JPS58110568A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:The titled compound of formulaI(R is lower alkanoyl, lower alkoxycarbonyl, furoyl, lower alkanesulfonyl, etc.; A is lower alkylene; the C- bond between the 3- and 4-positions of the carbostyril skeleton is single or double) and its salt. EXAMPLE:6-[4-(3,4,5-Trimethoxybenzoyl)-1-piperazinylacetyl]-3,4-dihydr ocarbostyril.monohydrochloride.3/2-hydrate. USE:A cardiotonic drug useful for the remedy of cardiac diseases such as congestive heart failure, etc. It has high positive inotropic activity and coronary vessel flow increasing activity, and nevertheless has weak activity to increase the heart rate. PROCESS:The compound of formulaIcan be prepared e.g. by reacting 3,4-dihydrocarbostyril with the compound of formula III (X and X' are halogen) in a solvent in the presence of a Lewis acid, and reacting the resultant compound of formula IV with the piperazine derivative of formula V in the absence of a solvent or in an inert solvent.

Description

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

The carbostyril derivative of the present invention has the following general formula % [wherein R is lower grade]. Lucanoyl group, lower? Ruco↑dicarbonyl group, )0yl group, lower? lukansulfonyl group, 1-3 groups selected from lower P lutol, low @P ruco + si, halopun, cyano, P trino and nido D groups as substituents on the phenyl ring] -< is Refers to a pensoyl group which may have a lower aryl group or a phenylsulfonyl group which may have a lower aryl group substituted on the phenyl ring F. A indicates lower Al↑Ren-o. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. The present invention also includes salts of the carbostyril derivative represented by the above general formula (1), ie, pharmacologically acceptable acid addition salts of the derivative.

The compound of the present invention represented by the above general formula (1) and its pharmacologically acceptable acid addition salts have an effect of enhancing myocardial contraction, causing a inducing effect (positive inotropic effect), and an effect of increasing coronary flow. Therefore, it is effective as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure, HF syndrome, atrial fibrillation, flutter, and paroxysmal atrial tachycardia. In particular, secondary compounds are
It has an excellent positive inotropic effect and an effect of increasing coronary blood flow, but is characterized by an extremely weak effect of increasing heart rate.

As each group defined by R in the above general formula (1), the following groups can be specifically exemplified.

Low class? Lucanoyl &---fortriyl, a7tyl, zuohisayil, butyryl, isobutyryl, pentanoyl, tz
1 carbon number such as rt-butylcarbonyl, hesanoyl group, etc.
-6's? Also based on Lucanoi.

Low class? ruco + dicarbonyl & --- meth ↑ dicarbonyl, etho + cycarunyl, zuOpoya dicarbonyl, isopropof cyclodicarbonyl, zuto+dicarbonyl, tlrt
-Alco+ having 1-6 carbon atoms such as buto, dicarbonyl, benzylo-dicarbonyl, he+silo+dicarbonyl group, etc.
A lower alkanesulfonyl group containing a dicarbonyl group - methanesulfonyl, ethanesulfonyl, panesulfonyl, isopanesulfonyl, butanesulfonyl, tansulfonyl, pentansulfonyl, etc. C1-6 alkanesulfuranyl groups such as sulfonyl groups.

Lower phenyl ring as a substituent? benzyl &---pen which may have 1-3 groups selected from ru↑ru, lower Pruco+cy, ha0py1cyano, amino and nido0 groups or lower alk+17ydio↑cy group・Noil,
2-13- or 4-rioohetriyl, 2-13-
or 4-fluorobennoyl, 2-13- or 4-diOmhennoyl, 2- or 4-iodopendiyl, 3.5-670% bydiyl, 2,6-di[]0 ps. Noyl, 3,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4,5-1-cyclobenzyl J triyl 2-13- or 4-methylpen9yl, 2-1
3- or 4-1 tilbeniJ%)yl, 3-isodu0
Jirupesi noi 1, go to 4-↑Silpen reire, 3,4
-dimethylpenlyyl, 2,5-dimethylpenlyyl,
3.4.5-trimethylpenlyyl, 2-13- or 4-med+sibe:/diyl, 2-. 3-4. L<ti
4-1to+sibenlyyl, 4-isoduO+sibe:Jdiyl, 4-to+silo+sibenlyyl, 3.4-dimeth↑cypenlyyl, 3,4-shed+cypenlyyl, 3,
4.5-1-rimeth + cypenlyl, 2,5-dimeth↑
Sibenlyyl, 2-13- or 4-di-D-penlyyl, 2,4-dinito-D-benlyyl, 2-13- or 4-domo-minohenlyyl, 2,4-di-P-trinobendiyl,
2,3-diaminopenlyl, 3,4-diaminopenlyl, 2,5-diaminopenlyl, 3,4,5-
Torito Sannobenriyl, 2-13- or 4-cyanobenlyl, 2,4-dicyanobenlyyl, 3,4-methylenedio+cyhenriyl, 3.44-methylenedio+cybenfil, 2,3-methylenedioyl +Sibenriil, 3
-Alkyl groups with 1-6 carbon atoms on the phenyl ring, such as methyl-4-ri00benryyl, 2-200-6-methylhenlyyl, 2-meth↑cy3-ri00benlyyl groups, carbon atoms 1-6 Pruco + cy group, hegen atom, shidono group,
A benzoyl group which may have as a substituent 1-3 groups selected from the group consisting of an amino group and a nido-O group or a C1-4 alkyl+dio+si group; Phenylsulfonyl salts that may have a Pru+ru group: phenylsulfonyl, toluenesulfonyl, 2-methylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-jOpylphenylsulfonyl, 2-butylphenylsulfonyl,
3-ttrt-dutylphenylsulfonyl, 3,4-
1-carbon atoms such as dimethylphenylsulfonyl, 3,4.5-1-dimethylphenylsulfonyl, 4-pentylphenylsulfonyl, 2-f-sylphenylsulfonyl group, etc.
A phenylsulfonyl group which may have 1 to 3 substituents of the Pru+ru group of 6.

Further, the lower alkali group defined by A in general formula (1) is specifically, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1- Methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene,
An example is an al+lene group having 1 to 6 carbon atoms such as a sameethylene group.

The method for producing the compound of the present invention will be described in detail below.

The compounds of the present invention can be produced by the methods shown in the following reaction schemes.

[Reaction Scheme-1] 1 (2) (4) (1) [In each formula, R, A, and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton are the same as above. X and X each represent a 0-pun atom. ] That is, the compound of the present invention is obtained by reacting 3,4-dihydrogalbostyryl with the compound of general formula (3), and then reacting the compound of general formula (4) with the compound of general formula (5). Manufactured by reacting Nojiperazine derivatives.

The above 3.4-dihydrocarbostyryl (2) and the general formula (
The reaction with the compound 3) is generally called the Friedel-Krach reaction, and is usually caused by the presence of a Lewis acid in the solvent.
It will be held in As solvents, those commonly used in reactions of this type can be used, such as carbon disulfide, nitropenzene, dilupenzene, dichloromethane, dichloroethane, trichloride, etc.
Ruethane, tetrachloroethane, etc. can be used. Any conventional Lewis acid can be suitably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be determined appropriately, but usually 3,
The amount is about 2 to 6 times the molar amount, preferably about 2 to 4 times the molar amount of 4-dihydrosulposol (2). 3,4-dihydrobostyril (2) of the compound of general formula (3)
), the amount used is usually at least the same amount, preferably equal to the amount minus 2 times the amount. The reaction temperature is selected appropriately, but is usually about 0-12oC, preferably 0-12oC.
It is preferable to change the temperature by about 70°C. The reaction time varies depending on the raw materials, catalyst, reaction temperature, etc. - Although it cannot be generalized, it is usually 0.5
The reaction is completed in about -6 hours.

The reaction of the thus obtained compound of general formula (4) with the jibezin derivative (5) is carried out without a solvent or in a common inert solvent at room temperature of about -200'C, preferably room temperature -120'C.
'c (7) fat condition de, 1-24 hours + ll Aromatic hydrocarbons such as bempine, toluene, and silane, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, dimethyl sulfonate, methyl phosphate tripamide, and acetate. Polar solvents such as , acetonitrile and the like can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. The basic compound also includes the Pipera":ry derivative itself, which is used as a raw material. If this is used in an excess amount, there is no need to use other basic compounds, but for example, norium carbonate, sodium carbonate, water, etc. Tertiary compounds such as sodium oxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, triglyamine, golysine, denoline, etc. can be used.The above reaction can be carried out as necessary. The reaction can also be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triatride as a reaction accelerator. The ratio of use with 5) is not particularly limited and is appropriately selected within a wide range, but
Normally, it is preferable to set the latter in excess of the former by an equal amount of 7 ru by 5 times t.

Incidentally, the diperazine derivative represented by the general formula (5) used as a raw material in the above partially includes new compounds, and these can be used in the method shown in the reaction scheme -2 or -3 described later. It can be easily produced in the same manner using perazine instead of the carbostyryl derivative represented by (6).

