Carbostyril derivatives and process for preparing the same

Carbostyril derivative represented by the formula (I): ##STR1## wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom, a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group; R.sup.4 represents a hydrogen atom or an alkyl group, R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenylalkyl group, or R.sup.5 and R.sup.6 may, when taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen or oxygen atoms as hetero atoms; and the ring A has a partial structure: ##STR2## wherein R.sup.3 represents a hydrogen atom, a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group, with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 when R.sub.3 is present, or at least one of R.sub.1 and R.sub.2 when R.sub.3 is absent, represents a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group; the pharmaceutically acceptable acid addition salts of the above carbostyril compounds represented by the formula (I), and processes for preparing the above carbostyril compounds represented by the formula (I).

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to carbostyril derivatives and a process for 
preparing the same. More particularly, this invention relates to 
carbostyril derivatives represented by the formula (I) hereinafter 
described, the pharmaceutically acceptable acid addition salts thereof, 
and a process for preparing the same. 
2. Description of the Prior Art 
It is well known that certain carbostyril derivatives exhibit useful 
pharmaceutical activities. Representative compounds of this type have been 
disclosed in Journal of Medical Chemistry, Vol. 15, No. 3, pp. 260-266 
(1972), Japanese Patent Publication No. 38789/1971 and Chemical Abstracts, 
62, 16212e (1965), etc. However, these prior art references do not teach 
that the compounds having a [1-acyloxy-2-(unsubstituted 
or-substituted-amine)]alkyl group at the 5-position and/or an acyloxy 
group at the 8- and/or 2-position of the carbostyril or 
3,4-dihydrocarbostyril moiety possess an excellent .beta.-adrenoreceptor 
stimulating activity. 
The carbostyril and 3,4-dihydrocarbostyril derivatives having a 
1-hydroxy-2-(substituted-amino)alkyl group at the 5-position and having a 
substituent at the 1- and/or 8-position of the carbostyril or 
3,4-dihydrocarbostyril moiety and the pharmaceutically acceptable acid 
addition salts thereof are disclosed in Dutch Patent Application No. 74 
16844 and U.S. Pat. Nos. 536,515, filed Dec. 26, 1974, 536,516, filed Dec. 
26, 1974, 536,703, filed Dec. 26, 1974, 536,704, filed Dec. 26, 1974 and 
536,705, filed Dec. 26, 1974, as having a .beta.-adrenoreceptor 
stimulating activity and being useful as a therapeutic agent such as a 
bronchodilator, a peripheral vasodilator, an antihypertensive agent and 
the like, particularly for treating bronchial asthma. 
It has now been found that the carbostyril and 3,4-dihydrocarbostyril 
derivatives having the formulae (I) also exhibit an excellent 
.beta.-adrenoreceptor stimulating activity. 
SUMMARY OF THE INVENTION 
An object of the present invention is to provide carbostyril derivative 
represented by the formula (I): 
##STR3## 
wherein R.sup.1 and R.sup.2, which may be the same or different, each 
represents a hydrogen atom, a cycloalkylcarbonyl group, a 
cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group; R.sup.4 represents a hydrogen atom or an alkyl 
group, R.sup.5 and R.sup.6, which may be the same or different, each 
represents a hydrogen atom, an alkyl group, a cycloalkyl group, or a 
phenylalkyl group, or R.sup.5 and R.sup.6 may, when taken together with 
the nitrogen atom to which they are attached, form a 5- or 6-membered 
substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen 
or oxygen atoms as hetero atoms; and the ring A has a partial structure: 
##STR4## 
wherein R.sup.3 represents a hydrogen atom, a cycloalkylcarbonyl group, a 
cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group, with the proviso that at least one of R.sup.1, 
R.sup.2 and R.sup.3 represents a cycloalkylcarbonyl group, a 
cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group; and the pharmaceutically acceptable acid 
addition salts thereof. 
Another object of this invention is to provide processes for preparing the 
above carbostyril compounds represented by the formula (I).

DETAILED DESCRIPTION OF THE INVENTION 
The term "alkyl" as used herein for R.sup.4, R.sup.5, and R.sup.6 means a 
straight or branched chain alkyl group having 1 to 4 carbon atoms and 
includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, 
sec-butyl, tert-butyl group and the like. 
The term "cycloalkylcarbonyl" as used herein means a cycloalkylcarbonyl 
group having 4 to 8 carbon atoms, for example, a cyclopropylcarbonyl, 
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 
cycloheptylcarbonyl group and the like. 
The term "cycloalkylalkanoyl" as used herein means a cycloalkylalkanoyl 
group having 3 to 7 carbon atoms in the cycloalkyl moiety and 2 to 4 
carbon atoms in the alkanoyl group, for example, a cyclopropylacetyl, 
4-cyclopentylbutanoyl, 3-cyclohexylpropanoyl, 3-cycloheptylbutanoyl, 
3-cyclohexyl-2-methylpropanoyl group and the like. 
The term "benzoyl" as used herein means a benzoyl group which may be 
substituted with one to three substituents selected from the group 
consisting of a halogen atoms, a hydroxyl group, a straight or branched 
chain alkyl group having 1 to 4 carbon atoms, an alkylenedioxy group 
having 1 to 4 carbon atoms such as a methylenedioxy group, an 
ethylenedioxy group and the like, an alkoxy group having 1 to 4 carbon 
atoms such as a methoxy group, an ethoxy group, an isopropoxy group and 
the like. Typical examples of benzoyl groups are a benzoyl, 
o-methylbenzoyl, m-ethylbenzoyl, p-isopropylbenzoyl, p-chlorobenzoyl, 
p-fluorobenzoyl, o-bromobenzoyl, 3,4-ethylenedioxybenzoyl, 
p-methoxybenzoyl, o-hydroxybenzoyl, p-isopropoxybenzoyl, 
3,4-diethoxybenzoyl, 3,4,5-trimethoxybenzoyl group and the like. 
The term "cycloalkyl" as used herein means a cycloalkyl group having 4 to 6 
carbon atoms, for example, a cyclobutyl, cyclopentyl, cyclohexyl group and 
the like. 
The term "phenylalkyl" as used for R.sup.5 and R.sup.6 means a phenylalkyl 
group which may be substituted with 1 to 3 substituents such as those 
previously described for the benzoyl group, containing 1 to 4 carbon atoms 
in the alkyl moiety which may be straight or branched chain. Typical 
examples of phenylalkyl groups are a benzyl, 2-phenylethyl, 
3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 
2-methyl-3-phenylpropyl, 1-methyl-2-phenylethyl, 3,4-dimethoxyphenetyl, 
3,4,5-trimethoxyphenethyl, 3,4-ethylenedioxyphenetyl group and the like. 
The term "phenylalkylcarbonyl" as used herein means phenylalkylcarbonyl 
groups having the same phenylalkyl moiety as the phenylalkyl group 
previously described for R.sup.5, for example, a phenylacetyl, 
2-phenylethylcarbonyl, p-methylphenylacetyl, 4-phenylbutylcarbonyl, 
2-phenyl-1-methylethylcarbonyl, 3,4-dimethoxyphenetylcarbonyl, 
3-(4-chlorophenyl)butylcarbonyl group and the like. 
The term "alkanoyl" as used herein means a straight or branched chain 
alkanoyl group having 2 to 6 carbon atoms, for example, an acetyl, 
propionyl, butyryl, 2-methylbutyryl, pentanoyl, 2,2-dimethylpropionyl, 
3-methylbutanoyl, hexanoyl, 3,3-dimethylbutyryl group and the like. 
The term "5- or 6-membered substituted or unsubstituted heterocyclic ring" 
as used herein means heterocyclic groups containing 1 or 2 nitrogen or 
oxygen atoms as hetero atoms such as a pyrrolidino, piperidino, 
morpholino, piperazino or a like group which can be unsubstituted or 
substituted with an alkyl group having 1 to 4 carbon atoms, such as a 
methyl, ethyl, isopropyl, tert-butyl group and the like, for example, a 
2-methylpiperidino, 3-methylpiperidino, N-methylpiperazino group and the 
like. 
The term "halogen" as used herein includes fluorine, chlorine, bromine and 
iodine, preferably, chlorine and bromine. 
The term "pharmaceutically acceptable acid addition salts" as used herein 
means those formed with non-toxic inorganic and organic acids which are 
well known in the art such as, for example, hydrochloric acid, hydrobromic 
acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, lactic 
acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, 
malic acid, mandelic acid, methanesulfonic acid, benzoic acid and the 
like. 
The chemical structure representing carbostyril compounds of the present 
invention used throughout the sepcification and claims of this invention, 
i.e., the partial structure having the formula: 
##STR5## 
includes both a carbostyril compound and a 3,4-dihydrocarbostyril compound 
of the partial structure: 
##STR6## 
respectively. Such definition is also applied to the compounds having the 
formula (Id) below. 
The corbostyril compounds and the 3,4-dihydrocarbostyril compounds may be 
present as keto and enol forms with respect to the 2-position, and can be 
acylated at the 2-position as illustrated below. 
##STR7## 
The carbostyril compounds represented by the formula (I) includes the 
compounds represented by the formulae (Ia), (Ib), (Ic) and (Id). 
##STR8## 
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined 
above. 
The carbostyril compounds of the present invention can be prepared from the 
compounds of the formula (IV) or (V) by acylation according to the 
processes shown in the Reaction Scheme below. 
