JPS5913722A - Cardiotonic agent - Google Patents

Abstract

PURPOSE:To prepare a cardiotonic agent containing a specific carbostyryl derivative as an active component, having excellent positively inotropic activity and coronary blood flow increasing activity, and extremely low side effects such as increase in pulse rate, etc. CONSTITUTION:The objective agent contains the compound of formula I [R<1> is H, alkyl, alkenyl, alkynyl, or phenylalkyl; R is alkanoyl, alkoxycarbonyl, furoyl, (substituted)benzoyl, (substituted)phenylsulfonyl, etc.; A is alkylene; the bond between the 3- and 4-carbon atoms of carbostyryl skeleton is single or double] and its salt, e.g. 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinylacetyl]-3,4- dihydrocarbostyryl.-monohydrochloride.sesquihydrate. The compound of formula I can be prepared by reacting the carbostyryl derivative of formula II with the compound of formula III (X<1> and X' and halogen), and reacting the resultant novel compound of formula IV with the piperazine derivative of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cardiotonic agent.
It is characterized by having seeds as an active ingredient.

R1 [In the formula, R represents a hydrogen atom, a lower alkyl group, a lower p-rukenyl group, a lower al-nyl group, or a phenyl lower plu+ru group. R is a lower alkanoyl group, a lower alkoxydicarbonyl group, an Oyl group, a lower alkanesulfonyl group, a phenyl term, and a substituent on the phenyl term is lower alkyl, lower alkoxy, halogen, cyano, amino, or nido D group. A pendiyl group which may have 1-3 of the groups selected from or a lower alkyl + dioxyl group, a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl apex, a substituent on the phenyl apex Phenyl lower alkenyl b which may have 1-3 lower alkoxy groups as a group
OA representing a luponyl group or a phenol lower P 11/+ group represents a lower alumone group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton represents a single bond or a double bond.] Examples of each group defined by RL, R, and A in the above general formula (1) include 1& of e, respectively, i.e., lower a1
As a ↑ru group, a straight chain or branched chain having 1 to 6 carbon atoms such as methyl, ethyl), progone, isobutyl, butyl, tert-butyl, pentyl, and ↑yl group can be used. Examples of 1-class P-rukenyl groups include di-nyl, P-lyl, 2-,
l) Tenyl, 3-dithenyl, ■-methyII, P-lyl,
Examples include straight chain or branched 1-kenyl groups having 2-6 carbon atoms such as 2-pentynyl and 2-h-cenyl groups. Hinyl, 2-
Butynyl, 3-butynyl, 1-methyl-2-duchinyl, 2-pentynyl, 2-he↑cynyl group, etc. with 2-6 carbon atoms
Examples of straight-chain or branched aryl groups include benzyl, 2-phenylethyl, 1-phenylethyl, and 3-phenyl! 1,1-dimethyl-2-phenylethyl, 5-phenylherethyl, 6-phenylhysteryl, 2-methyl-3-phenylproyl8 A linear or branched chain having 1 to 6 carbon atoms such as; phenyl having one noryl group; An example is the ar+ru group.

As lower alkanoyl groups, tolu-31 and acetyl-1
Examples include straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, such as dihionyl, butyryl, isolatyryl, pentanoyl, tert-butylcarbonyl, and hesanoyl groups; As, meth + dicarbonyl, etho 10 dicarbonyl, zurobo + dicarbonyl, iso 0 100 dicarbonyl, but + dicarbonyl, tzr
l-buto+dicarbonyl, pentyl-o↑dicarbonyl,
+ Shiruo ↑ Shika 1 A1 with a linear or branched P-ruco group having 1 to 6 carbon atoms, such as a carbonyl group, can be exemplified. Examples of the 1-bonyl group include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isodzDI, yslbonyl, butanesulfonyl, tr'rl
- Straight chain or branched P having 1 to 6 carbon atoms, such as latance 1, honi 1, penta y sulfonyl, hyalance 1 and carbonyl group, etc.
An example of a carbonyl group is a substituent on the phenyl top: lower a;
1- of a group selected from J, cyano, amino and nido D groups
Examples of the pendiyl group which may have 3 or lower alkyl and ydio+cy groups include benyJlyyl, 2-93-
or 4-rioo benzyl, 2-13-moshike 4
~Fluorobenyl J')yl, 2-93- or 4-D/jbennoyl, 2- or 4-3-do(~yl, 3,5-dikuoobenzoyl, 2,6-dikuodbenzoyl) 3,4-diku00beynoyl,3,4-
difluorobey Ethylbenryyl, 3-isojOpyruben-noyl, 4-he+silben-fil, 3,4-dimethylben-noyl, 2,5-dimethylhen-9yl, 3.4.5-
)limethylben',')yl, 2-93- or 4
-Methylbenzoyl, 2-93- or 4-etho+shibe: Jlyl, 4-isoduOpo+shibeshi-noyl, 4-
He + Shiluo + Shibe: J soil, 3゜4-dimethocybenlyyl, 3,4-shed + Shibelyyl, 3,4.5-
1-rimeth+cypen9yl, 2I5-dimeth↑sibeyl, 2-93- or 4-diT]benlyyl, 2
, 4-dinitobenzoyl, 2-13- or 4-aminopenoyl, 2,4-diaminopendiyl, 2,
3-diaminopendiyl, 3,4-diaminopendiyl, 2,5-cyanopendiyl, 7'fil, 3,4.5-trianopendiyl, 2-93- or 4-cyanopendiyl, 2,4-dicyclop-nobensoyl, 3,4-methylenediodecipediyl, 3,4-ethylenedio+dibenzoyl, 2,3-methylene:Jdio↑cipennoyl, 3-methyl=4-dibenzoyl Noil, 2-chloro0-
6-methylp,/diyl, 2-meth+cy3-chloro0
Straight-chain or branched alkyl group with 1-6 carbon atoms, IK chain or branched P-ruco+cy group with 1-6 carbon atoms, halogen atom, cyano group on phenyl top such as pennoyl group , an amino group and a nido D group, or a besilyyl group which may have as a substituent a linear or branched C1-4 alkyl group. Examples of phenylsulfonyl groups that may have a lower alkyl group as a substituent on the phenyl ring include phenylsulfonyl, toluefsulfonyl, 2-methylphenylsulfonyl, 3-ethylphenylsulfonyl, and 4-JOdi. luphenylsulfonyl, 2-butylphenylsulfonyl, 3-tcrt-butylphenylsulfonyl, 3,
4-dimethyl, 1-dimethyl, 3,4.5-1
-limethylphenylsulfonyl, 4-pentylphenylsulfonyl, 2-he+silphenyls; Having 1-3 straight chain or branched alkyl groups having 1-6 carbon atoms such as thihonyl group as a substituent An example is a phenylless 1-butyl group.

Lower alk as a substituent on top of phenyl]↑Claw 1-3
Examples of the phenyl lower alkenylcarbonyl group which may have 2-carbonyl groups include cinna-7yl, 4-phenyl-3-dutenoyl, 4-phenyl-2-butenoyl, 5-phenyl-4-peytenoyl, 5-phenyl-3 -Pentenoyl, 5-phenyl-2-pentenoyl, 6-phenyl-5
- to + hinoyl, 6-phenyl-4- to + t-noyl, 6
-Phenyl-3-to+senoyl, 6-phenyl-2-↑hinoyl, 2-methyl-4-phenyl-3-latenyl, 2-methylbenzoyl, ■-methyl-cinna7yl,
2-93- or 4-methylbenzoyl, 2-13-
or 4-ethysu7yl, 2-13- or 4-dupo+shicyysu°Cyl, 2-duto+cycinna7yl, 3-(tert-but↑shi)cinnatyl, 4
- pentyl + cicinnatyl, 3- to + silo + cicinnat yl, 3,5 ~ dimeth + cicinnat yl, 2,6
-dimeth + cicinna7yl, 3,4-dimetho + cicinna7yl, 3,4-di1to + cicinna7yl, 3.5-shed + cicinna7yl, 3.4.5-trimeth + cicinna7yl , 4-etho+diphenyl-3-latenoyl, 4
- (3-tert-but↑diphenyl)-2-butenoyl, 5- (4-'t+silo+diphenyl)-4-
Pentenoyl, 6-(3I4-dimeth+diphenyl)-
5-+senoyl, 2-methyl-(2,5-shed+senoyl), ■-methy+senoyl-(3-
meth+cyphenyl)ystyl, 6-(3,4,
5-tono1to↑diphenyl)-3-to + phenyl group such as senoyl group and a linear or branched atom having 1 to 6 carbon atoms at the top
Straight-chain or branched carbon atoms having 3-6 carbon atoms, which may have 1-3 groups
Examples of the pheno + cyclo lower alkyl group that can be exemplified by the 15bonyl group include dimethyl in pheno, diethyl in 2-pheno, 2-pheno + ciprohyl, 3
- PhenoyasizuOhiJ, 1-methyl-2-pheno↑diethyl, 2-pheno↑shirachi1, 3-phenoyasibutyl, 4-phenodiptyl, 1,1-dimethyl-2-pheno+ Cyptino, 2-pheno+cypentyl, 3-pheno+cypentyl, 4-pheno↑cyhe↑cyl, and other straight-chain or branched alkaline carbon atoms having a phenodecyl group as a substituent. An example is the 1,000-ru group.

