Carbostyril derivative or a pharmaceutically acceptable acid addition salt thereof, having excellent platelate aggregation inhibitory effect, calcium antagonism, hypotensive effect and phosphodiesterase inhibitory effect are useful as prophylactic or treating agents for thrombosis, circulation improving agents for coronary blood flow such as coronary vasodilators, hypotensive agents and phosphodiesterase inhibitors. Furthermore, the carbostyril derivatives are weak in heart rate increasing activity and also in cardiac muscle contraction increasing activity, and the carbostyril derivatives are useful agents for curing and treating heart diseases such as cardiac angina and myocardial infarction caused by hypercoagulability of the platelets. Processes are disclosed for preparation of the carbostyril derivatives.

The present invention relates to a novel carbostyril derivative and its 
salts, having excellent platelet aggregation inhibitory effect, calcium 
antagonism, hypotensive effect and phosphodiesterase inhibitory effect, 
processes for preparing the same and a pharmaceutical composition 
containing the same as the active ingredient. 
The carbostyril derivative of the present invention is novel and has not 
been known in any literature and is represented by the general formula (1) 
as follows: 
##STR1## 
[where R is a hydrogen atom or a group of the formula 
##STR2## 
(wherein R.sup.3, R.sup.4 and R.sup.5 are each a lower alkyl group; A is a 
lower alkylene group which may have a hydroxyl group or a lower 
alkanoyloxy group as the substituent; R.sup.6 is a nitro group, a lower 
alkyl group which may have halogen atoms as the substituent, a halogen 
atom, a lower alkoxy group, a lower alkylthio group, a lower 
alkoxycarbonyl group; R.sup.7 is a lower alkyl group or a cycloalkyl 
group; B is a lower alkylene group; n is 0 or 1; and m is 0 or an integer 
of 1, 2 or 3); R.sup.1 is a hydrogen atom, a hydroxyl group, a lower 
alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a 
2-tetrahydropyranyloxy group or a group of the formula, 
##STR3## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B m and n are the 
same as defined above); R.sup.2 is a hydrogen atom, a lower alkyl group or 
a group of the formula, 
##STR4## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are 
the same as defined above); provided that, among the symbols of R, R.sup.1 
and R.sup.2, the only one of them should be of a group of the formula, 
##STR5## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are 
the same as defined above); and the carbon-carbon bond between 3- and 
4-positions in the carbostyril skeleton is a single or double bond]. 
The carbostyril derivative represented by the general formula (1) of the 
present invention is excellent in platelet aggregation inhibitory effect, 
calcium antagonism, hypotensive effect; therefore the carbosytril 
derivative (1) is useful as prophylactic or treating agent for thrombosis, 
circulation improving agent for coronary blood flow such as coronary 
vasodilator, hypotensive agent and phosphodiesterase inhibitor. 
Specifically, the carbostyril derivative (1) of the present invention is 
very weak both in the heart rate increasing activity and in the cardiac 
muscle contraction increasing activity. Furthermore, the carbostyril 
derivative (1) of the present invention has an excellent absorption 
property to the living body. 
Generally, cardiac angina is a disease which causes myocardial ischemia due 
to the imbalance of supply and demand (consumption) of oxygen in the 
cardiac muscles, and myocardial infarction is a disease which causes 
myocardial ischematic necrosis due to the hematogenic dyscrasis to the 
cardiac muscles. Thus, in treating and curing cardiac angina and 
myocardial infarction, the factors for exacerbating heart failure should 
be eliminated as much as possible, so as to relieve the myocardiac 
dyscrasia. In this connection, attention should be paid necessarily for 
decreasing the oxygen demand in the cardiac muscles, as well as for 
increasing the oxygen supply to the cardiac muscles. 
Since, as explained above, the carbostyril derivative (1) of the present 
invention is very weak in the heart rate increasing activity, and in the 
cardiac muscle contraction increasing activity, both of which cause an 
increase of oxygen demand in the cardiac muscles, the carbostyril 
derivative (1) of the present invention is quite useful as prophylactic or 
treating agent for curing the heart diseases, for example cardiac angina 
and myocardial infarction, caused by hypercoagulability of the platelets, 
as well as being quite useful as a hypotensive agent. 
An object of the present invention is to provide a novel carbostyril 
derivative and its salt, having the above-mentioned excellent 
pharmacological activities. 
Another object of the present invention is to provide processes for 
preparing said carbostyril derivative. 
A further object of the present invention is to provide a pharmaceutical 
composition containing said carbostyril derivative as the active 
ingredient.

As to the lower alkyl group which may have halogen atoms as the 
substituents, an alkyl group having 1 to 6 carbon atoms which may have 1 
to 3 halogen atoms as the substituents, such as methyl, ethyl, propyl, 
isopropyl, butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 
2,2-difluoroethyl, 1,1-dichloroethyl, trichloromethyl, dichloromethyl, 
tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloroethyl, 
1,2-dichloroethyl, 3,3,3-trichloropropyl, 3-fluoropropyl, 4-chlorobutyl 
and 3-chloro-2-methylethyl groups can be exemplified. 
As to the lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms 
such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, 
pentyloxy and hexyloxy groups can be exemplified. 
As to the lower alkenyloxy group, an alkenyloxy group having 2 to 6 carbon 
atoms such as vinyloxy, alloyloxy, 2-butenyloxy, 3-butenyloxy, 
1-methylallyloxy, 2-pentenyloxy and 2-hexenyloxy groups can be 
exemplified. 
As to the lower alkynyloxy group, an alkynyloxy group having 2 to 6 carbon 
atoms such as ethynyloxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 
1-methyl-2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 
1-methyl-2-propynyloxy, 2-pentynyloxy, and 2-hexynyloxy groups can be 
exemplified. 
As to the lower alkylene group which may have a hydroxyl group or a lower 
alkanoyloxy group as the substituent, an alkylene group having 1 to 6 
carbon atoms which may have, as the substituent, a hydroxyl group or an 
alkanoyloxy group having 1 to 6 carbon atoms in the alkyl moiety, such as 
methylene, ethylene, methylmethylene, trimethylene, 2-methyltrimethylene, 
2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 
2-ethyltrimethylene, 1-methyltrimethylene, hydroxymethylene, 
1-hydroxyethylene, 1-hydroxymethylmethylene, 3-hydroxytrimethylene, 
2-hydroxytrimethylene, 1-hydroxytrimethylene, 
3-hydroxy-2-methyltrimethylene, 2,2-dimethyl-1-hydroxytrimethylene, 
4-hydroxytetramethylene, 3-hydroxytetramethylene, 3-hydroxypetamethylene, 
5-hydroxypentamethylene, 2-hydroxyhexamethylene, 
2-ethyl-1-hydroxytrimethylene, 3-hydroxy-1-methyltrimethylene, 
4-hydroxyhexamethylene, acetyloxymethylene, 2-acetyloxyethylene, 
1-propionyloxyethylene, 1-butyryloxymethylmethylene, 
3-pentanoyloxytrimethylene, 2-acetyloxytrimethylene, 
1-formyloxytrimethylene, 3-hexanoyloxy-2-methyltrimethylene, 
2,2-dimethyl-1-acetyloxytrimethylene, 4-butyryloxytetramethylene, 
3-pentanoyloxytetramethylene, 3-acetyloxypentamethylene, 
5-hexanoyloxypentamethylene, 2-acetyloxyhexamethylene, 
2-ethyl-1-propionyloxytrimethylene, 3-butyryloxy-1-methyltrimethylene and 
4-hexanoyloxyhexamethylene groups can be exemplified. 
As to the halogen atom, fluorine atom, chlorine atom, bromine atom and 
iodine atom can be exemplified. 
As to the lower alkylthio group, an alkylthio group having 1 to 6 carbon 
atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, 
tert-butylthio, pentylthio and hexylthio groups can be exemplified. 
As to the lower alkoxycarbonyl group, an alkoxycarbonyl group having 1 to 6 
carbon atoms in the alkyl moiety such as methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, 
pentyloxycarbonyl and hexyloxycarbonyl groups can be exemplified. 
As to the lower alkyl group, an alkyl group having 1 to 6 carbon atoms such 
as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl 
groups can be exemplified. 
As to the cycloalkyl group, a cycloalkyl group having 3 to 8 carbon atoms 
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 
cyclooctyl groups can be exemplified. 
As to the lower alkyklene group, the alkylene group having 1 to 6 carbon 
atoms such as methylene, ethylene, methylmethylene, trimethylene, 
2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, 
pentamethylene, hexamethylene, 2-ethyltrimethylene and 
1-methyltrimethylene groups can be exemplified. 
The carbostyril derivative represented by the general formula (1) of the 
present invention can be prepaed by various methods, and examples of 
preferable processes are shown as follows: 
##STR6## 
[wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, 
A, B, n, m and the carbon-carbon bond between 3- and 4-positions in the 
carbostyril skeleton are the same as defined above; R.sub.a is a hydrogen 
atom or a hydroxyl group; R.sub.a.sup.1 is a hydrogen atom, a hydroxyl 
group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy 
group or a 2-tetrahydropyranyloxy group; R.sub.a.sup.2 is a hydrogen atom, 
a hydroxyl group or a lower alkyl group; X is a halogen atom; provided 
that, among R, R.sup.1 and R.sup.2, only one of them should be a group of 
the formula, 
##STR7## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are 
the same as defined above)]. 
Thus a carbostyril derivative represented by the general formula (1) can be 
prepared by reacting a hydroxycarbostyril derivative represented by the 
general formula (2) with a compound represented by the general formula (3) 
under dehydrohalogenating reaction conditions. The dehydrohalogenating 
reaction is carried out in the presence of a basic compound as the 
dehydrohalogenating agent. As to the basic compound, any basic compound 
known in the art can be used, for example an inorganic basic compound such 
as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 
carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or 
silver carbonate; an alcoholate such as sodium methylate or sodium 
ethylate, an organic basic compound such as triethylamine, pyridine or 
N,N-dimethylaniline are examplified. 