##STR9## 
According to the process shown in the Reaction Scheme above, the starting 
materials of the present invention represented by the formula (IV) can be 
prepared by: 
(1) reacting 8-hydroxycarbostyril or 8-hydroxy-3,4-dihydrocarbostyril of 
the formula (IX): 
##STR10## 
with an .alpha.-haloalkanoic acid halide of the formula (VIII): 
##STR11## 
wherein R.sup.4 represents a hydrogen atom or an alkyl group having 1 to 4 
carbon atoms; and X and X', which may be the same or different, each 
represents a halogen atom, to obtain a 
5-(.alpha.-haloalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-haloalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of the formula 
(VII): 
##STR12## 
wherein R.sup.4 is as defined above; 
(2) reacting the resulting 5-(.alpha.-haloalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-haloalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of the formula 
(VII) with an amine of the formula (VI): 
##STR13## 
wherein R.sup.5 and R.sup.6 each represents a hydrogen atom, an alkyl 
group, a cycloalkyl group or a phenylalkyl group, or R.sup.5 and R.sup.6 
may, when taken together with the nitrogen atom to which they are 
attached, form a 5- or 6-membered heterocyclic ring, to obtain a 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of 
the formula (V): 
##STR14## 
wherein R.sup.4, R.sup.5 and R.sup.6 are as defined above; and, optionally 
(3) reducing the resulting 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of 
the formula (V) with hydrogen by a catalytic reduction or a reduction 
using a reducing agent. 
The .alpha.-haloalkanoic acid halide of the formula (VIII) which can be 
used in this invention includes .alpha.-chloropropionyl chloride, 
.alpha.-bromopropionyl chloride, .alpha.-chlorobutyryl chloride, 
.alpha.-bromobutyryl chloride, .alpha.-bromobutyryl bromide, 
.alpha.-chlorovaleryl chloride and the like. 
The reaction between the carbostyril compound of the formula (IX) and the 
.alpha.-haloalkanoic acid halide of the formula (VIII) can be conducted 
using a Lewis acid as a catalyst, for example, aluminum chloride, aluminum 
bromide, zinc chloride, ferric chloride, stannic chloride, boron 
trifluoride, in an amount of about 2 to about 10 moles, preferably 3 to 6 
moles, per mole of the starting carbostyril of the formula (IX). The 
.alpha.-haloalkanoic acid halide of the formula (VIII) can be used in an 
equimolar amount to a large excess relative to the carbostyril of the 
formula (IX) but generally is used in an amount of from about 2 to about 
20 moles, most preferably 2 to 10 moles, per mole of the starting 
carbostyril of the formula (IX). The reaction can be carried out in the 
absence of a solvent or in the presence of an appropriate solvent such as 
carbon disulfide, nitrobenzene, diethyl ether, dioxane and the like and in 
the presence of the above enumerated catalyst, advantageously under 
anhydrous conditions, at room temperature (about 0.degree. to 30.degree. 
C.) to about 150.degree. C., preferably from room temperature to about 
80.degree. C. for a period of about 1 to about 20 hours, preferably 4 to 
10 hours. The above solvent is usually used in a volume of about 0.5 to 
20, preferably 2 to 10, times the volume of the reactants. 
The amines of the formula (VI) which can be used in the reaction with the 
5-(.alpha.-haloalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-haloalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of the formula 
(VII) include ammonia, alkylamines, for example, methylamine, ethylamine, 
n-propylamine, isopropylamine, n-butylamine, sec-butylamine, 
tert-butylamine, cyclopentylamine, cyclohexylamine; phenylalkylamines, for 
example, benzylamine, .alpha.-methylbenzylamine, 
.alpha.,.alpha.-dimethylbenzylamine, phenethylamine, 
.alpha.,.alpha.-dimethylphenethylamine and the like; and substituted or 
unsubstituted heterocyclic amines, for example, pyrrolidine, piperidine, 
morpholine, piperazine, 2-methylpiperidine, 3-methylpiperidine, 
N-methylpiperazine and the like. 
This reaction between the amine of the formula (VI) and the 
5-(.alpha.-haloalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-haloalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of the formula 
(VII) can be effected in the absence of a solvent since the amine reactant 
itself also serves as a solvent, but it is advantageous to conduct the 
reaction in an appropriate solvent. Suitable examples of solvents which 
can be used include lower alcohols such as methanol, ethanol, isopropanol 
and the like, ethers such as dioxane, diethyl ether and the like, esters 
such as ethyl acetate, aromatic hydrocarbons such as benzene, toluene, 
xylene and the like, nitrile solvents such as acetonitrile and the like. 
Ethanol and isopropanol are preferred. 
This reaction can be effected using an equimolar amount to, especially in 
the absence of a solvent, a large excess of the amine of the formula (VI), 
preferably from about 2 to about 10 moles of the amine per mole of the 
5-(.alpha.-haloalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-haloalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of the formula 
(VII) at about atmospheric pressure to about 10 atmospheres at a 
temperature of from room temperature to the refluxing temperature of the 
reaction system, preferably at a temperature of 40.degree. to 100.degree. 
C., in an appropriate solvent or using the amine of the formula (VI) per 
se as a solvent to obtain a 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of 
the formula (V). 
The reduction of the 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxycarbostyril or 
5-(.alpha.-substituted-aminoalkanoyl)-8-hydroxy-3,4-dihydrocarbostyril of 
the formula (V) to the starting compounds of the present invention 
represented by the formula (IV) can be conducted by a conventional 
reduction using a reducing agent such as lithium aluminum hydride, sodium 
borohydride and the like, or a conventional catalytic reduction in the 
presence of a catalyst such as palladium black, palladium-carbon, Raney 
nickel, platinum black, platinum oxide and the like and hydrogen. 
The above reducing agent can be used in an amount of from about 2 to about 
10 moles, preferably 2 to 5 moles, per mole of the carbostyril compound of 
the formula (V) in a solvent while cooling under atmospheric pressure at a 
temperature of from about 0.degree. to about 100.degree. C., preferably 
20.degree. to 50.degree. C. When sodium borohydride is used as a reducing 
agent, the solvent is preferably water or an alcohol such as methanol, 
ethanol and the like, and when lithium aluminum hydride is used as a 
reducing agent, the solvent is preferably a non-aqueous solvent such as 
anhydrous diethyl ether, ethyl acetate, tetrahydrofuran and the like. 
The catalytic reduction can be carried out using the above catalyst in an 
amount of from about 0.05 to about 1 mole, preferably 0.1 to 0.5 mole, per 
mole of the carbostyril compound of the formula (V) in a solvent, for 
example, water or an alcohol such as methanol, ethanol or isopropanol 
under a hydrogen atmosphere at a pressure of from about atmospheric 
pressure to about 100 atmospheres, preferably atmospheric pressure to 50 
atmospheres, at a temperature of from room temperature to about 
150.degree. C., preferably room temperature to 120.degree. C., 
advantageously with agitating the reduction system. It is advantageous to 
carry out the above catalytic reduction at a temperature higher than about 
50.degree. C. at atmospheric pressure or at a temperature higher than room 
temperature under atmospheric pressure. 
The 8-hydroxycarbostyril or 8-hydroxy-3,4-dihydrocarbostyril compounds of 
the formula (IV) obtained above can then be acylated using a carboxylic 
acid halide or a carboxylic acid anhydride as an acylating agent to 
produce the compounds of the formulae (Ia), (Ib), (Ic) and (Id). 
Alternatively, the compound of the formula (Ia) can be produced by 
acylating the compound of the formula (V) with a carboxylic acid halide or 
a carboxylic acid anhydride as an acylating agent to produce the compound 
of the formula (III) and reducing the resulting compound of the formula 
(III) in the same manner as described for the reduction of the compound of 
the formula (V) to the compound of the formula (IV). 
The acylation of 8-hydroxycarbostyril or 8-hydroxy-3,4-dihydrocarbostyril 
of the formulae (V) and (IV) obtained above can be conducted using various 
procedures well known in the art for acylation of the hydroxyl group. 
Typical procedures which have been found particularly useful in preparing 
the carbostyril derivatives of this invention are described hereinafter in 
detail. 
The carbostyril compounds of the formula (IV) contain 3 hydroxyl groups 
including an enol group at the 2-position, and a competitive acylation 
between these hydroxyl groups is involved in these compounds, i.e., 
8-hydroxyl group&gt;2-hydroxyl group or a hydroxyl group in the side chain at 
the 5-position of the carbostyril nucleus; 8-hydroxyl group&gt;a hydroxyl 
group in the side chain at the 5-position of the 3,4-dihydrocarbostyril 
nucleus. Further, O-acylated carbostyril compounds having the formulae 
(Ia), (Ib), (Ic) and (Id) tend to be reactive to acid or alkali hydrolysis 
or catalytic reduction, i.e., 2-O-acyl&gt;8-O-acyl or 5-O-acyl, to regenerate 
hydroxyl groups by cleaving acyl groups. Thus, a wide variety of acylated 
carbostyril derivatives can be produced by appropriately selecting the 
acylation conditions as well as hydrolysis and/or reduction conditions. 
The acylation procedures used in the present invention can be classified as 
Acylation Method (A) to Acylation Method (D) according to the acylation 
positions, as hereinafter described in greater detail. 
It is to be noted that the terms "carboxylic acid halide" and "carboxylic 
acid anhydride" used herein for acylating agents are those containing an 
acyl moiety corresponding to the acyl group R.sup.1, R.sup.2 or R.sup.3 as 
described above. 
Under the acylation conditions employed in Acylation Method (A), at least 
one hydroxyl group attached to the 2-position, attached to the side chain 
at the 5-position and attached to the 8-position of the carbostyril or 
3,4-dihydrocarbostyril derivatives can be acylated thereby producing a 
2-acylated compound, an 8-acylated compound or a compound having an acyl 
group in the side chain attached to the 5-position of the carbostyril or 
3,4-dihydrocarbostyril compound, as a single compound or a mixture 
thereof. The resulting acylated product can be isolated by conventional 
procedures, for example, solvent extraction, fractional recrystallization, 
column chromatography, thin-layer chromatography or a combination of these 
isolation procedures to obtain a single acylated product of the present 
invention. 
