Novel carbostyril derivatives having platelet aggregation inhibitory action, antiinflamatory action, antiulcer action, vasodilatory action and phosphodiesterase inhibitory action and are useful for preventing or curing thrombus, arteriosclerosis, hypertension, asthma and other like diseases, and also useful as an antiinflamatory or anti-ulcer agent, represented by the formula ##STR1## wherein R.sup.1 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, phenyl-C.sub.1-4 alkyl-; R.sup.2 is hydrogen, a halogen atom, hydroxy, phenyl-C.sub.1-4 alkoxy; R.sup.3 is hydrogen, hydroxy, C.sub.1-4 alkyl; R.sup.4 is C.sub.3-8 cycloalkyl, substituted or unsubstituted phenyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkyl, 2-(3,4-dimethoxyphenyl)-ethyl, R.sup.5 is hydrogen, C.sub.1-8 alkyl, C.sub.2-4 alkenyl, phenyl, C.sub.3-8 cycloalkyl, phenyl-C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkyl, m is an integer of 1 - 3, l and n which may be same or different, and are respectively 0 or an integer of 1 - 7 and the sum of l and n is not exceeding 7, the carbon-carbon bond at 3- and 4-positions in the carbostyril skelton is either single or double bond.

The present invention relates to novel carbostyril derivatives. 
The compounds provided according to the present invention are novel 
carbostyril derivatives and salts thereof represented by the following 
general formula: 
##STR2## 
wherein R.sup.1 is a hydrogen atom, an alkyl group having 1 to 4 carbon 
atoms, an alkenyl group having 2 to 4 carbon atoms or a phenylalkyl group 
formed from combination of a phenyl group and an a straight-chain or 
branched-chain alkylene group having 1 to 4 carbon atoms, R.sup.2 is a 
hydrogen atom, a halogen atom, a hydroxy group or a phenylalkoxy group 
formed from combination of a phenyl group and an alkyleneoxy group having 
1 to 4 carbon atoms, R.sup.3 is a hydrogen atom, a hydroxy group or an 
alkyl group having 1 to 4 carbon atoms, R.sup.4 is a substituted or 
unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted 
or unsubstituted phenyl group, a cycloalkylalkyl group formed from 
combination of a cycloalkyl group having 3 to 8 carbon atoms and an 
alkylene group having 1 to 4 carbon atoms, or 2-(3,4-dimethoxyphenyl)ethyl 
group, R.sup.5 is a hydrogen atom, an alkyl group having 1 to 8 carbon 
atoms, an alkenyl group having 2 to 4 carbon atoms, a phenyl group, an 
unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl 
group formed from combination of a substituted or unsubstituted phenyl 
group and an alkylene group having 1 to 4 carbon atoms, or a 
cycloalkylalkyl group formed from combination of a cycloalkyl group having 
3 to 8 carbon atoms and an alkylene group having 1 to 4 carbon atoms; m is 
an integer of 1 to 3, and l and n, which may be the same or different, and 
are respectively 0 or an integer of 1 to 7, and the sum of l and n is not 
exceeding 7; the carbon-carbon bond at 3- and 4-positions in the 
carbostyril skelton is either single or double bond. 
The compounds of the present invention have a platelet aggregation 
inhibitory action, antiinflamatory action, antiuler action, vasodilatory 
action and phosphodiesterase (PDE) inhibitory action and are useful for 
preventing or curing thrombus, arteriosclerosis, hypertension, asthma and 
other like diseases, and also useful as an antiinflamatory or anti-ulcer 
agent. 
In the general formula (1), as to the alkyl group having 1 to 4 carbon 
atoms represented by R.sup.1 and R.sup.3 may be more definitely specified 
as methyl group, ethyl group, propyl group, isopropyl group, butyl group, 
isobutyl group, sec-butyl group, tert-butyl group or the like. As to the 
alkyl group having 1 to 8 carbon atoms represented by R.sup.5 may be more 
definitely specified as methyl group, ethyl group, propyl group, isopropyl 
group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, 
pentyl group, isopentyl group, neopentyl group, 2-methylbutyl group, hexyl 
group, isohexyl group, 2-ethylbutyl group, heptyl group, 3-methylhexyl 
group or octyl group. As to the alkenyl group having 2 to 4 carbon atoms 
represented by R.sup.1 and R.sup.5 may be definitely specified as vinyl 
group, allyl group, isopropenyl group or 2-butenyl group. As to the 
phenylalkyl group represented by R.sup.1 may be a phenylalkyl group formed 
from combination of a straight-chain or branched-chain alkylene group 
having 1 to 4 carbon atoms and a phenyl group, and examples of such 
phenylalkyl group are benzyl group, 2-phenylethyl group, 1-phenylethyl 
group, 3-phenylpropyl group, 4-phenylbutyl group and 
1,1-dimethyl-2-phenylethyl group. The halogen atom represented by R.sup.2 
may be chlorine atom, bromine atom, iodine atom or fluorine atom. The 
phenylalkoxy group represented by R.sup.2 may be the one formed from 
combination of the above-said phenylalkyl group and an oxygen atom, and 
examples of such phenylalkoxy group include benzyloxy group, 
2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 
4-phenylbutoxy group and 1,1-dimethyl-2-phenylethoxy group. The 
unsubstituted cycloalkyl group having 3 to 8 carbon atoms represented by 
R.sup.4 and R.sup.5 include, for example, cyclopropyl group, cyclobutyl 
group, cyclopentyl group, cyclohexyl group, cycloheptyl group and 
cyclooctyl group. The substituted cycloalkyl group having 3 to 8 carbon 
atoms represented by R.sup.4 may be the above-said type of cycloalkyl 
group which has undergone substitution with one or two same or different 
substituents such as for example an alkyl group such as methyl, ethyl, 
propyl, isopropyl, butyl or tert-butyl group; an alkoxy group such as 
methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy group; a 
halogen atom such as chlorine atom, bromine atom, iodine atom or fluorine 
atom; an alkanoylamino group such as acetylamino, propionylamino, 
butyrylamino or isobutyrylamino group; an alkanoyloxy group such as 
acetyloxy, propionyloxy, butyryloxy or isoburyloxy group; an 
alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl group; an alkanoyl 
group such as acetyl, propionyl, butyryl or isobutyryl group; an 
alkylcarbamoyl group such as N-methylcarbamoyl, N-ethylcarbamoyl, 
N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, 
N,N-diethylcarbamoyl or N-methyl-N-propylcarbamoyl group; an alkylamino 
group such as N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, 
N-ethylamino, N-isopropylamino, N-methyl-N-ethylamino or N,N-dibutylamino 
group; a nitro group, a carboxy group, a hydroxyl group, an aminosulfonyl 
group, a carbamoyl group or an amino group. The substituted phenyl group 
represented by R.sup.4 may be one which has undergone substitution with 
one or two substituent groups such as above-mentioned. The cycloalkylalkyl 
groups represented by R.sup.4 and R.sup.5 may be those formed from 
combination of a cycloalkyl group having 3 to 8 carbon atoms and a 
straight-chain or branched alkylene group having 1 to 4 carbon atoms, and 
as examples of such cycloalkylalkyl groups, one may cite the following: 
4-cyclohexylbutyl group, 2-cyclopentylethyl group, cyclohexylmethyl group, 
2-cyclopentylpropyl group, 3-cyclohexylpropyl group, cyclopentylmethyl 
group, 2-cyclohexylethyl group, 2-cyclohexylpropyl group, 
2-cycloheptylethyl group, 3-cyclobutylpropyl group, 
1,1-dimethyl-2-cyclohexylethyl group, and 1-methyl-2-cyclopentylethyl 
group. The substituted or unsubstituted phenylalkyl group represented by 
R.sup.5, may be any of the above-mentioned phenylalkyl groups or those 
phenylalkyl groups which have, as substituent, one or two above-said 
alkoxy groups having 1 to 4 carbon atoms on the phenyl ring, and more 
definite examples of such phenylalkyl groups are 4-ethoxybenzyl, 
2-(3,4-dimethoxyphenyl)ethyl, 1-(3,5-dimethoxyphenyl)ethyl, 
3-(2-butoxyphenyl)propyl, 4-(3,4-dimethoxyphenyl)butyl and 
1,1-dimethyl-2-(3,4-diethoxyphenyl)ethyl groups. 
Listed below are the representative examples of the compounds provided 
according to this invention. 