The dehydrohalogenating reaction can be carried out in the presence of a 
solvent, and as to the solvent, any inert solvent which does not give any 
adverse effect to the reaction can be used, for example, alcohols such as 
methanol, ethanol, propanol, butanol and ethylene glycol; ethers such as 
dimethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; ketones 
such as acetone and methyl ethyl ketone; atomatic hydrocarbons such as 
benzene, toluene and xylene; esters such as methyl acetate and ethyl 
acetate; and aprotic polar solvents such as N,N-dimethylformamide, 
dimethyl sulfoxide and hexamethylphosphoryl triamide can be exemplified. 
The dehydrohalogenating reaction can be also carried out in the presence of 
a metal iodide for example sodium iodide or potassium iodide. 
The ratio of the amount of the compound (2) to the amount of the compound 
(3) is not specifically restricted and can be selected from a wide range, 
and generally an equimolar quantity to 5 times the molar quantities, 
preferably an equimolar quantity to 2 times the molar quantities of the 
latter is used to the former. 
The reaction temperature is also not specifically restricted, and generally 
the reaction can be carried out at a room temperature to 200.degree. C., 
preferably from 50.degree. to 160.degree. C. 
The reaction is generally carried out for 1 to 30 hours, preferably for 2 
to 10 hours. 
##STR8## 
[wherein R, R.sup.1, R.sup.2, R.sub.a, R.sub.a.sup.1, R.sup.2, R.sup.3, 
R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m, n, X and the carbon-carbon 
bond between 3- and 4-positions in the carbostyril skeleton are the same 
as defined above; R.sub.b is a hydrogen atom or a group of the formula, 
##STR9## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.b.sup.1 
is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower 
alkenyloxy group, a lower alkynyloxy group, a 2-tetrahydropyranyloxy group 
or a group of the formula, 
##STR10## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.b.sup.2 
is a hydrogen atom, a lower alkyl group or a group of the formula, 
##STR11## 
(wherein R.sup.7, A, B and n are the same as defined above); provided 
that, among R, R.sup.1 and R.sup.2, only one of them should be a group of 
the formula, 
##STR12## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are 
the same as defined above); similarly, among R.sub.b, R.sub.b.sup.1 and 
R.sub.b.sup.2, only one of them should be a group of the formula, 
##STR13## 
(wherein R.sup.7, A, B and n are the same as defined above)]. 
In the above-mentioned Reaction scheme--2, the reaction of a 
hydroxycarbostyril derivatives (2) with a compound (4) can be carried out 
under a reaction condition similar to that of a compound (2) with a 
compound (3) in the Reaction scheme--1. 
The reaction of a compound (5) with a compound (6) is carried out under 
conventional esterification reaction conditions. This reaction is carried 
out in the presence of a catalyst, and as to the catalyst, any catalyst 
widely used in a conventional esterification may be used. Typical examples 
of the catalysts are inorganic acids such hydrochloric acid gas, 
concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron 
trifluoride and perchloric acid; organic acids such as trifluoroacetic 
acid, trifluoromethansulfonic acid, naphthalenesulfonic acid, 
p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid; 
trifluoromethanesulfonic acid anhydride, thionyl chloride, and acetone 
dimethylacetal. Furthermore, an acidic ion-exchange resin can also be used 
as the catalyst. 
The amount of the catalyst to be used is not specifically restricted, 
generally an amount of the catalyst used in a conventional esterification 
reaction is applied. 
The reaction can be carried out either in the absence of or in the presence 
of a solvent. As to the solvent, any solvent commonly used in an 
esterification reaction can be used effectively, specifically, organic 
hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons 
such as dichloromethane, dichloroethane, chloroform and carbon 
tetrachloride; ethers such as diethyl ether, tetrahydrofuran, dioxane and 
ethylene glycol monomethyl ether are exemplified. 
In the above-mentioned reaction, the ratio of the amount of a compound (5) 
to the amount of a compound (6) can be selected from a wide range, and in 
order to obtain the desired product of the present invention in good 
yield, generally a large excess amount of the latter is used to the former 
in the absence of a solvent, alternatively, in the presence of a solvent, 
the latter is used in an equimolar quantity to 5 times the molar 
quantities, preferably an equimolar quantity to 2 times the molar quantity 
of the former. Additionally, the yield of the desired product can be 
increased by removing the water formed in the reaction system by using a 
dehydrating agent such as anhydrous calcium chloride, anhydrous cupric 
sulfate, anhydrous calcium sulfate or phosphorus pentoxide. 
The reaction temperature is not specifically restricted, and can be 
selected from a wide range; generally, the reaction can be carried out in 
the range of from -20.degree. to 200.degree. C., preferably from about 
0.degree. C. to 150.degree. C. 
The reaction time is dependent on the type of the raw material, and the 
reaction conditions employed, and generally the reaction is completed in 
about 10 minutes to 20 hours. 
##STR14## 
[wherein R.sub.c is a hydrogen atom or a group of the formula, 
##STR15## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.c.sup.1 
is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower 
alkenyloxy group, a lower alkynyloxy group, a 2-tetrahydropyranyloxy group 
or a group of the formula, 
##STR16## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.c.sup.2 
is a hydrogen atom, a lower alkyl group or a group of the formula, 
##STR17## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.d is a 
hydrogen atom or a group of the formula, 
##STR18## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.d.sup.1 
is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower 
alkenyloxy group, a lower alkynyloxy group, a 2-tetrahydropyranyloxy group 
or a group or a group of the formula, 
##STR19## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.d.sup.2 
is a hydrogen atom, a lower alkyl group or a group of the formula, 
##STR20## 
(wherein R.sup.7, A, B and n are the same as defined above); R.sub.e is a 
hydrogen atom or a group of the formula, 
##STR21## 
(wherein R.sup.6, R.sup.7, A, B, m and n are the same as defined above); 
R.sub.e.sup.1 is a hydrogen atom, a hydroxyl group, a lower alkoxy group, 
a lower alkenyloxy group, a lower alkynyloxy group, a 
2-tetrahydropyrayloxy group or a group of the formula, 
##STR22## 
(wherein R.sup.6, R.sup.7, A, B, m and n are the same as defined above); 
R.sub.e.sup.2 is a hydrogen atom, a lower alkyl group or a group of the 
formula, 
##STR23## 
(wherein R.sup.6, R.sup.7, A, B, m and n are the same as defined above; 
R.sub.f is a hydrogen atom or a group of the formula, 
##STR24## 
(wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are the same as 
defined above); R.sub.f.sup.1 is a hydrogen atom, a hydroxyl group, a 
lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a 
2-tetrahydropyranyloxy group or a group of the formula, 
##STR25## 
(wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are the same as 
defined above); R.sub.f.sup.2 is a hydrogen atom, a lower alkyl group or a 
group of the formula, 
##STR26## 
(wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are the same as 
defined above); provided that, among R.sub.c, R.sub.c.sup.1 and 
R.sub.c.sup.2, only one of them should be a group of the formula, 
##STR27## 
(wherein R.sup.7, A, B and n are the same as defined above); among 
R.sub.d, R.sub.d.sup.1 and R.sub.d.sup.2, only one of them should be a 
group of the formula, 
##STR28## 
(wherein R.sup.7, A, B, and n are the same as defined above); among 
R.sub.e, R.sub.e.sup.1 and R.sub.e.sup.2, only one of them should be a 
group of the formula, 
##STR29## 
(wherein R.sup.6, R.sup.7, A, B, m and n are the same as defined above); 
and among R.sub.f, R.sub.f.sup.1 and R.sub.f.sup.2, only one of them 
should be a group of the formula, 
##STR30## 
(wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m and n are the same as 
defined above)]. 
In the Reaction scheme--3 as mentioned above, the reaction of a compound 
(5) with a compound (7) is carried out in a suitable solvent in the 
presence of a catalyst. As to the catalyst, the examples include basic 
compounds such as organic bases, for example triethylamine, pyridine and 
N,N-dimethylaniline; inorganic bases, for example sodium acetate and 
potassium carbonate; and acidic compounds such as sulfonic acids, for 
example p-toluenesulfonic acid, and Lewis acids, for example boron 
trifluoride. As to the solvent, the examples include aromatic hydrocarbons 
such as benzene, toluene and xylene; esters such as methyl acetate and 
ethyl acetate; halogenated hydrocarbons such as methylene chloride, 
chloroform and 1,2-dichloroethane; ethers such as diethyl ether, 
tetrahydrofuran, dioxane, monoglyme and diglyme; ketones such as acetone 
and methyl ethyl ketone; and aprotic polar solvents such as 
N,N-dimethylformamide, eimethyl sulfoxide, hexamethylphosphoryl triamide 
and N-methylpyrrolidone. 
The ratio of the amount of compound (5) to the amount of compound (7) is 
generally at least an equimolar quantity, preferably 1 to 2 times the 
molar quantities of the latter to the former. 
The amount of the catalyst is not specifically restricted, and generally 
1/100 to 10 times the molar quantities, preferably 1/10 to 5 times the 
molar quantities of the catalyst to the compound (5) is used. 
The reaction is generally carried out at -20.degree. to 200.degree. C., 
preferably at -20.degree. to 100.degree. C., and is completed generally in 
10 minutes to 20 hours. 
