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as above, and R ⁴ represents a lower alkyl group] That is, the general formula (Ib The compound represented by ) can also be produced by reacting a hydrazine derivative (b) with a tri-lower alkyl orthoformate ().
This reaction is carried out without a solvent or in the presence of a solvent. The solvent used is a high boiling point solvent such as aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as dimethoxyethane, diphenyl ether, and dioxane. The reaction temperature is 50-250°C, preferably 80-200°C, and the reaction time is 1-40 hours, preferably 1-20 hours. The ratio of the hydrazine derivative (b) and the tri-lower alkyl orthoformate () to be used is selected from a range of 1 to a large molar excess of the latter relative to the former, preferably 2 to 50 times by molar.

The thiocarbostyryl derivative, which is the compound of the present invention, can also be converted into another target substance, the carbostyril derivative, as shown in the following reaction formula-V.

[In the formula, R ¹ and R ² are the same as above] In the reaction formula -, the reaction of converting compound (b) to compound (c) is carried out by heating in an acidic solvent in the presence or absence of a mineral acid. It can be obtained by Examples of acidic solvents include trifluoroacetic acid, acetic acid, and propionic acid. Mineral acids used include hydrochloric acid, sulfuric acid, nitric acid, and the like. Preferably, the reaction is carried out in sulfuric acid-acetic acid. The reaction temperature is 50-200℃, preferably 100-120℃, and the reaction time is usually 5-20℃.
Finish in time.

In the compound of the present invention, a compound unsubstituted at the 1-position can be converted into a compound substituted at the 1-position by the method shown in the following reaction formula.

[In the formula, R ² ' represents a lower alkyl group, phenyl lower alkyl group, or lower alkenyl group, and X represents a halogen atom. A, R ¹ , Z, B and the carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above.] The reaction between the compound of general formula (d) and the compound () can be carried out in an appropriate manner, for example, in the presence of a basic compound. It is best to carry out the test in a suitable solvent. As a basic compound,
Examples include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. In addition, as a solvent, for example,
Examples include ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethysulfoxide, and hexamethylphosphoric triamide. The ratio of the compound of general formula (d) and the compound of general formula () to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably It is preferable to use about equimolar to twice the molar amount. The reaction is usually carried out at around 0 to 70°C, preferably around 0°C to room temperature, and generally
It will finish in about 0.5 to 12 hours.

Among the compounds represented by the general formula (), those having a basic group can form a salt with a pharmaceutically acceptable acid. Such acids include sulfuric acid, nitric acid,
Examples include inorganic acids such as hydrochloric acid and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, succinic acid, fumaric acid, and acetic acid.

The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation methods, extraction methods, recrystallization methods, column chromatography, and preparative thin layer chromatography.

The compounds of the invention can be administered to animals and humans neat or with conventional pharmaceutical carriers. There are no particular restrictions on the dosage form, and conventional forms can be selected and used as appropriate; for example, oral dosage forms such as tablets, granules, and oral solutions, and parenteral dosage forms such as injections may be employed. The amount of the active ingredient to be administered is appropriately selected from a wide range, but in order to achieve the desired effect, it is recommended to administer 0.1 to 300 mg per day.
It is preferable to administer mg/Kg once or in divided doses. It also contains 1 to 500 mg of active ingredient in dosage unit form.
It is better to include it.

In the present invention, oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. For example, tablets may contain gelatin, starch, lactose,
It is mixed with conventional pharmaceutical excipients such as magnesium stearate, talc, gum arabic, etc., and shaped. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. Moreover, parenteral preparations such as injections are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving or suspending the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline.

Next, raw material compounds for producing the compounds of the present invention and production examples of the compounds of the present invention are listed below as Reference Examples and Examples.