[Reaction Scheme-2] (6) (1-a) [In each formula, A and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyryl skeleton are the same as above. R is a lower alkanoyl group, a lower alko+dicarbonyl group, a)0yl group, or a substituent on the phenyl ring, such as lower Prudel, lower Ruko+Si, AOpun,
It represents a benlyyl group which may have 1 to 3 groups selected from cyano, amino, and nido groups or a lower alkyl+dio+si group. ] That is, among the compounds of the present invention, those represented by the above general formula <L-11) are obtained by reacting the carbostyryl derivative of the general formula (6) with the carboxylic acid of the general formula (7) or an active compound of the carboxy group thereof. The above reaction may be carried out by a normal amide bond forming reaction.

Examples of the #P amide synthesis reaction include the following method.

(a) Mixed-anhydride method, that is, a method in which carboxylic acid (7) is reacted with P or R carboxylic acid to form a mixed acid anhydride, which is then reacted with the derivative of general formula (6).

0 active ester method, i.e., carboxylic acid (7) is converted into an active ester such as a do-nito phenyl ester, an N-shido0+shichohelic acid imide ester, and a l-1-shido+shichoheliaryl ester. A method of reacting a derivative of general formula (6) with.

09 Carbosiimide method, i.e. carposi acid (7),
Method b in which a derivative of general formula (6) is condensed in the presence of an activating agent such as dimethylcarbodiimide, carbonylsilyl, 11%)-(b) Other methods, such as carbon #(7) is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and a method of reacting the derivative of general formula (6) with the carboxylic acid anhydride, carboxylic acid (7)
A method of reacting a derivative of the general formula (6) with an ester of a lower alcohol and a derivative of the general formula (6) under high pressure and high temperature. A method in which carboxylic acid (7) is activated with a phosphorus compound such as triphenylphosphine or diethyl sulfate, and a method in which a derivative of general formula (6) is reacted with the activated carboxylic acid (7).

The mixed acid anhydride used in the mixed acid anhydride method shown in (O) above is obtained by the usual Schotten-Baumann reaction, and is usually reacted with the derivative of general formula (6) without isolation. The compound of the present invention having the general formula CL-tl) is produced by the following steps. The Soten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound, the derivative of the above general formula (6) itself or a compound commonly used in the Schotten-Baumann reaction, such as triethylamine,
Trimethylamine, lysine, dimethylaniline, ■-
Methyl heptalforine, 1,5-diazapisic o (4,3
+O) None:, l-5CDB'ri, 1,5-diazadischif0 [fu4.0] Undacene-5 (DBU), 1,4
-Ziazajishi90c2,2-2]199:,tCDAB
CO)Ill(D Organic bases and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. are mentioned. The reaction is carried out at -20-100"C, preferably o-5oc, and the reaction time is Approximately 5 minutes
10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the derivative of general formula (6) is about -
The reaction is carried out at 20-150°C, preferably about 10-50°C, and the reaction time is 5 minutes-10 hours, preferably 5 minutes-5 hours. Mixed anhydride methods are generally carried out in a solvent.

The solvent used is a solvent commonly used in the mixed acid anhydride method, specifically, hepified hydrocarbons such as methylene chloride, RI00 form, and ZinOO ethane, and aromatic hydrocarbons such as benzene, toluene, and t-silene. , diethyl ether, tetrahydrofuran, ethers such as dimeth+thiane, methyl acetate,
Examples include monoesters such as ethyl acetate, non-polyte polar solvents such as N,N-dimethylformamide, dimethylsulfocytate, and hexamethylphosphoric triamide.

Examples of the aryl carboxylic acids used in the mixed acid anhydride method include 00 methyl formate, 70 methyl formate, 90°C ethyl formate, 00 isobutyl formate, and the like. In this method, the ratio of the carboxylic acid (7) and the derivative of the general formula (6) of the FIL↑ru80kayamoto carboxylic acid (6) is usually at least an equal amount of the latter to the former, preferably about the same amount. The amount is 1-2 times the temperature.

Also, the carboxylic acid parite shown in the above) and the general formula (6)
When employing a method of reacting with a derivative of , the reaction is carried out in a suitable solvent in the presence of a tetrafunctional compound. As the basic compound, a wide variety of known compounds can be used. For example, in addition to the basic compounds used in the above-mentioned Schisten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. can be mentioned. . Examples of solvents include, for example, the solvents used in the Schotten-Baumann reaction described above, as well as alcohols such as methanol, ethanol, 2-butanol, 3-methoxy-1-tanol, ethyl tO sorb, methyl ceO sorb, etc. Examples of the solvent include silane, attonitrile, attonitrile, etc., or a mixed solvent of two or more of the above-mentioned solvents. The ratio of carboxylic acid parite to the derivative of general formula (6) is not particularly limited and may be appropriately selected within a wide range, but it is usually at least the same amount, preferably approximately 5 times the amount of Good. The reaction is usually -20-
The reaction is carried out at about 180'C, preferably O-150'C, and the reaction is generally completed in 5 minutes to 30 hours.

J Reaction Scheme-3] (6) (14) [A in each formula
And the carbon-carbon bonds between the 3rd and 4th positions of the carnestyril skeleton are the same as above. R represents a lower alkanesulfonyl group or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. X2 represents a hepone atom. ] That is, among the compounds of the present invention, those represented by the above general formula <1-b) can also be produced by reacting the carbostyryl derivative of general formula (6) with a compound represented by general formula (8). can.

The reaction between the derivative of the general formula (6) and the compound of the general formula (8) is performed using the general formula (6) as detailed in the reaction scheme-2 above.
Conditions similar to those for the reaction of derivatives of with carboxylic acid halides F
will be implemented.

The compound of the present invention can also be produced as follows.

[Reaction scheme-4j (4) (it) (b)
(1) [In each formula, X, R, A and the 3rd and 4th positions of the carnestyril skeleton
The carbon-carbon bond with the position is the same as above. R1X3 represents a D hepne atom, a lower alkanesulfonyloxy group, an aral + sulfonyloxy group, or a hydroxyl group. ] That is, the compound of the present invention can be obtained by reacting a compound of general formula (4) with a compound of formula - or formula (b), and then reacting the resulting compound of general formula (2) with the compound after debenzylation or deacylation reaction. It is produced by reacting the compound of general formula (b) with.

In the above, a compound of general formula (4) and a compound of formula (2) or (
The reaction with the compound b) can be carried out under the same conditions as the reaction with the compound Tojipelagishi derivative (5) of general formula (4) shown in Reaction Scheme-1 above.

The debenzylation reaction of the compound of the general formula (b) obtained above can be carried out under the conditions F of the usual de-N-benzylation reaction. For example, specifically, the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, etc. in a suitable solvent,
It takes about 0.5 to 3 hours at 0° C. to room temperature. Examples of solvents include water, methanol, ethanol,
Lower alcohols such as isopropanol, geo+san,
Ethers such as tetrahedron, acetic acid, etc. can be used.

Further, the desilation reaction of the compound of the general formula ○bar is carried out in the same manner as a usual hydrolysis reaction. For example, it is carried out in water or an alcohol such as methanol or ethanol using an inorganic base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or hydrobromic acid.

In this way, a compound of general formula (to) is obtained. The reaction between the compound and the compound of general formula 04 is carried out as follows depending on the type of compound of general formula α◆ used, particularly the group represented by X.

In general formula 04, the halogen atom represented by ethanesulfonyl, iso,
Pasisulfonyluo↑shi, puat\sulfonyluoshishi,
Examples include butanesulfonyloxy, l I : r t ~ butanesulfonyloxy, pentansulfonyloxy, he+sanesulfonyloxy, and the like, and specific examples of the aral+rusulfonyloxy group include Henzylsulfonyl, 2-phenylethylsulfonyl, 4-phenylbutylsulfonyl, 4-methylbenzylsulfonyl, 2-methylbenzylsulfonyl, 4-phenylsulfonyl Substituted or unsubstituted aral or sulfonyl group such as 0-by-dibenzylsulfonyl group, 4-metho+dibenzylsulfonyl group, 3-dibenzylsulfonyl group, α-naphthylmethylsulfonyl group, etc. The onasi group may be exemplified, i.e., when using a compound in which The reaction between the compound of formula (2) and the compound of general formula (2) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. As an inert solvent,
For example, low-grade aromatic hydrocarbons such as Penbisi, Toluay, + Shiren exclusive, methanol, ethanol, isopropanol, butanol, etc. Alcohols, acetic acid, ethyl acetate, dimethylsaccharide, homocyto, dimethylformamide, hedegumethylphosphoric acid triazide, etc. can be mentioned. 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; sodium methylate; Compounds of the general formula (to) and the general The proportion of the compound to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually used at least in an equal amount to the former, preferably at least 5 times the amount of Mori. Good. The reaction is usually carried out over 40-120' (
1 degree, preferably Vi50-100. 'Carried out at C.
Generally, the reaction is complete in about 5 to 30 hours.