Specifically, the lower alkali group defined by A in the general formula () is, for example, methicine, 1ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-Methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, he+
+ft chain or branched P having 1-6 carbon atoms such as rimethylene y group
11. An example is +y group.

In addition, in the above general formula (1), the carbon-carbon bond between the 3rd and 4th positions of the carpostyl 1 skeleton may be a single bond, or it may be bonded to either the 7th or 8th position of the double bond. The inventors have discovered that the carbostyril derivative represented by the above general formula (1) and its salts, that is, the derivative, has pharmacological effects (-1, therefore, for example, depressive symptoms, Heart disease such as sexual fibrillation, flutter, and paroxysmal atrial tachycardia
It is a cardiotonic agent that is of no use in the treatment of heart disease, and while it has an additive action, it also has the special feature of having extremely weak side effects such as an increase in heart rate (7-C).

1, uF The above general formula (
The method for producing carbostyril derivatives and salts thereof in 1) will be described in detail.

The carbostyryl derivative represented by the general formula (1) (hereinafter simply referred to as "the compound of the present invention") may be produced, for example, according to the methods shown in the above reaction schemes -1 to -8 [Reaction scheme -1] 1 (1) [In each formula, the carbon-carbon bonds between R, R, A and the 3rd and 4th positions of the nocolpostyryl skeleton are the same as above. The invention compound can be produced by reacting a perazine derivative of general formula (3) with a novel compound of general formula (2) that is known or obtained, for example, by the method shown in Reaction Scheme-9 described below. The reaction is solvent-free,
Alternatively, the reaction is completed in a normal inert solvent at a temperature of about -200'C, preferably room temperature -1200F, for a period of 1-24 hours. Inert solvents include, for example, ethers such as dio' + sulfur, tetrahydrofuran, ethylene glyco-1, dimethyl ether, and diethyl ether, aromatic hydrocarbons such as penzene, toluene, + cyanone, etc. Lower allols such as methanol, ethanol, and isodupanol, polar solvents such as dimethylformamide, dimethylsulfo+cyto, he+kemethylphosphoric acid triamide, acetone, and P-7 tonitrile may be used.''The second reaction is more advantageous. This is carried out using a basic compound as a deoxidizing agent. The basic compound includes the Shijiperazine derivative itself, which is used as a raw material, and if this is used in excess, there is no need to use other basic compounds, but for example, potassium carbonate, sodium carbonate, sodium hydride, carbonate sodium hydrogen,
Tertiary amines such as sodium amide, sodium hydride, triethylamine, tridurohylamine, and hyridyl-1 denoline can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide, sodium iodide, or the like, or methyl phosphoric acid triatriide, as a reaction promoter, if necessary. Compound of general formula (2) in the above reaction, pelagie, / derivative (3
) is not particularly limited and can be appropriately selected within a wide range, but it is usually preferable to use 4°C excess of the latter with respect to the former, preferably 5 times as much. The diperazine derivative represented by the general formula (3) used as a raw material includes some new compounds, and these can be used as a compound of the general formula (4) in the method shown in the reaction scheme-2 or -3 described later. It can be easily produced in the same manner using diperazine instead of the carbostyril derivative represented by.

[Reaction scheme-2] 0
U(4)
(1-a) [In each formula, A, R and the carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton are the same as above. R is a group selected from a lower P-lkanoyl group, a lower alkoxydicarbonyl group, a furoyl group, a substituent on the phenyl ring, a lower P-lkanoyl group, a lower alkanoyl group, a lower alkyl group, a halogen, a cyano, an amine, and a nitro group. 1-3 pieces or lower al + rangeo t
It refers to a befuroyl group which may have a sil group or a phenyl lower alkyl carbonyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl group. ] That is, among the compounds of the present invention, those represented by the above general formula (L-) are obtained by reacting the carpostyl derivative of the general formula (4) with the carboxylic acid of the general formula (5) or an active compound of the carboxyl group. The above reaction may be carried out by a conventional amide bond forming reaction.
．． As the amide bond forming reaction, for example, the following method can be mentioned:
1 sil + ruha O carboxylic acid is reacted to form a mixed acid anhydride,
A method of reacting this with a derivative of general formula (4).

([U)Activated ester method, i.e. 1 and bonic acid (5),
t-two 0 Feni! 1, and active esters such as N-shidoro, shifusuccinic acid iside ester, 1-shidoro+shihensotriazole ester, etc., and the general formula (4)
A method of reacting derivatives of
That is, the derivative of the general formula (4) is added to the carboxylic acid (5), dicyclohide, dicarbodiimide, carboni! Regiimi 5
Other methods include condensation in the presence of an activating agent such as y-reel, etc. For example, carboxylic acid (5) is converted to carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and then the general formula A method of reacting derivatives of (4) with the general formula (
4) A method of reacting the derivative under high pressure and high temperature, carbo,
:/ IVI/(5) acid halide (acid halide)
A method of reacting a derivative of the general formula (4), fulponic acid (5) is reacted with triphenylphosphine, diethyl chloride []
A method of activating a glue such as D phosphate with a compound and reacting it with a derivative of general formula (4), etc. In the mixed acid anhydride method shown above (see above), the mixed acid anhydride required in C4 is the usual method. Schotten-Baumann reaction, in which the compound of the present invention of general formula (1-a) is produced by reacting it with a derivative of general formula (4) without isolation usually. is carried out in the presence of a basic compound.As a basic compound, the above general formula (
4) Derivative itself or Schotten-Baumashi reaction KIj
Compounds for It, such as trimethylamine, trimethylamine, dilysine, dimethylanily, ■-methyl heptalpholine, ■,5-diapdicyclo(4,3,OJnonene-5 (DBN), 1,5-diaza Jishifu D [5゜4
, O]Undehyne-5 (DI3U), ■, Organic bases such as 4-diazadicyclo(2,2,2J octane (DABCO)) and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium carbonate hydrogen carbonate, etc. The reaction Vi-20-100'c is preferably 0-50
The reaction between the obtained mixed acid anhydride and the derivative of general formula (4) is carried out at 10C and the reaction time is preferably about 5 minutes to 10 hours and about 5 minutes to 2 hours. -20-15
The mixed acid anhydride process is generally carried out in a solvent. The solvent is a mixed acid anhydride. Solvents commonly used in the process, specifically Methyl chloride, RiOOOO12M, Zik090RotaneU'f
ionized hydrocarbons, payf! Aromatic hydrocarbons such as , toluene, and silene, 1-methyls such as diethyl ether, tetrahydride, dimeth+thiane, esters such as methyl acetate and ethyl acetate, N, Non-j such as N-dimethylformPmide, dimethylsulfo+cyto, he+17methylphosphate triP3F.

Examples include tonic polar solvents. As the Al + RuD carboxylic acid used in the mixed acid anhydride method, methyl formate, methyl heptaformate, chloro[]ethyl formate,
Dv: Examples include ethyl formate and isobutyl chloroformate. The ratio of the carboxylic acid (5) to the alkyl halocarpoylic acid and the derivative of general formula (4) in the line method is:
Usually, the latter is at least an equal amount of the former, preferably about 1 to 2 times the amount of the former.
When employing a method of reacting with a derivative of , the reaction is carried out in the presence of a basic compound and in a suitable solvent.

As basic compounds, commonly known ones can be widely used.
For example, in addition to the basic compounds used in the above-mentioned Shottesi-Baumann reaction, sodium hydroxide, potassium hydroxide,
Examples of the solvent include sodium hydride, hydrogen (hypotalium), etc. (In addition to the solvents used in the 3-Baumann reaction, methanol, ethanol, dibutanol, 3-tanol, Meth ↑ C 11 Tano 1 C, Ethyl C D Solp, Nuchil H D True J4 Al:] -, 11/ A mixed solvent of two or more of the following solvents, such as Yajiri gin, Athitone, Al to Nitrile, etc. The proportion of corboxylic acid halide (relative to the derivative of general formula (4)) is not particularly limited and may be appropriately selected within a wide range; The reaction is usually carried out at about -20 to 1,000 dO, preferably at -150'C, and is generally completed in 5 minutes to 30 hours.