Under acylation conditions employed in Acylation Methods (B) to (C), an 
8-hydroxyl group, a 5-hydroxyl group or both 5- and 8-hydroxyl groups of 
the carbostyril or 3,4-dihydrocarbostyril compounds can be selectively 
acylated by taking advantage of the difference in reactivity between these 
hydroxyl groups with an acylating agent. 
ACYLATION METHOD (A) 
This acylation method can be advantageously conducted in a conventional 
manner using a carboxylic acid halide or carboxylic acid anhydride as an 
acylating agent in the absence of a solvent or in the presence of an inert 
solvent, for example, ethers such as dioxane, tetrahydrofuran and the 
like, halogenated hydrocarbons such as methylene chloride, 
1,2-dichloroethane and the like, carboxylic acids such as acetic acid, 
propionic acid, trichloroacetic acid, trifluoroacetic acid and the like, 
pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid 
triamide and the like. 
The amount of acylating agents used in this acylation method is not 
critical, but is preferably about 0.5 mole to a molar excess per mole of 
the carbostyril compound to be acylated. 
The acylation can be advantageously carried out at a temperature of from 
about -30.degree. C. to about 200.degree. C., preferably room temperature 
of 70.degree. C., for a period of from about 1 hour to about 24 hours. As 
is apparent to one skilled in the art, the higher the acylation 
temperature is the shorter is the acylation time. 
Alternatively, an inorganic basic compound or an organic tertiary amine can 
be used in the acylation reaction as a hydrogen halide acceptor. Typical 
examples of such hydrogen halide acceptors are sodium hydroxide, potassium 
hydroxide, sodium bicarbonate, sodium carbonate, triethylamine, 
trimethylamine, pyridine, quinoline and the like. 
ACYLATION METHOD (B) 
This acylation method can be used for acylation of the hydroxyl group at 
the 8-position of the carbostyril or 3,4-dihydrocarbostyril compounds. 
The acylation can be conducted by first reacting a carbostyril compound 
having a hydroxyl group at the 8-position with an alkali metal compound in 
an inert solvent to convert the hydroxyl group to an alkali metal salt 
thereof in a usual manner. Suitable inert solvents which can be used in 
this acylation include alcohols such as methanol, ethanol and the like, 
ethers such as dioxane, tetrahydrofuran and the like, and halogenated 
hydrocarbons such as methylene chloride, 1,2-dichloroethane and the like. 
Examples of alkali metal compounds which can be used in this acylation 
method include alkali metal alkoxides such as sodium methoxide, sodium 
ethoxide, potassium ethoxide and the like, alkali metals such as sodium 
metal, potassium metal and the like, and alkali metal hydroxides such as 
sodium hydroxide, potassium hydroxide and the like. 
After completion of the conversion, the solvent is removed by evaporation, 
and the resulting alkali metal salt is then reacted with a carboxylic acid 
halide as an acylating agent in a solvent at a temperature of about 
0.degree. C. to about 70.degree. C., preferably at 0.degree. C. to room 
temperature, for a period of about 1 to 12 hours to obtain an 8-acylated 
carbostyril compound. Suitable solvents which can be used for this purpose 
include ethers such as dioxane, tetrahydrofuran and the like, halogenated 
hydrocarbons such as methylene chloride, 1,2-dichloroethane and the like, 
pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid 
triamide and the like. 
Thus, the hydroxyl group at the 8-position can be selectively acylated by 
first converting the hydroxyl group into an alkali metal salt thereof and 
then acylating the resulting alkali metal salt. 
Alternatively, the above acylation method can be conducted without removal 
of the solvent used for the conversion of the 8-hydroxyl group into an 
alkali metal salt thereof, if the solvent is inert to the acylating agent 
used in the subsequent acylation step. Suitable examples of such solvents 
are those solvents other than alcohols described above. 
In this acylation method, the alkali metal compound and the acylating agent 
can be used in an amount of about 0.5 to about 2 moles, preferably an 
equimolar amount of 1.3 moles, per mole of the carbostyril or 
3,4-dihydrocarbostyril compound to by acylated. 
Further, the acylation can be carried out without converting an 8-hydroxyl 
group into an alkali metal salt thereof if pyridine is used as a solvent 
for acylation. In such a procedure, the acylation can be conducted using a 
carboxylic acid halide or a carboxylic acid anhydride as an acylating 
agent in an approximately equimolar amount to about 1.5 moles per mole of 
the carbostyril or 3,4-dihydrocarbostyril compound to be acylated at a 
temperature of about 0.degree. C. to 70.degree. C., preferably at 
0.degree. C. to room temperature, for a period of about 30 minutes to 
about 12 hours. 
ACYLATION METHOD (C) 
This acylation method can be used for acylation of the hydroxyl group in 
the side chain attached to the 5-position of the carbostyril or 
3,4-dihydrocarbostyril compounds. 
The acylation can be conducted by first protecting the 8-hydroxyl group 
with an appropriate protective group, and then acylating the 5-hydroxyl 
group with an acylating agent, followed by removing the protective group 
by catalytic reduction. 
Suitable examples of protective groups which can be used are a benzyl 
group, a p-nitrobenzyl group and the like. 
The acylation can be advantageously carried out using a conventional 
procedure employing a carboxylic acid halide or a carboxylic acid 
anhydride as an acylating agent in an amount of about 0.5 mole to a molar 
excess, preferably an equimolar amount to 1.3 moles, of the acylating 
agent per mole of the carbostyril or 3,4-dihydrocarbostyril compound to be 
acylated, at a temperature of about -30.degree. C. to about 200.degree. 
C., preferably room temperature to 70.degree. C., for a period of from 
about 1 hour to about 24 hours in the presence or absence of a solvent. 
Suitable solvents which can be used in this acylation method are those 
described above for Acylation Method (A). 
The inorganic basic compound or the organic tertiary amines as described 
for Acylation Method (A) can also be used in this acylation method as a 
hydrogen halide acceptor. 
The catalytic reduction for the removal of the protective group at the 
8-position can be conducted by a conventional procedure well known in the 
art for removal of a benzyl group from an --O--benzyl group, and 
advantageously carried out by catalytically reducing the 8-protected 
carbostyril or 3,4-dihydrocarbostyril compound in the presence of a 
catalyst such as palladium, palladium-carbon, palladium black, Raney 
nickel and the like, at a temperature of from room temperature to about 
50.degree. C. at a pressure ranging from atmospheric pressure to about 3 
atms. for a period of about 1 to 12 hours in the presence of a solvent 
such as methanol, ethanol, benzene, toluene, diethyl ether, dioxane and 
the like. However, it is to be noted that these processing parameters and 
type of solvents are not critical and can widely be varied depending upon 
the type of acylating agent used. 
ACYLATION METHOD (D) 
This acylation method can be used for acylation of both the hydroxyl group 
at 8-position and the hydroxyl group in the side chain attached to the 
5-position of the carbostyril or 3,4-dihydrocarbostyril compound. 
The acylation can be conducted using a carboxylic acid halide or a 
carboxylic acid anhydride as an acylating agent in the absence of a 
solvent or in the presence of an inert aprotic solvent, for example, 
ethers such as dioxane, tetrahydrofuran and the like, halogenated 
hydrocarbons such as methylene chloride, 1,2-dichloroethane and the like; 
a strongly acidic to weakly acidic solvent, for example, carboxylic acids 
such as acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic 
acid and the like; or pyridine, dimethyl sulfoxide, dimethylformamide, 
hexamethylphosphoric acid amide and the like, at a temperature of 
approximately room temperature to about 150.degree. C., preferably 
50.degree. to 90.degree. C., for a period of about 1 to about 6 hours. 
Particularly preferred solvents are strongly acidic to weakly acidic 
solvents such as trifluoroacetic acid, trichloroacetic acid, propionic 
acid, acetic acid and the like, or a mixture of the aprotic solvent 
described above and the strongly acidic to weakly acidic solvent. An 
inorganic basic compound or an organic tertiary amine as set forth above 
the Acylation Method (A) can also be used in this acylation reaction when 
an aprotic solvent is used for the acylation. In this acylation method, 
the acylating agent can be used in an amount of about 1.5 moles to a molar 
excess, preferably 2.0 moles to 2.5 moles, per mole of the carbostyril or 
3,4-dihydrocarbostyril compound to be acylated. 
Further, carbostyril or 3,4-dihydrocarbostyril compounds in which R.sup.1, 
R.sup.2 and R.sup.3 represent different acyl group, for example, compounds 
of the formula (Id) in which R.sub.1 and R.sub.2 represent different acyl 
groups and compounds of the formula (Id) in which R.sup.1, R.sup.2 and 
R.sup.3 represent different acyl groups, can be obtained using various 
combinations of Acylation Methods (A) to (D). As is apparent to one 
skilled in the art, these compounds can also be derived from compounds of 
the formulae (Ia), (Ib), (Ic), (Id) and (III) by using various 
combinations of acylation, hydrolysis and/or reduction procedures as 
previously described. 