The reaction of compound (8) thus prepared with compound (9) is also 
carried out in a suitable solvent in the absence or presence of a 
catalyst. The examples of solvents include alcohols such as methanol, 
ethanol, propanol, isopropanol, butanol and ethylene glycol; ethers such 
as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; 
aromatic hydrocarbons such as benzene, toluene and xylene; halogenated 
hydrocarbons such as methylene chloride, chloroform and 
1,2-dichloroethane; aprotic polar solvents such as N,N-dimethylformamide, 
dimethyl sulfoxide, and hexamethylphosphoryl triamide; carboxylic acids 
such as acetic acid and propionic acid; and pyridine. The examples of the 
catalysts include organic bases such as pyridine, piperidine, 
triethylamine, diethylamine and 1,5-diazabicyclo[5,4,0]undecene-5 (DBU); 
metal alcoholates such as sodium ethylate and sodium methylate; inorganic 
bases such as sodium hydroxide, potassium hydroxide, potassium carbonate 
and potassium acetate; mineral acids such as hydrochloric acid and 
sulfuric acid; carboxylic acids such as acetic acid and propionic acid; 
and Lewis acids such as boron trifluoride. 
The ratio of the amount of compound (8) to the amount of compound (9) is 
generally at least an equimolar quantity, preferably an equimolar quantity 
to 2 times the molar quantities of the latter to the former. The amount of 
the catalyst is similar to that used in the reaction of compound (5) with 
compound (7). 
The reaction is generally carried out at -20.degree. to 200.degree. C., 
preferably at -20.degree. to about 150.degree. C., and is completed 
generally in 10 minutes to 50 hours. 
The reaction of compound (10) with compound (11) can advantageously be 
carried out in the presence of a solvent. As to the solvent, any inert 
solvent which does not give any adverse effect can be used, and the 
examples of the solvents include ketones such as acetone; halogenated 
hydrocarbons such as chloroform; alcohol such as methanol, ethanol, 
propanol, isopropanol and ethylene glycol; ethers such as diethyl ether, 
tetrahyrofuran, dioxane, monoglyme and diglyme; aromatic hydrocarbons such 
as benzene, toluene and xylene; esters such as methyl acetate and ethyl 
acetate; carboxylic acids such as acetic acid and propionic acid; organic 
bases such as pyridine; and aprotic polar solvents such as 
N,N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoryl 
triamide. 
The ratio of the amount of compound (10) to the amount of compound (11) is 
generally an equimolar to 10 times, preferably equimolar quantities to 2 
times the molar quantity. 
The reaction is generally carried out at -20.degree. to 200.degree. C., 
preferably 50.degree. to 150.degree. C., and generally the reaction is 
completed in 10 minutes to 20 hours, to obtain a compound represented by 
the general formula (1a). 
The reaction of a compound (8) with a compound (9) can be carried out 
without separating the intermediate product (10); thus compounds (8), (9) 
and (11) can be reacted simultaneously in a one pot reaction to obtain the 
desired product represented by the general formula (1b). 
##STR31## 
(wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B, m, n, 
X and the carbon-carbon bond between 3- and 4-positions in the carbostyril 
skeleton are the same as defined above; R.sup.8 is a lower alkyl group, a 
lower alkenyl group, a lower alkynyl group or a 2-tetrahydropyranyl group; 
and OTHP is a 2-tetrahydrophyranyloxy group). 
According to the above-mentioned Reaction scheme--4, among compounds as 
represented by the general formula (1), compounds wherein R is a group of 
the formula, 
##STR32## 
and R.sup.1 is a 2-tetrahydropyranyloxy group, i.e., a compound 
represented by the general formula (1b), can be hydrolyzed to obtain the 
corresponding compound (i.e., a compound represented by the general 
formula (1c) wherein R.sup.1 is a hydroxyl group; further, a compound (1c) 
can be reacted with a compound (12) to obtain the corresponding compound, 
i.e., a compound represented by the general formula (1d), wherein R.sup.1 
is a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy 
group or a 2-tetrahydropyranyloxy group. 
The hydrolysis of a compound (1b) can be carried out in the absence or 
presence of a suitable solvent with an acid. As to the solvent, water, a 
lower alcohol such as methanol, ethanol or isopropanol; an ether such as 
dioxane, or tetrahydrofuran; a ketone such as acetone; acetic acid; or a 
mixed solvent of these solvents can be exemplified. As to the acid, a 
mineral acid such as hydrochloric acid or sulfuric acid; a 
p-toluenesulfonic acid such as pyridine p-toluenesulfonate; or a 
carboxylic acid such as acetic acid or propionic acid can be exemplified. 
The ratio of the amount of the acid is at least an equimolar quantity; 
generally a large excess quantity of acid can be used relative to the 
amount of a compound (1b). The reaction temperature is generally 
-20.degree. to 200.degree. C., preferably -20.degree. to 50.degree. C., 
and the reaction is completed generally in 0.5 to 5 hours. 
The reaction of a compound (1c) thus obtained with a compound (12) can be 
carried out under the condition of a conventional alkylating reaction, for 
example the reaction is carried out in the presence of a basic compound. 
As to the basic compound to be used in this reaction, an alkali metal such 
as sodium metal or potassium metal; a hydroxide, a carbonate, a 
hydrogencarbonate or alcoholate of said alkali metal; an aromatic amine 
such as pyridine or piperidine; and an organic basic compound such as 
triethylamine, or 1,8-diazabicycloundecene-7 can be exemplified. The 
reaction can advantageously proceed in a suitable solvent. As to the 
solvent used, water; a lower alcohol such as methanol, ethanol, 
isopropanol or n-butanol; a ketone such as acetone or methyl ethyl ketone; 
a halogenated hydrocarbon such chloroform or dichloroethane; an aromatic 
hydrocarbon such as benzene, toluene or xylene; or a protic polar solvent 
such as N,N-dimethylformamide or dimethyl sulfoxide can be exemplified. 
The ratio of the amount of a compound (1c) to the amount of a compound (12) 
is at least one and preferably ranges from one to two. The reaction 
temperature is generally -20.degree. to 200.degree. C., preferably about 
0.degree. to 100.degree. C. and the reaction is completed generally in 10 
minutes to 20 hours. 
Among compounds as represented by the general formula (1), those wherein 
R.sup.2 is a group of the formula 
##STR33## 
and wherein R.sup.1 is a hydroxyl group, a lower alkoxy group, a lower 
alkenyloxy group, a lower alkynyloxy group or a 2-tetrahydropyranyloxy 
group can also be converted from the corresponding compound wherein 
R.sup.1 is a 2-tetrahydropyranyloxy group by a method similar to that 
described in the above-mentioned Reaction scheme--4. 
In the above-mentioned Reaction scheme--1, compound (3) wherein n is 0 as 
used for the starting material can be easily prepared by a method as shown 
in the following Reaction scheme--5. 
##STR34## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, A, m and X are the same as 
defined above). 
The reaction of a compound (9) with a compound (13) can be carried out 
under reaction conditions similar to those employed in the reaction of a 
compound (8) with a compound (9) in the above-mentioned Reaction 
scheme--3. 
The reaction of a compound (14) with a compound (11) can be carried out 
under reaction conditions similar to those employed in the reaction of a 
compound (10) with a compound (11) in the above-mentioned Reaction 
scheme--3. 
The reaction of compounds (9), (13) and (11) can be carried out by without 
separating the intermediate product (14); thus compounds (9), (13) and 
(11) can be reacted simultaneously in a one pot reaction to obtain the 
desired product represented by the general formula (3a). 
Among carbostyril derivatives represented by the general formula (1), the 
compounds having a lower alkylene group which may have a hydroxyl group as 
the substituent can be prepared by a method as shown in the following 
Reaction scheme--6. 
##STR35## 
[wherein R.sub.a, R.sub.a.sup.1, R.sub.a.sup.2, R.sup.3, R.sup.4, R.sup.5, 
R.sup.6, m, X and the carbon-carbon bond between 3- and 4-positions in the 
carbostyril skeleton are the same as defined above; R.sub.g is a hydrogen 
atom or a group of the formula, 
##STR36## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and m are the same as defined 
above); R.sub.g.sup.1 is a hydrogen atom, a hydroxyl group, a lower alkoxy 
group, a lower alkenyloxy group, a lower alkynyloxy group, a 
2-tetrahydropyranyloxy group or a group of the formula, 
##STR37## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and m are the same as defined 
above); R.sub.g.sup.2 is a hydrogen atom, a lower alkyl group or a group 
of the formula, 
##STR38## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and m are the same as defined 
above); R.sub.h is hydrogen atom or a group of the formula, 
##STR39## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and m are the same as defined 
above; and R.sup.9 is a lower alkanoyl group); R.sub.h.sup.1 is a hydrogen 
atom, a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, a 
lower alkynyloxy group, a 2-tetrahydrophranyloxy group or a group of the 
formula, 
##STR40## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9 and m are the same as 
defined above); R.sub.h.sup.2 is a hydrogen atom, a lower alkyl group or a 
group of the formula, 
##STR41## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9 and m are the same as 
defined above); provided that, among R.sub.g, R.sub.g.sup.1, and 
R.sub.g.sup.2, only one of them should be a group of the formula, 
##STR42## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and m are the same as defined 
above); further, among R.sub.h.sup.1 and R.sub.h.sup.2, only one of them 
should be a group of the formula, 
##STR43## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9 and m are the same as 
defined above)]. 
The reaction of a compound (6) with an epihalogenohydrin (15) can be 
carried out in the absence or presence of a suitable solvent, and in the 
presence of a basic compound. 
As to the basic compound used in this reaction, inorganic basic compounds 
such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium 
carbonate, sodium methylate, sodium ethylate, sodium hydride, sodium 
metal, potassium metal and sodium amide; and organic basic compounds such 
as piperidine, pyridine and triethylamine can be examplified. 
As to the solvent used in this reaction, lower alcohols such as methanol, 
ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; 
ethers such as diethyl ether, dioxane, diethylene glycol dimethyl ether; 
aromatic hydrocarbons such as benzene, toluene and xylene; water, 
dimethylformamide, dimethyl sulfoxide and hexamethylphosphoryl triamide; 
and mixed solvents thereof can be exemplified. 
The ratio of the amount of the compound (15) to the amount of the compound 
(6), in this reaction, is usually an equimolar quantity to a large excess 
amount, preferably 5 to 10 times the molar quantities of the former to the 
latter. 