[Reaction scheme-3] (4) (1-b) [A in each formula
, R and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyril skeleton are the same as above (C.
X2 represents a lower alkanesulfonyl group or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. ] That is, among the compounds of the present invention, those represented by the above general formula <L-b) are
WZ formula (6) is added to the carbostyril derivative of general formula (4).
It can also be produced by reacting a compound represented by:

The reaction between the derivative of the general formula (4) and the compound of the general formula (6) is carried out using the general formula (4) described in detail in the reaction scheme-2 above.
) can be carried out in the same manner as the reaction of the derivative with carboxylic acid halide.Also, the compound of the present invention can also be produced by the following method. [Reaction Scheme-4] 1? ” (2) (7) (8)1 (1) [In each formula, x, R, I?, A and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyril skeleton are the same as above. In other words, the compound of the present invention is a compound of the general formula (2) with a compound of the formula (7).
Alternatively, the compound of formula (8) is reacted to obtain the general formula (9
In the above, the compound of general formula (2) and the compound of formula (7) are produced by reacting the compound of formula (2) with the compound of general formula ) or (
The reaction with the compound of formula (8) can be carried out under the same conditions as the reaction of the compound of the general formula (2) shown in the reaction scheme-1 with the perazine derivative (3). 9) The di-1 conversion reaction is carried out under the conditions F of the usual de-N-benzyl reaction.For example, in a suitable solvent, a catalytic reduction catalyst such as palladium-carbon, In the presence of palladium black, etc., the process is carried out at OC at room temperature for about 0.5 to 3 seconds. [7] Examples of solvents include water, lower alcohols such as methanol, ethanol, and isozypanol, ethers such as di-1-san and tetrahydrofuran, vinegar,
In addition, the dehydylation or deacylation reaction of the compound of general formula (9) can be carried out in the same manner as a normal 1-water decomposition reaction.7 For example, water, methanol-112, ethanol, etc. The reaction is carried out using an inorganic base such as sodium hydroxide or potassium hydroxide or an acid such as hydrochloric acid or hydrobromic acid in an alkaline alcohol, to obtain a compound of the general formula (IO). The reaction between compound 11 and the compound of general formula 01) is performed using the general formula μυ
Depending on the mm of the compound, especially the group represented by

In the general formula Oυ, the radical f- represented by
Sulfonylo+shi, ethanesulfonyshi+shi, isof
o bisulfonylo↑shi, fo pansulfonylo+shi,
Examples of the butanesulfonyl group include butanesulfonyl group, 1erl -) tacysulfonyl group, pesita y sulfonyl group, and hesulfonyl group. Heshiji 1 and sulfonyluo↑
shi, 2-phenylethylsulfonyl+shi, 4-phenylsulfonyl+shi, 4-methylbenzylsulfonylu+shi, 2-methylpeyzirus 1, honi 1 and saiko, 4-nido 0 benzylsulfonyl Nil A + Shi, 4-Metho↑
Shipee J Jills 1 Shihoni! Substituted or unsubstituted P such as 1 + 2, 3 - 0 lupendylsulfony 1 + 2, α-naphthylmethylsulfonyl + 2 group, etc. For example, when using a compound of the general formula υ in which The reaction between the compound of formula 〇* and the compound of general formula θυ is generally carried out in a suitable inert solvent in the presence or absence of a Ja-based condensing agent. Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, and silene, lower alcohols such as methanol, ethanol, isodupanol, and ttanol, acetic acid, ethyl acetate, dimethylforpho+cyto, and dimethyl. Examples include formamide, hesamethylphosphoric acid triazide, and the like. Examples of basic condensing agents include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide; and sodium methylate and sodium methylate. Examples include tertiary amines such as metal alcoholade hyridine, triethylamine, and diperazine derivatives represented by general formula (3).The usage ratio of the compound of general formula QQ and the compound of general formula (11) is: Although there is no particular limitation and the amount may be appropriately selected within a wide range, the latter is usually used in at least an equimolar amount to the former, preferably in an equivalent amount of 5 to 7 times the amount of the former. The reaction is usually 40-
The reaction is carried out at about 120'C, preferably 50-100C, and the reaction is generally completed in about 5-30 hours.Also, when using a compound of general formula 〇〇 in which X represents a hydroxyl group. The compound of general formula 〇〇 and the general formula (1
The reaction with the compound of 1) generally involves the presence of a dehydration condensation agent F,
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, scorched phosphoric acid, and metaphosphoric acid, phosphorous acids such as sulfuric acid, and anhydrous acids such as phosphorus pentoxide. Phosphoric acids, hydrochloric acid,
Examples include acids such as sulfuric acid and oxalic acid, metal phosphates such as sodium phosphate, porium phosphate, ferric phosphate, and aluminum phosphate, activated alumina, sodium bisulfate, and Raney-nicke salts. In addition, examples of the solvent include high boiling point solvents such as dimethylformamide and tetrarif.The ratio of the compound of general formula 〇〇 and the compound of general formula Oυ to be used is not particularly limited and can be appropriately selected within a wide range. However, it is preferable that the latter be approximately equal to or smaller than the former, <+-1 degrees Celsius or less.
It's good to be in Europe at 7:1. The amount of the dehydration condensation agent used is not particularly limited and can be appropriately selected from a wide range.
For the compound of
It is preferable to use a temperature of 1.5-5 times Celsius. The above reaction is 1
For the purpose of preventing the atomization reaction, it is preferable that the reaction be carried out in an inert gas stream, such as a carbon dioxide or nitrogen stream.1. stomach.

Although the reaction described in (-) can be carried out either under normal pressure or under pressure, it is preferable to carry out the reaction under normal pressure. The reaction temperature is usually about 100-350'C, preferably 125-255'C, and the reaction is generally completed in about 3-10 hours.In the above reaction, the compound of general formula 01) is It may be used in the form of

[Reaction scheme-5] 1 (1) [In the formula, R, l? , Δ, The reaction between the carbostyril derivative of the general formula U and the compound of the general formula 〇] is generally carried out in a solvent in the presence of isic acid, according to a reaction called the Friederk fluoride reaction. Things that can normally be used in the reaction, such as carbon disulfide, nido0 penpin, riD rubé:, /I! y1
diku-D-lumeta y, dichloroethane, trichloroethane,
Tetrachloroethane etc. can be used. Any conventionally used Lewis acids are preferably used, such as trinium chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, etc. .

The amount of Lewis acid to be used must be determined appropriately, but it is usually 1.
] The amount of the compound of general formula 〇 used relative to the carbostyryl derivative 02 is usually at least about 7 times the amount of the carbostyryl derivative 02, preferably about 2 to 4 times the amount of the lupostyryl derivative t12. The amount should preferably be 7 to -2 times the amount. The reaction temperature is selected appropriately, but is usually 0-
120'CC variation is preferably about 0-70'C. The reaction time varies depending on the raw materials, catalyst, reaction temperature, etc. and is not constant, but the reaction usually ends in about 0.5-6 hours [Reaction Scheme-6] 0C (1-C) (1
-d) [In the formula, R, R and A are the same as above.] Conventional catalytic reduction conditions are applied to the reduction of the compound of general formula D-d). The catalyst used is palladium,
Examples include metals such as palladium-carbon, zlatina, and Raney nickel, and it is preferable to use such metals in normal catalytic amounts.Also, examples of solvents that can be used include methanol, ethanol, iso-dpanol, di- ! -tj:
, /, THF, He+san, Schiff 0 to 1'' San, ethyl acetate, etc. The reduction reaction can be carried out either under normal pressure or under increased pressure, but usually under normal pressure -20K.
The reaction temperature is preferably about 0-150'C, preferably room temperature -100'C.

The dehydrogenation reaction of the compound of general formula (1-t) is carried out in an appropriate solvent using an oxidizing agent. Examples of the oxidizing agent used include 2,3-dimethylsiloxane, 5,6-dicyazuben, and nonanone. , tri-O-ranyl (2,3,5,6-titrac DO penz+non), etc., N-proheptasuccinimide, -ri-L]O-succinimide, bromine, etc. Mention may be made of hydrogenation catalysts such as hydrogenation agents, carbon dioxide, palladium on carbon, palladium black, acidic 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.
Usually 1-5 times °C for the compound of general formula <1-d)
It is preferable to use 1-2 times the amount, preferably 1-2 times the amount.

If a hydrogenation catalyst is still to be used, it is better to use a normal catalyst tt. Also, as a solvent, dio#Fsan, THF, diethanol, dimethane, etc., benzene, toluene, etc. , + aromatic hydrocarbons such as silene and cumene, dichloromethane, dichloromethane, dichloroethane, chloride (coform, heropinated hydrocarbons such as carbon tetrachloride, ditanol, anyl alcohol, hel = al such as sanol) ~ Polar solvents such as acetic acid, l) MF, DM,
Examples include polar aprotic solvents such as 50, hesamethyl phosphoric acid triatridine, etc. The reaction is usually carried out at -300°C.
C1 is preferably carried out at room temperature - 200'C, and the reaction is generally completed in 1 to 40 hours.

Further, among the 16 compounds of the present invention, the 1-H compound in which R is a hydrogen atom and the carbon-carbon bond between the 3- and 4-positions of the carbostyril skeleton is a double bond is shown in Reaction Scheme-7 of F. As such, lactam-lactim can be tautomeric.