Thus, the carbostyril derivatives of the present invention represented by 
the formula (I) can be prepared by the following alternative procedures: 
(1) A carbostyril derivative represented by the formula (I): 
##STR15## 
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined 
above, and the ring A has a partial structure: 
##STR16## 
wherein R.sup.3 is as defined above, with the proviso that at least one of 
R.sup.1, R.sup.2 and R.sup.3 represents a cycloalkylcarbonyl group, a 
cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group, and pharmaceutically acceptable acid addition 
salts of the carbostyril derivative of the formula (I) can be prepared by 
acylating a carbostyril derivative represented by the formula (X): 
##STR17## 
wherein R.sup.4, R.sup.5 and R.sup.6 are as defined above, and the ring A 
has a partial structure: 
##STR18## 
and R.sup.7, R.sup.8 and R.sup.9, which may be the same or different, each 
represents a hydrogen atom, a cycloalkylcarbonyl group, a 
cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group, with the proviso that at least one of R.sup.7, 
R.sup.8 and R.sup.9 represents a hydrogen atom, with a carboxylic acid 
halide or a carboxylic acid anhydride at a temperature of about 
-30.degree. C. to about 200.degree. C. for about 1 hour to about 24 hours. 
Thus, compounds of the formulae (Ia) and (Ib) can be prepared from the 
compounds of the formulae (IV) and (Ic), respectively. 
(2) A carbostyril derivative represented by the formula (Ia) or (Ib): 
##STR19## 
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined above, 
R.sup.1 represents a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, 
a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group, and 
pharmaceutically acceptable acid addition salts of the carbostyril 
derivative of the formula (Ia) or (Ib) can be prepared by reacting a 
carbostyril or 3,4-dihydrocarbostyril compound of the formula (Ic) or 
(IV): 
##STR20## 
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined above, with 
an alkali metal compound to convert the 8-hydroxyl group of said 
carbostyril or 3,4-dihydrocarbostyril compound of the formula (Ic) or (IV) 
into an alkali metal salt thereof, and acylating the resulting carbostyril 
or 3,4-dihydrocarbostyril compound with a carboxylic acid halide or a 
carboxylic acid anhydride at a temperature of about 0.degree. C. to about 
70.degree. C. for about 1 to 12 hours, according to the process (1) above. 
(3) A carbostyril derivative represented by the formula (Ia) or (Ib): 
##STR21## 
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined above, 
R.sup.1 represents a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, 
a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group, and 
pharmaceutically acceptable acid addition salts of the carbostyril 
derivatives of the formula (Ia) or (Ib) can be prepared by acylating a 
carbostyril or 3,4-dihydrocarbostyril compound represented by the formula 
(Ic) or (IV): 
##STR22## 
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined above, with a 
carboxylic acid halide or a carboxylic acid anhydride in an amount of an 
approximately equimolar amount to about 1.5 moles per mole of said 
carbostyril or 3,4-dihydrocarbostyril compound of the formula (Ic) or (IV) 
in the presence of pyridine at a temperature of about 0.degree. C. to 
about 70.degree. C. for about 30 minutes to about 12 hours, according to 
the process (1) above. 
(4) A carbostyril derivative represented by the formula (Ib) or (Ic): 
##STR23## 
wherein R.sup.1, R.sup.4, R.sup.5 and R.sup.6 are as defined above, 
R.sup.2 represents a cycloalkylcarbonyl group, a cycloalkylalkanoyl group, 
a benzoyl group, an alkanoyl group or a phenylalkylcarbonyl group, and 
pharmaceutically acceptable acid addition salts of the carbostyril 
derivative of the formula (Ib) or (Ic) can be prepared by protecting an 
8-hydroxyl group of a carbostyril or 3,4-dihydrocarbostyril compound of 
the formula (Ia) or (IV) 
##STR24## 
wherein R.sup.1, R.sup.4, R.sup.5 and R.sup.6 are as defined above, with a 
protective group, subjecting the resulting 8-protected 8-acyl carbostyril 
and 3,4-dihydrocarbostyril compound to acylation with a carboxylic acid 
halide or a carboxylic acid anhydride in an amount of at least about 0.5 
mole per mole of said 8-protected 8-acyl carbostyril and 
3,4-dihydrocarbostyril compound at a temperature of about -30.degree. C. 
to about 200.degree. C. for about 1 hour to about 24 hours, and 
catalytically reducing the resulting compound at a temperature of room 
temperature to about 50.degree. C. under a pressure of atmospheric 
pressure to about 3 atms. for about 1 hour to about 12 hours in the 
presence of a solvent to remove the 8-protective group, according to the 
process (1) above. 
(5) A carbostyril derivative represented by the formula (Ib): 
##STR25## 
wherein R.sup.4, R.sup.5 and R.sup.6 are as defined above, and both 
R.sup.1 and R.sup.2 are the same and represent a cycloalkylcarbonyl group, 
a cycloalkylalkanoyl group, a benzoyl group, an alkanoyl group or a 
phenylalkylcarbonyl group, and said addition salts of the carbostyril 
derivative of the formula (Ib) can be prepared by acylating a carbostyril 
or 3,4-dihydrocarbostyril compound of the formula (IV): 
##STR26## 
wherein R.sup.4, R.sup.5 and R.sup.6 are as defined abobe, with a 
carboxylic acid halide or a carboxylic acid anhydride in an amount at 
least about 1.5 moles per mole of said carbostyril or 
3,4-dihydrocarbostyril compound of the formula (IV) at a temperature of 
approximately room temperature to about 150.degree. C. for about 1 hour to 
about 6 hours, according to the process (1) above. 
Representative compounds of the present invention having the formulae (Ia), 
(Ib), (Ic) and (Id) are as follows: 
8-Cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Cycloheptylcarbonyloxy-5-(1-hydroxy-2-tert-butylaminoethyl)-3,4-dihdrocar 
bostyril, 
8-Cyclopropylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Cyclopentylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Cyclobutylacetoxy-5-(1-hydroxy-2-ethylaminobutyl)carbostyril, 
8-(3-Cyclohexylpropanoyloxy)-5-(1-hydroxy-2-isopropylaminopentyl)-3,4-dihyd 
rocarbostyril, 
8-(3-Cyclohexyl-2-methylpropanoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)ca 
rbostyril, 
8-Cyclohexylacetoxy-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dihydrocarbosty 
ril, 
8-Benzoyloxy-5-(1-hydroxy-2-isorpopylaminobutyl)carbostyril, 
8-(4-Chlorobenzoyloxy)-5-(1-hydroxy-2-tert-butylaminobutyl)carbostyril, 
8-(4-Fluorobenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-(2-Bromobenzoyloxy)-5-(1-hydroxy-2-butylaminopropyl)-3,4-dihydrocarbostyr 
il, 
8-(3,4-Ethylenedioxybenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dih 
ydrocarbostyril, 
8-(3-Methoxybenzoyloxy)-5-(1-hyroxy-2-isopropylaminobutyl)-3,4-dihydrocarbo 
styril, 
8-(4-Isopropoxybenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-(4-Methylbenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-(3-Ethylbenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dihydrocarbos 
tyril, 
8-(2-Propylbenzoyloxy)-5-(1-hydroxy-tert-butylaminoethyl)carbostyril, 
8-(4-Isopropylbenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Cyclohexylcarbonyloxy-5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)ca 
rbostyril, 
8-Cyclobutylcarbonyloxy-5-(1-cycloheptylcarbonyloxy-2-tert-butylaminobutyl) 
carbostyril, 
8-(4-Methylbenzoyloxy)-5-(1-cyclobutylcarbonyloxy-2-isopropylaminoethyl)car 
bostyril, 
8-(3,4-Methylenedioxybenzoyloxy)-5-(1-p-methylbenzoyloxy-2-isopropylaminobu 
tyl)carbostyril, 
8-Cyclohexylacetyloxy-5-(1-p-chlorobenzoyloxy-2-isopropylaminobutyl)-3,4-di 
hydrocarbostyril, 
8-Cyclohexylcarbonyloxy-5-(1-benzoyloxy-2-isopropylaminobutyl)-3,4-dihydroc 
arbostyril, 
8-Cyclohexylcarbonyloxy-5-(1-cyclohexylacetoxy-2-isopropylaminobutyl)carbos 
tyril, 
8-Cyclohexylcarbonyloxy-5-(1-hydroxy-2-.alpha.,.alpha.-dimethylphenethylami 
nobutyl)carbostyril, 
8-(p-Methylbenzoyloxy)-5-(1-hydroxy-3',4'-dimethoxyphenethylaminobutyl)carb 
ostyril. 