The reaction is generally carried out at a temperature ranging from 
0.degree. C. to 150.degree. C., preferably at room temperature to 
100.degree. C., and is completed in 10 minutes to 30 hours. 
The reaction of the compound (16) with the compound (2) can be carried out 
in the absence or presence of an inert solvent at room temperature to 
200.degree. C., preferably at 60.degree. C. to 120.degree. C., and is 
completed in a several hours to 24 hours. 
As to the solvent used in the reaction, any solvent which does not give any 
adverse effect to the reaction can be used, for example esters, aromatic 
hydrocarbons, lower alcohols, and aprotic polar solvents such as 
dimethylformamide, dimethyl sulfoxide and hexamethylphosphoryl triamide 
used in the reaction of the compound (6) with the compound (11) can also 
be used. 
As to the basic compound used in this reaction, the examples include 
inorganic compounds such as potassium carbonate, sodium carbonate, sodium 
hydroxide, sodium hydrogencarbonate, sodium amide, and sodium hydride; and 
organic basic compounds such as triethylamine, tripropylamine, pyridine 
and quinoline. 
The ratio of the amount of the compound (2) to the amount of the compound 
(16) is generally an equimolar quantity to a large excess quantity, 
preferably an equimolar quantity to 5 times the molar quantity and, the 
most preferably, an equimolar quantity to 1.2 times the molar quantity of 
the former to the latter. 
The acylation reaction of the compound (13) can be carried out in the 
presence of an acylating agent such as a lower alkonoic acid, for example 
acetic acid or propionic acid; a lower alkanoic acid anhydride, for 
example acetic anhydride, or a lower alkanoic acid halide, for example 
acetyl chloride or propionyl bromide. In case of using an acid anhydride 
or an acid halide as the acylating agent, the acylating reaction is 
carried out in the presence of a basic compound. As to the basic compound 
used in this acylating reaction, the examples include alkali metals such 
as sodium metal and potassium metal; hydroxides, carbonates and 
hydrogencarbonates of these alkali metals; and aromatic amine compounds 
such as pyridine and piperidine. The acylation reaction can either proceed 
in the absence or presence of a solvent, and generally the reaction is 
carried out in the presence of a suitable solvent. As to the solvent, a 
ketone such as acetone or methyl ethyl ketone; an ether such as dioxane; 
an aromatic hydrocarbon such as benzene, toluene or xylene; water or 
pyridine can be exemplified. 
The acylating agent is used in at least an equimolar quantity to the 
starting material, and generally an equimolar quantity to a large excess 
quantity of the acylating agent is used relative to the starting material. 
The reaction proceeds at 0.degree. to 150.degree. C., and generally may be 
carried out at 0.degree. to 80.degree. C. The reaction is completed in 
about 0.5 to 20 hours. 
In case of using a lower alkanoic acid as the acylating agent, the 
acylating reaction can advantageously proceed by adding a mineral acid 
such as sulfuric acid or hydrohyloric acid; or a sulfonic acid such as 
p-toluenesulfonic acid, benzenesulfonic acid or ethanesulfonic acid as the 
dehydrating agent in the reaction system, and by keeping the reaction 
temperature preferably at 50.degree. to 120.degree. C. 
The following is a description of Reaction scheme 
##STR44## 
[wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, B, m and the 
carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton 
are the same as defined above; R.sub.i is a hydrogen atom or a group of 
the formula, 
EQU --O--A--COOH 
(wherein A is the same as defined above); R.sub.i.sup.1 is a hydrogen atom, 
a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, a lower 
alkynyloxy group, a 2-tetrahydropyranyloxy group or a group of the 
formula, 
EQU --O--A--COOH 
(wherein A is the same as defined above); R.sub.i.sup.2 is a hydrogen atom, 
a lower alkyl group or a group of the formula, --O--A--COOH (wherein A is 
the same as defined above); R.sub.j is a hydrogen atom or a group of the 
formula, 
##STR45## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B and m are the 
same as defined above); R.sub.j.sup.1 is a hydrogen atom, a hydroxyl 
group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy 
group, a 2-tetrahydropyranyloxy group or a group of the formula, 
##STR46## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B and m are the 
same as defined above); R.sub.j.sup.2 is a hydrogen atom, a lower alkyl 
group or a group of the formula, 
##STR47## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B and m are the 
same as defined above); provided that, among R.sub.i, R.sub.i.sup.1 and 
R.sub.i.sup.2, only one of them should be a group of the formula, 
EQU --O--A--COOH 
(wherein A is the same as defined above); further, among R.sub.j, 
R.sub.j.sup.1 and R.sub.j.sup.2, only one of them should be a group of the 
formula, 
##STR48## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, A, B and m are the 
same as defined above)]. 
The reaction as shown in the above-mentioned Reaction scheme--7 is a 
process for reacting a carboxyalkoxycarbostyril derivative (17) with an 
amine (18) by a conventional amide-bond formation reaction. In the present 
invention, any carboxyalkoxycarbostyril compound in which the carboxy 
group is activated may be used in place of a compound represented by the 
general formula (17). 
In carrying out the amide-bond formation reaction, conventional amide-bond 
formation reaction conditions can easily be applied. Examples include (a) 
a mixed acid anhydride method: in which a carboxylic acid (17) is reacted 
with an alkylhalocarboxylic acid to prepare the corresponding mixed acid 
anhydride, then an amine (18) is reacted therewith; (b) activated ester 
method: in which a carboxylic acid (17) is converted into the 
corresponding activated ester, for example p-nitrophenyl ester, 
N-hydroxysuccimide ester or 1-hydroxybenzotriazole ester, then an amine 
(18) is reacted therewith; (c) dehydrocondensation method: in which a 
carboxylic acid (17) is reacted with an amine (18) in the presence of a 
dehydrating agent by a method of dehydrocondensation; and (d) other 
methods: for example, a method in which a carboxylic acid (17) is treated 
with a dehydrating agent such as acetic anhydride to obtain a carboxylic 
acid anhydride, then an amine (18) is reacted with said carboxylic acid 
anhydride; a method in which an ester prepared by reacting a carboxylic 
acid (17) with a lower alcohol is reacted with an amine (18) at a high 
temperature under a high pressure; and a method in which a carboxylic acid 
halide, i.e., an acid halogenide of a carboxylic acid (17) is reacted with 
an amine (18). Among these methods, (a) a mixed acid anhydride method and 
(c) dehycro-condensation method are preferable. 
As to the alkylhalocarboxylic acid used in the mixed acid anhydride method, 
methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl 
bromoformate or isobutyl chloroformate can be exemplified. The mixed acid 
anhydride can generally be prepared by a Schotten-Baumann reaction, and 
the mixed acid anhydride is reacted with an amine (18) without separated 
from the reaction system to prepare the compound of the present invention. 
The Schotten-Baumann reaction is carried out in the presence of a basic 
compound. As to the basic compound used in this reaction, any compound 
used customarily in a Schotten-Baumann reaction may be used, for example, 
an organic basic compound such as triethylamine, trimethylamine, pyridine, 
dimethylaniline, N-methylmorpholine, 1,5-diazabycyclo[4,3,0]nonene-5 
(DBN), 1,5-diazabicyclo[5,4,0]undecene-5 DBU) or 
1,4-diazabicyclo[2,2,2]octane (DABCO); or an inorganic basic compound such 
as potassium carbonate, sodium carbonate, potassium hydrogencarbonate or 
sodium hydrogencarbonate can be exemplified. 
This reaction is carried out at -20.degree. to 100.degree. C., preferably 
at 0.degree. to 50.degree. C., and the reaction time is 5 minutes to 10 
hours, preferably 5 minutes to 2 hours. Next, the reaction of the mixed 
acid anhydride thus obtained with an amine (18) is carried out at 
-20.degree. to 150.degree. C., preferably at 10.degree. to 50.degree. C., 
and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 
hours. 
The mixed acid anhydride method is generally carried out in a suitable 
solvent. As to the solvent used in this reaction, any solvent customarily 
used in a mixed acid anhydride method can also be used, for example, a 
halogenated hydrocarbon such methylene chloride, chloroform or 
dichloroethane; an aromatic hydrocarbon such as benzene, toluene or 
xylene; an ether such as diethyl ether, tetrahydrofuran or 
dimethoxyethane; an ester such as methyl acetate or ethyl acetate; or an 
aprotic polar solvent such as N,N-dimethylformamide, dimethyl sulfoxide or 
hexamethylphosphoryl triamide can be exemplified. 
The ratio of the amounts of a carboxylic acid (17), an alkylhalocarboxylic 
acid and an amine (18) is generally at least an equimolar quantity each of 
an alkylhalocarboxylic acid and an amine (18) to the amount of a 
carboxylic acid (17); preferably 1 to 1.5 times the molar quantities each 
of an alkylhalocarboxylic acid and an amine (18) are used relative to the 
amount of a carboxylic acid (17). 
As to the dehydrating agent used in the dehydrocondensation method, there 
is not any specific restriction thereto and any dehydrating agent can be 
used; specifically, N,N-dicyclohexylcarbodiimide (DCC), DCC-N-hydroxy 
succinimide (HOSU), DCC-N-hydroxybenzotriazole (HOBT), 
DCC-N-hydroxy-5-norbornene-2,3-dicarboxyimide (HONB), diphenylphosphoryl 
amide (DPPA) or diethylphosphoryl cyanidate (DEPC) can be exemplified. 