[Reaction scheme-7] 0 0<1-t
) (1-/) [In the formula, R and A are the same as in Oil 2. ] [Reaction scheme ~8-1 1 <1-y) <1-h)1' [In the formula, R and X are the same as above. R is R other than a hydrogen atom
Indicates a group] In the above, the compound of the general formula (1-f) and the compound of the general formula (,1
4) The reaction with the compound can be carried out, for example, by the presence of a basic compound F.
It is preferable to conduct the reaction in a suitable solvent. Examples of the basic IL compound 7 include, for example, sodium hydroxide, caripanom,
Examples of solvents include sodium, sodium atrifluoride, potassium trichloride, etc. Solvents include L-thiols such as ethylene dilicol dimethyl ether, and aromatic hydrocarbons such as toluene and trichloride. Compounds of general formula (-t-q) and compounds of general formula 04) can be mentioned. There is no particular limitation on the ratio of the former and the latter can be selected as appropriate within a wide range, and it is usually better to use the latter at least 7 degrees or more, preferably twice as much as the former. The reaction is usually carried out at about 0-70'C, preferably around OC-room temperature, and the reaction is generally completed in about 5-12 hours.
Ru.

Furthermore, among the compounds of the present invention, a compound having an amino group as a substituent on the phenyl apex can be used to reduce a corresponding compound in which the substituent on the phenyl ring is an O group. This reduction can be carried out under the usual conditions for reducing an aromatic nido D group to an aromatic atrino group. More specifically, a method using a reducing agent such as Higashi sulfuric acid sorter, sulfur dioxide gas, or a catalytic reduction method using a reduction catalyst such as palladium-carbon may be used. The compound of formula (2) may be a known compound described, for example, in West German Patent No. 3107601 VC, or it may be a new compound, and can be produced, for example, by the method f shown in the radical reaction scheme-9.

[Reaction scheme-9] cnoi10 (2) [R in the formula
, The compound of the present invention thus obtained can be easily converted into an acid addition salt by reacting it with a pharmaceutically acceptable acid. Nucleic acids that can be used include, for example, 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, chloride acid, and benzoic acid. The target compound thus obtained in each step of + is i
fh can be easily isolated and purified by conventional separation means. The separation method includes, for example, a solvent extraction method, a dilution method,
Examples include a recrystallization method, column chromatography, 'j+noparatip thin layer D mud talaffy, and the like.

Naoki Yomei naturally includes optical isomers.

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

The formulation is prepared using commonly used diluents or excipients such as fillers, bulking agents, 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, pills, preparations, night tablets, suspensions, emulsions, granules, and forceps. , suppositories, and injections (gamma night tablets, suspensions, etc.). When molding into a tablet form, -C is
As a carrier, a wide range of conventionally known carriers can be used for this decomposition.
For example, lactose, white sugar, sodium chloride, sucrose, urea,
Excipients such as DeyJJ, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water, ethanol, Panol, glucose solution, fundzun solution, T! 5 gin solution, carbo + dimethyl sululose, shilac, methylcellulose, potassium phosphate, polydimethyl pyrrolid y
binders such as dried starch, sodium p+b4yate, campene powder, sanaran powder, sodium carbonate hydrogen,
Calcium carbonate, polio + diethylene sulfate fatty acid esters, sodium lau 91 sulfate, heptanoglyceride stearate, starch, disintegrants such as lactose, sucrose,
Disintegration inhibitors such as stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary amneptinium bases, sodium lauryl acid, humectants such as jirihiri υ, starch, starch, lactose, jJ Adsorbents such as ollin, baytonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene)! /Lubricants such as glycol can be used.

Furthermore, the tablet may be formed into a pill form, which may be coated with a conventional coating if necessary, such as sugar-coated tablets, hyaline-encapsulated tablets, broken intestinal fluid tablets, film-coated tablets, double tablets, or multilayer tablets. In this case, a wide variety of carriers can be used as C, such as glucose, lactose, sugar beet, cacao butter, hydrogenated vegetable oil, citrus oil, and yam.
Excipients such as cilantro, binders such as powdered maggots, powdered tomato powder, pirati, ethanol, and disintegrants such as naran, agar, etc. can be used. Suppository form! 7ml/
7- When molding, a wide range of conventionally known carriers can be used, such as polyethylene silico-1, cacao butter, high-grade P-1, esters of higher alcohols, pyratine, semi-synthetic silicerite, etc. When prepared as an injectable solution, the solutions and suspensions are preferably sterile and isotonic with blood, and are easy to form into solutions, emulsions, and suspensions. In this case, all diluents customary in this digestion can be used, such as water, ethyl alcohol, etc.
In addition, it is possible to use polyol, diethylene chloride, ethyl isostearyl sulfide, polyol, isostearyl sulfide, polyol, diethylene trifluoride, fatty acid ester, etc. In some cases, sufficient salt, glucose, or chestnuts may be included in the strong U agent to prepare a non-toxic solution, and the usual solubilizing agents, buffering agents, soothing agents, etc. Fully added C is also good 9
Furthermore, if necessary, coloring agents, preservatives, perfumes, flavoring agents, flavoring agents, and other pharmaceuticals may be included in the pharmaceutical preparation.

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 administration method of the inotropic agent of the present invention, and it may be administered in a manner depending on the various formulation forms, age, gender and other conditions of the patient, and the severity of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules, and forceps are administered orally; injections are administered alone or with glucose, amino acids, etc.
It is administered intravenously mixed with regular replacement fluids, and if necessary, it is administered alone intramuscularly, intradermally, cutaneously, or intraperitoneally. If ′≠~j, it is administered rectally.

The dosage of the cardiac inotrope of the present invention is selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc., but usually the active ingredient, the compound of general formula (1), is Approximately 0.0 per kg of body weight per day. tJL -L O'Q It is preferred that the active ingredient is contained in a dosage unit form of 0.1-
Reference examples and production examples of the compounds of the present invention are given below as examples.Reference example 1 3.4-dihydrocarbostyryl 200y, RiD Lua Jochiril 90541160w1g and carbon disulfide 300w Anhydrous aluminum chloride crushed under water-cooled stirring into a mixture of
Gradually add 60f at an internal temperature of 5-15'C. After addition, stir under reflux for 40 minutes. After removing 2 by decantation, pour the residue into a large amount of ice water to remove the precipitated crystals, wash thoroughly with water, wash with meth-2 and dry. 280y of 6-(2-chloroacetyl)-3,4-di Recrystallize from 1 ethanol to obtain colorless needle crystals.

ml 230-231 'C Reference example 2 6-(α-riOOacetyl 1b)-3,4-diester I
4.4 g of perazine and 5 ml of triethylamine were added to a solution of 6.7 ml of L/postyryl, 1 ml of dimethic anhydride, and 0 ml of dimethyl anhydride, and the mixture was stirred at 50-60'C for 1 hour. Pour the reaction solution into a large amount of water and add 100 ml of water.
Finish and extract. After washing the 00 form layer with water and dehydrating it,
The residue was suspended in methanol-chloroform and converted into a hydrochloride with hydrochloric acid/methanol to form colorless needle-like crystals of 6-(4-(L-hyperazinyl acetyl)).
-3,4-dihydrochloride 1 Bostyril hydrochloride, 3
3.5y of hydrate is obtained.

+n p 265-267 'c (decomposition) reference example
3 6-chloro1-di-3,4-di-trocarpostil L: 3. To a suspension of Of in dimethyl chloride and 20 ml of formamide, while stirring at room temperature, 20 g/solution of 1.9 y of dimethylformamide was gradually added. After cooling, stir at 50-60'C for 2 hours. All the precipitated crystals were collected, washed with methanol and dried to obtain 3.5y of crude crystals of 6-. To 3.5 y of crude crystals of nium acetyl-3,4-distrocarpostili 1 and 0 light, 5 zi of ethanol, 6 W of concentrated hydrochloric acid/
, and stirred at room temperature for 12 hours. The crystals were added and recrystallized with methanol-water to give colorless powdery crystals of 6-rtrinoacetyl-3,4-didrocarbostyryl 1 hydrochloride 1. ．．
Obtain 2g.

tnfi 300'C or higher Example 1 6-(α-chloroacetyl)-3,4-dishide D power 1 Bostyril 6.7y m Water dimethylformadrol
4-(3,4,5-trimethodecibenlyyl)piperazine 14.3f and triethyl acetate in a 0 wl solution:
, and stirred at 50-60'C for 1 hour. Pour reaction 'D' into a large amount of water, and extract the organic layer with chloroform. After washing the 00 form layer with water and dehydrating, the 00 form layer was distilled off, the residue was crystallized with ethanol, and the crystals were collected. The crystals were clouded with methanol, mixed with hydrochloric acid/methanol to form a hydrochloride, and recrystallized from ethanol to give colorless needle-like crystals of 6-(4-(3,4,
5-) Rimeth+Siben Noyl)-1-diperazinylacetyl J-3,4-dihydrocarbostyryl monohydrochloride/hydrate 6.31 is obtained.

ml 213-217'c (decomposition) Colorless needle crystals In the same manner as in Example 1, using appropriate starting materials, the compounds of Examples 2-24 are obtained.