6-(N-Allyl-N-cyclopentylaminocarbonylmethoxy)-carbostyril 
6-(N-Methyl-N-cycloheptylaminocarbonylmethoxy)-carbostyril 
6-(N-Methylanilinocarbonylmethoxy)-3,4-dihydrocarbostyril 
6-[2-(N-Ethyl-N-cyclooctylaminocarbonyl)-ethoxy]carbostyril 
6-[2-(N-Allyl-N-cycloheptylaminocarbonyl)-ethoxy]-3,4-dihydrocarbostyril 
6-[3-(N-Cycloheptylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril 
6-[3-(N-Allyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Ethyl-N-cyclohexylaminocarbonyl)-propoxy]-3,4-dihydrocarbostyril 
6-[3-(N-Butyl-N-cyclooctylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Methyl-N-cyclooctylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Butyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
6-[3-(o-Chloroanilinocarbonyl)propoxy]carbostyril 
6-[3-(p-Methoxyanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril 
6-[3-(m-Hydroxyanilinocarbonyl)propoxy]carbostyril 
6-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril 
6-[3-(N,N-Diphenylaminocarbonyl)propoxy]carbostyril 
6-[3-(N-Methyl-o-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril 
6-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-carbostyril 
6-[3-(N-Cyclopentyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Cyclohexylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril 
6-[4-(N-Ethyl-N-cyclohexylaminocarbonyl)-butoxy]carbostyril 
6-[4-(N-Methylanilinocarbonyl)butoxy]-3,4-dihydrocarbostyril 
6-[4-(o,o-Dimethylanilinocarbonyl)butoxy]-carbostyril 
6-[5-(N-Methyl-N-cyclohexylaminocarbonyl)-pentyloxy]carbostyril 
6-[5-(N-Cyclohexylanilinocarbonyl)pentyloxy]-carbostyril 
6-[6-(N-Methyl-N-cyclohexylaminocarbonyl)-hexyloxy]-3,4-dihydrocarbostyril 
6-[6-(N-Ethylanilinocarbonyl)hexyloxy]carbostyril 
5-(N-Methyl-N-cycloheptylaminocarbonylmethoxy)-3,4-dihydrocarbostyril 
5-[2-(N-Methyl-N-cyclohexylaminocarbonyl)-ethoxy]carbostyril 
6-[8-(N-Ethyl-N-cyclohexylaminocarbonyl)-octyloxy]carbostyril 
5-[3-(N-Allyl-N-cyclopentylaminocarbonyl)-propoxy]carbostyril 
5-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
5-[3-(N-Propylanilinocarbonyl)propoxy]-carbostyril 
5-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril 
5-[4-(N-Methyl-N-cyclohexylaminocarbonyl)-butoxy]-3,4-dihydrocarbostyril 
5-[5-(N-Methyl-N-cyclohexylaminocarbonyl)-pentyloxy]carbostyril 
7-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
7-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril 
8-[3-(N-Ethyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
6-[3-(N-Octyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
5-[3-(N-Heptyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostryil 
6-{3-[N-Cyclohexyl-N-(2-phenylethyl)-aminocarbonyl]propoxy}carbostyril 
5-(o-Chloro-p-nitroanilinocarbonylmethoxy)-3,4-dihydrocarbostyril 
6-[3-(o-Carboxyanilinocarbonyl)propoxy]-carbostyril 
6-[3-(N-Ethyl-p-aminosulfonylanilinocarbonyl)-propoxy]carbostyril 
6-[3-(N-Methyl-o-carbamoylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril 
6-{3-[N-Methyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Phenyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy}carbostyril 
6-{1-[o-(N-Methylcarbamoyl)anilinocarbonyl]-ethoxy}carbostyril 
5-[1-(o-Carboxyanilinocarbonyl)ethoxy]-3,4-dihydrocarbostyril 
1-Allyl-5-[1-(p-methoxyanilinocarbonyl)-ethoxy]-3,4-dihydrocarbostyril 
1-Ethyl-6-[3-(N-methylanilinocarbonyl)-propoxy]carbostyril 
1-Benzyl-6-[3-(N,N-diphenylaminocarbonyl)-propoxy]carbostyril 
6-[2-Methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
6-[2-Butyl-3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbost 
yl 
6-[4-Methyl-5-(N-propyl-N-cyclohexylaminocarbonyl)heptyloxy]carbostyril 
5-[2-Methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
8-[2-Methyl-3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbos 
tyril 
5-Chloro-6-[3-(N-ethyl-o-methylanilinocarbonyl)propoxy]carbostyril 
5-Fluoro-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)-propoxy]carbostyril 
5-Chloro-6-[2-methyl-3-(N-methyl-N-cyclohexylamiocarbonyl)propoxy]-3,4-dihy 
drocarbostyril 
5,6,7-Tribromo-8-[3-(N-methylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyr 
il 
5,6,7-Trichloro-8-[5-(N-ethyl-N-cyclohexylamino)pentyloxy]carbostyril 
8-Bromo-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
8-Bromo-6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyr 
il 
6,8-Dichloro-5-[3-(N-ethylanilinocarbonyl)-propoxy]-3,4-dihydrocarbostyril 
5,7-Dichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
5,7,8-Trichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyri 
l 
8-Hydroxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarb 
ostyril 
5-Benzyloxy-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
7-Hydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
5,8-Dihydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydro 
carbostyril 
1-(4-Phenylbutyl)-5-[3-(N-ethyl-N-cyclopropylaminocarbonyl)propoxy]-3,4-dih 
ydrocarbostyril 
1-(2-Butenyl)-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
6,8-Dichloro-1-methyl-5-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbos 
tyril 
8-Hydroxy-1-ethyl-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbosty 
ril 
1-Methyl-7-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbosty 
ril 
5-{1-[N-Ethyl-N-(3-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril 
5-{3-[N-Methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocar 
bostyril 
6-{3-[N-Methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Methyl-N-(3-hydroxycyclohexyl)-aminocarbonyl]propoxy}carbostyril 
6-[3-(N-4-Methoxycyclohexylaminocarbonyl)-propoxy]-3,4-dihydrocarbostyril 
6-{3-[N-Methyl-N-(4-acetyloxycyclohexyl)-aminocarbonyl]propoxy}carbostyril 
6-{2-Methyl-3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]propoxy}-3,4-d 
ihydrocarbostyril 
1-Benzyl-6-[3-(N-4-ethoxycycloheptylaminocarbonyl)propoxy]carbostyril 
8-Hydroxy-5-{1-[N-methyl-N-(3-methylcyclohexyl)-aminocarbonyl]propoxy}carbo 
styril 
5,6,8-Trichloro-6-{3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propo 
xy}-3,4-dihydrocarbostyril 
6-{3-[N-Methyl-N-(2-hydroxy-5-methylcyclohexyl)-aminocarbonyl]propoxy}carbo 
styril 
6-{3-[N-ethyl-N-(4-nitrocyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbos 
tyril 
6-{3-[N-Methyl-N-(2-carboxycyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Ethyl-N-(2-N-methylcarbamoylcyclohexyl)aminocarbonyl]propoxy}carbos 
tyril 
5-{3-[N-Methyl-N-(2-N,N-diethylcarbamoylcyclohexyl)aminocarbonyl]propoxy}-3 
,4-dihydrocarbostyril 
6-{3-[N-Ethyl-N-(2-carbamoylcyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Methyl-N-(4-chlorocyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Methyl-N-(3,4-dimethoxycyclohexyl)-aminocarbonyl]propoxy}carbostyri 
l 
6-{3-[N-Allyl-N-(4-aminosulfonylcyclohexyl)-aminocarbonyl]propoxy}-3,4-dihy 
drocarbostyril 
6-{3-[N-Methyl-N-(3-acetylcyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Methyl-N-(4-acetylaminocyclohexyl)-aminocarbonyl]propoxy}-3,4-dihyd 
rocarbostyril 
6-{3-[N-Methyl-N-(4-N,N-dimethylaminocyclohexyl)aminocarbonyl]propoxy}carbo 
styril 
6-{3-[N-Methyl-N-(2,6-dimethylcyclohexyl)-aminocarbonyl]propoxy}carbostyril 
6-{3-[N-ethyl-N-(2,5-dimethoxycyclohexyl)-aminocarbonyl]propoxy}-3,4-dihydr 
ocarbostyril 
6-{3-[N-Methyl-N-(2,5-dichlorocyclohexyl)-aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Cyclohexylmethyl-(2-chlorocyclohexyl)aminocarbonyl]propoxy}carbosty 
ril 
6-{3-[N-Methyl-N-(2-aminocyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbo 
styril 
6-[2-Hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril 
5-[2-Hydroxy-3-(N-ethyl-p-methylanilinocarbonyl)-propoxy]-3,4-dihydrocarbos 
tyril 
6-[2-Hydroxy-3-(N-methylanilinocarbonyl)propoxy]-carbostyril 
1-Ethyl-6-[2-hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dih 
ydrocarbostyril 
6-{3-[N-Methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbos 
tyril 
6-{3-[N-Allyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}-3,4-di 
hydrocarbostyril 
6-{3-[N-Benzyl-N-(2-3',4'-dimethoxyphenylethyl)-aminocarbonyl]propoxy}carbo 
styril 
6-{3-[N-Phenyl-N-(2-3',4'-dimethoxyphenylethyl)-aminocarbonyl]propoxy}carbo 
styril 
6-{3-[N-Cyclohexyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}ca 
rbostyril 
6-{2-Methyl-3-[N-ethyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propox 
y}carbostyril 
5-Chloro-6-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propo 
xy}carbostyril 
1-Methyl-6-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propo 
xy}-3,4-dihydrocarbostyril 
8-Hydroxy-5-{3-[N-methyl-N-(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]prop 
oxy}carbostyril 
6-{3-[N-Octyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-{3-[N-Heptyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocar 
bostyril 
6-{3-[N-Octyl-N-(2-chlorocyclohexyl)aminocarbonyl]propoxy}carbostyril 
6-[3-(N-Cyclohexyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyril 
6-{3-[N-(2-Cyclopentyl-1-methylethyl)aminocarbonyl]propoxy}carbostyril 
6-{2-[N-(2-Cyclopentylethyl)aminocarbonyl]-ethoxy}-3,4-dihydrocarbostyril 
The compounds of this invention can be produced according to various 
processes such as for example expressed by the following reaction process 
formula-1 and reaction process formula-2: 
##STR3## 
wherein X is a halogen atom, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, 
R.sup.5, m, l, n and carbon-carbon bond at 3- and 4-positions in the 
carbostyril skeleton are all same as defined above. 