Similar to the reaction of the mixed acid anhydride with an amine (18), 
this reaction can also be carried out in a solvent in the presence of the 
above-mentioned dehydrating agent at -20.degree. to 200.degree. C., 
preferably at 0.degree. to 150.degree. C., for about generally 5 minutes 
to 20 hours. The ratio of the amount of carboxylic acid (17) to the amount 
of an amine (18) is generally at least an equimolar quantity; preferably 1 
to 1.5 times the molar quantity of the amine (18) is used relative to the 
amount of the carboxylic acid (17). The ratio of the amount of the 
dehydrating agent is not specifically restricted, and generally, at least 
an equimolar quantity, preferably an equimolar quantity to 1.5 times the 
molar quantity of the dehydrating agent may be used relative to the amount 
of the carboxylic acid. 
Amines (18) used as the starting materials in the above-mentioned Reaction 
scheme--7 contain novel compounds which can be prepared by a method as 
shown in the following Reaction scheme--8. 
##STR49## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, B, X and m are the 
same as defined above). 
The reaction of a compound (3a) with a compound (19) can be carried out 
under conditions similar to those employed in the reaction of a compound 
(2) with a compound (3) in the above-mentioned Reaction scheme--1. 
In the above-mentioned Reaction scheme--1, compound (3) as used for the 
starting material, wherein n=1 can be prepared by a method as shown in the 
following Reaction scheme--9. 
##STR50## 
(wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, A, B and m are 
the same as defined above). 
The reaction of a compound (18) with a compound (20) can be carried out 
under conditions similar to those employed in the amide bond formation 
reaction in the Reaction scheme--7. 
Among carbostyril derivatives represented by the general formula (1), the 
compounds having a lower alkylene group A; which may have a lower 
alkanoyloxy group can be prepared by acylating a carbostyril derivative 
represented by the general formula (1) wherein A is a lower alkylene group 
which has a hydroxyl group as the substituent. This acylating reaction can 
be carried out under conditions employed in the acylating reaction of a 
compound (1f) in the Reaction scheme--6. 
The compounds represented by the general formula (1) having the basic group 
can easily be converted into the corresponding salts by being treated with 
pharmaceutically acceptable acids. Examples of such acids include 
inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid and 
hydrobromic acid. 
Compounds of the present invention thus prepared can easily be isolated and 
purified by conventional methods of separation such as precipitation, 
extraction, recrystallization, column chromatography and preparative 
thin-layer chromatography. 
Compounds of the present invention represented by the general formula also 
include their optical isomers. 
Compounds of the present invention represented by the general formula can 
be administered, either singly or together with conventional 
pharmaceutically acceptable carriers, to animals as well as to humans. No 
particular restriction is made on the administration unit forms; thus a 
compound of the present invention represented by the general formula (1) 
can be used in any desired administration unit form. Suitable 
administration unit forms include oral administration forms such as 
tablets, granules and solutions; and parenteral administration unit forms 
such as injections. 
The dosage of compounds represented by the general formula (1) as the 
active ingredient to be administered is not subjected to any particular 
restriction and can be selected from a wide range. For the purpose of 
attaining the desired pharmacological effects, it is recommended to select 
the dosage from the range of 0.06 to 10 mg per kg of body weight per day. 
It is also suggested to provide 1 to 500 mg of the compound of the present 
invention as the active ingredient in each of the desired administration 
unit form. 
Compounds of the present invention can be shaped into the desired peroral 
preparation from such as tablets, capsules and solutions by use of 
conventional methods. For the purpose of shaping the composition into the 
form of tablets, the compound of the present invention is mixed with a 
pharmaceutically acceptable excipient such as gelatin, starch, lactose, 
magnesium stearate, talcum powder or gum arabic. Capsules can be prepared 
by mixing a compound of the present invention with inert pharmaceutically 
acceptable fillers or diluents and filling the mixture obtained into rigid 
gelatin capsules or soft capsules. Syrups or elixiers may be prepared by 
mixing a compound of the present invention with a sweetening agent such as 
sucrose; antisceptics such as methyl- or propyl-parabens; colorants, 
seasoning agents and/or other suitable additives. Parenteral preparations 
can also be prepared by conventional methods; thus a compound of the 
present invention is dissolved in a sterilized liquid vehicle. As to 
preferable vehicles, water or saline water can be used. Liquid 
preparations having desired transparency, stability and parenteral use 
adaptability can be prepared by dissolving approximately 1 to 500 mg of 
the active ingredient in a solution of polyethylene glycol having a 
molecular weight of 200 to 5,000, which is soluble in both water and 
organic solvents. Desirably, such liquid preparations may contain a 
lubricant such as sodium carboxymethyl cellulose, methyl cellulose, 
polyvinyl pyrrolidone or polyvinyl alcohol. 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 and buffer solutions. For further 
additional ensurance of stability, the parenteral compositions may be 
frozen after filling and dehydrating by known lyophilization techniques. 
The lyophilized powder of the parenteral composition can be reconstituted 
into a normal use form just before the use. 
Preparation of tablets-1 
1,000 Tablets for peroral use, each containing 5 mg of 
5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethoxy}carbostyril, are prepared from the following ingredients. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
5-{2-[2,6-Dimethyl-5-methoxy- 
5 
carbonyl-4-(3-nitrophenyl)-1,4- 
dihydropyridin-3-carboxy]ethoxy}- 
carbostyril 
Lactose (Japanese Pharmacopoeia) 
50 
Corn starch 25 
(Japanese Pharmacopoeia) 
Crystalline cellulose 25 
(Japanese Pharmocopoeia) 
Methylcellulose 1.5 
(Japanese Pharmocopoeia) 
Magnesium stearate 1 
(Japanese Pharmocopoeia) 
______________________________________ 
The 
5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl-1,4-dihydropyridin-3 
-carboxy]ethoxy}carbostyril, lactose, corn starch and crystalline cellulose 
are mixed well, and the mixture is added to a 5%-aqueous solution of 
methyl cellulose and then granulated. The granules obtained are passed 
through a 200 mesh sieve and then dried carefully. The dried granules are 
mixed with magnesium stearate through a 200 mesh sieve then pressed into 
the form of tablets. 
Preparation of tablets-2 
1,000 Tablets for peroral use, each containing 5 mg of 
6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-hydroxypropoxy}-3,4-dihydrocarbostyril are prepared from the 
following ingredients, by a method similar to that described in the 
above-mentioned Preparation of tablets-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{3-[2,6-Dimethyl-5-methoxycarbonyl- 
5 
4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-hydroxypropoxy}-3,4- 
dihydrocarbostyril 
Lactose (Japanese Pharmacopoeia) 
50 
Corn starch (Japanese Pharmacopoeia) 
25 
Crystalline cellulose 25 
(Japanese Pharmacopoeia) 
Methylcellulose 1.5 
(Japanese Pharmocopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of tablets-3 
1,000 Tablets for peroral use, each containing 5 mg of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide are prepared 
from the following ingredients, by a method similar to that described in 
the above-mentioned Preparation of tablets-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
N--{2-[1,4-Dihydro-2,6-dimethyl- 
5 
5-methoxycarbonyl-4-(3-nitrophenyl)- 
pyridin-3-carboxy]ethyl}-N--cyclohexyl- 
4-(6-carbostyriloxy)butyramide 
Lactose (Japanese Pharmacopoeia) 
50 
Corn starch (Japanese Pharmacopoeia) 
25 
Crystalline cellulose 25 
(Japanese Pharmacopoeia) 
Methyl cellulose 1.5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of capsules-1 
1,000 Capsules of two-piece rigid gelatin capsules for peroral use, each 
containing 10 mg of 
6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethoxy}carbostyril, are filled using the following ingredients. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{2-[2,6-Dimethyl-5-methoxycarbonyl- 
10 
4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethoxy}carbostyril 
Lactose (Japanese Pharmocopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder (Japanese Pharmacopoeia) 
5 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
The above components are finely ground, then stirred and mixed sufficiently 
to a uniform mixture and then filled into gelatin capsules of a size 
convenient for peroral administration. 
Preparation of capsules-2 
1,000 Capsules of two-piece rigid geleatin capsules for peroral use, each 
containing 10 mg of 
5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-propoxy-3,4-dihydrocarbostyril, are filled using the 
following ingredients. 
______________________________________ 
Amount (g) 
______________________________________ 
5-{3-[2,6-Dimethyl-5-methoxycarbonyl- 
10 
4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-propoxy-3,4- 
dihydrocarbostyril 
Lactose (Japanese Pharmacopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder 5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
The above components are finely ground, then stirred and mixed sufficiently 
to a uniform mixture and then filled into gelatin capsules of a size 
convenient for peroral administration. 
Preparation of capsules-3 
1,000 Capsules of two-piece rigid gelatin capsules for peroral use, each 
containing 10 mg of 
6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]2-acetoxypropoxy}-3,4-dihydrocarbostyril, are filled using the 
following ingredients, by a method similar to that described in 
Preparation of capsules-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{3-[2,6-Dimethyl-5-methoxycarbonyl- 
10 
4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-acetoxypropoxy}-3,4- 
dihydrocarbostyril 
Lactose (Japanese Pharmacopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder 5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of capsules-4 
1,000 Capsules of two-piece rigid gelatin capsules for peroral use, each 
containing 10 mg of 
6-{4-[2,6-dimethyl-5-methoxycarbonyl-4-(2-methylthiophenyl)-1,4-dihydropyr 
idin-3-carboxy]butoxy}-3,4-dihydrocarbostyril, are filled using the 
following ingredients, by a method similar to that described in 
Preparation of capsules-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{4-[2,6-Dimethyl-5-methoxycarbonyl- 
10 
4-(2-methylthiophenyl)-1,4-dihydro- 
pyridin-3-carboxy]butoxy}-3,4- 
dihydrocarbostyril 
Lactose (Japanese Pharmacopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder 5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of capsules-5 
1,000 Capsules of two-piece rigid geletin capsules for peroral use, each 
containing 10 mg of 
N-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide, are filled 
using the following ingredients, by a method similar to that described in 
Preparation of capsules-1. 