/ / / 'Husband/jili example 25 6-(1-peralenyl 9-ash, -3,4-di-sido 0, lJ rubostyril 2.09 and to-1 noech)
Reamiy l-4ml to 201t of dimethylformamide
Dissolve it in F1.3,4.5-t- and stir at room temperature.
Ume 1-↑Shihey9 Iruku D Ride 2.2g 5ml
dimethic acid) and then gradually add the Moore three F solution to h', lr F
1. After heating at room temperature, the reaction mixture was poured into a large amount of saturated saline solution and extracted with a small sieve. After washing with water, drying with anhydrous sulfuric acid, distilling off the 00 form, and crystallizing the remaining 1 with ethyl alcohol.
take. The crystals were suspended in a mixed solvent of 1,000 and 1,000 ml of methanol, and made into a hydrochloride with 1,000 ml of salt/ethanol. The solvent was distilled off, and ethanol was added to the residue for crystallization.

Recrystallize with ethanol and 6-(4-(3,4,5
-) Rimeth↑Sibenriyl-1-hiberazinyl acetyl)
〕=3,4-dihydrocarbostyril monohydrochloride 3
213-217 'C (decomposition) colorless needle crystals Using appropriate starting materials in the same manner as in Example 25,
h'lJ notes MQVAI2-12.15-21.23 and 24 are obtained.

Example 26 6-(1-hyperazinyl ahythyl l-3.4-dihydro 117 bostyryl 1.6 g and triethyl ahythyl l-3.
Suspend 5 g in Schiff 00 methane 10 M1, stir with water cooling, and cool a solution of 1.49 toluenesulfonyl dichloromethane for 10 hours. Then, stir at room temperature for an additional 3 hours, and then stir for 1 hour under water cooling. Add the precipitated crystals, add 1 chlorofluorochloride, and recrystallize from Moony chill to obtain 6-C4-C
0.4 f of 3,4-dihydrocarbostyryl (sulfonyl)-1-diperazinyl acetyl J was obtained.

254-256'C (decomposes as colorless powder) Compounds of Examples 13 and 22 are obtained in the same manner as in Example 26 and using appropriate starting materials.

Example 27 6-(α-P trinoanoacetyl-3,4-dishdrocarpos f.ril 5.Oy, (3,4,5-1-rimeth+sibenlyl) A mixture of asanin 1O, tl and 7.6 g of polyphosphoric acid was
React at 170'C for about 6 hours. After that, the reaction solution was allowed to cool, and about 500 g of water (!
Extract with sodium hydroxide and chloroform. After dehydration with potassium carbonate, chloroform is distilled off and the hydrochloride is prepared with salt preparation 11/ethanol. Recrystallize from 1 ethanol and ml213-21'7 C (decomposition), colorless needle-like crystals of 6-(4-(3゜4.5-1-rimetho+sibenlyl)-1-hyperazinylahythyl)-3,4-dididrocarbostyryl monohydrochloride. / hydrate 1.5f
Get fc.

In the same manner as in Example 27, using appropriate starting materials, the compounds of Examples 2-24 were obtained. .Soy and 3.4.5- Trime 1゛ + Shipen゛Noi 1 [His (2-ri00ech)shi)] A3y
After stirring and refluxing a mixture of 17, Of and methanol for 15 hours, 3.06 g of sodium carbonate was added and the mixture was stirred and refluxed for 8 hours. I'll collect the crystals that will precipitate in the future.
j: a + tjl / ethanol to form hydrochloride, recrystallize from ethanol ゛C, m door 21.3-217'C (
decomposition), colorless needle-like crystals of 6-(4-(3,4,5-trimeth↑shibenryill, )-1-piperazinyl acepyl,]-3,4-dihydrochloride 1 and boschili 1 - Obtain 7.3 g of monohydrochloride 3/2 hydrate.

The compounds of Examples 2-24 are obtained in the same manner as in Example 28 using appropriate starting materials. Example 29 To dimethylformamide l 00 tie, 3.4.5
Add 3.6 g of -trimethoxybenzoic acid and 1,8-syazuji-Schiff [co(5,4,0) undehyde: J-71.65 g] to C1 external water-cooled stirring F. 1.
Drop 5ryt F. After stirring at 11 F for 30 minutes, a solution of 2.27 f of 6-(1-piperazinyl acepul)-3,4-dihydrocarbostyryl dissolved in 40M1 of dimethylformamide was added, and the mixture was heated to room temperature. Stir for 5 hours. After the reaction, the solvent was distilled off and the residue was dissolved in chloroform.
Extract with 0*i, dilute HaNOFC03 water, water, dilute hydrochloric acid,
After washing with water and distilling off the form, remove the remaining k with hydrochloric acid/
Constitute the hydrochloride with ethanol. Recrystallized from ethanol to obtain 6-(
4-(3,4,5-trimethoxychloride-1-piperazinyl acetyl J-3,4-dishido JJpurustyryl monohydrochloride trihydrate 2.11 is obtained.

Colorless needles Similar to Example 29, using appropriate starting materials -Cm
The compound of Example 2-24 of iJ is obtained.

Example 30 6-(1-piperazinylacepule)-3,4-dihydrocarbostyryl2. '769 and 3.4.5-1-rimeth↑cybenzoic acid 2.25 f and diA+Fj 20tsl
In addition to a mixed solvent of methyl chloride and methane chloride, a solution of 2.1 g of methylcarboxylic acid dissolved in 5 ml of methionone chloride was added to a solution of 2.1 g of methylcarboxylidene dissolved in 5 ml of methionone chloride under external water-cooling stirring [,7V, to N-dicycloD].
Drop while keeping the temperature at 0-20"C.After dropping F, add 3 drops at the same temperature.
．． Stir for 5 hours. The precipitated crystals were removed, and the solution was concentrated to dryness under reduced pressure. The resulting residue was dissolved in 100 tons of methylene chloride, and the organic layer was dissolved in 5% aqueous salt solution and 5% aqueous rifttrium carbonate solution. After sequentially washing with water, drying with anhydrous sodium sulfate, distilling off the solvent under reduced pressure F, and dissolving the residue with hydrochloric acid/
Hydrochloride salt in methanol and recrystallization from ethanol to give colorless needle-like crystals of 6-(4-(3,4,5-1-rimetho+cipensoyl)-1-goverazinyla-7tyl J-3)
, 0.8 g of 4-dihydrocarbostyryl monosulfate 3/2 hydrate is obtained, melting point 213-217c (decomposition). 2
-12.15-21.23 and 24 compounds fc are obtained.

Example 31 Succinimide 3,4.5-) Rimet↑Shibe:J')
Eight 136q and 6-(1-hyperazinyl acyl)-
3,4-dihydrocarbostyril 144 da was dissolved in 2 ml of dimethylform P3F and stirred day and night. Water was added to the reaction mixture, extracted with chloroform, and washed with water and saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was converted into a hydrochloride with hydrochloric acid/methanol.

Recrystallized from ethanol to give 6-(4-(3,4,5
-1-limeth+cype: J-cylb) -1-hyperazinyl at-tyl) -3,4-dihydrocarbostyryl
110 Mg of 1-hydrochloride/2-hydrochloride was obtained.

ml' 213-217C (decomposition) Compounds i (I) Examples 2-12, 15-21, 23 and 24 are obtained from appropriate starting materials in the same manner as in Example 31.

Example 32 6-etho+dicarbonyl 3.4 to 100 t of ethanol
．． Add 2.19y of 5-1-limethot and 0.5g of sodium ethylate and 2.48f of 6-(1-hyperazinylP-Hichi IC,)-,3,4-dihydrocarbostyryl. During autoclaving, 110 atmospheres,
React for 6 hours at 40-150'C.

From now on, the reaction solution will be condensed under reduced pressure by
After dissolving in 0 rsl and washing with 1% 2GO3 aqueous solution, dilute hydrochloric acid, and water in this order, drying with Na2SO4, the solvent was distilled off, and the resulting residue was dissolved in silica pur column column. : Wako C-200, eluent: chloroform:methanol (V/V) = 20:
After purification by step 1), it is converted into a hydrochloride with hydrochloric acid/methanol. Recrystallized from ethanol to give colorless needle-shaped 6-
(4-(3,4,5-trimetho+cypenlyl)-1
-3,4-dihydrocarbostyryl 11-! Li Shi Liao/Water O ■ Items 250 ~
get.

9 Noto 213-217'C (decomposition Example 2-1 using appropriate starting materials in 17 as in Example 32)
2.15-21.23 and 24 (Hymonide compounds are obtained.