Furthermore, when using a compound in which X represents a hydroxyl group among the compounds of general formula 〇4, the reaction between the compound of general formula (to) and the compound of -ff formula
It is carried out without solvent F or in a suitable solvent. Examples of dehydration condensation agents include condensed phosphoric acids such as polyphosphoric acid, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, and metaphosphoric acid, anhydrous substances such as biphosphorous acid, I# cheek, and phosphorus pentoxide. Acids such as phosphoric acid, hydrochloric acid, sulfuric acid, boric acid, etc., metal phosphates such as sodium phosphate, poron phosphate, ferric phosphate, phosphoric acid, etc., activity? Examples include sodium chloride, sodium bisulfate, and Raney nickel. Examples of the solvent include high boiling point solvents such as dimethylformamide and tetralin.1 The ratio of the compound of general formula (2) and the compound of general formula (2) to be used is not particularly limited and may be within a wide range. The latter can be selected as appropriate, but usually the former is equal to or less than the latter, preferably equal to or less than 2.
The amount of the dehydration condensing agent to be used is not particularly limited and can be appropriately selected from a wide range;
Usually catalytic amount or more, preferably 0.5-
It is preferable to use about 5 times °C ffl. The above reaction is preferably carried out in an inert gas stream, such as carbon dioxide or nitrogen stream, for the purpose of preventing oxidation reactions.

The above reaction can be carried out either at normal pressure or under pressure, but it is preferable to carry out the reaction at normal pressure F. The reaction temperature is usually about 100-350'C, preferably 12
The temperature is S -'255°C, and the reaction is generally completed in about 3 to 10 hours. In the above reaction, the compound of general 204 may be used in the form of a salt [Reaction scheme-5] (1) [In the formula, "・'・The carbon-carbon bond with the position is the same as above.] The degree of the compound of general formula (2) and the compound of general formula (2) is the same as that of the general formula (2).
The reaction can be carried out under the same conditions as the reaction between the compound of formula (3) and the compound of general formula (3).

[Degree equation-6] ()O [In the formula, R and A are the same as above. ] Normal catalytic reduction conditions are applied to the reduction of the compound of general formula (1-d). Examples of the catalyst that can be used include metals such as palladium, palladium-carbon, plana i, and Raney nickel, and it is preferable to use such metals in normal catalytic amounts. Examples of solvents that can be used include methanol, ethanol, isopropanol, and
Examples include s fH' s, cyclo, ethyl acetate, and the like. The reduction reaction can be carried out both at normal pressure and under elevated pressure, but it is usually carried out under normal pressure -20 to 90°C.
/d, preferably at normal pressure -101 W/d.

The reaction temperature is usually about 0-150'C, preferably room temperature -100'C.

Further, the dehydrogenation reaction of the compound of general formula (1-) is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include 2,3-;
Benryanones such as Obenry+Non), M-prosuccinimide, N-Riooctahedylimide, hepifying agents such as bromine, t-rene bodium carbon dioxide, palladium black, oxidation Mention may be made of hydrogenation catalysts such as palladium and Raney nickel. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually 1-5 times the amount of the compound of general formula (x-d), preferably 1-2 times the amount of the oxidizing agent. It is best to use the same amount.

Further, when a hydrogenation catalyst is used, a normal amount of catalyst may be used. In addition, as a solvent, diofine, THF, ethers such as jetanol in methane, dimeth+thiane, aromatic hydrocarbons such as penpine, toluene, +thione, and cumene, Zig00 methane, Zig00 ethane, and 00 form, carbonated hydrocarbons such as carbon tetrachloride, butanol, ? Examples include alcohols such as alcohols, alcohols, polar solvents such as acetic acid, and non-polar solvents such as DMF, DMSOl, and methyl phosphate triphosphate. . The reaction is usually carried out at room temperature -300'C, preferably room temperature -200'C, and is generally completed in about 1 to 40 hours.

Furthermore, among the compounds of the present invention represented by the general formula (1), compounds in which the carbon-carbon bond between the 3-position and the 4-position of the carbostyryl skeleton are two-way bonds, as shown in reaction scheme-7, f.
Lactamulactim can be tautomeric.

[Reaction formula-7] 0 Q<L
-d) (1-t) [In the formula, R and A are the same as above. ] 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 nucleic acids 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, phosphoric 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. The separation means include, for example, solvent extraction method, dilution method, recrystallization method, columnar extraction method, pre-bar tape thin layer method, etc.
An example of this is Madclawy et al.

Incidentally, the present invention naturally also includes optical isomers.

The compound of the present invention represented by general formula (1) or a salt thereof is usually used in the form of a common pharmaceutical preparation.

The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, 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, emulsions, powders, solutions, suspensions, emulsions, granules,
Examples include forceps, suppositories, injections (solutions, suspensions, etc.).When forming tablets, a wide range of carriers known for this decomposition can be used, such as lactose, sucrose, etc. , sodium chloride, glucose, urea, sugar
, excipients such as charcoal-based calcium, kaolin, crystalline cellulose, silicic acid, water, ethanol, polymer, monosulfur, glucose solution, bubble solution, gelatin solution, carboxydimethylcellulose , shellac, methylcellulose, potassium phosphate, binder such as polyvinylhydrone, dried dandelion, sodium alkiophosphate, kasiten powder,
Usanaran powder, sodium bicarbonate, calcium carbonate,
Disintegrants such as polyol + diethylene sorbitan fatty acid esters, thorium lauryl, stearin #7-nocryceride, dunan, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary amneptinium bases, lauryl Absorption enhancers such as sodium sulfate,
Moisturizing agents such as glycerin and Danlan, Danlan, lactose,
Adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, hontsu powder, and polyethylene glycol can be used.

Furthermore, if necessary, the tablets can be coated with a conventional coating to form nine tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, intestinal fluid-coated tablets, film-coated tablets, double tablets, or multilayer tablets.

When shaping into an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, Zanzin, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; Binding agents such as powdered powder, powdered tomato powder, gelatin, and ethanol, and disintegrants such as lamialan and kacchi can be used. When molding into a half-open form, a wide range of conventionally known carriers can be used, such as polyethylene dilicol, cacao butter, higher alcohols, higher alcohol esters, pyratine, semi-synthetic silicerite, etc. can. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood;
When forming emulsions and suspensions, any diluent commonly used in this field can be used, such as water, ethyl alcohol, hylentalicol, isostearyl silicide, etc. Alcohol, polio↑isoste silica! Lil? Luco-5, polio+thiamine, solpitan fatty acid ester, etc. can be used. In this case, the cardiotonic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isodominant solution, and ordinary solubilizing agents, buffers, soothing agents, etc. may be added. 7. Furthermore, coloring agents, preservatives, fragrances, flavoring agents, W flavoring agents, and other pharmaceutical agents may be included in the pharmaceutical preparation, if necessary.

The amount of the compound of general formula (1) or its salt to be contained in the cardiotonic agent of the present invention is not particularly limited and can be selected from a wide range, but is usually 1-70% by weight, preferably 1% by weight based on the total composition.
-30% by weight.

There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and administration may be carried out in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.

For example, tablets, emulsions, solutions, suspensions, emulsions, granules and forceps are administered orally. In the case of an injection, it can be administered intravenously alone or mixed with normal replacement fluids such as glucose or amino acids, and if necessary, it can be administered alone intramuscularly, intradermally, cutaneously, or intraperitoneally.

If it is partially opened, it is administered rectally.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc., but the dosage of the compound of general formula (1), which is usually the active ingredient, is 1&g body weight per day. It is preferable to use about 0.01-10# per unit. It also contains 0.11-21) OW of the active ingredient in dosage unit form.
It is better to use gold-containing materials.

Hereinafter, FK reference examples and examples will be given.