The starting materials used in this invention, that is, hydroxycarbostyril 
derivatives represented by the general formula (2), haloamide represented 
by the general formula (3), carboxyalkoxycarbostyril derivatives 
represented by the general formula (4) and amines represented by the 
general formula (5) may be all either known compounds or novel compounds 
and can be prepared according to the reaction process formulae -5 to -11 
shown later. 
The process expressed by the reaction process formula-1 is an ordinary 
method for carrying out a dehydrohalogenation reaction of a 
hydroxycarbostyril derivative represented by the general formula (2) with 
a haloamide represented by the general formula (3). The halogen atom in 
the haloamide may be bromine, chlorine or iodine atom. This 
dehydrohalogenation reaction is accomplished by using a basic compound as 
dehydrohalogenating agent. The basic compound used in said reaction may be 
selected from a wide variety of known basic compounds including inorganic 
bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, 
potassium carbonate, sodium hydrogencarbonate, potassium 
hydrogencarbonate, silver carbonate, etc.; alkali metals such as sodium, 
potassium, etc.; alcoholates such as sodium methylate, sodium ethylate, 
etc.; and organic bases such as triethylamine, pyridine, 
N,N-dimethylaniline, etc. The above reaction can be carried out in the 
absence or presence of a solvent. The solvent used in this reaction may be 
of any known inert type which gives no adverse effect to the reaction. 
Among the examples of such solvent are alcohols such as methanol, ethanol, 
propanol, butanol, ethylene glycol, etc.; ethers such as diethyl ether, 
tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; ketones such as 
acetone, methyl ethyl ketone, etc.; aromatic hydrocarbons such as benzene, 
toluene, xylene, etc.; esters such as methyl acetate, ethyl acetate, etc.; 
and aprotic polar solvents such as N,N-dimethylformamide, 
dimethylsulfoxide, hexamethylphosphoric triamide. It is advantageous to 
carry out the said reaction in the presence of a metallic iodide such as 
sodium iodide or potassium iodide. The ratio of amount of 
hydroxycarbostyril derivative (2) with haloamide (3) in the above method 
is not subject to any specific restriction and may be suitably selected 
from a wide range, but usually, it is desirable that the latter is used in 
equimolar to 5 times the molar quantity, preferably equimolar to double 
the molar quantity of the former. The reaction temperature is also not 
subject to any particular definition, but the reaction is usually carried 
out at room temperature to 200.degree. C., preferably at 50.degree. to 
150.degree. C. The reaction time is usually 1 to 30 hours, preferably 1 to 
15 hours. 
The process expressed by the reaction process formula-2 is a method for 
reacting a carboxyalkoxycarbostyril derivative represented by the general 
formula (4) with an amine represented by the general formula (5) according 
to an ordinary mode of amide bond forming reaction. The compound of the 
general formula (4) used in the invention may be substituted by a compound 
in which the carboxy groups were activated. It is also possible to use a 
compound having the activated amino groups in place of the amine 
represented by the general formula (5). The known amide bond forming 
reaction conditions may be easily applied to the practice of the amide 
bond forming reaction in this invention. For instance, the following 
methods are available for said reaction: (a) mixed acid anhydride method, 
thus on alkylhalocarboxylic acid is reacted with a carboxylic acid (4) to 
form a mixed acid anhydride and the latter is further reacted with an 
amine (5); (b) active ester method, thus a carboxylic acid (4) is 
converted into an active ester such as p-nitrophenyl ester, 
N-hydroxysuccinic acid imidoester, 1-hydroxybenzotriazole ester or the 
like and then such active ester is reacted with an amine (5); (c) 
carbodiimide method, thus an amine (5) is reacted with a carboxylic acid 
(4) in the presence of a dehydrating agent such as 
dicyclohexylcarbodiimide, carbonyldiimidazole, etc., to effect dehydration 
condensation; (d) other methods, thus a carboxylic acid (4) is converted 
into a carboxylic acid anhydride with a dehydrating agent such as acetic 
acid anhydride and then the carboxylic acid anhydride is reacted with an 
amine (5); high pressure and high temperature method, thus an amine (5) is 
reacted with an ester of a carboxylic acid (4) with a lower alcohol under 
a high pressure and high temperature condition; a method of reacting an 
amine (5) is reacted with an acid halide of a carboxylic acid (4), namely 
a carboxylic acid halide. Most preferrable method among these methods is 
mixed acid anhydride method. The alkylhalocarboxylic acid used in the 
mixed acid anhydride method may be for example methyl chloroformate, 
methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl 
chloroformate or the like. The mixed acid anhydride may be obtained by an 
usual Schotten-Baumann reaction, and this substance, usually without 
isolation, is reacted with an amine (5) to produce the compound of the 
present invention. The Schotten-Baumann reaction is carried out in the 
presence of a basic compound. Such basic compound may be commonly used for 
the Schotten-Baumann reactions and may be for example an organic base such 
as triethylamine, trimethylamine, pyridine, N,N-dimethylaniline, 
N-methylmorpholine, etc.; or an inorganic base such as potassium 
carbonate, sodium carbonate, potassium hydrogencarbonate, sodium 
hydrogencarbonate, etc. Said reaction is usually carried out at a 
temperature within the range of -20.degree. to 100.degree. C., preferably 
0.degree. to 50.degree. C., for the period of 5 minutes to 10 hours, 
preferably 5 minutes to 2 hours. The reaction between the obtained mixed 
acid anhydride and an amine (5) is carried out at a temperature of 
-20.degree. to 150.degree. C., preferably 10.degree. to 50.degree. C., for 
the period of 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The 
mixed acid anhydride method is usually carried out in a solvent. Any type 
of solvent commonly used in the mixed acid anhydride method may be 
employed, for example halogenated hydrocarbons such as methylene chloride, 
chloroform, dichloroethane, etc.; aromatic hydrocarbons such as benzene, 
toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, 
dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, etc.; 
and aprotic polar solvents such as N,N-dimethylformamide (DMF), 
dimethylsulfoxide, hexamethylphosphoric acid triamide, etc. In this 
method, the carboxylic acid (4), alkylhalocarboxylic acid and amine (5) 
are usually used in the equimolar ratio to each other, but the 
alkylhalocarboxylic acid and amine (5) may be used in 1 to 1.5 times the 
molar quantity of the carboxylic acid (4). 
The compounds of the invention can be also produced according to the 
processes expressed by the following reaction process formula-3 and 
reaction process formula-4. A compound of the general formula (1b) can be 
obtained by dehydrogenating a compound of the general formula (1a), while 
a compound of the general formula (1a) can be obtained by reducing a 
compound of the general formula (1b). A compound of the general formula 
(1d) can be produced from a dehydrohalogenation reaction of a compound of 
the general formula (1c) with a compound of the general formula (6). 
##STR4## 
wherein R.sup.1 ' is an alkyl group with 1 to 4 carbon atoms, an alkenyl 
group with 2 to 4 carbon atoms or a phenylalkyl group, and R.sup.1, 
R.sup.2, R.sup.3, R.sup.4, R.sup.5, m, l, n, X and carbon bond at 3- and 
4-positions in the carbostyril skeleton are same as defined above. 
However, R.sup.2 of the compound (1b) used as starting material for the 
reduction reaction in reaction process formula-3 is a hydrogen atom or a 
hydroxy group. 