8-(p-Chlorobenzoyloxy)-5-(1-hydroxy-2-3'-phenyl-1'-methylpropylaminobutyl)c 
arbostyril, 
8-Cyclohexylcarbonyloxy-5-(1-hydroxy-2-phenethylaminobutyl)carbostyril, 
8-Cyclohexylacetoxy-5-(1-cyclohexylcarbonyloxy-2-benzylaminobutyl)carbostyr 
il, 
8-Cyclohexylcarbonyloxy-5-(1-p-methylbenzoyloxy-2-phenethylaminobutyl)carbo 
styril, 
8-p-Chlorobenzoyloxy-5-(1-p-chlorobenzoyloxy-2-benzylaminobutyl)carbostyril 
8-Cyclopentylcarbonyloxy-5-(1-cyclopentylcarbonyloxy-2-3',4'-dimethoxyphene 
thylaminobutyl)carbostyril, 
8-(3-Cyclohexylpropanoyloxy-5-(1-hydroxy-2-ethylaminobutyl)carbostyril, 
8-(3,4-Methylenedioxybenzoyloxy)-5-(1-3',4'-methylenedioxybenzoyloxy-2-isop 
ropylaminopropyl)carbostyril, 
8-(3,4-Dimethoxybenzoyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Cyclohexylcarbonyloxy-5-(1-benzoyloxy-2-isopropylaminobutyl)carbostyril, 
8-Phenylacetoxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-(3,4-Dimethoxyphenethylcarbonyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)ca 
rbostyril, 
8-(2-Phenyl-1-methylethylcarbonyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)-3 
,4-dihydrocarbostyril, 
8-(p-Methylphenylacetoxy-5-(1-hydroxy-2-tert-butylaminobutyl)carbostyril, 
8-(3-p-Chlorophenylbutylcarbonyloxy)-5-(1-hydroxy-2-tert-butylaminopropyl)- 
3,4-dihydrocarbostyril, 
8-Acetoxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Butyryloxy-5-(1-butyryloxy-2-tert-butylaminobutyl)-carbostyril, 
8-Hexanoyloxy-5-(1-hydroxy-2-phenethylaminobutyl)-3,4-dihydrocarbostyril, 
8-(2,2-Dimethylpropionyl-5-(1-hydroxy-2-phenethylaminobutyl)carbostyril, 
8-Hydroxy-5-(1-hydroxy-2-isopropylaminoethyl)-2-(2-methylbutyryl)quinoline, 
8-(3,3-Dimethylbutyryloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
8-Acetoxy-5-(1-propionyloxy-2-isopropylaminobutyl)carbostyril, 
8-(2,2-Dimethylpropionyloxy)-5-(1-cyclohexylcarbonyloxy-2-ethylaminobutyl)c 
arbostyril, 
8-(3-Methylbutanoyloxy)-5-(1-benzoyloxy-2-tert-butylaminobutyl)-3,4-dihydro 
carbostyril, 
2,8-Diacetoxy-5-(1-acetoxy-2-isopropylaminobutyl)quinoline, 
8-(3,3-Dimethylbutyryloxy)-5-[1-phenylacetyloxy-2-(3,4-dimethoxyphenethylam 
ino)butyl]-2-cyclohexylcarbonyloxyquinoline, 
2,8-(4-Methylbenzoyloxy)-5-[1-(4-methylbenzoyloxy)-2-(3,4-methylenedioxyphe 
nethylamino)butyl]quinoline, 
8-(2,2-Dimethylpropionyloxy)-5-[1-hydroxy-2-(3,4-methylenedioxyphenethylami 
no)butyl]carbostyril, 
8-Acetoxy-5-(1-hydroxy-2-N,N-diethylaminobutyl)carbostyril, 
8-(3,3-Dimethylbutyryloxy)-5-(1-hydroxy-2-N,N-methylethylaminobutyl)-3,4-di 
hydrocarbostyril, 
8-(p-Methylbenzoyloxy)-5-(1-p-methylbenzoyloxy-2-N,N-dipropylaminobutyl)car 
bostyril, 
8-(2,2-Dimethylpropionyloxy)-5-(1-hydroxy-2-morpholinobutyl)carbostyril, 
8-(p-Methylbenzoyloxy)-5-(1-hydroxy-2-piperadinobutyl)3,4-dihydrocarbostyri 
l, 
8-Cyclohexylcarbonyloxy-5-(1-cyclohexylcarbonyloxy-2-piperidinobutyl)carbos 
tyril, 
8-Propionyloxy-5-(1-hydroxy-2-pyrrolidinobutyl)-3,4-dihydrocarbostyril, 
8-Acetoxy-5-(1-hydroxy-2-N-methylpiperazinobutyl)carbostyril, 
2,8-Diacetoxy-5-(1-acetoxy-2-imidazolidinoethyl)-3,4-dihydrocarbostyril, 
and 
8-(p-Methylbenzoyloxy)-5-[1-hydroxy-2-(2,5-dimethylpiperazino)butyl]carbost 
yril. 
The present invention is further illustrated in greater detail by the 
following Reference Examples and Examples, but these Examples are given 
for illustrative purpose only and are not to be construed as limiting the 
present invention. Unless otherwise indicated, all parts, percents, ratios 
and the like are by weight. 
REFERENCE EXAMPLE 1 
(A) 2.7 g of 8-hydroxycarbostyril and 37 ml of chloroacetyl chloride were 
dissolved in 250 ml of nitrobenzene, and 85 g of aluminum chloride was 
added slowly to the solution. The resulting mixture was then stirred at a 
temperature of 70.degree. C. for 20 hours. 500 ml of a 10% hydrochloric 
acid aqueous solution was added to the mixture and nitrobenzene was 
removed by steam distillation. After allowing the mixture to cool, the 
precipitated crystals were separated by filtration, washed with 300 ml of 
hot water and recrystallized from methanol to obtain 14.0 g of 
5-chloroacetyl-8-hydroxycarbostyril as light yellow crystals having a 
melting point of 285.degree.-287.degree. C. (with decomposition). 
12.6 g of 5-chloroacetyl-8-hydroxycarbostyril obtained above was suspended 
in 130 ml of isopropanol, and 25.5 g of isopropylamine was added dropwise 
to the suspension while stirring followed by stirring for 3 hours at a 
temperature of 55 to 60.degree. C. After allowing the mixture to cool, the 
mixture was adjusted to a pH of 2-3 with concentrated hydrochloric acid. 
The precipitated crystals were separated by filtration, washed with 
acetone and recrystallized from a mixture of methanol and 
dimethylformamide to obtain 6.5 g of 
5-isopropylaminoacetyl-8-hydroxycarbostyril hydrochloride represented by 
the formula (V) as light yellow crystals having a melting point of 
286.degree.-288.degree. C. (with decomposition). 
(B) 1.0 g of 5-isopropylaminoacetyl-8-hydroxycarbostyril hydrochloride 
obtained in (A) above was dissolved in 40 ml of water, and, in the 
presence of 0.5 g of a palladium-carbon catalyst, hydrogen gas was bubbled 
into the solution while maintaining the solution at a temperature of 
35.degree.-40.degree. C. with stirring to reduce the starting material. 
After completion of the reduction, the catalyst was removed by filtration, 
and the filtrate was concentrated to dryness under reduced pressure. 
Addition of ethanol to the residue followed by concentration to dryness 
was repated to completely remove any remaining water, and acetone was 
added to the residue to crystallize the product. The crystalline product 
thus obtained was recrystallized from ethanol-acetone to obtain 0.4 g of 
5-(2-isopropylamino-1-hydroxyethyl)-8-hydroxycarbostyril hydrochloride of 
the formula (IV) having a melting point of 210.degree.-212.degree. C. 
(with decomposition) as a light yellow amorphous compound. 
REFERENCE EXAMPLE 2 
50 ml of pyridine was added to 2.5 g of 
8-hydroxy-5-(.alpha.-isopropylaminobutyryl)carbostyril, and 5 ml of 
isobutyryl chloride was added dropwise to the mixture while cooling with 
ice-water and stirring followed by stirring for 2 hours. After addition of 
about 500 ml of diethyl ether, the precipitate formed was washed with 
diethyl ether and stirred in a small amount of cold water. The precipitate 
was separated by filtration, washed successively with a small amount of 
water, acetone and diethyl ether to obtain a crystalline product which was 
then recrystallized from acetone to obtain 2.1 g of 
8-isobutyryloxy-5-(.alpha.-Isopropylaminobutyryl)carbostyril hydrochloride 
having a melting point of 231.degree.-233.degree. C. (with decomposition). 
REFERENCE EXAMPLE 3 
20 ml of pyridine was added to 1 g of 
8-hydroxy-5-(.alpha.-isopropylaminobutyryl)carbostyril, and 2 ml of 
isobutyryl chloride was added dropwise to the mixture while cooling with 
ice-water and stirring followed by stirring for 3 hours and for 2 hours at 
a temperature of 35.degree.-40.degree. C. After addition of about 200 ml 
of diethyl ether, the precipitate formed was stirred in a small amount of 
cold water and then washed successively with acetone and diethyl ehter. 
The resulting crystalline product was then recrystallized from acetone to 
obtain 0.6 g of 
2,8-bis(isobutyryloxy)-5-(.alpha.-isopropylaminobutyryl)quinoline 
hydrochloride having a melting point of 214.degree.-215.degree. C. (with 
coloration and decomposition). 
EXAMPLE 1 
12 ml of pyridine was added to 0.4 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, and 0.6 ml of 
isobutyryl chloride was added dropwise to the mixture while cooling with 
ice-water and stirring followed by stirring for 3 hours. After addition of 
about 200 ml of diethyl ether, the precipitate formed was washed 
thoroughly with diethyl ether and dissolved in 50 ml of water. The 
solution was washed with dichloroethane and the aqueous layer was 
concentrated to dryness. Acetone was added to the residue to crystallize 
the product which was then recrystallized from acetone to obtain 0.33 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-isobutyryloxycarbostyril 
hydrochloride having a melting point of 228.degree.-229.degree. C. (with 
coloration and decomposition). 
EXAMPLE 2 
25 ml of pyridine was added to 1 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril 
hydrochloride, and 3 ml of isobutyryl chloride was added dropwise to the 
mixture while cooling with ice-water and stirring followed by stirring for 
3 hours. After addition of about 200 ml of diethyl ether, acetone was 
added to the precipitate formed to obtain a crystalline product. The 
product thus obtained was recrystallized from acetone to obtain 0.8 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-isobutyryloxy-3,4-dihydrocarbostyril 
hydrochloride having a melting point of 239.degree.-240.degree. C. (with 
coloration and decomposition). 
EXAMPLE 3 
1 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril 
hydrochloride was dissolved in 10 ml of isobutyric anhydride, and several 
drops of concentrated sulfuric acid was added to the solution. After 
stirring the mixture for 2 hours at a temperature of 60.degree. C., 100 ml 
of diethyl ether was added to the mixture and the precipitate formed was 
separated by filtration. The precipitate was then dissolved in 20 ml of 
water and the solution was adjusted to a pH of 7-7.5 with a saturated 
aqueous solution of sodium bicarbonate while cooling with ice. The 
resulting mixture was extracted three times with 20 ml portions of diethyl 
ether. The combined extracts were dried over anhydrous sodium sulfate and 
concentrated under reduced pressure while cooling. The residue thus 
obtained was recrystallized from a mixture of diethyl ether and petroleum 
ether to obtain 0.75 g of 
5-(1-isobutyryloxy-2-isopropylaminobutyl)-8-isobutyryloxycarbostyril 
having a melting point of 124.degree.-125.degree. C. 