Reference example 1 3.4-Dihydrocarbostyryl 200f, RiOl
Lua and chill chloride 160s/and binary Ihi carbon 30
0 wl of anhydrous P chloride ground in a water-cooled stirred mixture
Gradually add 460f of trinium 11 at an internal temperature of 5-15°C. After addition, stir under reflux for 40 minutes. After removing C52 with a dacant, the residue was poured into a large amount of ice water and the precipitated crystals were collected in a furnace, thoroughly washed with water, washed with methanol, and dried to form 2801F.
6-(2-ri OIL, Pt pre-oil)-3,4-dihydride 0
Recrystallize from ethanol to obtain colorless needle crystals.

m7: 230-231'C Reference Example 2 4.4f of diperazine and 5d of triethylamine were added to a solution of 6.7g of 6-(α-ri00acetyl)-3,4-dihydrocarbostyryl and 60-resistant anhydrous dimethylformamide. Add and stir at SO-60'C for 1 hour. The reaction solution was poured into a large amount of water and extracted with RI00 form. The 00 form layer was washed with water and dehydrated, and the 00 form was distilled off. The residue was suspended in methanol 00 form and converted into a hydrochloride with hydrochloric acid/methanol to give colorless needle crystals of 6-(4-(1- piperazinyl) a7tyl)-3,4-dihydrocarbostyryl
3.5f of monohydrochloride trihydrate is obtained.

mdo 26 S -267'C (decomposition) Reference example 3 6-di-DLP heptatiltyl, 4-di-di-drocarbostyryl 3. To a suspension of Of in 20 ml of dimethylformamide, 20 s/solution of Hetosamine 1.9F in dimethylformamide is gradually added while stirring at room temperature. 50 after fiF
Stirring at -60'C for 2 hours yields 3.5f of crude crystals of precipitated nium acetate-3,4-dihydrocarnestyryl chloride. Next, go to 6- + trinium P seven chiru 3
, 4-Coarse crystals of dishidrocarbostyryl rimelide 3
．． Add 15 g of ethanol and 6 ml of concentrated hydrochloric acid to 52,
Stir for 12 hours at room temperature, remove the crystals, and add methanol.
6-Atrinoacetyl-3, which recrystallizes from water to form colorless powder crystals.
1.21 of 4-dihydrocarnestyril monohydrochloride is obtained.

m door 300″C or more Example 1 6-(α-ri00a-7tyl)-3,4-dihydrocarbostyril 6.7g anhydrous dimethylformamide 60s
4-(3,4,5-trimetho+sibenlyyl)piperazine 14.3F and triethylamine 5d are added to the solution and stirred at 50-60'C for 1 hour.

The reaction solution was poured into a large amount of water, and the organic layer was extracted with 00 form. The 00 form layer is washed with water and dehydrated, and then the 00 form is distilled off. Crystallize the residue with ethanol and count the crystals. The crystals were suspended in methanolic OO form, converted to hydrochloride with hydrochloric acid/methanol, and recrystallized from ethanol to give colorless needle-like crystals of 6-(4-(3,4,5-trimethoxybenliylrun-1-piperazinyl). acetyl)-3,
4-dihydrocarnestyril monohydrochloride/hydrate 6
．． Get 3f.

mdo 213-217'c (decomposition) Colorless needles In the same manner as in Example 1, using appropriate starting materials, the compound of Example 2-17 is obtained.

Example 2 6-[4-(4-metho+cypenlyl)-1-hyperazinyl a7tyl)-3,4-dihydrocarnestyryl 1
Tetra-acid monohydrate mp 225-228'c Colorless powder crystal Example 3 6- (4-(4-cyanobenryyl)-1-diperazinylacetyl,) -3,4-dish Dolocarnestyril/dihydrate 254-258'C Colorless granular crystals Example 4 6-(4-(4-methylbenryyl)-1-diperazinyl-7tyl)-3,4-dihydro Carbostyril monohydrochloride monohydrate 242-244'C Colorless powder crystal Example 5 6-(4-(3,4-methylenediosilyl)-
1-Piperazinylacetyl)-3,4-dihydrocarnestyril monohydrochloride monohydrate 207-210
'C Colorless powder crystal Example 6 6- (4-(3,4-dikuOObenryl)-1=hyperazinyl acetol) -3,4-dihydrocarnestyril monohydrochloride 1/2 hydrate 227.5-229'C (decomposed) colorless powder crystal Example 7 6-(4-(4-di-0-pesylyl)-1-berazinyla-7tyl)-3,4-dihydrocarnestyryl. 1 Hydrochloride 242-245°C (decomposition) Colorless granular crystals Example 8 6-(4-(2-)0yl)-1-diperazinyl acetyl J-3,4-dihydrocarbostyryl. l Hydrochloride mp 252-255'C (decomposition) Colorless needle crystals *stream side 9 6-(4-formyl-1-piperazinyl acetyl)-3
, 4-dihydrocarbostyril 167.5-16
9°C Colorless powder crystal Example 10 6-(4-etho+dicarbonyl-1-diperazinyl acetyl)-3,4-dididrocarbostyryl monohydrochloride.
Monohydrate mp 235-237'C (decomposition) Colorless needle crystals Example 11 6-(4-acetyl-1-diperazinyl acetyl)-3
, 4-Dishidrocarbostyril・1 fill! salt 1
/Dihydrate mp 249-252 'C (decomposition) Colorless powder crystal Example 12 6-(4-dihydrate-1-piperazinyl acetyl)
-3,4-dihydrocarnestyryl monohydrochloride mp 226-228'c (decomposition) Colorless needle crystals Example 13 6-(4-methanesulfonyl-1-diverazinyl a7tyl) -3,4-dihydryl Dolocarbostyril/l hydrochloride/
3/2 hydrate mp 191-194 'C (decomposition) Colorless powdery crystal '4i! Oval Example 14 6-(4-unit=toluenesulfonyl-1-e-verazinyl P7-1)-3,4-dihydrocarbostyryl mp 254-256°C (decomposition) Colorless powder crystal Example 15 6 -(4-Penryi L-1-hyperazinyl atthyl)-
34-Dihydrocarbostyryl 1/4 hydrate mp 207-210'C Colorless granular powder crystal Example 16 6-(4-(3-900benryyl)-1-diverazinyldocetyl)-3, 4-Dididrocarbostyryl 1 lohydrate mp 231-234 'C Colorless powder crystal Example 17 6-(4-(3,4-dimeth+sibenryyl)-1-piperazinyl Pt-thyl)-3, 4-dihydrosulposulposol mp 186-188 'C Colorless powder crystal Example 18 6-(1-piperazinyl)methylgalbonyl-3,4-
Dishidrocarbostyril 2. Of and triethylamine 1,4- are dissolved in 20 d of dimethylformamide, and a solution of 5 d dimethylformamide of 2,2 f of 3,4,5-trimethoxybenryylchloride is slowly added thereto at room temperature and with stirring. After stirring at room temperature for 30 minutes, the reaction mixture is poured into a large amount of saturated brine and extracted with 900 form.After washing with water, it is dried over anhydrous sodium sulfate, and chloroform is distilled off.

The residue was crystallized with ethanol and collected. The crystals are suspended in a mixed solvent of methanol and 200% form, and the hydrochloride salt is prepared using hydrochloric acid/ethanol.The solvent is distilled off, and ethanol is added to the residue for crystallization. Recrystallize with ethanol and 6-
(4-(3,4,5-)rimeth or sibenlyyl-1-diperazinyl atthyl)-3,4-dihydrocarbostyryl hydrochloride-3/.

Obtain 1.2f of hydrate.

mdo 213-217'C (decomposition) Colorless needles In the same manner as in Example 18, using appropriate starting materials, the compounds of Examples 19-32 are obtained.

Example 19 6-(4-(4-metho+sibenlyyl)-1-hiberazinylacetyl)-3,4-dididrocarbostyryl 1
Hydrochloride monohydrate ml'225-228'C Colorless powder crystal Example 20 6-(4-(4-cyanobenlyyl)-1-piperazinylacetyl)-3,4-dishidorocarbo Styril 1
Filter hydrate 254-258°C Colorless granular crystals Example 21 6-(4-(4-Methyl-henlyyl)-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl 1
Hydrochloride monohydrate W1 unit 242-244℃ Colorless powder crystal Example 22 6- (4-(3,4-methylenedio↑cypenlyl)
-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate ml' 207-2
10'C Colorless powder crystal Example 23 6-(4-(3,4-dig00benryyl)-1-diperazinylacetyl)-3,4-dihydrocarbostyryl monohydrochloride 1/ Dihydrate 227.5-229'C (decomposed) colorless powder crystal Example 24 6-(4-(4-nido-Openlyyl)-1-berazinyl-7-yl)-3,4-dihydrate Hedrocarbostyryl monohydrochloride 242-245'C (decomposition) Colorless granular crystals Example 25 6-(4-(2-]Oyl)-1-piperazinylacetyl)-3,4-di I'm not sure what to do.

1 Hydrochloride mp 252-255'C (decomposition) Colorless needle crystals Example 26 6-(4-etho+dicarbonyl-1-piperazinylacetyl) -3,4-dihydrocarbostyryl 1 hydrochloride 1 Hydrate 235-237 '0 (Decomposition) Colorless needle crystals Example 27 6-(4-acetyl-1-piperazinyl acetyl)-3
, 4-dihydrocarbostyryl, 1-salt, 1-filahydrate 249-252 'C (decomposition) Colorless powder crystal Example 28 6-(4-dihydrocarbostyryl-1-piperazinyl?hythyl) )
-3,4-Dihydrocarbostyril 1 hydrochloride 226-228℃ (decomposition) Colorless needle crystals) -3,4-Dihydrocarbostyril 167
．． 5-169°C Colorless powder crystal Example 30 6-(4-Henryyl-1-diperazinylacetyl)-
34-, ;e Dolocarbostyril quarter hydrate mp 207-210'c Colorless granular crystals 1j! Example 31 6-(4-(3-benryl)-1-hyperazinyl?7!tz) -3,4-dihydrocarbostyryl/dihydrate 231-234'C Colorless powder Crystalline Example 32 6-C4-(3,4-dimetho+sibesilyl)-1-piperazinyl acetyl) -3,4-dihydrocarbostyryl 186-188°C Colorless powder crystal Example 33 6 -(1-veracinyl acef Jb) -314-
1.6F and triethylamine: suspended in 11.5ft-jig 00 methane 10m,
Water-cooled stirring F door - Toluethysulfonyl chloride F 1.4
Drop a methane solution of 10m/diku00 at t. The mixture is then stirred at room temperature for a further 3 hours and then on ice for 1 hour.