In reaction process formula-3, the dehydrogenation of a compound of the 
general formula (1a) can be accomplished according to an usual method by 
subjecting the compound to a dehydrogenation reaction in a suitable 
solvent by using an oxidizing agent. As to oxidizing agents which may be 
used in this reaction are, for example, benzoquinones such as 
2,3-dichloro-5,6-dicyanobenzoquinone (hereinafter referred to as DDQ), 
chloranil (2,3,5,6-tetrachlorobenzoquinone), etc.; metallic catalysts such 
as selenium dioxide, palladium carbon, palladium black, platinum oxide, 
Raney nickel, etc.; and brominating agents such as N-bromosuccinimide, 
bromine, etc. As solvents which may be used in this reaction are, ethers 
such as dioxane, tetrahydrofuran, 2-methoxyethanol, dimethoxyethane, etc.; 
aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated 
hydrocarbons such as methylene chloride, dichloroethane, chloroform, 
carbon tetrachloride, etc.; alcohols such as butanol, amyl alcohol, 
hexanol, etc., and aprotic polar solvents such as N,N-dimethylformamide, 
dimethylsulfoxide, hexamethylphosphoric triamide, etc. This reaction is 
usually carried out at the temperature within the range of room 
temperature to 300.degree. C., preferably 50.degree. to 200.degree. C., 
for the period of 1 hour to 2 days, preferably 1 to 20 hours. In case of 
using a benzoquinone or brominating agent as oxidating agent, it is 
usually used in an amount of 1 to 5 times, preferably 1 to 2 times the 
moles of compound (1a), and in case of using a metallic catalyst as 
oxidating agent, it may be used in an ordinary amount employed in an usual 
catalytic reaction. 
In the reaction process formula-3, the catalytic reduction of the compound 
(1b) can be accomplished in the usual way by hydrogenating said compound 
in a suitable solvent by using a catalyst. Any known type of catalysts may 
be used for this reduction reaction. As examples thereof, one may cite 
platinum catalysts such as platinum wire, platinum plate, platinum sponge, 
platinum black, platinum oxide, colloidal platinum, etc.; palladium 
catalysts such as palladium sponge, palladium black, palladium oxide, 
palladium-barium sulfate, palladium-barium carbonate, palladium carbon, 
palladium silica gel, colloidal palladium, etc.; platinum group catalysts 
such as asbestos-filled rhodium, iridium, colloidal rhodium, ruthenium 
catalysts, colloidial iridium, etc., nickel catalysts such as reduced 
nickel, nickel oxide, Raney nickel, Urushibara nickel, nickel catalysts 
produced from thermal decomposition of nickel formate, nickel boride, 
etc.; cobalt catalysts such as reduced cobalt, Raney cobalt, Urushibara 
cobalt, etc; iron catalysts such as reduced iron, Raney iron, etc.; copper 
catalysts such as reduced copper, Raney copper, Ullmann copper, etc.; and 
other metallic catalysts such as zinc. The solvent used in the above 
reaction may be, for example, a lower alcohol (such as methanol, ethanol, 
isopropanol, etc.), water, acetic acid, an acetic acid ester (such as 
methyl acetate, ethyl acetate, etc.), ethylene glycol, an ether (such as 
diethyl ether, tetrahydrofuran, dioxane, etc.), an aromatic hydrocarbon 
(such as benzene, toluene, xylene, etc.), a cycloalkane (such as 
cyclopentane, cyclohexane, etc.), an n-alkane (such as n-hexane, 
n-pentane, etc.). The reaction is carried out under normal hydrogen 
pressure or under pressure, preferably under 1 to 20 atm., and at the 
temperature between room temperature and boiling point of the solvent, 
preferably between room temperature and 100.degree. C. 
In the reaction process formula-4, the reaction between the compound (1c) 
and the compound (6) is carried out by reacting the compound (1c) in the 
form of an alkali metal salt with the compound (6). The reaction for 
obtaining an alkali metal salt from the compound (1c) is conducted in the 
presence of an alkali metal compound. The alkali metal compound used here 
may be, for example, a metallic hydride such as sodium hydride, potassium 
hydride, etc.; an alkali metal such as metallic sodium, or sodium azide. 
This reaction is usually carried out in a solvent. Among the solvents 
usable in this reaction are aromatic hydrocarbon solvents such as benzene, 
toluene, xylene, etc.; ether solvents such as diethyl ether, 
1,2-dimethoxyethylene, dioxane, etc.; and aprotic polar solvents such as 
dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.; 
but the last-said aprotic polar solvents are most preferable. The alkali 
metal compound is usually used in an amount of 1 to 5 times, preferably 1 
to 3 times the molar quantity of the compound (1c). The reaction 
temperature may be suitably selected from a wide range, usually 0.degree. 
to 200.degree. C., but the reaction advances most advantageously within 
the range of room temperature to 50.degree. C. This reaction provides a 
compound (1c) where the nitrogen at 1-position has been substituted with 
an alkali metal. The reaction for obtaining the compound (1d) from an 
alkali metal salt of the above-obtained compound (1c) with the compound 
(6) is a condensation reaction. This condensation reaction may be 
accomplished easily in a usual way, but generally this reaction advances 
in a most preferred mode by reacting both compounds at room temperature in 
a solvent, for example, dimethylformamide. The amount of the compound (6) 
used may be suitably selected from a wide range, but usually it is 
desirably used in an amount of 1 to 5 times, most preferably 1 to 3 times 
the moles of the alkali metal salt of the compound (1c). 
The process of the present invention is not limited to the above-described 
two-stage operation; it is of course possible to carry out the reaction by 
introducing the three compounds, that is, the compounds of the general 
formulae (1c) and (6) and said alkali metal compound simultaneously into 
the reaction system, and in this case, too, it is possible to obtain the 
compound of the present invention through the same course of reaction as 
said above. 
Among the compounds represented by the general formula (2) used as the 
starting material in the present invention, the compound (2b) having a 
halogen atom as to R.sup.2 can be easily obtained by halogenating the 
compound (2a) (known compound) which is among the compounds represented by 
the general formula (2) and which has a hydrogen atom as to R.sup.2, as 
expressed by the following reaction process formula-5. 
##STR5## 
wherein X is a halogen atom, and R.sup.1, m and carbon bond at 3- and 
4-positions in the carbostyril skeleton are as defined above. 
The halogenation reaction of the compound (2a) can be accomplished 
advantageously by using a known halogenating agent. Examples of such 
halogenating agent are fluorine, chlorine, bromine, iodine, xenon 
difluoride, sulfuryl chloride, sodium hypochlorite, hypochlorous acid, 
hypobromous acid, bleaching powder, etc. The amont of the halogenating 
agent may be suitably selected from a wide range in accordance with the 
number of the halogen atoms to be introduced into the compound (2a). In 
case of introducing one halogen atom, said halogenating agent is usually 
used in an amount of 1 to 2 times, preferably 1 to 1.5 times the molar 
quantity of the compound (2a), and in case of introducing two halogen 
atoms, said halogenating agent is used in an amount of 1.5 times the moles 
to large excess, preferably 2 to 3 times the moles of the compound (2a). 
In case of introducing three halogen atoms, said agent is used in an 
amount of 2.5 times the moles to large excess, preferably 3 to 5 times the 
moles of the compound (2a). Such halogenation reaction is usually 
conducted in a suitable solvent such as for example water, methanol, 
ethanol, chloroform, carbon tetrachloride, acetic acid or a mixture 
thereof. The reaction temperature is not subject to any particular 
definition and can be suitably selected from a wide range, but usually the 
reaction is carried out at the temperature of around -20.degree. to 
100.degree. C., preferably 0.degree. C. to room temperature. The reaction 
is completed within the period of about 30 minutes to 10 hours. 
Among the compounds of the general formula (2b) used as starting material 
for the production of the compounds of this invention, the compound (2c) 
having the formula where m is 1 can be easily produced according to the 
process shown in the following reaction formula-6. 
##STR6## 
wherein R.sup.6 is an alkyl group, and R.sup.1, X and carbon bond at 3- 
and 4-positions in the carbostyril skeleton are as defined above. 
According to this process, a known acyloxycarbostyril derivative 
represented by the general formula (7) is halogenated and the obtained 
acyloxy-halogenocarbostyril derivative represented by the general formula 
(8) is hydrolyzed to produce a hydroxy-halogencarbostyril derivative 
represented by the general formula (2c). The halogenation reaction 
conditions are same as described above, and the hydrolysis reaction 
conditions may be same as described below. 
Among the compounds represented by the general formula (4), those compounds 
which have a halogen atom, a hydroxy group or a phenylalkoxy group at the 
site of R.sup.2 are novel compounds, and such compounds can be obtained 
from the process shown in the following reaction process formula-7. 
##STR7## 
wherein R.sup.2 ' is a halogen atom, a hydroxy group or a phenylalkoxy 
group, R.sup.7 is an organic residue, X is a halogen atom, and R.sup.1, 
R.sup.3, m, l, n and carbon bond at 3- and 4-positions in the carbostyril 
skeleton are as defined above. 
According to this process, a hydroxycarbostyril derivative represented by 
the general formula (2d) is reacted with an ester derivative represented 
by the general formula (9) to obtain an ester carbostyril derivative 
represented by the general formula (4a), and the thus obtained compound of 
the general formula (4a) is hydrolyzed to produce a corresponding 
carboxyalkoxycarbostyril derivative represented by the general formula 
(4b). 