EXAMPLE 4 
3 ml of isobutyric anhydride was added to 1 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, and the mixture 
was stirred for 30 minutes at a temperature of 60.degree. C. Petroleum 
ether was added to the reaction mixture, and the mixture was adjusted to a 
pH of 1-2 with concentrated hydrochloric acid. The precipitate formed was 
separated by filtration and, after drying the precipitate, it was 
recrystallized from a mixture of methanol and diethyl ether to obtain 1.1 
g of 5-(1-isobutyryloxy-2-isopropylaminobutyl)-8-isobutyryloxycarbostyril 
hydrochloride monohydrate having a melting point of 
198.degree.-199.degree. C. 
EXAMPLE 5 
3 ml of isobutyric anhydride was added to 0.7 g of 
5-(1-hydroxy-2-ethylaminobutyl)-8-hydroxycarbostyril, and the mixture was 
stirred for 30 minutes at a temperature of 60.degree. C. Petroleum ether 
was added to the reaction mixture, and the mixture was adjusted to a pH of 
1-2 with concentrated hydrochlric acid. The precipitate formed was 
separated by filtration and, after drying the precipitate, it was 
recrystallized from a mixture of methanol and diethyl ether to obtain 0.8 
g of 5-(1-isobutyryloxy-2-ethylaminobutyl)-8-isobutyryloxycarbostyril 
hydrochloride having a melting point of 197.degree.-198.degree. C. 
EXAMPLE 6 
20 ml of pyridine was added to 1 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, and 3 ml of 
isobutyryl chloride was added dropwise to the mixture while cooling with 
ice-water and stirring followed by stirring for an additional 2 hours. The 
precipitate formed was separated by filtration, and about 500 ml of 
diethyl ether was added to the filtrate. The precipitate formed was washed 
thoroughly with diethyl ether, and water was added to the precipitate. The 
water-insoluble substance was separated by filtration, washed with water 
and, after drying, recrystallized from a mixture of acetone and diethyl 
ether to obtain 1.2 g of 
2,8-diisobutyryloxy-5-(1-isobutyryloxy-2-isopropylaminobutyl)quinoline 
hydrochloride having a melting point of 187.degree.-188.degree. C. 
EXAMPLES 7-10 
__________________________________________________________________________ 
##STR27## Melting Point 
Examples 
R.sup.4 
R.sup.5 
R.sup.1 R.sup.3 B (.degree.C.) 
__________________________________________________________________________ 
7 C.sub.2 H.sub.5 
C.sub.2 H.sub.5 
##STR28## 
##STR29## 
##STR30## 
183-185 (Hydrochloride) 
8 C.sub.2 H.sub.5 
C.sub.2 H.sub.5 
##STR31## 
H 
##STR32## 
214-216 (with coloration and 
decomposi- tion) (Hydrochloride) 
1 
9 H 
##STR33## 
##STR34## 
H 
##STR35## 
217-219 (with coloration and 
decomposi- tion) (Hydrochloride) 
2 
10 C.sub.2 H.sub.5 
##STR36## 
COCH.sub.3 
H 
##STR37## 
201-203 (Hydrochloride) 
__________________________________________________________________________ 
EXAMPLE 11 
5.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was 
dissolved in 100 ml of methanol, and a methanolic solution of 10% sodium 
methylate was added to the resulting solution in an equimolar amount 
relative to the starting carbostyril compound. The mixture was 
concentrated to dryness and the resulting residue was dissolved in 100 ml 
of dimethylformamide. 2.9 g of cyclohexanecarboxylic acid chloride was 
then added while cooling with ice-water and the mixture was stirred for 
one hour at a temperature of 0.degree. C. The precipitate formed was 
separated by filtration and washed successively with dimethylformamide and 
diethyl ether to obtain 4.0 g of 
8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril 
having a melting point of 186.5.degree.-187.5.degree. C. (after 
recrystallization from chloroform-diethyl ether). 
EXAMPLE 12 
5.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was 
dissolved in 150 ml of methanol, and a 15% methanolic solution of sodium 
methylate was added to the solution in an equimolar amount relative to the 
starting carbostyryl compound. The mixture was concentrated to dryness and 
the resulting residue was dissolved in 100 ml of dimethylformamide. 3.0 g 
of p-toluylic acid chloride was added to the solution while cooling with 
ice-water, and the resulting mixture was stirred for 1.5 hours at room 
temperature. The precipitate formed was separated by filtration, and 
washed successively with dimethylformamide and diethyl ether to obtain 4.2 
g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxycarbostyril 
having a melting point of 197.degree.-198.degree. C. (after 
recrystallization from chloroform-diethyl ether). 
EXAMPLE 13 
3.28 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril 
hydrochloride was dissolved in 50 ml of methanol, and a 10% methanolic 
solution of sodium methylate was added to the solution in an amount of 2 
moles per mole of the starting carbostyril compound. The resulting mixture 
was concentrated to dryness, and the residue was dissolved in 
dimethylformamide. 1.6 g of cyclohexanecarboxylic acid chloride was added 
to the solution and the mixture was stirred for 2 hours at a temperature 
of 10.degree. C. The reaction mixture was poured into ice-water and the 
mixture was extracted with chloroform. A mixture of diethyl ether and 
petroleum benzene was added to the extract to obtain 1.2 g of crystalline 
8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dihydrocar 
bostyril having a melting point of 148.degree.-149.degree. C. (after 
recrystallization from chloroform-n-hexane). 
EXAMPLE 14 
3.28 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril 
hydrochloride was dissolved in 50 ml of methanol, and a 20% methanolic 
solution of sodium methylate was added to the solution in an amount of 2 
moles per mole of the starting carbostyril compound. The mixture was then 
concentrated to dryness, and the residue was dissolved in 
dimethylformamide. 1.7 g of p-toluylic acid chloride was added to the 
solution while cooling with ice-water and the mixture was stirred for 4 
hours at room temperature. The reaction mixture was poured into ice-water 
and extracted with chloroform. A mixture of diethyl ether and petroleum 
benzene was added to the chloroform extract to obtain 1.94 g of 
crystalline 5-(1-hydroxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxy-3,4-d 
ihydrocarbostyril having a melting point of 151.5.degree.-152.5.degree. C. 
(after recrystallization from chloroform-n-hexane). 
EXAMPLE 15 
1 g of 
5-(1-hydroxy-2-.alpha.,.alpha.-dimethylphenethylaminoethyl)-8-hydroxycarbo 
styril hydrochloride was suspended in 30 ml of methanol, and a 15% 
methanolic solution of sodium methylate was added in an amount of 2 moles 
per mole of the starting carbostyril compound. The mixture was then 
concentrated to dryness, and the residue was dissolved in 30 ml of 
dimethylformamide. 0.44 g of cyclohexanecarboxylic acid chloride was then 
added to the solution while cooling with ice-water, and the mixture was 
stirred for 4 hours at room temperature. The reaction mixture was poured 
into ice-water and extracted with chloroform. Diethyl ether was added to 
the extract to obtain 0.17 g of crystalline 
8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-.alpha.,.alpha.-dimethylphenethylam 
inoethyl)carbostyril having a melting point of 158.degree.-159.degree. C. 
(after recrystallization from chloroform-n-hexane). 
EXAMPLE 16 
In the same manner as described in Example 15 but using the corresponding 
3,4-dihydrocarbostyril starting material in place of the carbostyril 
starting material, 
8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-.alpha.,.alpha.-dimethylphenethylam 
inoethyl)-3,4-dihydrocarbostyril having a melting point of 146.5.degree. to 
148.degree. C. was obtained. 
EXAMPLE 17 
3.36 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril 
hydrochloride was dissolved in 20 ml of trifluoroacetic acid, and 8.8 g of 
cyclohexanecarboxylic acid chloride was added to the solution. The mixture 
was then heated at a temperature of 85.degree. C. while refluxing. The 
reaction mixture was concentrated and diethyl ether was added to the 
residue to crystallize the product. The crystals thus obtained were 
separated by filtration and washed with diethyl ether. The resulting 
crystals were extracted successively with a saturated aqueous solution of 
sodium bicarbonate and chloroform, and the organic layer was washed with 
water, dried and concentrated to dryness. The resulting residue was 
crystallized from a mixture of diethyl ether and petroleum benzene to 
obtain 3.59 g of 
5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)-8-cyclohexylcarbonyloxyc 
arbostyril having a melting point of 162.degree. to 163.degree. C. (after 
recrystallization from chloroform-n-hexane). 
EXAMPLE 18 
3.36 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril 
hydrochloride was dissolved in 20 ml of trifluoroacetic acid, and 7.75 g 
of p-toluylic acid chloride was added to the solution. The mixture was 
then heated at a temperature of 85.degree. C. while refluxing. The 
reaction mixture was concentrated and diethyl ether was added to the 
concentrate to crystallize the product. The crystals thus obtained were 
separated by filtration and washed with diethyl ether. The crystals were 
extracted successively with a saturated aqueous solution of sodium 
bicarbonate and chloroform, and the organic layer was washed with water, 
dried and concentrated to dryness. The resulting residue was crystallized 
from a mixture of diethyl ether and petroleum benzene to obtain 1.14 g of 
5-(1-p-methylbenzoyloxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxycarbost 
yril having a melting point of 154.degree.-155.5.degree. C. (after 
recrystallization from chloroform-n-hexane). 