The precipitated crystals were collected and recrystallized from 00 form-ether to obtain 6-(4-C-toluenesulfonyl)=1-diperazinyl-3,4-didrocasilyl 0.4f. obtain.

254-256°C (decomposition) Colorless powdery crystal In the same manner as in Example 33, using appropriate starting materials, the compound of Example 34 is obtained.

Example 34 6-(4-mexulfonyl-1-hiberazinylacetyl) -3,4-dishidoohL-unstyryl-1-hydrochloric acid
3/2 hydrate 191-194'C (decomposition) Colorless powder crystal Example 35 6-(α-aminoacetyl)-3,4-: J and postyryl 5.01, (3,4 ,5-trimeth+
A mixture of 10.8 F of amici and 7.6 f of polyphosphoric acid was added to 16
React for about 6 hours at 0-170'c. Thereafter, the reaction solution was allowed to cool, and 500 ml of a stick was added dropwise to dissolve it. 48
Neutralize with % sodium hydroxide and extract with 200% form. After dehydration with potassium carbonate, the RIOO homogene is distilled off, and the hydrochloride is prepared with concentrated hydrochloric acid/ethanol. Recrystallization from ethanol yields 213-217"C (decomposition), colorless needle crystals of 6-(4-(3°4.5-trimethoxybenlyyl)).
-1-piperazinylacetyl) -,3,4-=l human O-carbostyryl monohydrochloride 3/2 hydrate 1.5F is obtained.

Compounds of Examples 36-51 are obtained in the same manner as in Example 35 using appropriate starting materials.

Example 36 6-(4-(4-metho+sibenlyyl)-1-piperazinyl acetyl)-3,4-dididrocarbostyryl 1
Hydrochloride monohydrate 225-228°C Colorless powder crystal Example 37 6-(4-(4-cyanohenlyyl)-1-piperazinylacetyl)-3,4-dihydrocarbostyryl 1 filtrate hydrate 254-258°C Colorless granular crystal Example 38 6-(4-(4-methylbayryl)-1-verazinyl P°C chill) -3,4-dihydrocarbostyryl 1
Hydrochloride monohydrate 242-244℃ Colorless powder Example 39 6-[:, 4-(3,4-Methyrezidiocypenliyl)-1-piverazinyl a7tyl) -3,4-,; e.

Drocarnestyril monohydrochloride monohydrate mp 20
7-210°C Colorless powder Example 40 6- (4-(3,4-zig00penlyyl)-1-diverazinyl acetyl) -3,4-dihydrocarbostyryl monohydrochloride. 1/2 hydrate 227.5-229°C (decomposition) colorless powder Example 41 6-(4-(4-nitrobeniJlyl)-1-piperazinyla-7ol) -3,4- Jishido Oh Rupostiril・
1 Hydrochloride 242-245℃ (decomposition) Colorless granular crystals Example 42 6-(4-(2-)Oyl)~1-Verazinyl?Cetyl]-3.4-tJcyto0 Carbostyryl 1 Hydrochloride 252-255℃ (decomposition) Colorless needle crystals Example 43 6-(4-form-3-1-di-verazinyl)-3
,4-didrocasilyl-7167,5-169
°C Colorless powder Example 44 6-(4-ethodicarbonyl-1-piperazidi-I leacetyl +-3,4-di-didrocarbostyryl hydrochloride monohydrate m) 235-237'G ( Decomposed colorless needle crystals Example 45 6] (4-A7TYL-1-GOVERAZINYLACETYL)-3
, 4-dihydrocarnestyril 1 hydrochloride 14 permanent compound 1'249-252' C (decomposition) colorless powder Example 46 6-(4-di-dionyl-1-hyperazinyl acetyl )
-3,4-di-dishdrocarbostyryl-1 hydrochloride-p 226-228'C (decomposition) Colorless needle crystals Example 47 6-(4-methanesulfonyl-1-diperazinyl attyl>-3,4 - Dishidrocarbostyril monohydrochloride 3
/dihydrate mono/ 191-194°C (decomposition) Colorless powder Example 48 6-(4-toluenesul-1- and verazinyl?7tyl>-3,4-dihydrocarbostyryl m door 254-256℃ (decomposition) Colorless powder Example 49 6-(4-penlyyl-1-diperazinyl?7tyl)-
3,4-dihydrocarnestyryl quarter hydrate 207-210°C Colorless granular crystals Example 50 6-(4-(3-200penlyylun-1-diperazinylacetyl J-3, 4-didrocarbostyril 1/
Dihydrate 231-234'C Colorless powder crystal Example 51 6- (4-(3,4-dimeth+cypenlyl)-1-
piperazinyl acetyl) -3,4-dihydrocarbostyryl 186-188°C Colorless powder crystals! ! l! Example Stream side 6-(α-aminoacetyl)-3,4-dihydrocarbostyryl 11.9F and 3,4,5-trimetho+sibenno[disu(2-ri00ethyl)]amine 17.Of
and 70 ysl of methanol are stirred and refluxed for 15 hours. From now on, sodium carbonate will be 3.06 f! and stir and reflux for 8 hours. Count the number of crystals that will be deposited in the future. The hydrochloride was prepared with concentrated hydrochloric acid/ethanol and recrystallized from ethanol.
- (4-(3,4,5-trimeth+cybendiyln-
7.3f of 1-diperazinyl acetyl-3,4-dididrocarbostyryl monohydrochloride 3/2 hydrate is obtained.

Compounds of Examples 53-68 are obtained in the same manner as in Example 52 using appropriate starting materials.

Example 53 6-(4-(4-metho+sibesilyl)-1-goberazinyl P-sevenyl J-3,4-dihydrocarbostyryl
Monohydrochloride/monohydrate 225, ++ 228°C Colorless powder crystal Example 54 6-(4-(4-cyanopenly)-1-piperazinylacetyl)-3,4-dihydrochloride Carbostyryl 1 hydrate 254-258℃ Colorless granular crystal Example 55 6-(4-(4-Methylhenlyyl)-1~Goberajini5?Setish)-3,4-dihydryl Carposzolyl hydrochloride hydrate 242-244°C Colorless powder crystal Example 56 6-C4-(3,4-methylenedio+cypesilyl)-
1-piperazinylacetylt, ) -3,4-dihydrocarbostyryl l#1 acid salt monohydrate mp 20
7-2106c Colorless powder crystal Example 57 6-(4-(3,4-zig00pesylyl)-1-goberazinyl acetyl)-3,4-dihydrocarbostyryl 1 hydrochloride Hydrate 227.5-229''C (decomposition) colorless powder crystal Example 58 6-(4-(4-nidopenlyyl)-1-gerazinylacetyl)-3+4-,:;L 242-245°C (decomposition) Colorless granular crystals Example flow side 9 6-(4-(2-)0yl)-1-berazinyl acetyl) -3,4-dihydrocarbostyryl hydrochloride 252-255°C (decomposition colorless needle crystals Example 60 6-(4-$lumiru-l-verazinyl acetyl) -3
, 4-dihydrocarbostyril 167.5-16
9°C Colorless powder crystal Example 61 6-(4-etho+dicarbonyl-1-goberazinyl?7tyl)-3,4-dididrocarbostyryl 1 hydrochloride
Monohydrate 18 units 235-237°C (decomposition) Colorless needle crystal Example 62 6-(4-acetyl-1-diverazinyl?7tyl)-3
, 4-dihydrocarbostyryl 1-hydrochloride 1-filahydrate 249-252°C (decomposition) Colorless powder crystal Example 63 6-(4-jodionyl-1-diperazinyl acetyl )
-3,4-Dihydrocarbostyryl 1-hydrochloride 226-228°C (decomposition) Colorless needle crystals Example 64 6-(4-Meta-ysulfonyl-1-goverazinyl acetyl) -3 , 4-dishidoroa 1-lupostyril monohydrochloride 5/2 hydrate 191-194°C (decomposition) Colorless powder crystal Example 65 6-(4-toluenesulfonyl-1-duberazini) ruacetyl)-3,4-dihydrocarbostyryl mp 254-256'c (isolated colorless powder crystal Example 66 6-(4-pesylyyl-1-goberazinyl docetyl)
-3,4-Dihydrocarbostyryl L/, hydrate mdo 207-210 'c Colorless granular crystal Example 67 6-(4-(3-rioobehenyl)-1-goberazinyl acetyl ) -3,4-dihydrocarbostyryl 1
/Dihydrate 231-234℃ Colorless powder crystal Example 68 6- (4-(3,4-dimeth+cypenlyl)-1-
Verazinil? ) -3,4-didrocarbostyril 186-188 'C Colorless powder crystal Example 69 To 100 d of dimethylformamide, 3.4,5-trimetho+cybenzoic acid 3.6 F and 1. 8-1 Jiazajishifu (
5,4,0) Tsurideshiri-71,6! Add M and add 1.511 Il of isobutyl sulfuric acid dropwise to an external water-cooled stirrer. - Add a solution of dihydrocarbostyryl 2.27F dissolved in dimethyl chloride 40s/ml and stir at room temperature for 5 hours. After the reaction, the solvent is distilled off and the residue is diluted with about 300 ml of 00 form. Extract and wash with dilute aqueous NaHCOs, water, dilute hydrochloric acid, and water. ri0
After distilling off all of the residue, the residue was made into a hydrochloride with salt a/ethanol. Recrystallized from ethanol, mdo 213-21
7″C (decomposition) of 6-(4-(3,4,5-trimethoxybenlyyl-1-diberazinylacetyl)-3,4
~ Dishidrocarbostyril monohydrochloride 3/2 hydrate 2
．． Get 11.