The reaction between the compound (2d) and the compound (9) can be 
accomplished under the ordinary dehydrohalogenation reaction conditions. A 
variety of basic compounds may be used as the dehydrohalogenating agent in 
this reaction. Examples of such basic compounds include inorganic bases 
such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 
carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; 
alkali metals such as sodium, potassium, etc.; and organic bases such as 
triethylamine, pyridine, N,N-dimethylaniline, etc. Such reaction can be 
conducted either in the presence or in the absence of a solvent. A variety 
of solvents that take no part in the reaction can be used. Recommended 
examples of such solvents for use in this reaction are alcohols such as 
methanol, ethanol, propanol, etc.; ethers such as diethyl ether, 
tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, etc.; aromatic 
hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc.; and 
ketones such as acetone, methyl ethyl ketone, etc. The ratio of the 
amounts of compound (2d) to compound (9) is not subject to any specific 
limitations but can be suitably selected from a wide range. Usually, 
however, the latter is used in an amount of 1 to 5 times, preferably 1 to 
2 times the moles of the former. The reaction temperature may be also 
suitably selected from a wide range, but usually the reaction is carried 
out at a temperature between room temperature and 200.degree. C., 
preferably between 50.degree. and 150.degree. C., for the period of 
usually about 1 to 10 hours. 
The hydrolysis reaction of the compound (4a) is usually conducted in the 
presence of a catalyst. The catalyst used may be of any type commonly 
employed for the hydrolysis reactions, and as typical examples of such 
catalyst, the following may be cited: basic compounds such as sodium 
hydroxide, potassium hydroxide, barium hydroxide, etc.; mineral acids such 
as sulfuric acid, hydrochloric acid, nitric acid, etc.; and organic acids 
such as acetic acid, aromatic sulfonic acid, etc. The amount of such 
catalyst used in the reaction is not defined to any specific extent but 
may be suitably selected from a wide range. Such hydrolysis reaction can 
be accomplished in an ordinary way but it proceeds advantageously in a 
solvent. It is possible to use a variety of solvents which take no part in 
the reaction, such as for example water, alcohols such as methanol, 
ethanol, isopropanol, etc.; ketones such as acetone, methyl ethyl ketone, 
or mixtures thereof. The reaction temperature is not critical and can be 
suitably selected from a wide range, but usually the reaction is practiced 
at a temperature between room temperature and 200.degree. C., preferably 
between 50.degree. and 150.degree. C. The reaction is completed in usually 
about 5 minutes to 10 hours. 
The amines of the general formula (5) used as the starting material in the 
present invention can be produced easily by various methods such as those 
expressed by the following reaction processes formulae-8, -9 and -10. 
##STR8## 
In the above formulae, R.sup.4 ' is a substituted or unsubstituted phenyl 
group or phenylalkyl group, R.sup.4 " is a substituted or unsubstituted 
cyclohexyl or cyclohexylalkyl group, X is a halogen atom, and R.sup.4 and 
R.sup.5 are as defined above. 
According to the reaction process formula-8, the amine represented by the 
general formula (5) can be easily obtained by subjecting a known amine of 
the general formula (10) and a known halogen compound of the general 
formula (11) to a dehydrohalogenation reaction in the presence of a basic 
compound. According to the reaction process formula-9, the amine 
represented by the general formula (5) can be produced by subjecting a 
known amine of the general formula (12) and a known halogen compound of 
the general formula (13) to a dehydrohalogenation reaction in the presence 
of a basic compound. These reactions can be simply accomplished similar to 
a dehydrohalogenation reaction between the compound of the general formula 
(2) and the compound of the general formula (3). 
According to the reaction process formula-10, the cyclohexylamine 
derivative or cyclohexylalkylamine derivative represented by the general 
formula (5b) can be easily produced by reducing the benzene nucleus of a 
known compound of the general formula (5a). Various known nuclear 
hydrogenation reaction methods may be used for effecting the reduction of 
the benzene nucleus, but in the present invention, the catalytic reduction 
method is most advantageous. Such catalytic reduction is carried out in a 
solvent by using a catalyst according to a commonly employed method. The 
catalyst used in this reduction reaction may be of the type commonly 
employed for the nuclear hydrogenation reactions. Examples of such 
catalyst are platinum catalysts such as platinum black, platinum oxide, 
colloidal platinum, etc.; palladium catalysts such as palladium black, 
palladium carbon, colloidal palladium, etc.; rhodium catalysts such as 
asbestos-filled rhodium, rhodium alumina, etc.; ruthenium catalysts, 
nickel catalysts such as Raney nickel, nickel oxide, etc.; and cobalt 
catalysts. The solvent used in this reaction may be, for example, a lower 
alcohol (such as methanol, ethanol, isopropanol, etc.), water, acetic 
acid, acetic acid ester, ethylene glycol, an ether (tetrahydrofuran, 
dioxane, etc.) and a cycloalkane (such as cyclohexane, cyclopentane, 
etc.). This reaction is carried out under hydrogen pressure (preferably 1 
to 100 atm.) at a temperature between room temperature and 100.degree. C. 
for a period of 1 hour to 2 days. 
The haloamides of the general formula (3) used as another starting material 
in the present invention can be obtained in various ways, for example, by 
reacting an amine of the general formula (5) and a known halocarboxylic 
acid of the general formula (14) as shown by the following reaction 
process formula-11. 
##STR9## 
wherein R.sup.3, R.sup.4, R.sup.5, l, n and X are all as defined above. 
The reaction between the compound (5) and compound (14) can be accomplished 
in the same way as the above-said amide bond generating reaction. It is 
also possible in this invention to substitute the compound (14) with a 
compound having an activated carboxyl group. 
Among the compounds of the present invention represented by the general 
formula (1), the compounds having a hydrogen as to R.sup.1 and also having 
the double carbon-carbon bonds at 3- and 4-positions in the carbostyril 
skeleton may be prepared in the form of lactam-lactim type tautomeric 
compounds ((1e) and (1f)) as shown in the following reaction process 
formula-12. 
##STR10## 
wherein R.sup.2, R.sup.3, R.sup.5, m, l and n are as defined above. 
Among the compounds represented by the general formula (1), those compounds 
which have an acidic group can easily form salts with the pharmaceutically 
acceptable basic compounds. Such basic compounds include the inorganic 
base compounds, for example metallic hydroxides such as sodium hydroxide, 
potassium hydroxide, lithium hydroxide, calcium hydroxide, barium 
hydroxide, aluminum hydroxide, etc.; metal carbonates such as sodium 
carbonate, potassium carbonate, potassium hydrogencarbonate, sodium 
hydrogencarbonate, etc.; alkali metal alcoholates such as sodium 
methylate, potassium ethylate, etc.; and alkali metals such as sodium, 
potassium, etc.; and the organic basic compounds such as morpholine, 
piperazine, piperidine, diethylamine, aniline, etc. Of the compounds 
represented by the general formula (1), those having a basic group can 
easily form salts with the usual pharmaceutically acceptable acids which 
include inorganic acids such as sulfuric acid, nitric acid, hydrochloric 
acid, hydrobromic acid, etc.; and organic acids such as acetic acid, 
p-toluenesulfonic acid, succinic acid, benzoic acid, etc. 
The thus obtained compounds of the present invention can be easily isolated 
and refined by the usual separation means such as precipitation, 
extraction, recrystallization, column chromatography and preparative thin 
layer chromatography. 
The compounds of the present invention can be administered, either in the 
form as they are or together with a pharmaceutically acceptable carrier, 
to animals as well as to human being. No particular restriction is placed 
on the administration unit forms and the compounds can be used in any 
desired unit form. Suitable administration unit forms include such oral 
administration forms as tablets, capsules, granules, etc.; and parenteral 
administration forms such as injections. The dosage of the active 
ingredient to be administered is not subject to any particular definition 
and admits of selection from a wide range, but in order to obtain a 
desired pharmacological effect, it is recommended to select said dosage 
from the range of 0.06 to 10 mg per kg body weight per day. It is also 
suggested to contain 1 to 500 mg of the active ingredient in each unit 
dose of the administration forms. 
The compounds of the present invention can be formed into the desired 
peroral preparations such as tablets, capsules, solutions, etc., according 
to a common method. For preparation of tablets, a compound of the present 
invention is mixed with a pharmaceutically acceptable excipient such as 
gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like 
and shaped into tablets. Capsules can be obtained by mixing a compound of 
this invention with an inert pharmaceutically acceptable filler or diluent 
and filling the mixture into rigid gelatin capsules or soft capsules. 
Sirup or elixir may be prepared by mixing a compound of the present 
invention with a sweetening such as sucrose, antiseptic such as methyl- 
and propyl-parabens, colorant, seasoning and/or other suitable additives. 
Parenteral preparations can be also obtained according to a common method. 
In this case, the compound of the present invention is dissolved in a 
sterilized liquid vehicle. Preferred vehicle is water or saline water. 