1441q Example 33 6-(1-Hyperazinyl nitrate + 1.halbostyril 1.OLj and triethylamine 0.67 shoulder t)M
To the F10*/solution, gradually add one volume of the water-cooled, stirred Fm-Re00PySoilkI]lite 780q υMF2 solution. After adding drops F, stir at room temperature for 2 hours. The reaction mixture was poured into a large amount of half-saturated brine and extracted with 000 form. After washing with water, it was dried over anhydrous sodium sulfate. The 000 form was distilled off under reduced pressure.
1 and recrystallize. Dissolve the crystals in methanol solution and make salt + 1 salt with concentrated hydrochloric acid/1 tank IV. After evaporation of all the solvent, dissolve the residue in ethanol and dissolve the crystals.
Recrystallization from methanol yielded 6-(4-(3-chlorobey-noyl)-1-diperazinyl acetyl) with 370 η of 11.
J carbostyril hydrochloride hydrate is obtained.

212-2150 (decomposition) Colorless powdery crystal Compounds of Examples 34-42 are obtained in the same manner as in Example 33.

Example 43 6-(α-chloroDPI=chill)carbostyril 6.6 g
To 11 volumes of anhydrous dimethyl chloride and 11 volumes of Mua trichloromethane, add 4-
Add 14jf of (3,4,5-1-rimeth↑cypensoyl)piperazine and 5 ml of trichothylatriamine, and add 50-
The reaction solution was stirred at 60'C for 1 hour, poured into a large amount of water, and the organic layer was extracted using an OO membrane.

After washing and dehydrating the O-11 layer, the DO-11 layer is distilled off. Crystallize the residue with ethanol to obtain 1 crystal.
75, the crystals were suspended in methanol-chloroform, converted to hydrochloride with hydrochloric acid/ethanol, and recrystallized from methanol to give colorless powdery crystals of 6-[4-(3,4,5-1
-rimeth↑sibensoyl)-1-diverazinyl ahityl Jha1 and bostyril monohydrochloride 3/2 water Part 116.
Get Of. Decomposition 9 As in Example 43, using appropriate starting materials, the compounds of Examples 33.34-39.41 and 42 are obtained.

Example 44 6~(α-atrisonoacetylcarbostyryl 4.9f,
(3,4,5-trimeth + Sibey Noil) [G (2
-Shido O + Siethylph] P3 (J, l:! g and polyliffic acid 7.6 p) m, compound t16tJ-170'C
Allow to react for about 6 hours. Thereafter, the reaction solution was allowed to cool, and about 500 d of water was added dropwise to dissolve it. Neutralize with 48% sodium hydroxide and extract oil with RioO form.

After dehydration with hrium carbonate, RI00H1SHI8 was distilled off, converted to hydrochloride with concentrated hydrochloric acid/ethanol, and recrystallized from methanol to give 201-2040 (decomposition), 6 as colorless powdery crystals. - (4-(3,4,5-trimethoxycypenliyl)
-1.4 y of verazinyl acetyl J carbostyril monohydrochloride 3/2 hydrated product was obtained.

Compounds of Examples 33.34-39.41 and 42 are obtained in a similar manner to Example 44 using appropriate starting materials.

Example 45 6-(α-aminoacetylcarbostili 1 to 11.8
f, I: 3,4.5~trimetho+cypensoyl [dis(2-chloroethyl)]A3-JL7',09 A mixture of 70 tnl of methanol was stirred and refluxed for 155 hours.

Future Carbonate Notorium 3. Add tJ6f, stir and reflux for 8 hours, then collect the crystals that precipitate.-Hydrochloric acid/ethanol-1 to obtain the hydrochloride, recrystallize from methanol, m.
a201-204'c (decomposition), colorless powdery crystal 6-
(4-(3,4,5-1-rimeth+sibenryyl)-1
- Obtain 7.1y of carbostyryl monohydrochloride 3/2 hydrate.

The compounds of Examples 33-39, 41 and 42 are obtained in the same manner as in Example 45 using appropriate starting materials.

Example 46 To 100 liters of dimethic acid and formamide, 3.69 ml of 3,4,5-trimeth + dibenzoic acid and 1,8-diaza dichloromethane were added.
(5+4+OJ undecesci'7 1.6! IM and all added, external water-cooled stirring
．． 5 Drop the shoulder t. After dropping F, stir for 30 minutes and add 6-
(1-hyperazinyl acetyl)carbostyryl 2.25
After the reaction, the solvent was distilled off, and the residue was extracted with about 3 ml of dimethylformamide and diluted with dilute N. aIfC(-' 3 Wash with water, water, dilute hydrochloric acid, and water. After distilling off the OO form, the residue was made into a hydrochloride with hydrochloric acid/ethanol-1. Recrystallized from methanol.
6-[4-(3,4,5
-1-Limeth + Shibeshi Soil 1-Diperazinyl atyl" Carbostyril 1tJi + Toshishio / 2 Wednesday/Thursday 1 item 2
．． Get Of. Colorless powder crystal Compounds of Examples 33-39, 41 and 42 are obtained in the same manner as in Example 46 using appropriate starting materials.

Example 47 6-(1-hyperazinyl acetyl)carbostyryl 27
．． /4f and 3.4.5-1-rimeth+cybenzoic acid 2.2
5 f and geo + yn 20 tql and methichloride, :/2
In addition to the mixed solvent with 0 shoulder t, external water cooling stirring de, N, N
A solution of 2.1y of dicarboxylic acid 2.1y dissolved in methylene chloride:,15ynl is added dropwise to -disyc0 while maintaining the temperature at 10-20'C. After stirring at the same temperature for 3.5 hours, the precipitated crystals were removed, and the furnace liquid was evaporated to dryness under reduced pressure.The resulting residue was dissolved in 1 OOml of methylene chloride, and the organic layer was After washing in this order with % hydrochloric acid aqueous solution and 5% thorium carbonate hydrogen carbonate aqueous solution, anhydrous sulfur t411:j-
Dry with thorium, remove the solvent under reduced pressure F, and dissolve the residue in hydrochloric acid/
6-C4-(3,4,5-,1-rimetho+cypesi-noyl)-1-hyperazi'nylacetyl was obtained by recrystallizing from methanol to form a colorless powdery crystal.
Carbostyril 1 salt o salt - 3/2 water 80 substance 0.8
Fl'k? 8 le. Melting point 201-204'C (decomposition) Analogously to Example 47, the compounds of Examples 33-39, 41 and 42 are obtained from appropriate starting materials.

Example 48 Cohelic acid imide 3. 136 ml of 4.5-trimetho+silate and 1431 mg of 6-(1-hyperazinyl acetylcarbostyryl) were dissolved in 2 ml of dimethylformamide and stirred day and night. Water is added to the reaction mixture, extracted with 000 form, and washed with water and saturated brine. After drying over sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is made into a hydrochloride with hydrochloric acid/ethanol. Methanol Recrystallized from 6-(4-(3,4,5-1-rimetho+
cibensoyl)-1-dipelagini 1bacetyl]carbostyryl”IJ?tMatn.

103 Da of trifiltrate hydrate is obtained.

PFIp 201-204'c (decomposition) Colorless powdery crystals The compounds of Examples 33-39, 41 and 42 were obtained from appropriate starting materials in the same manner as in Example 48. +dicarbonyl 3
．． 4. Add 2.19 f of 5-1-rimeth + sibeshisoate, 0.59 of sodium ethylate, and 2.469 of 6-(1-piperazinylahityl) carbostyril, and heat to 110 atm and 140-150 C in an autoclave. and react for 6 hours. From now on, the reaction solution was evaporated under reduced pressure, the residue was dissolved in 200 tnl of 1% 12
After washing with Co3 aqueous solution, dilute hydrochloric acid, and water in this order, Na2
・50. After drying with , the solvent was distilled off, and the resulting residue was purified by silica pur column column D-mudography (silica pul:wa]tsu C-200, eluent: chloroform:methanol (V/V) = 20 = 1). After making M with hydrochloric acid/ethanol, it was converted to hydrochloride and then recrystallized from methanol.
Obtain 232q of colorless powdery crystals of 6-(4-(3,4,5-1-rimetyl)-1-verazinyl carbostyril monohydrochloride 3/2 hydrate) .

mp 201-204'c (Decomposition) Using appropriate starting materials in the same manner as in Example 49, the compounds of Examples 33-39, 41 and 42 are obtained.