Colorless Needles Compounds of Examples 70-83 are obtained in a similar manner to Example 69 using appropriate starting materials.

Example 70 6-(4-(4-Methoyasibendiylun-1-piperazinyl P-7tyl)-3,4-di-do-0-carbostyryl-1
Hydrochloride hydrate 225-228℃ Colorless powder crystal Example 71 6-(4-(4-cyanopenlyl)-1-diveraziniacetyl)-3,4-=Je-0 carbostyryl・1
/Dihydrate 254-258"C Colorless granular crystal Example 72 6-(4-(4-Methylpenlyyl)-1-dipelazini V-7tyl) -3,4-dihydrocarpostily;・
Monohydrochloride/monohydrate 242-244'C Colorless, powdery crystals Example 73 6- (4-(3,4-methycindione + sulfuric acid)-1-hyperazinylate) Chill)-3,4-dihydrocarbostyryl i* salt monohydrate #/ 20
7-210'C Colorless powder crystal Example 74 6- (4-(3,4-dicoohenryyl)-1-goberazinyl P-7tyl) -3,4-dihydrocarbostyryl monohydrochloride. 1 filtrate hydrate 227.5-229'C (decomposed) colorless powder crystal Example 75 6-(4-(4-dipenlyyl)-1-gerazinyl acetyl)-3,4 -dihydro t3 lupostyryl 1
Hydrochloride Shinohe 242-245'C (decomposition) Colorless granular crystals Example 76 6-(4-(2-]0yl)-1- and veradinyrea t-thyl) -3,4-dihydrocarbostyryl lad salt m door 252-255°C (decomposition) Colorless needle crystal Example 77 6-(4-eth↑dicarbonyl-1-diperazinylacetyl)-3,4-dihydrocarbostyryl 1 hydrochloride
1 Hydrate 235-237°C (decomposition colorless needle crystal Example 78 6-(4-acetyl-1-hyperazinyl acetyl) -
3,4-didrocarbostyryl monohydrochloride monohydrate 249-252°C (decomposition) Colorless powder crystal Example 79 Sechiru)
-3,4-dihydrocarbostyryl 1-hydrochloride 226-228''C (decomposition) Colorless needle crystal Example 80 6-(4-formyl-1-diverazinyl acetyl)-3
, 4-jishido 0 carbostyril m door 167.5-16
9'c Colorless powder crystal Example 81 6-(4-pecilyl-1-hyperazinyl Pt)
-3,4-didrocarbostyryl 1/4 hydrate 207-210 'C Colorless granular crystal Example 82 6-(4-(3-ri00penlyryl-1-diperazinyl Ft-tyl) - 3,4-didrocarbostyryl 1
Filter hydrate-p 231-234'C Colorless powder crystal Example 83 6- (4-(3,4-dimethoxyhenryyl)-1-
piperazinyl acetyl)-3,4-dishidorocarbostyryl ml 186-188 'c Colorless powder crystal Example 84 6-(1-goberazinyl P cetyl)-3,4-dishido D
Power 1 and Boss Chiril 2. I6f and 3.4.5-1-rimeth↑cybenzoic acid 2.25 F are dioxidized: , 20 m
In addition to a mixed solvent of 201d of methyl chloride and 201d of methyl chloride, a solution of ↑zylcarnesi triF2.19 dissolved in 5 ml of methylene chloride was added to external water-cooled stirring f,N,N-dicycloO.
Drop while maintaining the temperature at 0-20"C. 3.
Stir for 5 hours. The precipitated crystals are removed, and the p solution is concentrated to dryness under reduced pressure. The obtained residue was dissolved in 100 d of methylene chloride, and the organic layer was washed with a 596 aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and water in this order, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. is converted into hydrochloride with hydrochloric acid/methanol. Recrystallization from ethanol yields colorless needle-like crystals of 6-(4-(3,4,5-)rimetho+shihenriyl)-1-verazinyl a7tyl)-3,4-dihydrocarbostyryl monohydrochloride.・3/2 hydrate 0.8
Get 2. Melting point 213-217″C (decomposition) Example 84
In the same way as above, from any suitable starting material! j! Example flow side-8
Compound 3 is obtained.

Example 85] Octalimide 3,4.5-) Rimeth+Shihenriate 13611F and 6-(1- and berazinyl acetyl-3,4-dihydrocarbostyryl 144 cape were dissolved in dimethylformamide 2d, - Stir day and night.Water is added to the reaction mixture, extracted with linoleum, and washed with water and saturated brine.After drying over sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is diluted with hydrochloric acid/methanol to give a hydrochloride. Recrystallized from ethanol to obtain 6-(4-(3,4,5-trimethoxypen9yl)-1-piperazinylacetyl)
-3,4-dihydrocarbostyryl monohydrochloride trilohydrate 110■ is obtained -p 213-217'C (decomposition) Sj! Compounds of Examples 70-83 are obtained from appropriate starting materials in the same manner as in the Example stream.

Example 86 6-Etho↑dicarbonyl 3.
4.5- 2.19 g of trimeth + cyhenliate and sodium ethylate o, sy and 6-(1-piperazinyl?thiyl>-3,4-di-hydrocarbostyryl 2
．． Add 48 liters and place in autoclave at 110 atm, 1
React at 40-150″C for 6 hours.

From now on, compress the reaction solution under reduced pressure with F# and remove the residue with 00 form 20
After washing with 1% 2CO, aqueous solution, dilute hydrochloric acid, and water in this order, the solvent was distilled off after drying with Ha 2 SOa, and the resulting residue was added to a silica gel column. -200, eluate:
After purification with 200 form:methanol (V/V) = 20:1), it is converted into a hydrochloride using hydrochloric acid/methanol. Recrystallization from ethanol gave colorless needle-like crystals of 6-[4-(3,
I
[250q of il salt 3/2 hydrate are obtained.

ml 213-217°C (decomposition) Compounds of Examples 70-83 are obtained in the same manner as in Example 86 using appropriate starting materials.

Example 87 6-(l-piperazinyl)acetylcarbostyryl 1.
0 g and triethylamine 0.67 d in a DMF 10 d solution with ice-cooled stirring.
Slowly add 0q of DMF21d solution. After dropping, the mixture was stirred for 2 hours in a room. The reaction mixture was poured into a large amount of half-saturated saline and extracted with RI00 form. After washing with water, it is dried over anhydrous sodium sulfate, and the OO form is distilled off under reduced pressure. The residue is crystallized from ether, filtered and recrystallized from ethanol.

The crystals were dissolved in methanol solution 0000 and converted into a hydrochloride with concentrated hydrochloric acid/ethanol. After distilling off the solvent, the residue was crystallized with ethanol, filtered, and recrystallized with methanol to give 37
0q's 6-(4-(3-ri Oo pen 9i It,)-1-
Piperazinyl ester hydrochloride hydrate is obtained.

24 units 212-215'C (decomposition) Colorless powdery crystal Compounds of Examples 88-96 are obtained in the same manner as in Example 87.

Example 88 6-(4-(3,4-dimeth+Sivesilii 1 and 2 1-
Hyperazinil Pt-chill] carbostyril hydrochloride 3/
Dihydrate-1'206-207'C (decomposition) (methanol)
Colorless powder crystal Example 89 6- (4-(3,4-metallic acid)
-1-Verazinyl acetyl]carbostyryl monohydrohydrate 249-251 'C (decomposition (methano-roof 00 form) colorless granular crystals Example 90 6-(4-(4-meth+) 6-(4-(4-methylhenriyl)-1-goverazinyl t-tyl) carbostyryl hydrochloride trilohydrate mjb 215-217℃ (decomposition) (methanol) colorless powder crystal Example 91 6-(4-(4-methylhenriyl) )-1-Goverazinyl a7tyl] carbostyril hydrochloride.