Liquid preparations having desired transparency, stability and parenteral 
use adaptability can be obtained by dissolving approximately 1 to 500 mg 
of the active ingredient in a solution of polyethylene glycol which is 
soluble in both water and organic solvents. Desirably, such liquid 
preparations contain a lubricant such as sodium carboxymethyl cellulose, 
methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol or the like. 
Said liquid preparations may also contain a bactericide and fungicide such 
as benzyl alcohol, phenol or thimerosal and, if necessary, an isotonic 
agent such as sucrose or sodium chloride, a local anesthetic, stabilizer, 
buffer, etc. For additional ensurance of stability, the parenteral 
compositions may be freezed after filling and dehydrated by the known 
freeze-drying techniques. The freeze-dried powder can be returned to the 
normal use form just before use. 
PREATION OF TABLETS 
1,000 Tablets for peroral use, each containing 5 mg of 
6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril, are 
prepared from the following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-[3-(N-Methyl-N-cyclohexylamino- 
carbonyl)propoxy]carbostyril 
5 
Lactose (J.P. = Japanese 
50 
Pharmacopoeia) 
Corn starch (J.P.) 25 
Crystalline cellulose (J.P.) 
25 
Methyl cellulose (J.P.) 
1.5 
Magnesium stearate (J.P.) 
1 
______________________________________ 
The above specified 
6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, lactose, 
corn starch and crystalline cellulose are mixed well, and the mixture is 
added with a 5% aqueous solution of methyl cellulose and then granulated. 
The obtained granules are passed through a 200 mesh sieve and then dried 
carefully. 
PREATION OF TABLETS 
1,000 Tablets for peroral use, each containing 5 mg of 
6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril, 
are preared in the similar way from the following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{3-[N-Methyl-N-(4-acetoxy- 
cyclohexyl)aminocarboxyl]- 
propoxy}carbostyril 5 
Lactose (J.P.) 50 
Corn starch (J.P.) 25 
Crystalline cellulose (J.P.) 
25 
Methyl cellulose (J.P.) 
1.5 
Magnesium stearate (J.P.) 
1 
______________________________________ 
PREATION OF CAPSULES 
1,000 Pieces of two-piece rigid gelation capsules for peroral use, each 
containing 10 mg of 
6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, are prepared 
from the following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-[3-(N-Methyl-N-cyclohexyl- 
aminocarbonyl)propoxy]carbostyril 
10 
Lactose (J.P.) 80 
Starch (J.P.) 30 
Talc (J.P.) 5 
Magnesium stearate (J.P.) 
1 
______________________________________ 
The above components are finely ground, then stirred and mixed sufficiently 
to form a uniform mixture and then filled into the gelatin capsules with a 
size convenient for peroral administration. 
PREATION OF CAPSULES 
1,000 Pieces of two-piece rigid gelatin capsules for peroral use, each 
containing 10 mg of 
6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril, 
are prepared in the similar way from the following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{3-[N-Methyl-N-(4-acetoxy- 
cyclohexyl)aminocarbonyl]- 
10 
propoxy}carbostyril 
Lactose (J.P.) 80 
Starch (J.P.) 30 
Talc (J.P.) 5 
Magnesium stearate (J.P.) 
1 
______________________________________ 
PREATION OF INJECTIONS 
A sterile aqueous solution suited for parenteral use is prepared from the 
following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-[3-(N-Methyl-N-cyclohexyl- 
aminocarbonyl)propoxy]carbostyril 
1 
Polyethylene glycol (J.P.), 
[molecular weight: 4,000] 
0.3 
Sodium chloride (J.P.) 0.9 
Polyoxyethylene sorbitan mono- 
oleate (J.P.) 0.4 
Sodium metabisulfite 0.1 
Methyl-p-hydroxybenzoate (J.P.) 
0.18 
Propyl p-hydroxybenzoate (J.P.) 
0.02 
Distilled water for injection 
100 ml 
______________________________________ 
A mixture of the above-prescribed methyl p-hydroxybenzoate, propyl 
p-hydroxybenzoate, sodium metabisulfite and sodium chloride, while 
stirred, is dissolved in about half the quantity of distilled water at 
80.degree. C. The obtained solution is cooled to 40.degree. C., and then 
6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, polyethylene 
glycol and polyoxyethylene sorbitan monooleate are dissolved in that order 
in said solution. This solution is further added with distilled water for 
injection to the final regulated volume and then sterilized by sterile 
filtration with a suitable filter paper. 
PREATION OF INJECTIONS 
A sterile aqueous solution suited for parenteral use is prepared in the way 
similar to the above from the following prescription. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{3-[N-Methyl-N-(4-acetoxycyclo- 
hexyl)aminocarbonyl]propoxy}- 
carbostyril 1 
Polyethylene glycol (J.P.) 
[molecular weight: 4,000] 
0.3 
Sodium chloride (J.P.) 0.9 
Polyoxyethylene sorbitan mono- 
oleate (J.P.) 0.4 
Sodium metabisulfite 0.1 
Methyl p-hydroxybenzoate (J.P.) 
0.18 
Propyl p-hydroxybenzoate (J.P.) 
0.02 
Distilled water for injection 
100 ml 
______________________________________ 
The results of the pharmacological tests on the compounds of this invention 
are shown below. 
PHARMACOLOGICAL TEST 1 
The platelet aggregation inhibitory effect is measured by using AG-II 
Aggregometer (manufactured by Bryston Manufacturing Co.). The blood sample 
used for the test is a 1/9 (by volume) mixture of sodium citrate and whole 
blood collected from rabbit. Said sample is subjected to 10-minute 
centrifugal separation at 1,000 r.p.m. to obtain a platelet rich plasma 
(PRP). The thus obtained PRP is separated, and the remaining blood sample 
is further subjected to 15-minute centrifugal separation at 3,000 r.p.m. 
to obtain a platelet poor plasma (PPP). 
The number of platelets in the PRP is counted by the Brecher-Clonkite 
Method, and the PRP is diluted with the PPP to prepare a PRP sample with 
platelet concentration of 300,000/mm.sup.3 for the adenosine diphosphate 
(ADP)-induced aggregation test. There is also prepared a PRP sample with 
platelet concentration of 450,000/mm.sup.3 for the collagen-induced 
aggregation test. 
0.6 ml of said PRP sample is added into 0.01 ml of a solution of a test 
compound of a predetermined concentration and the mixture is placed in a 
37.degree. C. thermostat for one minute. Then 0.07 ml of an ADP or 
collagen solution is added to the mixture. Transmittance of this mixture 
is determined and the change of transmittance is recorded by using the 
aggregometer at stirrer speed of 1,100 r.p.m. In this test, Auren Beronal 
buffer (pH 7.35) is used for the preparation of the ADP or collagen 
solution. ADP is adjusted to a concentration of 7.5.times.10.sup.-5 M, and 
the collagen solution is prepared by triturating 100 mg of collagen with 5 
ml of said buffer and the supernatant is used as collagen inducer. 
Adenosine and acetylsalicylic acid are used as controls for the 
ADP-induced aggregation test and the collagen-induced aggregation test, 
respectively. The platelet aggregation inhibitory effect is measured in 
terms of percent inhibition with respect to the aggregation rate of the 
controls. The aggregation rate is calculated from the following formula: 
EQU Aggregation rate=(c-a)/(b-a).times.100 
wherein 
a: transmittance of PRP 
b: transmittance of PRP containing a test compound and an aggregation 
inducer 
c: transmittance of PPP. 
The inhibitory effect of the tested compounds on collagen-induced 
aggregation in rabbit platelets is shown in Table 1, and such effect on 
ADP-induced aggregation is shown in Table 2. The compounds tested are as 
follows. 
TESTED COMPOUNDS 
COMPOUNDS OF THE PRESENT INVENTION (NOS. 1-24) 
______________________________________ 
No. 