Example 50 3.4-”/e dolocarbostyril 2 (Jf, 4-(
3,4,5-) Rimet + Jibey fly) -1-
Anhydrous aluminum chloride 469 ground in a water-cooled stirring oven is gradually added to a mixture of hyperazinyl 1y, 71.5f of Circide D and 30m/m of carbon disulfide at an internal temperature of 5-15C. Stir under reflux for 40 minutes after addition, and add 1 carbon disulfide.
After removing the cant, the residue is poured into a large amount of ice water to separate the precipitated crystals, which are thoroughly washed with water and then with methanol. After drying, suspend the crystals in methanol-chloroform,
The hydrochloride salt was prepared with hydrochloric acid/methanol, and recrystallized from [51Nol to give colorless needle-like crystals of 6-(4-(3,4,5-1-
Limeto+Shibey Noyl)-1-Hyperazini)ShiachiIL, )-,3,4-Dihydrocarbostyryl 1
Obtain 663ml of hydrochloride 3/2 hydrate 213-217'C (decomposition) Colorless needle crystals In the same manner as in Example 50, the compound of Example 2-24 was poured into a barrel. Example 51 Cal 4 (Styril L9.7 f, 4- (, 3, 4, 5
-1-claw 1゛+shi''
46 g of anhydrous armonium chloride pulverized in a water-cooled stirring oven was gradually added to the mixture of Step 1 at an internal temperature of 5-150°C. Stir under reflux for 40 minutes after addition. After removing carbon disulfide by decantation, the residue was poured into a large amount of ice water to collect precipitated crystals, thoroughly washed with water, and then washed with methanol.7 After drying, the crystals were suspended in methanol-chloroform. ! JlsaIJ-, converted to hydrochloride with hydrochloric acid/ethanol and recrystallized from methanol to give colorless powdery crystals of 6-[4-(,3,4,5-1-rimeth↑cypene noyl)-1- verazinyl ahityl]
Carbostyril °1 hydrochloride, 3/2 water solution 6.21
get.

201-21) 4C (decomposition) Colorless acicular crystals In the same manner as in Example 51, Example 33-39.41
and 42 compounds are obtained.

Example 52 6-(4-(2-pheno+diethyl)-1-diperazinyladityl)-3,4-di-Fθ force 1b boss chili 1 and 4
98 da, 50% oily hydrogen 1 hina 1-lium 70~ in dinutylformide 5 shoulder l? After stirring at room temperature for 1 hour, a solution of benzene chloride, ToO, 17*, in 3 ml of dimethylformamide was gradually added to tf'Fl.
Stir at room temperature for 4 hours. The reaction solution was poured into a large amount of water, organic substances were extracted with OO form, and the 900 form layer was washed with water.
Dry and distill off the filtrate.

Add 1-agricultural hydrochloric acid to the remaining t& and prepare white crystals of 1-benzyl-6-(4-(2-pheno↑ethylar)-goverazinylahiti ILI J-3+4-,:
/ Hydropower + 1 / Bostyril 1 hydrochloride 15 (obtain J# rn I, 2, '30-234 c (Decomposition) Elemental analysis value ((, ',, J1133N, 03-1fC
e-C) C//N Calculated value (%) 69.28 6.59 1J,
08 Actual measurement (%) 69. (J8 6.74
7.98 Example 53 6-(4-(2~pheno+diethyl)-1-goberazinyl athyl)-3,4-dihydrocarbostyryl 498
In the evening, 50% oily hydrogen 1 arsenium 70r4 dimethic acid 1
Mix 1 ml of salt with 5 ml of Muamide and incubate for 1 hour at room temperature.
After stirring, the mixture was added dropwise to a solution of 0.23 f of 1-himethyliodine in 3 yglml of dimethylformamide, and the mixture was stirred at room temperature for 4 hours. Pour the reaction solution into a large amount of water, and add 200% of the organic material.
Form extraction [7. The chloroform layer was washed with water and dried.7. The chloroform was distilled off. Salt was added to the residue to obtain white crystals of 1-methy+b-6-(4-(2-pheno+) 1-diperazinyl acetyl'J-3,
4-Dishidroha 117 + Tostyryl monohydrochloride 132
ml'115-120'C (decomposition) elemental analysis value (C214H29N303・IKg) CH
N Calculated value (%) 7o, 56 7.40 io,
29 rii 6 river nails 1 (%) 70.41
7.51 10.09 Example 54 6-(4-(2-pheno+siethi!b)~l-goberazinyl a7tyl) -3,4-dihydrocarbostyryl 4
98q, 50% oily hydrogenated sulfur chloride '70 MQ was mixed in I) M F 5 Ml, and after stirring at room temperature for 2 hours, 0.17 g of zuDpalkDride was added and stirred at room temperature for 7 hours. Reaction L night cell O D * Salt water J, 3
The organic matter was extracted with water, dehydrated, and the chloroform was distilled off.The residue was purified using a silica pur column column (comatogirafi), and concentrated hydrochloric acid was added. Hydrochloride, white crystals of 1-
(2-diOhinyl)-6-C4-(3,4-dimeth↑siben~noyl)-1-goberazinyl atthyl)-3,4
-Dihydrocarbostyryl monohydrochloride 85 capes are obtained.

,,/) 209-211'C (decomposition) elemental analysis value (
C26ft29N303-HCJ tL-t')c
tt u calculation value (first 6
6.73 6.46 8.98 fruit 61su Ii7M (
First 66.48 6.66 9.19
Example 55 6-(4-(2-pheno+diethyl)-1-diverazinyl ahythyl J-3,4-dididrocarbostyryl 49
8~, sodium anide 0.059 υA/F 5
After stirring at room temperature for 2 hours, Plilk [Jride O, LVf] was added and the mixture was stirred at room temperature for 10 hours. The reaction solution was poured into 3 mt of saturated saline solution, and the organic substances were extracted with chloroform.The chloroform layer was washed with water, dehydrated, and chloroform was distilled off. The distillate was purified by silica gel column chromatography and converted into a hydrochloride with concentrated hydrochloric acid to give white crystals of 1=allyl-5-(4-(3,4-
Dimeth+Cybe(/'-)yl)-1~diperazinyl acetyl)-,3,4-dihydrocarbostyryl 1 hydrochloride 91 ml 107-110''C (decomposition) Element Analysis value (C26H3□N303.lff and I, C)
CHN Calculated value (%) 66.44 6.86 L9
4 real ig! I [(', 6, 1 66.14
6.61 9.15 Example 56 8-(α-riooPt-thyl)-3,4-dididrocarbostyryl 6.7 II of anhydrous dimethylforma tridro0
On the night of village melting, 4-(3,4,5-trimet↑shi\n9
il) Perazine 14. ．． 3 y and triethylua E
y 5 ml gold added 5tJ-600 for 1 hour 111-
Pour the reaction solution into plenty of water, and extract the molar layer with chloroform. The chloroform layer is washed with water and dehydrated, and then the chloroform is distilled off. The residue was crystallized with ethanol, and the crystals were dissolved in chloroform. Trimet 1 Shihen・
4.7 g of dihydrocarbostyryl 1-hydrochloride is obtained.

! n p L 58-162 'c Elemental analysis value (as C25H29N30S/dCg)C
HN Total X, value (%) 64.09 6.45 8.
97 Actual measurement m (%) 64.26 6.34 9.
09 Example 57 5-(α-ri oop 7chi 11/)-,3,4-dishi l".

4-(J, 4.5-trimer-1-
Add 14.3y of ↑cyben9yl diperazine and 5me of triethylamine, and stir at 50-60"C for 1 hour.

Pour the reaction solution into a large amount of water, separate the organic layer, and extract with OO hole. [01] After washing the form layer with water and dehydrating it, chloroform is distilled off. The residue is crystallized with ethanol and the crystals are roasted. Suspend the crystals in methanol-chloroform and use a hydrochloric acid/methanol V trowel to obtain white crystals as hydrochloride.
-C4- (3,4,5-1-rimeto+shibeshi9i1shi)
-1-hyperazinyl acetate) -3,4-hyperazinyl acetate 1 to obtain 4.31 of bostyril 1 hydrochloride.

ml 157-162'C Elemental analysis value (as C25H29N305/HCl)C
If N Calculated value (%) 64.09 6.45 8.97 Actual measurement 64.26 6.34 9.09 Pharmacological test (a) Bentopardital sodium was administered to male and female mixed-breed adult dogs weighing 8-13 kq. Anesthetize by administering salt intravenously at a rate of 30'lQ/kLj. After intravenously administering the sodium salt of Heparin at a rate of 1000 U/kq, the animals were bled to death, and the hearts were removed at night.

Insert a needle from the right coronary artery toward the sinus node artery, and remove the right atrium with a needle.
Sodium salt of t-ba1 tar (30=&/kq,
Anesthetized by intravenous administration) and treated with heparici (1000 U
Blood was drawn from the carotid artery of a male-male mixed-breed adult dog weighing 18-27 kq (intravenous administration) through a peristaltic tube into a cannula inserted into the right coronary artery and directed into the right atrium. #I flow pressure is a constant pressure of 100 Iff.

The movement of the right U atrium is at a static tension of 21F, and the contraction force of the atrial muscle is measured via a force displacement transducer.The coronary artery blood flow is measured using an electromagnetic flowmeter. All records shall be recorded on an inscription record book. The details of this method have been reported by Chiba et al. (Japan, /, Phar
r-tatol,, 25.433-439 (1j
75, Naunyn 5thnntd
btrq '5Arth, Pharntatol
, 289, 315-325 (1975), ).