______________________________________ 
Amount (g) 
______________________________________ 
N--{2-[1,4-Dihydro-2,6-dimethyl- 
10 
5-methoxycarbonyl-4-(2-nitrophenyl)- 
pyridin-3-carboxy]ethyl}-N--cyclohexyl- 
4-(6-carbostyriloxy)-butyramide 
Lactose (Japanese Pharmacopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder 5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of capsules-6 
1,000 Capsules of two-piece rigid gelatin capsules for peroral use, each 
containing 10 mg of 
N-[2-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridin-3-carboxy 
)ethyl]-N-cyclohexyl-1-4-(6-carbostyriloxy)butyramide, are filled using the 
following ingredients, by a method similar to that described in 
Preparation of capsules-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
N--[2-(1,4-Dihydro-2,6-dimethyl- 
10 
5-methoxycarbonyl-4-phenylpyridin- 
3-carboxy)ethyl]-N--cyclohexyl- 
4-(6-carbostyriloxy)butyramide 
Lactose (Japanese Pharmacopoeia) 
80 
Starch (Japanese Pharmacopoeia) 
30 
Talcum powder 5 
(Japanese Pharmacopoeia) 
Magnesium stearate 1 
(Japanese Pharmacopoeia) 
______________________________________ 
Preparation of injections-1 
A sterile aqueous solution suited for parenteral use is prepared from the 
following ingredients. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
5-{3-[2,6-Dimethyl-5-methoxycarbonyl- 
1 
4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-hydroxy-3,4- 
dihydrocarbostyril 
Polyethylene glycol 0.9 
(Molecular weight: 4,000) 
(Japanese Pharmacopoeia) 
Sodium chloride 0.9 
(Japanese Pharmacopoeia) 
Polyoxyethylene sorbitan monooleate 
0.4 
(Japanese Pharmacopoeia) 
Sodium metabisulfite 0.1 
Methyl p-hydroxybenzoate 
0.18 
(Japanese Pharmacopoeia) 
Propyl p-hydroxybenzoate 
0.02 
(Japanese Pharmacopoeia) 
Distilled water for injection 
100 (ml) 
______________________________________ 
A mixture of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sodium 
metabisulfite and sodium chloride is dissolved with stirring in about half 
the quantity of distilled water at 80.degree. C. The solution obtained is 
cooled to 40.degree. C., and then the 
5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydroxypyridi 
n-3-carboxy]propoxy}-8-hydroxy-3,4-dihydrocarbostyril, polyethylene glycol 
and polyoxyethylene sorbitan monooleate are dissolved in that order in the 
solution. This solution is further mixed with water to the final regulated 
volume for injection and then sterilized by sterile filtration with 
suitable filter paper. 
Preparation of injections-2 
A sterile aqueous solution suited for parenteral use is prepared from the 
following ingredients. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
6-{4-[2,6-Dimethyl-5-methoxycarbonyl- 
1 
4-(2-trifluoromethylphenyl)-1,4- 
dihydropyridin-3-carboxy]butoxy}- 
carbostyril 
Polyethylene glycol 0.9 
(Molecular weight: 4,000) 
(Japanese Pharmacopoeia) 
Sodium chloride 0.9 
(Japanese Pharmacopoeia) 
Polyoxyethylene sorbitan monooleate 
0.4 
(Japanese Pharmacopoeia) 
Sodium metabisulfite 0.1 
Methyl p-hydroxybenzoate 
0.18 
(Japanese Pharmacopoeia) 
0.18 
Propyl p-hydroxybenzoate 
0.02 
(Japanese Pharmacopoeia) 
Distilled water for injection 
100 (ml) 
______________________________________ 
The injection preparations were prepared by a method similar to that 
described in Preparation of injections-1. 
Preparation of injections-3 
A sterile aqueous solution suited for parenteral use is prepared from the 
following ingredients, by a method similar to that described in 
Preparation of injections-1. 
______________________________________ 
Ingredient Amount (g) 
______________________________________ 
N--{2-[1,4-Dihydro-2,6-dimethyl-5- 
1 
methoxycarbonyl-4-(3-nitrophenyl)- 
pyridin-3-carboxy]ethyl}-N--cyclo- 
hexyl-4-(3,4-dihydrocarbostyril- 
6-yl)oxybutyramide 
Polyethylene glycol 0.3 
(Molecular weight: 4,000) 
(Japanese Pharmacopoeia) 
Sodium chloride 0.9 
(Japanese Pharmacopoeia) 
Polyoxyethylene sorbitan monooleate 
0.4 
(Japanese Pharmacopoeia) 
Sodium metabisulfite 0.1 
Methyl p-hydroxybenzoate 
0.18 
(Japanese Pharmacopoeia) 
Propyl p-hydroxybenzoate 
0.02 
(Japanese Pharmacopoeia) 
Distilled water for injection 
100 (ml) 
______________________________________ 
Pharmacological tests 
The results of the pharmacological tests on compounds of the present 
invention are shown below. 
Tested compounds used in the pharmacological tests are as follows: 
______________________________________ 
Tested 
Compound 
No. 
______________________________________ 
1. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}-8-propenyloxy-3,4-dihydrocarbostyril 
2. 5-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
ethoxy}-3,4-dihydrocarbostyril 
3. 6-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-ethoxy}-3,4-dihydrocarbostyril 
4. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-propoxy}-3,4-dihydrocarbostyril 
5. 6-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-propoxy}-3,4-dihydrocarbostyril 
6. 7-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-propoxy}-3,4-dihydrocarbostyril 
7. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}-8-hydroxy-3,4-dihydrocarbostyril 
8. 6-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}carbostyril 
9. 8-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}-3,4-dihydrocarbostyril 
10. 6-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
ethoxy}carbostyril 
11. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}-8-propoxy-3,4-dihydrocarbostyril 
12. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}-8-(2-propynyloxy)-3,4- 
dihydrocarbostyril 
13. 8-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
ethoxy}-3,4-dihydrocarbostyril 
14. 7-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4,-dihydropyridin-3-carboxy]- 
ethoxy}-3,4-dihydrocarbostyril 
15. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}carbostyril 
16. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}-3,4-dihydrocarbostyril 
17. 5-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}-3,4-dihydrocarbostyril 
18. 5-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}carbostyril 
19. 5-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}-8-alloyloxy-3,4-dihydrocarbostyril 
20. 6-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
ethoxy}carbostyril 
21. 6-{2-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
ethoxy}-3,4-dihydrocarbostyril 
22. 5-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
propoxy}carbostyril 
23. 6-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]- 
2-acetoxypropoxy}-3,4-dihydrocarbostyril 
24. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-trifluoromethylphenyl)-1,4-dihydropyridin- 
3-carboxy]butoxy}carbostyril 
25. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-trifluoromethylphenyl)-1,4-dihydropyridin- 
3-carboxy]butoxy}-3,4-dihydrocarbostyril 
26. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-methylthiophenyl)-1,4-dihydropyridin-3- 
carboxy]butoxy}-3,4-dihydrocarbostyril 
27. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-chlorophenyl)-1,4-dihydropyridin-3-carboxy]- 
butoxy}-3,4-dihydrocarbostyril 
28. 6-[4-(2,6-Dimethyl-5-methoxycarbonyl-4-phenyl- 
1,4-dihydropyridin-3-carboxy)butoxy] -3,4- 
dihydrocarbostyril 
29. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-methylphenyl-1,4-dihydropyridin-3-carboxy)]- 
butoxy}-3,4-dihydrocarbostyril 
30. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2-methoxycarbonyl)-1,4-dihydropyridin-3- 
carboxy]butoxy}-3,4-dihydrocarbostyril 
31. N--{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-(3-nitrophenyl)pyridin-3-carboxy]ethyl}- 
N--cyclohexyl-4-(6-carbostyriloxy)butyramide 
32. N--{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-(2-nitrophenyl)pyridin-3-carboxy]ethyl}- 
N--cyclohexyl-4-(3,4-dihydro-6-carbostyriloxy)- 
butyramide 
33. N--{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-(3-nitrophenyl)pyridin-3-carboxy]ethyl}-N-- 
cyclohexyl-4-(5-carbostyriloxy)butyramide 
34. N--{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-(2-nitrophenyl)pyridin-3-carboxy]ethyl}-N-- 
cyclohexyl-4-(6-carbostyriloxy)butyramide 
35. N--[2-(1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-phenylpyridin-3-carboxy)ethyl]-N--cyclohexyl- 
4-(6-carbostyriloxy)butyramide 
36. N--[2,(1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl- 
4-phenylpyridin-3-carboxy)ethyl]-N--ethyl-4- 
(6-carbostyriloxy)butyramide 
37. 4-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]propoxy}carbostyril 
38. 4-Methyl-6-{3-[2,6-dimethyl-5-methoxycarbonyl- 
4-(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]propoxy}carbostyril 
39. 6-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-2-hydroxypropoxy}-3,4-dihydro- 
carbostyril 
40. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3,4-dimethoxyphenyl)-1,4-dihydropyridin-3- 
carboxy]butoxy}-3,4-dihydrocarbostyril 
41. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3,4,5-trimethoxyphenyl)-1,4-dihydropyridin-3- 
carboxy] butoxy}-3,4-dihydrocarbostyril 
42. 6-{4-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(2,4-dichlorophenyl)-1,4-dihydropyridin-3- 
carboxy]butoxy}-3,4-dihydrocarbostyril 
43. 6-{3-[2,6-Dimethyl-5-methoxycarbonyl-4- 
(3-nitrophenyl)-1,4-dihydropyridin-3- 
carboxy]-2-acetoxypropoxy}carbostyril 
44. 6-[3-(2,6-Dimethyl-5-methoxycarbonyl-4- 
phenyl-1,4-dihydropyridin-3-carboxy)propoxy]- 
carbostyril 
______________________________________ 
Pharmacological test-1 
The platelet aggregation inhibitory effect was measured by using a Platelet 
Aggregation Tracer Model PAT-6M (manufactured by Nikoh Bio-Science Co., 
Ltd.) by a method according to Kimura, et al., [IGAKU-NO-AYUMI (Progress 
in Medicine), Vol. 114, No. 9, pp. 718-727, Aug. 30, 1980, and Nature, pp. 