EXAMPLE 19 
In the same manner as described in Example 18 but using the corresponding 
3,4-dihydrocarbostyril starting material in place of the carbostyril 
starting material, 
5-(1-p-methylbenzoyloxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxy-3,4-di 
hydrocarbostyril having a melting point of 141.degree.-143.degree. C. was 
produced. 
EXAMPLE 20 
3 ml of isobutyric anhydride was added to 500 mg of 
8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril, 
and the mixture was allowed to react for 1 hour at a temperature of 
60.degree. C. After completion of the reaction, 2 to 3 drops of 
concentrated hydrochloric acid and 5 ml of methanol were added to the 
reaction mixture while cooling with ice-water followed by addition of 
diethyl ether to crystallize the product. The crystals thus obtained were 
separated by filtration, washed with diethyl ether and recrystallized from 
a mixture of methanol and diethyl ether to obtain 480 mg of 
8-cyclohexylcarbonyloxy-5-(1-isobutyryloxy-2-isopropylaminobutyl)carbostyr 
il hydrochloride having a melting point of 214.degree. to 215.degree. C. 
(with decomposition). 
EXAMPLE 21 
4 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril 
hydrochloride was suspended in 20 ml of methanol, and sodium methylate 
prepared from 575 mg of sodium metal and 12 ml of absolute methanol was 
added to the suspension. The mixture was then concentrated to dryness, and 
the resulting residue was dissolved in 20 ml of diemthylformamide. 2.5 g 
of veratric acid chloride dissolved in 10 ml of dimethylformamide was then 
added dropwise to the mixture while cooling with ice-water. The mixture 
was then stirred for 1 hour, and the precipitate formed was separated by 
filtration, washed with diethyl ether and recrystallized from a mixture of 
chloroform and diethyl ether to obtain 4.3 g of 
8-(3,4-dimethoxyphenylcarbonyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carb 
ostyril having a melting point of 197.degree.-198.degree. C. 
EXAMPLE 22 
2 ml of cyclohexanecarboxylic acid and 2 ml of cyclohexanecarbonyl chloride 
were added to 1 g of 
8-toluyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril and the mixture 
was allowed to react for 1 hour at a temperature of 80.degree. C. After 
completion of the reaction, 2 to 3 drops of concentrated hydrochloric acid 
and 10 ml of methanol were added to the reaction mixture while cooling 
with ice-water followed by addition of diethyl ether to crystallize the 
product. The crystals thus obtained were separated by filtration, washed 
with diethyl ether and recrystallized from a mixture of methanol and 
diethyl ether to obtain 1.3 g of 
8-toluyloxy-5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)carbostyril 
hydrochloride having a melting point of 231.degree.-232.5.degree. C. 
EXAMPLE 23 
2 ml of cyclopropanecarboxylic acid and 1 ml of cyclopropanecarboxylic acid 
chloride were added to 500 mg of 
5-[1-hydroxy-2-(3,4-dimethoxyphenethylamino)ethyl]-8-hydroxycarbostyril 
hydrochloride, and the mixture was allowed to react for 1 hour at a 
temperature of 80.degree. C. After completion of the reaction, 10 ml of 
methanol was added to the reaction mixture while cooling with ice-water 
followed by addition of diethyl ether to crystallize the product. The 
crystals thus obtained were separated by filtration, washed with diethyl 
ether and recrystallized from a mixture of ethanol and acetone to obtain 
210 mg of 
5-[1-cyclopropylcarbonyloxy-2-(3,4-dimethoxyphenethylamino)ethyl]-8-cyclop 
ropylcarbonyloxycarbostyril hydrochloride having a melting point of 
167.degree.-168.degree. C. (with decomposition). 
EXAMPLE 24 
5 g of 5-(1-hydroxy-2-ethylaminobutyl)-8-hydroxycarbostyril was suspended 
in 20 ml of methanol, and sodium methylate prepared from 458 mg of sodium 
metal and 9.6 ml of absolute methanol was added to the suspension. The 
mixture was then concentrated to dryness, and the resulting residue was 
dissolved in 30 ml of dimethylformamide. 3.3 g of 
.beta.-cyclohexylpropionyl chloride was then added dropwise to the mixture 
while cooling with ice-water. The mixture was then stirred for 1 hour at 
room temperature, and diethyl ether was added to the mixture. The 
precipitate formed was separated by filtration, washed with diethyl ether 
and recrystallized from a mixture of methanol and diethyl ether to obtain 
3.86 g of 
8-(.beta.-cyclohexylpropionyloxy)-5-(1-hydroxy-2-ethylaminobutyl)carbostyr 
il having a melting point of 233.degree.-234.degree. C. (with 
decomposition). 
EXAMPLE 25 
5 g of 5-(1-hydroxy-2-ethylaminobutyl)-8-hydroxycarbostyril was suspended 
in 20 ml of methanol, and sodium methylate prepared from 460 mg of sodium 
metal and 9.6 ml of absolute methanol was added to the suspension. The 
mixture was then concentrated to dryness, and the resulting residue was 
dissolved in 20 ml of dimethylformamide. 2.9 g of phenylacetyl chloride 
was then added dropwise to the mixture while cooling with ice-water. The 
mixture was then stirred for 1 hour at room temperature, and diethyl ether 
was added to the mixture. The upper layer was removed by decantation, and 
diethyl ether was added to the lower layer to crystallize the product. The 
crystals thus obtained were separated by filtration, washed with diethyl 
ether and recrystallized from a mixture of chloroform and diethyl ether to 
obtain 4.43 g of 
5-(1-hydroxy-2-isopropylaminobutyl)-8-phenylacetoxycarbostyril having a 
melting point of 122.5.degree.-123.5.degree. C. 
EXAMPLE 26 
1 g of 5-(1-hydroxy-2-benzylaminobutyl)-8-hydroxycarbostyril hydrochloride 
was suspended in 20 ml of methanol, and sodium methylate prepared from 135 
mg of sodium metal and 2.8 ml of absolute methanol was added to the 
suspension. The mixture was then concentrated to dryness, and the 
resulting residue was dissolved in 10 ml of dimethylformamide. 490 mg of 
p-chlorobenzoyl chloride was then added dropwise to the mixture while 
cooling with ice-water. The mixture was then stirred for 1 hour, and water 
was added to the mixture. The mixture was then extracted with chloroform, 
and chloroform was removed by distillation. Diethyl ether was added to the 
residue to crystallize the product, and the crystals were separated by 
filtration, washed with diethyl ether and recrystallized from a mixture of 
chloroform and diethyl ether to obtain 110 mg of 
8-(p-chlorobenzoyloxy)-5-(1-hydroxy-2-benzylaminobutyl)carbostyril having 
a melting point of 125.degree.-126.degree. C. 
EXAMPLE 27 
1 g of 5-(1-hydroxy-2-tert-butylaminopropyl)-8-hydroxycarbostyril 
hydrochloride was suspended in 15 ml of methanol, and sodium methylate 
prepared from 155 mg of sodium metal and 3.3 ml of absolute methanol was 
added to the suspension. The mixture was then concentrated to dryness, and 
the resulting residue was dissolved in 10 ml of dimethylformamide. 593 mg 
of piperonylyl chloride dissolved in 5 ml of dimethylformamide was then 
added dropwise to the mixture while cooling with ice-water. The mixture 
was then stirred for 1 hour, and water was added to the mixture followed 
by extraction with chloroform. Chloroform was removed by distillation, and 
diethyl ether was added to the residue to crystallize the product. The 
crystals thus obtained were separated by filtration, washed with diethyl 
ether and recrystallized from a mixture of chloroform and diethyl ether to 
obtain 520 mg of 
8-(3,4-methylenedioxyphenylcarbonyloxy)-5-(1-hydroxy-2-tert-butylaminoprop 
yl)carbostyril having a melting point of 156.degree.-157.degree. C. 
EXAMPLES 28-31 
In the same manner as described in Example 1, each of the following 
compounds was prepared from an appropriate starting material: 
8-(3,3-dimethylbutyryloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril 
hydrochloride having a melting point of 234.degree.-235.degree. C. (with 
decomposition), 
8-isobutyryloxy-5-(1-hydroxy-2-tert-butylaminopropyl)carbostyril 
hydrochloride having a melting point of 222.degree.-224.degree. C. (with 
decomposition), 
8-(2,2-dimethylpropionyloxy)-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril 
hydrochloride having a melting point of 257.degree.-259.degree.0 C. (with 
decomposition), 
8-acetoxy-5-(1-hydroxy-2-ethylaminobutyl)carbostyril hydrochloride having a 
melting point of 212.5.degree.-214.degree. C. (with decomposition). 
EXAMPLE 32 
3 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was added 
to 200 ml of anhydrous chloroform, and 3 ml of isobutyric anhydride was 
added dropwise to the mixture. The resulting mixture was stirred for 5 
hours at room temperature, and the solvent was removed by distillation 
under reduced pressure. Petroleum ether was added to the residue, and the 
crystals formed were separated by filtration. The crystals were rendered 
neutral with 50 ml of a cold saturated aqueous solution of sodium 
bicarbonate, and insoluble material was separated by filtration and washed 
with water. The resulting material which was found to be a mixture of 
about 7 components by thin layer chromatography was then subjected to 
silica gel column chromatography using a silica gel of Grade C-200 (trade 
name of Wako Junyaku, Japan) and a mixture of chloroform and methanol 
(20:1 by volume) as an eluant to obtain an eluate containing four main 
components. The solvent was then removed by distillation from the eluate, 
and 5 ml of a saturated ethanolic solution of hydrogen chloride was added 
to the residue. Petroleum ether was added to the mixture, and the 
precipitated crystals were separated by filtration and recrystallized from 
acetone to obtain, as main components, 1.5 g of 
5-(1-isobutyryloxy-2-isopropylaminobutyl)-8-isobutyryloxycarbostyril 
hydrochloride monohydrate having a melting point of 
198.degree.-199.degree. C., 0.1 g of 
2,8-diisobutyryloxy-5-(1-hydroxy-2-isopropylaminobutyl)quinoline 
hydrochloride having a melting point of 201.degree.-203.degree. C. (with 
decomposition), 0.4 g of 5-(1-hydroxy-2 
-isopropylaminobutyl)-8-isobutyryloxycarbostyril hydrochloride having a 
melting point of 228.degree.-229.degree. C. (with coloration and 
decomposition), and 0.1 g of 
2-isobutyryloxy-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxyquinoline 
hydrochloride having a melting point of 225.degree.-226.5.degree. C. (with 
coloration and decomposition). 