______________________________________ 
1. 6-{3-[N-Methyl-N-(2-methylcyclohexyl)aminocarbonyl]- 
propoxy}carbostyril 
2. 6-{3-[N-Methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]- 
propoxy}carbostyril 
3. 6-{3-[N-Methyl-N-(4-acetyloxycyclohexyl)amino- 
carbonyl]propoxy} carbostyril 
4. 6-{3-[N-Methyl-N-(2-3',4'-dimethoxyphenylethyl)- 
aminocarbonyl]propoxy}carbostyril 
5. 6-{3-(N-Cyclohexyl-N-benzylaminocarbonyl)propoxy]- 
carbostyril 
6. 5-Chloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)- 
propoxy]carbostyril 
7. 6-{3-[N-Cyclohexyl-N-(2-chlorocyclohexyl)amino- 
carbonyl]propoxy}-3,4-dihydrocarbostyril 
8. 6-[2-Hydroxy-3-(N-methyl-N-cyclohexylamino- 
carbonyl)propoxy]carbostyril 
9. 6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)-2- 
methylpropoxy]carbostyril 
10. 8-Hydroxy-5-[3-(N-Methyl-N-cyclohexylamino- 
carbonyl)propoxy]-3,4-dihydrocarbostyril 
11. 6-{3-[N-Benzyl-N-(2-3',4'-dimethoxyphenylethyl)- 
aminocarbonyl]propoxy}-3,4-dihydrocarbostyril 
12. 6,8-Dichloro-5-[3-(N-ethylanilinocarbonyl)- 
propoxy]-3,4-dihydrocarbostyril 
13. 6-[3-(N-Cyclohexylaminocarbonyl)propoxy]carbostyril 
14. 6-[3-(N-Allyl-N-cyclohexylaminocarbonyl)propoxy]- 
3,4-dihydrocarbostyril 
15. 6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]- 
3,4-dihydrocarbostyril 
16. 6-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy]- 
carbostyril 
17. 6-[3-(N-Cyclohexylanilinocarbonyl)propoxy]carbostyril 
18. 6-[3-(N,N-Dicyclohexylaminocarbonyl)propoxy]-3,4- 
dihydrocarbostyril 
19. 6-[3-(Anilinocarbonyl)propoxy]-3,4-dihydrocarbo- 
styril 
20. 6-[3-(N-Ethylanilinocarbonyl)propoxy]carbostyril 
21. 6-[3-(o,o-Dichloroanilinocarbonyl)propoxy]-3,4- 
dihydrocarbonstyril 
22. 6-[4-(N-Butyl-N-cyclohexylaminocarbonyl)- 
buthoxy]-3,4-dihydrocarbostyril 
23. 5-[3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy] - 
3,4-dihydrocarbostyril 
24. 6-[3-(N,N-Diphenylaminocarbonyl)propoxy]-3,4- 
dihydrocarbostyril 
______________________________________ 
KNOWN COMPOUNDS (COMATIVE COMPOUNDS) (NOS. 25-46) 
______________________________________ 
No. 
______________________________________ 
25. 6-(1-Ethoxycarbonylethoxy)-3,4-dihydrocarbostyril 
26. 6-(1-Ethoxycarbonylethoxy)carostyril 
27. 1-Methyl-6-(1-ethoxycarbonylethoxy)-3,4-dihydro- 
carbostyril 
28. 7-(1-ethoxycarbonylethoxy)-3,4-dihydrocarbostyril 
29. 6-(3-Ethoxycarbonylpropoxy)-3,4-dihydrocarbostyril 
30. 6-(1-Amyloxycarbonylethoxy)-3,4-dihydrocarbostyril 
31. 6-(1-Isopropoxycarbonylethoxy)carbostyril 
32. 5-(3-Ethoxycarbonylpropoxy)-3,4-dihydrocarbostyril 
33. 6-(3-Amyloxycarbonylpropoxy)-3,4-dihydrocarbo- 
styril 
34. 6-(3-Ethoxycarbonylpropoxy)carbostyril 
35. 6-(6-Ethoxycarbonylhexyloxy)-3,4-dihydrocarbostyril 
36. 6-(6-Carboxyhexyloxy)-3,4-dihydrocarbostyril 
37. 8-(1-Ethoxycarbonylethoxy)-3,4-dihydrocarbostyril 
38. 6-(1-Methyl-1-carboxyethoxy)-3,4-dihydrocarbostyril 
39. 6-(3-Carboxypropoxy)carbostyril 
40. 6-(3-Cyclohexyloxycarbonylpropoxy)-3,4-dihydro- 
carbostyril 
41. 5-(N-Isopropylaminocarbonylethoxy)-3,4-dihydro- 
carbostyril 
42. 5-(Morpholinocarbonylmethoxy)-3,4-dihydro- 
carbostyril 
43. 5-(N,N-dimethylaminocarbonylmethoxy)-3,4-dihydro- 
carbostyril 
44. 1-Ethyl-5-[3-(N-benzylaminocarbonyl)propoxy]- 
3,4-dihydrocarbostyril 
45. 6-[3-(N-Propylaminocarbonyl)-2-methylpropoxy]- 
3,4-dihydrocarbostyril 
46. Aspirin 
______________________________________ 
TABLE 1 
______________________________________ 
Inhibition effect of carbostyril derivatives 
on collagen induced aggregation in rabbit 
platelet 
Concentration of the test 
Test compound solution 
compound 
10.sup.-4 
10.sup.-5 
10.sup.-6 
10.sup.-7 
No. mole mole mole mole 
______________________________________ 
Compounds 
1 --% 100.0% 
100.0% 21.1% 
of the 2 -- 100.0 89.7 -- 
present 3 90.8 84.8 61.9 -- 
invention 
4 82.9 46.5 19.2 -- 
5 -- 91.8 88.4 30.6 
6 100.0 53.3 12.3 -- 
7 91.5 89.9 50.3 -- 
8 85.5 86.8 2.9 -- 
9 100.0 100.0 100.0 11.2 
10 91.8 29.3 -- -- 
11 88.1 75.8 28.1 -- 
12 82.6 65.2 33.8 -- 
13 87.5 45.8 23.3 -- 
14 82.4 42.3 15.7 -- 
15 94.0 92.6 34.1 -- 
16 -- 90.5 90.2 57.0 
17 91.5 53.8 16.7 -- 
18 87.5 59.4 50.0 -- 
19 93.8 17.4 -- -- 
20 91.3 76.3 43.2 -- 
21 95.1 27.6 -- -- 
22 85.6 78.5 28.7 -- 
23 76.5 58.7 13.5 -- 
24 82.7 43.5 15.5 -- 
______________________________________ 
Known 25 71 20 2 -- 
compounds 
26 67 12 -6 -- 
(Reference 
27 36 -- 0 -- 
compounds) 
28 2 -- 8 -- 
29 92 38 8 -- 
30 88 8 0 -- 
31 55 25 3 -- 
32 90 8 5 -- 
33 48 22 6 -- 
34 100 86 18 -- 
35 31 13 6 -- 
36 15 14 2 -- 
37 5 -- 2 -- 
38 5 3 0 -- 
39 28 15 0 -- 
40 12 8 0 -- 
41 17 -- 0 -- 
42 5 0 0 -- 
43 27 13 0 -- 
44 7 0 0 -- 
45 12 5 0 -- 
46 65 9 7 -- 
______________________________________ 
TABLE 2 
______________________________________ 
Inhibition effect of carbostyril derivatives 
on ADP-induced aggregation in rabbit 
platelet 
Concentration of the test 
Test compound solution 
compound 
10.sup.-4 
10.sup.-5 
10.sup.-6 
10.sup.-7 
No. mole mole mole mole 
______________________________________ 
Compounds 
1 100.0% 73.0% 42.4% 4.3% 
of the 2 -- 90.3 54.3 -- 
present 3 91.5 75.0 20.8 -- 
invention 
4 70.4 16.1 6.9 -- 
5 -- 90.7 61.2 18.9 
6 87.2 5.4 -- -- 
7 89.8 82.9 38.4 -- 
8 91.7 41.1 -- -- 
9 92.8 70.4 5.8 -- 
10 53.9 18.4 -- -- 
11 87.5 12.5 16.9 -- 
12 71.7 33.8 12.7 -- 
13 39.6 24.8 18.0 -- 
14 41.3 25.7 15.1 -- 
15 88.3 26.8 10.8 -- 
16 -- 91.7 62.1 32.8 
17 82.5 38.7 12.3 -- 
18 86.4 37.5 12.6 -- 
19 24.6 16.2 -- -- 
20 82.5 31.7 13.5 -- 
21 36.8 5.3 -- -- 
22 71.5 32.7 10.5 -- 
23 73.6 26.1 8.7 -- 
24 43.2 22.3 13.4 -- 
Known 25 57 25 5 -- 
compounds 
26 86 54 -6 -- 
(Reference 
27 36 -- 0 -- 
compounds) 
28 -18 -- 14 -- 
29 100 97 10 -- 
30 100 79 20 -- 
31 74 38 7 -- 
32 65 18 2 -- 
33 82 58 0 -- 
34 100 90 25 -- 
35 37 15 10 -- 
36 13 8 7 -- 
37 3 -- 11 -- 
38 10 5 3 -- 
39 52 23 5 -- 
40 28 16 7 -- 
41 18 13 7 -- 
42 13 6 0 -- 
43 22 17 8 -- 
44 14 6 0 -- 
45 32 17 9 -- 
46 7 0 -- -- 
______________________________________ 
PHARMACOLOGICAL TEST 2 
A water suspension of test compound was administered at the dose of 30 
mg/kg to the overnight fasted male Wister rats and male beagle dogs, and 
after a predetermined period of time, blood was collected from said 
animals to obtain plasma. 2 to 3 Milliliters of 0.1 N-NaOH and 2 ml of 
CHCl.sub.3 were added to 1 ml of the obtained plasma, and the mixture was 
shaken and extracted in a shaker for 2 hours, and after centrifugal 
separation, the organic layer was washed with 2 ml of 0.1 N-HCl. This 
organic layer was then subjected to a freezing and thawing treatment, and 
after evaporating chloroform under nitrogen stream, the residue was 
redissolved in 100 .mu.l of chloroform and spotted on a thin layer plate 
of "Silica Gel 60 F.sub.254 " manufactured by Merck & Co., Inc. This was 
developed in a chloroform: butanol mixed solvent (5:1) and determined by 
measuring the spots with same Rf value as the test compound according to 
the absorbance method by using Shimazu CS-910 Thin Layer Chromato-scanner, 
and therefrom the concentration (.mu.g/ml) of test compound A in blood was 
determined. The results are shown in Table 3. 