The test compound ``IAv'' was injected into the artery through a 1-piece tube connected in close proximity to the honeycomb inserted into the right coronary artery.
Inject at valley fit of O-30tt 11. The positive inotropic effect of the test compound is expressed as a % change in the tension generated before compound administration, and the reduction in coronal flow is expressed as the absolute value (shoulder l/min) from administration 11. The results are shown below. Table 1 shows the number of (h) male and female mixed breed adult dogs with a body size of 8-13 kg.
30 me/k of thorium salt from Tubal
Administer intravenously at a rate of 1.0 g to induce anesthesia. The sodium salt of heparin was administered intravenously at a rate of 1000 U/#, followed by bleeding to death and the heart was removed. The blood drawn from the dog is applied at a constant pressure of 1 oomirq. The donor dog weighed 18-27 kq and was anesthetized in advance by intravenously administering 30 mQ/kQ of ventoparditar/J thorium salt, and 10 mQ/kQ of heparin/J thorium salt.
oOU/kq is administered intravenously. Using bipolar electrodes,
Mixed pressure C0,5-3V 15 times the v value), stimulation width 5 m5
The resting tension of the papillary muscles is 1.5y, and the generated tension of the papillary muscles is measured via a force displacement transducer.

The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of generated tension and blood flow are recorded on an ink recorder. The details of this method have already been reported by Endo and Hashimoto (Am, J-Physiθ1..218.1
459-1463.

1970).

The test compound is administered intra-arterially in 10-30 μl over 4 seconds. The inotropic effect of the test compound is expressed as a percentage of the tension generated before drug administration.The effect on the coronal female nail is expressed as the absolute value of ashing (me/min) from the administration riiJ.The results are shown in FrR2. (C) Using a male and female mongrel adult dog weighing 9-L5 kq, the rs was ventilated with tar storium 3 (J
Anesthetize with intravenous administration of m9/kq, followed by Bendopa 1 and tar sodium 4'Q/kg/
Continuous intravenous infusion of sr, using a ventilator to maintain a constant level of anesthesia, breathing rate of 18 times per minute, 2Q
Artificial respiration 12 under the condition of inspiratory volume of IIt / +t9,
The chest was opened.

The left ventricular contractile force was measured via an arched stray Y gauge attached to the outer wall of the left U ventricle.
7: Insert the tube and measure the systemic blood pressure through the pressure transducer, and drive the 5U meter to measure the 5U pulse rate using the blood pressure pulse wave. All parameters are ink. The drug was administered via a catheter inserted into the femoral vein. The force effect of the test compound was expressed as the absolute value of the compound dose. The results are shown in Table 3.Test Compound 2 Compound Name 1.6 [4-(4-Methylbenzoyl)-1-diperazinyl] -3,4-dihydrocarpostyl 1 and 1 Hydrochloride monohydrate 2.6-(4-(4-cyanoben fil)-1-diperazinyl P-cetyl J-3,4-dihydrocarbostyryl 1/2 hydrate, L6-(4- (4-Methylbenzoyl)-1-goberazinyl acetyl)-3,4-dihydrocarbostyryl.
monohydrochloride monohydrate 4.6-(4-(3,4-methydinedio+siben noyl)-1-diveracinyl acetyl) -3,4-dihydrocarbostyryl monohydrochloride・1 water 41] product 5.6-(4-(4-nitrobensoyl)-1-hyperazinyl acetyl J-3,4-dihydrocarbostyryl)
1-hydrochloride 6.6-(4-acytyl-1-diperazinylahityl)
-3,4-dihydrocarbostyryl 1 hydrochloride 1 filtrate 7.6-(4-etho+dicarbonyl-1-hyperazinylacetyl) -3,4-dihydrocarbostyryl 1
Hydrochloride 8.6-(4-methanesulfonyl-1-diperazinyl P
[Otsutyl)-3,4-dihydrof]lupostyryl monohydrochloride /dihydrate 9.6-(4-formyl-1-diperazinyl acetyl)
-3,4-dihydrocarbostyryl 10.6-(4-(
3,4-Dimeth+cipesi-noyl)-1-hyperazinyl Phythyl J -3,4-dithydrocarbostyryl 11.6-i-(,3-di00pen~noyl)-1-diperazinyl athyl ) -3,4-dihydrocarbostyryl 1/2 hydrate 12,6-C4-(3,4-methyI):,/dio+shen-noyl)-1-diperazinyl Pcetyryl carbostyryl 1/2 hydrate 13.6-(4-(3,4-diku00beynoyl)-
1-Verazinyl acetyl) -3,4-dihyde [cocalpostyryl monohydrochloride 1/2 water salt 14.6-(
4-)Dyl-1-diperazinyl acetyl) -3,4
-Dishidrocarbostyril 1-hydrochloride 15,6- (4-bay-noyl-1-goberazinylahityl) -3,4-dishidrocarbostyryl ”/4
Hydrate 16.6 [4-(3-rioopaysoy L)-1-
Piperazini IG Pt Chill' Carbostyryl Hydrochloride Water + 11 Things 17, 6- (4-(3,4-dimeth + Shihetsu Soil)
-1-Pelazinirahichi 1 Shi 1 Haruboschiri 1 Shi・L
M butyrate, water, r day 18.6-(4-(4-meth+cypenly 1)-1-
diverazinyl adithyl] carbostyril.

4-(4-methylpensoyl 1-1-diperazinyl 7-1-1) carpostyl 1-hydrochloride 3
/dihydrate 20. 6-(4-hensoyl-1-piperazinyl acetyl)carbostyryl hydrochloride 3/2 hydrate 21. 6-(4-(4-cyanobendiyl)-1-acid Salt /2 Water 411 22,6-C4-(,3,4,5-Trimer:J'-)I)-1-Perazinyl acetate]Hajshibostyril Hydrochloric acid Salt/3/2 water No. 11 23.6-(4-(4-nitrobey/soy 11.)
-1-Diperazine 1 and Ahitil' 1 and Bostyl dihydrochloride 1/2 water 11 24-6-(:4-(4-Metho+Shishinna7i:Sh)-
1-diperazinyl acetyl Ib J -3,4-dishido D
Power 1 Bostyril 1 Hydrochloride 1 Hydrate 25, 6- (
4-Shishinanai: Shi-1-L Niperajini) and Phicil)
-3,4-dihydrocarbostyril 1 hydrochloride 1/
Dihydrate 26.6-(4-(4-Atrinopeytyl)-1-hyperazinylahityl)carbostyryl 2-hydrochloride/1-hydrate 27.6-[E4-( 2-pheno+diethyl)-1-rubostyryl dihydrochloride 1/2 water + U substance 28.7?l,
Linone (control compound) 29, Dopta Sanshi (control compound) Table 1, Table 2, Table 3 onwards [Preparation examples using the compounds of the present invention are listed] Formulation Example 1 Hydrate Desipne 132#f Mazinesium Stare 1 )-to 18MQ lactose
45 grams 200 mg Tablets of the above composition were prepared in one tablet using a conventional method. Formulation Example 2 Bun Bun 127q Maginesium Steer 1 Note 181 g
200 mg Tablets containing the -10% composition were prepared in a conventional manner.

Formulation Example 3 - Dishidrocarbostyryl polyethylene: J silicone (molecular weight: 4000)
0.3y Zitorium chloride t
), 9P meta-type sodium sulfate 0.1
y Methyl-paraben 0.18f mouth-to-mouth paraben 0.02f distilled water for injection 1tJL) *t [2 Paraben J
, sodium metabisulfite and sodium chloride are dissolved in the above distilled water at 80°C with stirring. The obtained solution was cooled to 1tt40c, and the compound of the present invention, then polyethylene diglycol and polyoleate were dissolved in the solution of Ichihito, and then the solution was subjected to injection distillation. The final volume is adjusted by adding water, sterilized by filtration using a suitable filter paper, and the solution is dispensed into ampoules in lyxl portions to prepare an injection.

Formulation example 4 Denran 1271tg Matanesium Stare 1 note 18 shoulder q Lactose 45Q meter
200q One tablet of the above composition was manufactured by a conventional method.

(hereinafter “2”)

Claims (1)

[Scope of Claims] (i) General formula [wherein R represents a hydrogen atom, a lower aryl group, a lower alkenyl group, a lower aryl group, or a phenyl lower aryl group; R is a lower alkanoyl group, a lower alkoxy + dicarbonyl group, a ) Di group, a lower alkanesulfonyl group,
As a substituent on the top of phenyl, 1-3 groups selected from lower P, lower alk, hydrogen, cyano, amino, and nitro groups or lower alk, Idio↑
A ben-noyl group that may have a cy group, a phenylsulfonyl group that may have a lower alkyl group as a substituent on the phenyl ring, and a lower p-ruco+cy group with an IR substituent on the phenyl ring. Phenyl lower alkenyl carbonyl group or pheno + lower al↑ which may contain
Indicates a group. At least one selected from carbostyril derivatives and salts thereof represented by: A represents lower alkyl ↑ and y&; the carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton represents a single bond or a double bond; A cardiotonic agent characterized by containing seeds as an active ingredient.