3/2 hydrate-p 216-218'C (decomposition) Cl3)-l) colorless powder crystal Example 92 6-(4-penlyyl-1-diperazinyl attyl)bostyril hydrochloride 3/ Dihydrate mdoor 212-2
14'C (decomposition) (methanol) colorless powder crystal Example 93 6- (4-(4-cyanohenlyyl)-1-piperazinyl atf) carbostyryl salt 11 salt-3 rohydrate mdo 218 -220'C (decomposition) (methanol) colorless powder crystal Example 94 6-r-4-(3,4,5-trimethoxycypenliyl)-1-hyperazine Ptfl]carbostyryl hydrochloride 3/ Dihydrate-p 201-204'C (decomposition)・(:19)-L
) Colorless powder crystal Example 95 6-(4-(4-dibenryl)-1-diperazinyl acetyl) Calpos salt/salt/half hydrate 214-216 °C (decomposition) (tanol-water) Colorless powder crystal Example 96 6-(4-(4-P minohenlyyl)-1-goberazinyla-7tyl) carbostyryl dihydrochloride hydrate 300' C or higher (ethanol-water) Colorless powder crystal Example 97 6-(α-200 a-7-tylene) 6.6f of 6.6f of 4-(3
, 4,5-trimethoxybenlyyl) perazine 14.
1 and triethylamine 5 g/51) -60
Stir at 'C for 1 hour. The reaction solution was poured into a large amount of water, and the organic solution was extracted with OO form.

The 200 form layer is washed with water and dehydrated, and then the 200 form is distilled off. Crystallize the residue with ethanol and count the crystals. The crystals were suspended in methanol and ethanol to form a hydrochloride salt, and recrystallized from methanol to give colorless powdery crystals of 6-[4-(3,4,5-trimeth+sibesisoyl)-1- Diperazinyl acetyl carbostyryl 1 hydrochloride-34,11]6. Of you can get it. m
Compounds of Examples 87.88-93.95.96 are obtained in a similar manner to Example 97 using appropriate starting materials.

Example 98 6-(α-aminoacetyl carpos prelisu 4.9f,
(3,4,5-) Rimet+Shihenliil) [G(2-
A mixture of 10.81 ml of human 0+ethylph]amine and 7.6f polyphosphoric acid is reacted at 160-170°C for about 6 hours. Thereafter, the reaction solution was allowed to cool, and the Hondori 5θ0111 was added dropwise to dissolve, neutralized with 48% sodium hydroxide, and extracted with opform.

After dehydration with potassium carbonate, the ri00form is distilled off, and the hydrochloride is prepared with concentrated hydrochloric acid/1 ethanol. Recrystallization from methanol yields 201-204'C (decomposition), colorless powdery crystals of 6-(4-(3,4,5-)limethofcypenlyl).
-1-Piperazinyl Pt! 1.4 fl of carbostyril 1-hydrochloride 3-filter hydrate was obtained.

Analogously to Example 98 using appropriate starting materials, compounds of Examples 87.88-93.95.96 are obtained.

Example 99 6-(α-aminoaneptanalphocalpostyril 11.8F
and 3.4.5- t-rimeth + sichenriyl [jisu (2
-ri001chill)]amine17. Of and methanol 7
The 0yil mixture is stirred and refluxed for 15 hours.

Thereafter, 3.06 ml of sodium carbonate was added and the mixture was stirred and refluxed for 8 hours. Collect any crystals that will precipitate in the future. Concentrated hydrochloric acid/1 ethanol to make hydrochloride, recrystallize from methanol, 20 m
1-204'C (decomposition), 6-(4
-(3,4,5-)rimeth+cypensoyl)-1-diverazinyl at-tyl] carposol hydrochloride trilohydrate 7.11 is obtained.

Compounds of Examples 87.88-93.95.96 are obtained in the same manner as in Example 99 using appropriate starting materials.

Example 100 To 100 g of dimethylformamide, 3.6 g of 3,4.5-trimeth↑cybenzoic acid and 1,8-diazadisifu
C5, 4, 0) '7 Y -71,65 f To the external water-cooled stirrer, add 0 f isobutyl 1.
Drop 51. After 1liF, 30 rear wall 0 and 6-
(1-diperazinyl atthyl)carbostyryl 2.25
A solution of F in 40 ml of dimethylformamide is added, and the mixture is stirred at room temperature for 5 hours. After the reaction, the solvent was distilled off, the residue was extracted with 000 form, and diluted with dilute Na# (1
Wash with 03 water, water, dilute hydrochloric acid, and water.After distilling off the form, the residue is made into a hydrochloride with hydrochloric acid/ethanol.Recrystallize from methanol to obtain 201-204'C (
Decomposition 1) 6-C4-(3,4,5-trimethoxybenlyyl-1-diperazinylacetyl)carbostyryl.
1 salt 111 salt - 3 filtrate hydrate 2. (1 is obtained. Colorless powder crystals. Compounds of Examples 87.88-93.95.96 are obtained in the same manner as in Example 100 using appropriate starting materials.

Example 101 6-(1-piperazinyl acetyl)carbostyryl 27
．． 4'l and 3.4.5-trimetho+cybenzoic acid 2.2
5f and Geo+su:/20 ml and methylene chloride 20ml
Add 2.1f of dicarnediimide to external water-cooled stirred F,N,N-disk D in a mixed solvent with 5 methylene chloride.
The solution dissolved in water is added dropwise while maintaining the temperature at 10-20'C. After the dropwise addition, the mixture was stirred at the same temperature for 3.5 hours, the precipitated crystals were removed from the oven, and the p solution was concentrated to dryness under reduced pressure. The obtained residue was dissolved in 100 d of methylene chloride, and the organic layer was washed successively with a 5% aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure F to obtain a residue. is converted into hydrochloride with 4-acid/ethanol. Recrystallization from methanol gives colorless powdery crystals of 6-(4-(3
,4,5-trimeth+cypenlyl)-1-goberazinyl P-cetyl]carbostyryl monohydrochloride-5 filtrate hydrate 0
．． Get 8F. Melting point 201-204'c (decomposition) Analogously to Example 101, the compounds of Examples 87.88-93.95.96 are obtained from appropriate starting materials.

Example 102 Cohelic acid imide 3,4,5-trimetho+cypenleitate 136 da and 6-(1-diperazinylacetyl)carbostyryl 143 da were dissolved in dimethylform PE.

Dissolve in 2d and stir day and night. Water was added to the reaction mixture, extracted with 000 form, and washed with water and saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was made into a hydrochloride with hydrochloric acid/ethanol. Recrystallization from methanol yields 103 Mg of 6-(4-(3,4,5-trimeth↑shihenriyl)-1-diperazinyldocetyl)carbostyryl 1tJ [acid acid salt 3/2 hydrate.

1, 1' 201. -204°C (decomposition) Colorless powdery crystals Example 8 From appropriate starting materials in the same manner as in Example 102
Compounds 7.88-93.95.96 are obtained.

Example 103 Ethanol 100+? 6-etho + dicarbonyl 3.4
．． Add 2.199% of 5-trimeth+cyhenleitate, 0.51% of sodium ethylate, and 2.461% of 6-(1-diperazinyldocetyl)carbostyril and autoclave at 110 atm and 140-150'C for 6 hours. Make it react. From now on, the reaction solution will be concentrated under reduced pressure and the residue will be filtered.
Dissolved in 0 form 200d, 1% 2CO3 aqueous solution,
After sequentially washing with dilute hydrochloric acid and water, and drying with /Va2SO, the solvent was distilled off.
00, elution gI: Ri[111 form:methanol CV/
V) = 20 = 1), and then converted to hydrochloride with hydrochloric acid/ethanol. Recrystallization from methanol yields colorless powdery crystals of 6-(4-(3,4,5-trimeth+siberlyl)-1-hyperazinylacetyl)carbostyryl.
Monohydrochloride 3/2 hydrate 232j9 is obtained.

ml 201-204''C (decomposition) Using the appropriate starting materials in a similar manner to Example 103, the compound of Example S7.88-93.95.96 is obtained.

Example 104 314-dihydrocarnestyril 209.4-(3,4
,5-trimeth+cypenlyyl)-1-piperazinyl!
Setyruk 0 Ride 71. Water-cooled stirring of a mixture of Sf and carbon disulfide 30d crushed anhydrous aluminum chloride 46
9 was gradually added at an internal temperature of 5-15"C. After the addition, the mixture was refluxed and stirred for 40 minutes. After carbon disulfide was removed by duct, the residue was poured into a large amount of ice water to remove the precipitated crystals and thoroughly washed with water. , and then washed with methanol. After drying, the crystals were suspended in methanol OO form, made into a hydrochloride with hydrochloric acid/methanol, and recrystallized from ethanol to obtain colorless needle-like crystals of 6-
(4-(3,4,5-)rimethocybenlyl)-1
-Piperazinyl acetyl) -3,4-dihydrocarbostyryl monohydrochloride trifilohydrate 6.31 is obtained.