TABLE 3 
______________________________________ 
Test 
com- 
pound Test Concentration in blood (.mu.g/ml) 
No. animal 1 hr. 2 hr. 
4 hr. 
6 hr. 
8 hr. 
12 hr. 
______________________________________ 
Com- Rat 1.05 1.62 0.94 0.53 -- 0.48 
pounds 
1 
of the Beagle 0.28 0.31 0.21 0.13 0.08 0.05 
present dog 
in- Rat 0.90 0.74 1.10 0.28 -- 0.64 
vention Rat 1.06 3.80 0.71 0.32 -- 0.73 
16 Rat 0.88 0.88 0.83 0.02 -- 0.78 
Beagle 
dog 0.23 0.28 0.14 0.11 0.05 0.04 
Beagle 
dog 0.13 0.31 0.33 0.21 0.15 0.07 
18 Rat 1.32 1.74 1.02 0.69 0.56 0.42 
Beagle 
dog 0.36 0.23 0.32 0.17 0.13 0.06 
20 Rat 0.95 1.37 0.92 0.46 -- 0.28 
Beagle 
dog 0.32 -- -- 0.08 0.05 -- 
23 Rat 1.53 2.24 0.94 0.54 0.39 0.52 
Beagle 
dog 0.43 0.29 0.21 0.14 0.05 0.07 
Known Rat 0.01 0 0 -- -- -- 
com- 29 
pounds Beagle 
dog 0.01 0 0 -- -- -- 
Rat 0.01 0 0 -- -- -- 
34 Beagle 
dog 0 0 -- -- -- -- 
______________________________________ 
PHARMACOLOGICAL TEST 3 
The obstructive action against cyclic AMP phosphodiesterase was measured 
according to the activity measuring method described in "Biochimica et 
Biophysica Acta", Vol. 429, pp. 485-497 (1976) and "Biochemical Medicine", 
Vol. 10, pp. 301-311 (1974). 
That is, for determining the obstructive activity against cyclic AMP 
phosphodiesterase, 10 ml of a solution obtained by adding 1 mmol of 
MgCl.sub.2 into 50 mmol of tris-hydrochloric acid buffer with pH 7.4 was 
added to the platelets obtained by further centrifuging the abovesaid 
rabbit PRP at 3,000 r.p.m. for 10 minutes, and the suspended platelets 
were ground by a Teflon potter type homogenizer. This was followed by two 
times of freezing and thawing treatment and 300-second fracturing with 200 
watt supersonic waves. After additional 60-minute centrifugation with 
100,000 xg, the supernatant was collected to use it as a crude enzyme 
solution. 
10 Milliliters of this crude buffer solution was added to a 1.5.times.20 cm 
DEAE-cellulose column which has previously been buffered with 50 mmol of 
tris-acetate buffer (pH 6.0), followed by washing and elution with 30 ml 
of 50 mmol tris-acetate buffer, and this buffer solution was subjected to 
linear gradient elution with 0 to 0.5 moles of sodium acetate-tris-acetate 
buffer. The flow rate was 0.5 ml/min, and 5 ml of each fraction was 
batched out. This operation gave a fraction which has low activity of less 
than 2 n mole/ml/min with high (100 .mu.mole) cyclic AMP substrate 
concentration and still has high activity of over 100 p mole/ml/min with 
low (0.4 .mu.mole) cyclic AMP substrate concentration. This fraction was 
used as cyclic AMP phosphodiesterase. 
0.1 Milliliter of an aqueous solution of each test compound of a specified 
concentration was mixed with 40 mmol of tris-hydrochloric acid buffer (pH 
8.0, containing 50 .mu.g of cow serum albumin and 4 mmol of MgCl.sub.2) 
containing predetermined 1.0 .mu.mol of cyclic AMP (tritium cyclic AMP), 
and 0.2 ml of this mixed solution was used as substrate solution. 
0.2 Milliliter of the above-prepared cyclic AMP phosphodiesterase of a 
predetermined concentration was added to said substrate solution and the 
mixture was reaction at 30.degree. C. for 20 minutes, producing tritium 
5'-AMP from the tritium cyclic AMP. 
The reaction system was then immersed in boiling water for 2 minutes to 
stop the reaction, and then this reaction solution was cooled in ice water 
and, for converting the produced tritium 5'-AMP into tritium adenosine, 
the solution was added with 0.05 ml (1 mg/ml) of snake poison as 
5'-nucleotidase and reacted at 30.degree. C. for 10 minutes. The whole 
amount of this reaction solution was then added to a cation exchange resin 
(AG 500 W.times.4, 200-400 meshes, manufactured by Bio-Rad Co., column 
size: 0.5.times.1.5 cm), and the produced tritium anodesine alone was 
allowed to combine, washed with 6 ml of distilled water and eluted with 
1.5 ml of 3 N-ammonia water. The whole quantity of the elutant was added 
with 10 ml of a triton-toluene type scintillator and the produced tritium 
adenosine was measured by a liquid scintillation counter to determine the 
phosphodiesterase activity. 
In this way, the phosphodiesterase activation value (Vs) of the test 
compounds of the respective concentrations was determined, and the 
phosphodiesterase obstruction rate (%) was determined from said activation 
value (Vs) and control value (Vc) (obtained from water not containing any 
test compound) from the following formula: 
##EQU1## 
Known papaverine and 1-methyl-3-isobutylxanthine were used as controls. 
The results are shown in Table 4. 
TABLE 4 
______________________________________ 
Test Concentration of test compound solution 
compound 10.sup.-4 
10.sup.-5 
10.sup.-6 
10.sup.-7 
10.sup.-8 
10.sup.-9 
No. mole mole mole mole mole mole 
______________________________________ 
3 -- 98.5 95.5 88.4 61.1 13.4 
16 -- 80.5 87.5 79.3 22.3 7.1 
Papaverine 
100 99.8 91.4 57.3 -- -- 
1-Methyl-3- 
isobutyl- 
98.5 85.7 67.4 3.2 -- -- 
xanthine 
______________________________________ 
ACUTE TOXICITY TEST 
The test compounds were administered orally to the mice and LD.sub.50 
(mg/kg) of the compounds was determined. The results are shown in Table 5 
below. 
TABLE 5 
______________________________________ 
LD.sub.50 (mg) 
Male mice 
Test Oral 
compound administration 
______________________________________ 
Compounds 1 &gt;1000 
of the 2 &gt;1000 
present 3 &gt;1000 
invention 4 &gt;1000 
5 &gt;1000 
6 &gt;1000 
7 &gt;1000 
8 &gt;1000 
9 &gt;1000 
10 &gt;1000 
11 &gt;1000 
12 &gt;1000 
13 &gt;1000 
14 &gt;1000 
15 &gt;1000 
16 &gt;1000 
17 &gt;1000 
18 &gt;1000 
19 &gt;1000 
20 &gt;1000 
21 &gt;1000 
22 &gt;1000 
23 &gt;1000 
24 &gt;1000 
Known 25 &gt;1000 
compounds 26 &gt;1000 
27 800 .about. 1000 
28 &gt;1000 
29 &gt;1000 
30 &gt;1000 
31 900 .about. 1000 
32 &gt;1000 
33 &gt;1000 
34 &gt;1000 
35 750 .about. 1000 
36 &gt;1000 
37 900 .about. 1000 
38 800 .about. 1000 
39 &gt;1000 
40 500 .about. 800 
41 500 .about. 800 
42 400 .about. 600 
43 500 .about. 700 
44 500 .about. 600 
45 500 .about. 800 
______________________________________ 
CONSIDERATION ON PHARMACOLOGICAL DATA 
(1) The results of Tables 1 to 3 indicate that the platelet aggregation 
inhibitory effect of the compounds of this invention is equal to or higher 
than that of the known carboxy or esterocarbostyril derivatives and yet 
the compounds of this invention are far longer in said effect retention 
time than the known derivatives. 
It is also noted that the compounds of this invention are far higher in 
platelet aggregation inhibitory effect than the known amidocarbostyril 
derivatives and aspirin. 
(2) The results of Table 4 indicate that the compounds of this invention 
are far stronger in phosphodiesterase obstructing action than known 
1-methyl-3-isobutylxanthine and equal to or higher than papaverine and 
also selectively obstruct cyclic AMP phosphodiesterase.