927-929, 1962]. 
The blood sample used for the test was a 1:9 (by volume) mixture of 
"3.8%-CITRATE".RTM. (a registered trademark for 3.8%-sodium citrate, 
manufactured by Green Cross Corp.) and whole blood collected from rabbits. 
Said sample was subjected to 10-minute centrifugal separation at 1,000 
r.p.m. (200xG) to obtain a platelet rich plasma (PRP). The PRP thus 
obtained was separated, and the remaining blood sample was further 
subjected to 15-minute centrifugal separation at 3,000 r.p.m. (2,000xG) to 
obtain a platelet poor plasma (PPP). 
The number of platelets in the PRP was counted by the Brecher-Clonkite 
Method, and the PRP was diluted with the PPP to prepare a PRP sample with 
a platelet concentration of 600,000/microliter to prepare for an adenosine 
diphosphate (ADP)-induced aggregation test, and a collagen-induced 
aggregation test. 0.2 Milliliter of the PRP sample was added to 2 
microliters of a solution of a test compound of predetermined 
concentration and this mixture was placed in a 37.degree. C. thermostat 
for one minute. Then 20 microliters of an ADP or collagen solution was 
added to the mixture. In this test, the ADP solution was prepared by 
adjustment to a concentration of 7.5.times.10.sup.-5 M by using 
Auren-Beronal buffer solution (pH 7.35). Further, the collagen solution 
was prepared by adjustment to a concentration of 200 micrograms/ml by 
using collagen reagent of "Holm".RTM. (manufactured by Hormon-Chemie 
Munchen, GmbH.) which was diluted wih a physiological saline solution. 
The transmittance of the resultant test mixture was determined and the 
change of transmittance was recorded by using the aggregometer at a 
stirrer speed of 1,100 r.p.m. 
The platelet aggregation inhibitory effect of the test compound was 
measured in terms of inhibition rate (%) with respect to the aggregation 
rate of the controls. The aggregation rate was calculated from the 
following formula. 
EQU Aggregation rate=[(c-a)/(b-a)].times.100 
wherein 
a: transmittance of PRP 
b: transmittance of PPP 
c: transmittance of PRP containing a test compound and aggregation inducer. 
The percent inhibition is calculated from the following formula. 
EQU Inhibition rate (%)=[(A-B)/A].times.100 
wherein 
A: aggregation rate of the control 
B: aggregation rate of the test compound. 
The inhibitory effect of the test compounds on collagen-induced aggregation 
in rabbit platelets is shown in Table 1, similarly such effect on 
ADP-induced aggregation in rabbit platelets is shown in Table 2. 
TABLE 1 
______________________________________ 
Inhibition rate (%) of collagen-induced aggregation 
Test 
Compound Concentration of the test compound solution 
No. 10.sup.-4 mole 
10.sup.-5 mole 
______________________________________ 
1 51 15 
2 79 17 
3 100 97 
4 23 11 
5 38 12 
6 19 3 
7 15 3 
8 99 27 
9 16 2 
10 100 50 
11 10 -- 
12 10 -- 
15 100 26 
18 100 3 
19 17 -- 
20 100 100 
21 100 99 
22 100 21 
23 100 29 
24 100 30 
26 100 19 
27 61 -- 
28 63 -- 
29 69 -- 
30 100 3 
31 100 100 
32 100 34 
33 100 34 
34 100 100 
35 100 100 
36 100 100 
37 15 -- 
38 45 -- 
39 100 19 
40 15 -- 
41 35 -- 
42 39 -- 
43 100 100 
44 100 25 
______________________________________ 
TABLE 2 
______________________________________ 
Inhibition rate (%) of ADP-induced aggregation 
Test 
Compound Concentration of the test compound solution 
No. 10.sup.-4 mole 
10.sup.-5 mole 
______________________________________ 
1 19 1 
2 28 1 
3 100 27 
4 16 4 
5 20 4 
6 15 6 
7 14 3 
8 76 10 
9 12 7 
10 100 27 
11 11 -- 
12 14 -- 
15 100 20 
18 48 15 
19 17 -- 
20 100 65 
21 58 27 
22 62 13 
23 79 29 
24 100 62 
26 87 22 
27 42 -- 
28 52 -- 
29 59 -- 
30 89 -- 
31 100 84 
32 98 25 
33 98 25 
34 94 98 
35 100 89 
36 98 55 
37 17 -- 
38 31 -- 
39 76 -- 
40 14 -- 
41 30 -- 
42 26 -- 
43 100 100 
44 100 20 
______________________________________ 
Pharmacological test-2 
The change of blood flow in coronary artery and the change of blood 
pressure were measured by a method according to Yakura et al., [Japan 
Journal of Pharmacology, Vol. 57, pages 380-391 (1961)] and according to 
Taira, et al. [Clin. Exp. Pharmacol. Physiol., Vol. 6, pages 301-316, 
(1976)]. 
An adult bastard dog of either sex weighing 8-13 kg was anesthetized with 
sodium pentobarbital at the rate of 30 mg/kg by intraveneous 
administration, then the dog was fixed in supination and was 
theracotomized under a condition of forced breathing. After another 
intraveneous administration of sodium heparin at the rate of 500 U/kg, 100 
U/kg per hour, the dog was subjected to the following experiments. 
(1) Intra-arterial administration 
A glass cannula was cannulated to the left coronary artery through the 
right carotid so as to form an extracorporeal circulation path. The blood 
flow in coronary artery was measured by an electromagnetic blood flow 
meter equipped with a blood flow observation probe in the extracorporeal 
circulation path. A compound to be tested was administered by using a 
microsyringe through the branch prepared in the extracorporeal circulation 
path, and the increased amount of the blood flow in coronary artery was 
measured. Similarly, 30 micrograms or 100 micrograms of adenosin were 
administered and the increased amount of the blood flow in coronary artery 
was measured respectively, and the larger value among the measured data 
was considered as 100%, then the increased effect (%) of the blood flow in 
coronary artery caused by the test compound was calculated. The results 
are shown in Table 3 below. 
(2) Intraveneous administration 
Morawitz's cannula was cannulated to the coronary sinus venosus through the 
auricula dextra cordis, and the blood in vein was circulated to the right 
carotid. The blood flow was measured by an electromagnetic blood flow 
meter equipped with a blood flow observation probe in the extracorporeal 
circulation path of the vein. The systolic force was measured by a 
systolometer (pick-up) placed at the left ventricle of heart, the blood 
pressure was measured from the femoral artery, and the heart rate was 
measured from the pulse. A compound to be tested was administered through 
the cannula being cannulated in femoral vein. The increased amount of the 
blood flow in coronary artery after the administration of the test 
compound is shown in Table 4, also the change of blood pressure is shown 
in Table 5. In the Tables 3 to 5, the compounds to be tested were numbered 
similarly as those indicated in Tables 1 and 2. 
TABLE 3 
______________________________________ 
Increasing effect of blood flow 
in coronary artery (%) 
Test 
Compound 
Dosage (micrograms) 
No. 3 10 30 100 300 1000 
______________________________________ 
1 -- 28 95 123 133 -- 
2 -- 8 33 125 183 -- 
3 -- 6 13 40 53 -- 
4 22 65 96 107 117 -- 
5 13 24 67 85 98 -- 
6 11 24 55 87 108 -- 
7 -- 6 12 22 110 -- 
8 7 7 41 90 110 -- 
9 19 54 88 95 85 -- 
10 2 6 23 42 78 -- 
11 10 21 32 56 75 -- 
12 6 25 52 60 76 -- 
13 32 59 75 -- -- -- 
14 2 11 28 64 100 -- 
15 4 35 71 87 88 -- 
16 27 61 105 119 -- -- 
17 18 28 75 95 -- -- 
19 38 47 83 71 -- -- 
21 12 31 72 93 -- -- 
23 -- 6 63 136 141 -- 
24 9 75 192 239 225 -- 
25 28 106 244 269 -- -- 
26 -- 8 56 300 386 -- 
27 6 53 178 128 -- -- 
28 12 44 89 94 74 -- 
29 25 164 181 170 -- -- 
30 -- 20 145 175 -- -- 
31 -- -- 18.8 31.2 62.5 -- 
32 -- -- 9.2 30.8 64.6 93.8 
33 -- -- -- 10.8 43.1 83.1 
34 -- -- 5.7 21.4 62.9 92.9 
35 -- -- 3.8 26.9 63.5 105.8 
36 -- -- 5.3 30.7 74.7 100.0 
37 -- -- -- 6 31 -- 
38 -- 9 47 188 252 -- 
39 -- -- -- 3 33 -- 
40 -- 5 29 68 112 -- 
41 -- 6 20 31 109 -- 
42 -- 5 80 120 146 -- 
______________________________________ 
TABLE 4 
______________________________________ 
Increased amount of the blood flow 
in coronary artery (ml/min.) 