213-217'C (Decomposition) Colorless needle crystals *The compound of Example 2-17 is obtained in the same manner as in Stream 104.

Example 105 Carbostyryl 19.7f, 4-(3,4,5-trimethotcybeyl)-1-verazinyl acetyl D
46f of anhydrous aluminum chloride was crushed under water-cooled stirring of a mixture of 11.5f of Ride and 30d of carbon disulfide at an internal temperature of 5.
- Gradually add at 15"C. After addition, reflux and stir for 40 minutes. Remove carbon sulfide by ducting. [7] After that, pour the residue into a large amount of ice water to remove the precipitated crystals, wash thoroughly with water, and then remove with methanol. Wash side. After drying, remove the crystals from the methanol roof.
6-[4-
6.2f of (3,4,5-)rimetho+shihenryyl)-1-goverarenylacetyl]carbostyryl 1 hydrochloride 3/2 hydrate is obtained.

mdoor 201-204'C (decomposition) Colorless needle crystals In the same manner as in Example 105, Example 87.88-9
3.95.96 compounds are obtained.

Pharmacological test (a) Bentopardital sodium salt was intravenously administered to male and female hybrids weighing 8-13# at a rate of 30 W/H to anesthetize them. Heparin sodium salt 100 (1
After intravenous administration, the heart was explanted to death and the heart was removed from the right coronary artery toward the sinus node artery.
Insert the cannula and remove the right atrium along with the cannula.

Next, sodium salt of bentopal ditar (30q
/#, intravenous administration), and heparin treatment J1 (1
00OU/kg, intravenous administration) body di18-27k
Blood from the carotid artery of a male and female hybrid of Y was guided through a peristaltic pump to a cannula inserted into the right coronary artery to perfuse the right atrium. The I flow pressure is a constant pressure of 1001 nlHI.

Right, the motion of the 6 chambers is at a resting tension of 29 F, and the contractile force of the atrial muscle is measured via a force displacement transducer. Coronary blood flow is measured using an electromagnetic flowmeter. All records shall be recorded on an ink recorder. The details of this method have been reported by Chiba et al.
rmacol, 25, 433-4
39 (1975), Naunyn Stthmit
dbtry”5Artk, Pkarmatol,
289, 315-325 (1975)).

The test compound was injected into the artery for 10-30 min via a 1-tube connected proximally to a cannula inserted into the right coronary artery.
Inject in a volume of μl. The positive inotropic effect of the test compound is expressed as a % change in the tension generated before administration of the compound, and the change in coronary blood flow is expressed as the absolute value Cwtl 1 min from before administration.
Expressed as The results are shown in Table 1.

<b> Bentopardital sodium salt was intravenously administered to male and female hybrids weighing 8-13 to 4 at a rate of 30 ml/# and anesthetized. Heparin sodium salt 1
After intravenous administration at a rate of 000 U/pass, the animals were bled to death and the hearts were removed. The specimen mainly consists of papillary muscles and ventricular septum;
Through a cannula inserted into the anterior septal artery, blood from the donor dog is perfused at a constant pressure of l Q Q al//f. The donor dog weighs 18-27cm and is anesthetized in advance by intravenously administering 30,497 kli of ventoparditar sodium salt, and intravenously administering 100 (1/cm) of heparin and thorium salt. Using a bipolar electrode, Stimulate the papillary muscles with a square wave with a voltage 1.5 times the threshold (0,5-3F), a stimulation width of 5 Melt, and a stimulation frequency of 120 times per minute.The resting tension of the papillary muscles is 1.5 f, and the The tension generated in the muscle is measured via a force displacement transducer.

The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. The generated tension and blood flow rate are recorded on a diary recorder. The details of this method have already been reported by Endo and Hashimoto (Am-/.

Phν1101. ．． 21811459-1463? 1
97F)).

Test No. 1 human compound is administered intraarterially in a volume of 10-30 μl over 4 seconds. The inotropic effect of the test compound is expressed as a percent change in the tension generated before drug administration; the effect on the coronal plane Ilt is expressed as the change in absolute torsion (11/min) from before administration. The results are shown below in Table 2. Mofostyryl monohydrochloride monohydrate 2.6-(4-(4-cyanohenlyyl)-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl
1 filtrate hydrate 3.6-(4-(4-metho+cypendiylun-1-goberazinyl acetol) -3,4-dihydrocarbostyryl 1 hydrochloride hydrate 4.6- (4-( 3,4-dihydrocarbostyryl monohydrochloride hydrate 5.6-(4-(4-nido-Henryyl,) -1-Piperazinyl acetyl)-3,4-dihydrocarbostyryl 1-hydrochloride 6.6-(4-acetyl-1-piperazinyl acetyl)
-3,4-dihydrocarbostyryl 1 hydrochloride 1/
dihydrate 7,6- (4-etho+dicarbonyl-1-diperazinyldocetyl)-3,4-dihydrocarbostyryl 1 hydrochloride 8.6-<4-methanesulfony L-1- Diperazinyl acetyl)-3,4-dihyde 50 Galbostyryl monohydrochloride 3/2 hydrate 9.6-(4-formyl-1-diperazinyl at-tyl)
-3,4-dihydrocarbostyryl 10,6- (4-
(3,4-dimeth+shibendiylfu-1-hyperazinyleahythyl)-3,4-dihydrocarbostyryl11,6- (4-(3-ri00penlyl)-1-diperazinylacetyl)- 3,4-dihydrocarbostyryl decahydrate 12.6-(4-(3,4-methylenediosibesylyyl)-1-piperazinyl?t-tyl)carbostyryl 1
Filter hydrate 1.3.6- (4-(3,4-zig00penryll
, )-1-diperazinyl atthyl) -3,4-dihydrocarbostyryl 1-hydrochloride 1/2 hydrate 14.6-
(4-)0yl-1-piperazinyl acetyl)-3,4
-dihydrocarbostyryl 1-hydrochloride 15,6- (4-penlyyl-1-goberarenyl Pt
6-(4-(3-200benryyl)-1-piperazinyl atthyl) -3,4-dihydrocarbostyryl 1/4 hydrate 17. 6-(4-(3,4-dimeth+cypenlyl)-
1-Piperazinyl acetyl carbostyryl hydrochloride
Filter hydrate 18.6-(4-(4-metho+cipensoile)-1-piperazinyl acetyl)carbostyryl hydrochloride 3/2
Hydrate 19.6-(4-(4-Methylhenlyyl)-1-diperazinyl acetyl)carbostyryl hydrochloride dihydrate 20,6-(4-penryyl-1-diperazinyl) dinylahythyl) carbostyril hydrochloride/dihydrate 21.6-(4-(4-cyanopenlyl)-1-goberazinyl ahtyl) carbostyril hydrochloride 3/2 hydrate 22, 6-(4-(3,4,5-trimeth↑cypenlyyl)-1-goberazinyl a7tyl)carbostyryl hydrochloride 3/2 hydrate 23.6-(4-(4-nitropesilyl)-1 -diverazinyl?7] carbostyril hydrochloride 1/2 hydrate 24.2 murinone (control compound) Table 1 Table 2 Below, examples of production using the compounds of the present invention are listed 0 Formulation examples 1 Dan Zun 1321F Magnesium Stearate 18q Lactose 45jllF Tablets of the above composition were manufactured in a conventional manner.

Formulation example 2 -3,4-dihydrocarbostyridan 12'71 magnesium starch 1811
f total: 200 q Tablets of the above composition were manufactured in one tablet by a conventional method.

Formulation Example 3 Shidrocarbostyril 4'J: I-jL, (molecular weight: 4
000) 0.39 Sodium Chloride
0.9919 Sodium Bisulfite
0.1f methyl-paraben
o, is yupit] leech-paraben
0.029 Distilled water for injection
100s + t Note I ~ Lapen tilt, sodium metabisulfite and monothorium chloride at 80°C while stirring
The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene silidilicol and poly(diethylene sulfate) heptanooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, sterilized by IP treatment using an appropriate filter paper, and dispensed into ampoules in 1 d portions to prepare an injection.

Formulation example 4 De, Zu, 127 Damagnesium Stare 1811
F Lactose 45jlF One tablet of the above composition was manufactured by a conventional method.

(Above) Procedural amendment formula) % formula % 2, ``Jlo name force, Bo 2 fIJ L derivative 3,
Relationship between the person making the amendment and the tenancy: Patent applicant Otsuka Pharmaceutical Co., Ltd. 4, Agent 8. Amendment (7) Contents: Details. Engraving, the power to change the content L) As attached to the attached sheet

Claims (1)

[Scope of Claims] (0 general formula [in the formula, R is a lower alkanoyl group, a lower P+dicarbonyl group,]0yl group, a lower alkanesulfonyl group, a lower Prufl group as a Kl substituent on the top of phenyl, a lower 1-3 groups selected from Prukojushi, ha0pun, cyano, P, l:no and nido0 groups or lower al↑rendio+sil&
A represents a henryyl group or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the ring H. A represents a lower alkyl group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond] and a salt thereof.