Reference example 1 28g of methylcyclohexanecarboxylate and
Dissolve 15 g of 85% NH ₂ NH ₂ .H ₂ O in 50 ml of isopropyl alcohol and heat under reflux for 10 hours. After concentration,
Add water and collect the precipitated crystals, wash with water, and recrystallize from water to obtain 20 g (71.4%) of cyclohexane carbohydrazide in the form of colorless needles. Melting point 155.5
~156.5°C Reference Examples 2-3 The following compounds were obtained in the same manner as in Reference Example 1.

(2) Phenylacetohydrazide, colorless needle crystals, melting point 114.5-116.5℃, (3) Benzohydrazide, colorless needle crystals, melting point 112-
113℃ Reference Example 4 Add 15 g of 6-(3-carboxypropoxy) carbostyril and 9.3 ml of triethylamine to 200 ml of dimethylformamide, and add 5.7 ml of isobutyl chloroformate to this mixture under external ice-cooling and stirring.
drip. After the dropwise addition, the mixture was stirred for 30 minutes, then 11.5 g of cyclohexanecarbohydrazide was added, and the mixture was stirred for 2 hours at room temperature. Add the reaction solution to 700ml of saturated saline.
(contains 10 g of potassium carbonate) and stir overnight. When the precipitated crystals are collected, washed with water, and recrystallized from dimethylformamide, colorless needle-shaped N′-
Cyclohexanecarbonyl-4-[6-(1,2
15 g (66.5%) of dihydro-2-oxoquinolyloxy)]butyrohydrazide are obtained. Melting point 268~
269°C Reference Examples 5 to 9 The following compounds were obtained in the same manner as in Reference Example 4.

(5) N′-phenylacetyl-4-[6-(1,
2-dihydro-2-oxoquinolyloxy)]
Butyrohydrazide, pink needles, melting point 255.5~
256.5℃ (6) N′-acetyl-4-[6-(1,2-dihydro-2-oxoquinolyloxy)]butyrohydrazide, colorless needle crystals, melting point 250.5-251.5℃ (7) N′- Benzoyl-4-[6-(1,2-dihydro-2-oxoquinolyloxy)]butyrohydrazide, colorless solid, melting point 232.5-233.5℃ (8) N'-cyclohexanecarbonyl-4-[6
-(1,2,3,4-tetrahydro-2-oxoquinolyloxy)]butyrohydrazide, colorless needle crystals, melting point 253.5-254℃ (9) 4-[6-(1,2-dihydro-2 -oxoquinolyloxy)]butyrohydrazide, colorless needle crystals, melting point 223-226℃ Reference example 10 To 150 ml of dimethylformamide, add 10 g of 6-(3-carboxypropoxy) carbostyryl and 6.2 ml of triethylamine, and add external Add 5.7 ml of isobutyl chloroformate dropwise while stirring on ice. After the dropwise addition, stir for 30 minutes, add 4.99 g of methyldithiacarbazate, and stir at room temperature for 3 hours. The resulting reaction solution was mixed with 500 ml of saturated saline (K ₂ CO ₃ 5
g) and collect the precipitated crystals. After washing with water, recrystallization from dimethylformamide yields pale yellow crystals of N'-methylthiothiocarbonyl-4.
7.1 g of -[6-(1,2-dihydro-2-oxoquinolyloxy)]butyrohydrazide is obtained. melting point
221-225°C Example 1 100ml of triethyl orthoformate is added to 6g of 4-[6-(1,2-dihydro-2-oxoquinolyloxy)]butyrohydrazide, and heated under reflux for 20 hours. The reaction system remains in suspension. After the reaction, insoluble materials are removed and the mother liquor is concentrated. Approximately 100 ml of chloroform was added to the residue and heated to remove insoluble materials, the mother liquor was concentrated, and the residue was subjected to silica gel column chromatography (chloroform: methanol =
8:1). Recrystallization from ethanol yields 0.5 g (8%) of 6-[3-(1,3,4-oxadiazol-5-yl)propoxy]carbostyryl in the form of colorless needles. Melting point 201-202℃ Example 2 N'-cyclohexanecarbodenyl-4-[6
Add 120 g of polyphosphoric acid to 3 g of -(1,2-dihydro-2-oxoquinolyloxy)]butyrohydrazide and heat at an oil bath temperature of 190 to 210°C for 10 minutes with occasional stirring. After cooling, the reaction solution was poured into 400 ml of ice water and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (chloroform:methanol=20:1). Recrystallization from chloroform-petroleum ether gave yellow needle-shaped crystals of 6-[3-(2-cyclohexyl-1,
00.4 g (14%) of 3,4-oxadiazol-5-yl)propoxy]carbostyryl is obtained. melting point
160-161.5°C Examples 3-4 The following compounds were obtained in the same manner as in Example 4.