As set forth previously, the carbostyril derivatives of the present 
invention possess an excellent .beta.-adrenoreceptor stimulating activity. 
In particular, these compounds exhibit a long-lasting and selective 
activity on .beta..sub.2 -receptor and, therefore, they are particularly 
useful as bronchodilators, as illustrated by pharmacological activity 
shown in Reference Example 4 below. In determining the activity, 
Salbutamol was used as a Reference Compound (1), 
8-hydroxy-5-(1-hydroxy-2-ethylaminobutyl)carbostyril hydrochloride (IV) as 
a Comparative Compound (2) and the following test compounds (3) to (14) of 
the present invention: 
(3) 8-acetoxy-5-(1-acetoxy-2-isopropylaminobutyl)carbostyril hydrochloride 
(Ib), 
(4) 8-acetoxy-5-(1-hydroxy-2-ethylaminobutyl)carbostyril hydrochloride 
(Ia), 
(5) 8-(3-cyclohexylbutyryloxy)-5-(1-hydroxy-2-ethylaminobutyl)carbostyril 
hydrochloride (Ia), 
(6) 
8-(3,3-dimethylbutanoyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril 
(Ia), 
(7) 8-phenylacetoxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril 
hydrochloride (Ia), 
(8) 
8-cyclopropylcarbonyloxy)-5-[1-cyclopropylcarbonyloxy-2-(3,4-dimethoxyphen 
ethylamino)ethyl]carbostyril hydrochloride (Ib), 
(9) 8-(4-methylbenzoyloxy)-5-(1-hydroxy-2-ethylaminobutyl)carbostyril 
hydrochloride (Ia), 
(10) 2,8-diisobutyryloxy-5-(1-hydroxy-2-isopropylaminobutyl)quinoline 
hydrochloride (III), 
(11) 8-(4-chlorobenzoyloxy)-5-(1-hydroxy-2-benzylaminobutyl)carbostyril 
hydrochloride (Ia), 
(12) 
8-(4-methylbenzoyloxy)-5-[(1-(4-methylbenzoyloxy)-2-isopropylaminobutyl]-3 
,4-dihydrocarbostyril hydrochloride (Ib), 
(13) 
8-(4-methylbenzoyloxy)-5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)ca 
rbostyril hydrochloride (Ib), 
(14) 8-isobutyryloxy-5-(1-hydroxy-2-tert-butylaminopropyl)carbostyril (Ia). 
REFERENCE EXAMPLE 4 
The stimulating activity of the compounds of this invention on 
.beta.-adrenoreceptor was determined as follows: Male hydrid adult dogs, 
weighing 10 to 15 kg, were anesthesized with sodium pentobartital 
administered intravenously at a level of 30 mg/kg of body weight. Each of 
the anesthesized dogs was secured on its back and a cannula was inserted 
into the trachea. Artificial respiration was conducted using a device 
according to the Konzett-Rossler method (Konzett H. & Rossler R., 
"Versuchsanordnug zu Untersuchungen an der Bronchial Moskolatur", Arch. 
Exp. Path., Pharmack, 195, 71-74, 27-40 (1940). The volume of the air 
which overflowed at the time of inhalation was measured through a 
pneumotachometer to determine the bronchial resistance and the values 
obtained were recorded on a polygraph. 
In the above procedure, histamine was employed as a bronchoconstrictor at a 
dosage level of 10 .mu.g/kg of body weight, and an aqueous solution 
containing each of the test compounds and controls shown in Table 1 below 
was then administered to each of the anesthesized dogs through the femoral 
vein at the various dosage levels as shown in Table 1 below 1 minute 
before the administration of the histamine. Sodium pentobartital was 
infused during the procedure at a dosage level of 4 mg/kg of body 
weight/hr using an automatic injector in order to inhibit spontaneous 
respiration and to maintain the anesthetic condition constant over the 
test period. 
ED.sub.50 values were calculated using a Dose Response curve. At the same 
time the pulse was measured through a transducer and the value was 
recorded on a polygraph. From the polygraph, the ED.sub.25 was calculated 
and the results obtained are shown in Table 1 below. 
The separation ratio (S.R.) was calculated by dividing the ED.sub.25 values 
demonstrating pulse increase by the ED.sub.50 values showing abatement of 
bronchospasm. 
The persistance time was determined by administering to a subject a test 
compound in such a dose that a histamine-induced bronchospasm is inhibited 
completely (100%), in the same manner as described above and observing the 
persistance of the activity of the test compound with the lapse of time. 
The results obtained are shown in Table 2 below. 
TABLE 1 
__________________________________________________________________________ 
Relative Potency of Various BR(Relative -Stimulants on Histamine-induced 
Bronchial 
Resistance Increase in Terms of ED.sub.50 and on Heart Beat in Terms of 
ED.sub.25 
beats/min. as Compared to Isoproterenol as a Standard Compound 
Heart Rate (HR) 
ED.sub.50 
Bronchial Resistance(BR) 
ED.sub.25 beats/min 
Separation Ratio 
(.mu.g/kg) Relative 
(.mu.g/kg) Relative 
HR(Relative Potency) 
Compound No. 
Compound 
Isoproterenol 
Potency 
Compound 
Isoproterenol 
Potency 
BR(Relative 
__________________________________________________________________________ 
Potency) 
Salubutamol (1) 
0.52 0.09 6.1 2.8 0.061 45.9 7.52 
(2) 0.66 0.19 3.47 3.6 0.09 40.0 11.5 
(3) 0.82 0.14 5.85 4.5 0.07 64.4 11.0 
(4) 0.61 0.16 3.81 3.6 0.08 45.0 11.8 
(5) 0.67 0.13 5.15 6.5 0.10 65.4 12.7 
(6) 0.42 0.12 3.52 3.2 0.07 46.1 13.1 
(7) 0.17 0.15 1.13 1.39 0.11 12.6 11.2 
(8) 0.51 0.11 4.64 4.81 0.07 68.7 14.8 
(9) 0.16 0.15 1.06 1.7 0.11 15.5 14.5 
(10) 0.95 0.16 5.94 5.6 0.10 56.4 9.5 
(11) 0.91 0.14 6.50 4.2 0.09 46.7 7.2 
(12) 0.73 0.10 7.30 8.3 0.11 75.5 10.3 
(13) 0.71 0.12 5.92 6.02 0.09 66.9 11.3 
(14) 0.47 0.12 3.92 3.86 0.08 48.3 12.3 
__________________________________________________________________________ 
As is apparent from the above results, each of the test compounds exhibits 
an activity which is more selective to the .beta..sub.2 -receptor than 
that of Comparative Compounds (1) and (2). 
Referring now to Figure, the test compounds [Compounds (3), (4) and (10)] 
exhibit a long-lasting .beta.-stimulation activity on histamine-induced 
bronchospasm as compared with that of the comparative compound [Compound 
(2)] when the compounds are tested in anesthesized dogs. 
Further, the acute toxicity by intravenous administration was determined 
with respect to the test compounds shown in Table 2 below using 5 to 6 
groups each containing 10 male rats (dd strain; body weight: 18 to 22 g) 
which had been fasted for 12 hours prior to the test. The LD.sub.50 (50% 
lethal dose) results are as follows. 
TABLE 2 
______________________________________ 
LD.sub.50 
Compound (mg/kg, i.v.) 
______________________________________ 
(3) 112 
(4) 105 
(6) 107 
(8) 123 
(9) 132 
(12) 153 
(13) 147 
______________________________________ 
The compounds of the present invention can be administered at a dosage 
level of from 0.1 to 50 .mu.g/kg/day by oral, intravenous, intramuscular, 
intrarectal or inhalation administration. 
The compounds of the present invention are advantageously administered in 
the form of an aerosol spray formulation by inhalation. 
Typical examples of suitable formulations are given below, but it is to be 
noted that other dosage forms can also be prepared using other compounds 
of this invention according to the well-established pharmaceutical 
techniques. 
FORMULATION 1 
Tablest each containing the following components were prepared from the 
following components: 
______________________________________ 
Components Amount 
______________________________________ 
8-Acetoxy-5-(1-hydroxy-2-isopropyl- 
1.2 mg 
aminobutyl)carbostyril 
Corn Starch 69.8 mg 
Magnesium Stearate 9 mg 
Lactose 20 mg 
Total 100 mg 
______________________________________ 
FORMULATION 2 
An aerosol spray for inhalation containing the following components per 
dose was prepared and filled into an aerosol dispenser: 
______________________________________ 
Components Amount 
______________________________________ 
8-Acetoxy-5-(1-hydroxy-2-isopropylamino- 
60 mcg 
butyl)carbostyril 
Oleic Acid 10 mcg 
Dichlorodifluoromethane 57 mg 
Trichlorofluoromethane 25 mg 
______________________________________ 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.