(3) 6-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyril, yellow granular crystals, melting point 181-183℃ (4) 6-[3- (2-henzyl-1,3,4-oxadiazol-5-yl)propoxy]carbostyryl, yellow needle-like crystals, melting point 150-151°C Example 5 N'-cyclohexyl-4-[6-(1, 2,
Add 80 g of polyphosphoric acid to 2 g of (3,4-tetrahydro-2-oxoquinolyloxy)]butyrohydrazide and stir for 1 hour at an oil bath temperature of 130 to 140°C.
Pour the reaction solution into 200 ml of ice water, extract with chloroform, wash with water, and dry with sodium sulfate. After concentration, purify by silica gel column chromatography (ethyl acetate). Recrystallization from chloroform-petroleum ether gives colorless needle-like crystals of 6-[3-(2-
0.31 g (15.7%) of cyclohexyl-1,3,4-oxadiazol-5-yl)propoxy]-3,4-dihydrocarbostyryl is obtained. Melting point 112.5
~113°C Examples 6-8 The following compounds are obtained in the same manner as in Example 5.

(6) 1-allyl-6-[3-(2-cyclohexyl-1,3,4-oxadiazol-5-yl)propoxy]-3,4-dihydrocarbostyryl, colorless needle crystals, melting point 142.5~ 145.5℃ (7) 5-[3-(2-cyclohexyl-1,3,
4-Oxadiazol-5-yl)propoxy]-3,4-dihydrocarbostyryl, colorless needle crystals, melting point 162.5-165℃ (8) 6-[4-(2-cyclohexyl-1,3,
4-Oxadiazol-5-yl)propoxy]-3,4-dihydrocarbostyryl, colorless needle crystals, melting point 105-108°C Example 9 N'-acetyl-4-[6-
(1,2-dihydro-2-oxasoquinolyloxy)] Add 1 g of butyrohydrazide and heat to 120-140°C.
Stir for 2 hours. After cooling, add about 200ml of water and neutralize with potassium carbonate. Extract with chloroform, concentrate, and purify by silica gel column chromatography (chloroform:methanol = 10:1). Recrystallization from chloroform-petroleum ether yields a colorless solid 6-[3-(2-methyl-1,3,
4-oxadiazol-5-yl)propoxy]
0.23 g (24.4%) of carbostyril is obtained. melting point
168-170.5℃ Example 10 N′-Cyclohexanecarbonyl-4-[6-
(1,2-dihydro-2-oxoquinolyloxy)] 25 g of butyrohydrazide and 25 g of phosphorus pentasulfide are mixed and heated in an oil bath temperature of 190 to 210°C for 10 minutes. After cooling, pour into 5% aqueous sodium hydroxide solution,
Stir and remove insoluble matter. The mother liquor is acidified with hydrochloric acid and the precipitated crystals are collected. The resulting insoluble materials are combined and purified by silica gel column chromatography (chloroform:methanol=8:1). Purification was again performed using silica gel column chromatography (chloroform:methanol = 30:1), and recrystallization from chloroform resulted in yellow scale-like crystals of 6-[3-
6.5 g (25%) of (2-cyclohexyl-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbostyryl are obtained. Melting point 221-223℃ Example 11 N]-cyclohexanecarbonyl-4-[6-
(1,2,3,4-tetrahydro-2-oxoquinolyloxy)] 25 g of butyrohydrazide and 25 g of phosphorus pentasulfide are thoroughly mixed and reacted for 5 minutes at an oil bath temperature of 190 to 200°C. After cooling, pour into 800 ml of 2% aqueous sodium hydroxide solution and extract with chloroform.
Wash the chloroform layer in the order of water, dilute hydrochloric acid, and water.
Dry with sodium sulfate. The residue is purified by silica gel thin layer chromatography (chloroform:methanol = 8:1), and a fraction with an Rf value of 0.8 is taken. Recrystallized from ethanol to give a yellow solid 6-[3-(2
-Cyclohexyl-1,3,4-thiadiazol-5-yl)propoxy]-thiocarbostyryl
Obtain 1.4g (5.4%). Melting point 221-223℃ Example 12 6-[3-(2-cyclohexyl-1,3,4
Add 20 ml of 20% sulfuric acid and 10 ml of acetic acid to 1.5 g of -thiadiazol-5-yl)propoxy]-thiocarbostyril, and heat under reflux for 18 hours. The reaction solution was made alkaline with sodium hydroxide and extracted with chloroform. The chloroform layer is washed with water and diluted hydrochloric acid in that order, and dried over sodium sulfate. After concentration, it is purified by silica gel column chromatography (chloroform:methanol=30:1). When recrystallized from chloroform, colorless prismatic crystals of 6-[3
-(2-cyclohexyl-1,3,4-thiadiazol-5-yl)propoxy]carbostyryl 0.8 g (55.6%) is obtained. Melting point 224-227.5℃ Example 13 N'-methylthiothiocarbonyl-4-[6-
Add 100 g of p-toluenesulfonic acid and 300 ml of benzene to 10 g of butyrohydrazide (1,2,3,4-tetrahydro-2-oxoquinolyloxy), and reflux for 10 hours in a Dean Stark apparatus. . The reaction solution is concentrated, and the residue is extracted with chloroform, washed with an aqueous sodium bicarbonate solution and water, and then dried over sodium sulfate.
After concentration, recrystallization from aqueous methanol yields white crystals of 6-[3-(2-methylthio-1,3,4-
Thiadiazol-5-yl)propoxy]-3,
9.1 g (96.5%) of 4-dihydrocarbostyryl are obtained. Melting point 142.5-145℃ Example 14 6-[3-(2-methylthio-1,3,4-thiadiazol-5-yl)propoxy]-3,4
-Dissolve 1.7 g of dihydrocarbostyril in 30 ml of dimethylformamide, and add 50% dihydrocarbostyril while stirring on ice.
0.28 g of NaH (oil-based) is added, stirred for 1 hour under ice cooling, and then 0.85 g of methyl iodide is added dropwise thereto. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water and extracted with chloroform. After washing with water, concentrate and perform silica gel column chromatography (solvent:
Purify with ethyl acetate). Recrystallization from chloroform-petroleum ether gives colorless needle-shaped crystals of 1-methyl-6-[3-(2-methylthio-1,3,4-thiadiazol-5-yl)propoxy]3,4-
1.6 g of dihydrocarbostyril is obtained. Melting point 98~
100°C Examples 15-16 The following compounds were obtained in the same manner as in Example 14.

(15) 1-Benzyl-6-[3-(2-methylthio-1,3,4-thiadiazol-5-yl)
Propoxy]-3,4-dihydrocarbostyryl, colorless needle crystals, melting point 101-102℃ (16) 1-allyl-6-[3-(2-cyclopropyl-1,3,4-oxadiazole-5) -il)propoxy]carbostyryl, colorless needle crystals, melting point 62-65℃

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group, or a lower alkylthio group, R ² is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group, A is a lower alkylene group,
B and Z each represent an oxygen atom or a sulfur atom. Further, the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond] and a salt thereof.