Test 
Compound Dosage (micrograms/kg) 
No. 3 10 30 100 300 1000 
______________________________________ 
1 4 34 63 62 42 -- 
2 -- 3 13 38 52 -- 
3 2 1 3 14 38 -- 
4 3 8 22 62 90 -- 
5 3 12 47 89 77 -- 
6 -- 3 25 58 64 -- 
7 -- -- 1 15 47 -- 
8 -- 1 2 12 56 -- 
9 4 17 47 66 81 -- 
10 -- 2 5 23 43 -- 
11 7 26 58 56 73 -- 
12 5 30 74 63 -- -- 
31 -- -- -- 6 32 61 
32 -- -- -- 16 55 97 
33 -- -- -- 1 4 48 
34 -- -- -- 22 47 54 
35 -- -- -- 5 17 47 
36 -- -- -- 4 12 38 
______________________________________ 
TABLE 5 
______________________________________ 
Change of blood pressure 
Test 
Compound 
Dosage (micrograms/kg) 
No. 3 10 30 100 300 
______________________________________ 
1 -6 -17 -36 -42 -46 
2 -- -2 -6 -21 -34 
3 -- -1 -4 -18 -34 
4 -5 -15 -25 -34 -51 
6 -3 -5 -15 -32 -44 
7 -- -2 -4 -9 -14 
8 -- -- -3 -16 -33 
9 -14 -28 -36 -41 -36 
10 -- -5 -9 -13 -34 
11 -5 -18 -33 -41 -48 
12 -- -5 -23 -49 -- 
13 -7 -16 -32 -52 -- 
14 -- -- -2 -14 -32 
15 -- -- -3 -9 -27 
16 -3 -12 -27 - 42 -54 
17 -- -4 -14 -55 -76 
18 -- -5 -19 -33 -43 
19 -22 -34 -44 -55 -- 
20 -- -- -4 -8 -32 
21 -- -7 -12 -28 -42 
22 -- -2 -8 -18 -36 
24 -- -6 -18 -30 -44 
25 -9 -34 -46 -- -- 
26 -- -6 -10 -21 -42 
27 -4 -10 -27 -52 -- 
28 -1 -10 -7 -20 -47 
29 -7 -23 -45 -70 -80 
30 -- -1 -16 -38 -- 
31 -- -1 -4 -8 -23 
32 -- -1 -6 -8 -19 
35 -- -4 -6 -9 -26 
37 -- -- -1 -5 -18 
38 -- -2 -10 -35 - 57 
43 -- -- -4 -16 -23 
44 -- -1 -3 -6 -52 
______________________________________ 
REFERENCE EXAMPLE 1 
4.2 Grams of potassium hydroxide were dissolved in 200 ml of methanol, then 
10 g of 5-hydroxy-3,4-dihydrocarbostyril were added thereto. Next, 10 g of 
2-bromoethanol were added dropwise thereto under refluxing conditions. The 
reaction mixture was further refluxed for 4 hours, then was concentrated. 
To the residue thus obtained was added water, and the insoluble matter was 
collected by filtration, and was washed with water, then recrystallized 
from methanol to yield 2.1 g of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril 
in the form of colorless needle-like crystals. Melting point: 
176.degree.-178.degree. C. 
By a method similar to that described above, that were prepared compounds 
as follows: 
5-(3-Hydroxypropoxy)-8-propenyloxy-3,4-dihydrocarbostyril 
Colorless needle-like crystals (from chloroformhexane). 
Melting point: 80.0.degree.-81.5.degree. C. 
6-(2-Hydroxyethoxy)-3,4-dihydrocarbostyril 
Colorless needle-like crystals (water-containing methanol). 
Melting point: 153.degree.-155.degree. C. 
6-(4-Hydroxybutoxy)-3,4-dihydrocarbostyril 
Colorless needle-like crystals. 
Melting point: 132.degree.-133.degree. C. 
REFERENCE EXAMPLE 2 
2 Grams of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril and 2 ml of 
triethylamine were added to 50 ml of chloroform, then 1 g of diketene was 
added dropwise thereto, and the whole reaction mixture was stirred at room 
temperature for 2 days. The insoluble matter formed in the reaction 
mixture was removed by filtration, and the filtrate was concentrated, then 
the residue obtained was purified by silica gel column chromatography 
(eluant: chloroform), the eluate obtained was concentrated and the residue 
was recrystallized from chloroform-ether to yield 1.5 g of 
5-(2-acetoacetoxyethoxy)-3,4-dihydrocarbostyril in the form of colorless 
needle-like crystals. Melting point: 134.5.degree.-135.5.degree. C. 
By a method similar to that described above, there was prepared 
5-(3-acetoacetoxypropoxy)-8-propenyloxy-3,4-dihydrocarbostyril in the form 
of colorless powdery crystals (from chloroform-hexane). Melting point: 
66.degree.-67.degree. C. 
REFERENCE EXAMPLE 3 
Into 30 ml of ethanol, 2 g of 6-(2-acetoacetoxy)-3,4-dihydrocarbostyril and 
1 g of 3-nitrobenzaldehyde were added, then 0.1 ml of piperidine was added 
to the reaction mixture under an ice-cooled condition. The reaction was 
continued for 3 days at room temperature under stirring. Then the reaction 
mixture was concentrated, then ether was added thereto, and the 
precipitate formed was collected by filtration, then recrystallized from 
chloroform-ether to yield 1.3 g of 
6-{2-[2-(3-nitrobenzyliden)acetoacetoxy]ethoxy}-3,4-dihydrocarbostyril in 
the form of light yellowish powdery crystals. 
NMR: .delta.(CDCl.sub.3)=2.45 (3H, s), 2.46-2.70 (2H, m), 2.75-3.00 (2H, 
m), 4.00-4.27 (2H, m), 4.47-4.65 (2H, m), 6.50-6.70 (3H, m), 7.25-7.70 
(3H, m), 7.95-8.30 (3H, m). 
REFERENCE EXAMPLE 4 
10 Grams of 3-nitrobenzaldehyde and 11 g of 2-chloroethyl acetoacetate were 
dissolved in 100 ml of toluene, then hydrogen chloride gas was introduced 
to the solution under an ice-cooled condition. The reaction mixture was 
allowed to stand for 2 days at room temperature, and the mixture was 
concentrated. The residue obtained was extracted with chloroform, and the 
chloroform layer was washed with a saturated sodium chloride aqueous 
solution, and a saturated sodium hydrogencarbonate aqueous solution, then 
dried with anhydrous magnesium sulfate. Chloroform was removed by 
distillation, then the residue obtained was recrystallized from 
isopropanol to yield 10 g of 2-chloroethyl 
2-(3-nitrobenzylyden)acetoacetate in the form of colorless needle-like 
crystals. 
Melting point: 95.degree.-97.degree. C. 
REFERENCE EXAMPLE 5 
25 Grams of 3-chloropropyl 2-(3-nitrobenzyliden)acetoacetate which was 
prepared by a method similar to that described in Reference Example 3, and 
10 g of methyl 3-aminocrotonate were added to 100 ml of methanol, and the 
mixture was refluxed for 4 hours, then allowed to stand to cool overnight. 
The crystals precipitated were collected by filtration, recrystallized 
from isopropanol to yield 22.7 g of 3-chloropropyl methyl 
1,4dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate in the 
form of yellowish prism-like crystals. Melting point: 
144.degree.-145.degree. C. 
REFERENCE EXAMPLE 6 
13.2 Grams of o-trifluoromethylbenzaldehyde, 14.6 g of 4-chlorobutyl 
acetoacetate and 8.8 g of methyl 3-aminocrotonate were added to 50 ml of 
isopropanol, and the whole mixture was refluxed by heating for 4 hours. 
The reaction mixture was concentrated, and the residue was purified by a 
silica gel column chromatography (eluant=chloroform) to yield 18.2 g of 
4-chlorobutyl methyl 
1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxy 
late in the form of yellow oily substance. 
NMR: (CDCl.sub.3).delta.; 1.47-1.87 (4H, m), 2.23 (6H, d, J=2 Hz), 
3.23-3.50 (2H, m), 3.50 (3H, s), 3.80-4.20 (2H, m), 5.37-5.53 (1H, m), 
5.70 (1H, brs), 6.97-7.60 (4H, m). 
REFERENCE EXAMPLE 7 
2.8 Grams of metallic magnesium, 25 g of 
2-bromo-.alpha.,.alpha.,.alpha.-trifluorotoluene and 120 ml of ether were 
reacted to prepare a Grignard ragent by a conventional method, then 15 g 
of N-methylformanilide were added dropwise thereto, and the reaction 
mixture was allowed to stand for 3 hours. Under an ice-cooled condition, a 
dilute sulfuric acid was added to the reaction mixture. The ethereal layer 
was separated and was washed with a saturated sodium chloride aqueous 
solution and with a saturated sodium hydrogencarbonate aqueous solution, 
then was dried with anhydrous sodium sulfate, and was concentrated. The 
residue was purified by distillation under reduced pressure to yield 13.2 
g of 2-trifluoromethylbenzaldehyde. Boiling point: 62.degree.-65.degree. 
C. (at 17 mm-Hg). 
REFERENCE EXAMPLE 8 
18 Grams of 2-methylmercaptobenzyl chloride and 30 g of hexamine were added 
to 200 ml of chloroform and the mixture was refluxed for 2 hours. Then the 
reaction mixture was concentrated, and the residue obtained was refluxed 
with 100 ml of 20%-hydrochloric acid for 2 hours. After being cooled, the 
reaction mixture was extracted with chloroform, and the chloroform layer 
was washed with a saturated sodium chloride aqueous solution and with a 
saturated sodium hydrogencarbonate aqueous solution, then concentrated. 
The product was purified by distillation under reduced pressure to obtain 
9.00 g of 2-methylmercaptobenzaldehyde. Boiling point: 
143.degree.-147.degree. C. (at 15 mm-Hg). 
REFERENCE EXAMPLE 9 
6 Grams of 2-formylbenzoic acid and 6 g of potassium carbonate were added 
to 30 ml of dimethylformamide, then 6 g of methyl iodide were added 
dropwise thereto at room temperature with stirring. The reaction mixture 
was continuously stirred at room temperature overnight, then was 
concentrated. The residue obtained was extracted with chloroform, and the 
chloroform layer was washed with water, and was dried with anhydrous 
magnesium sulfate, then concentrated. The residue obtained was purified by 
distillation under reduced pressure to yield 3 g of methyl 
2-formylbenzoate. Boiling point: 95.degree. C. (at 0.5 mm-Hg). 
REFERENCE EXAMPLE 10 
3 Grams of methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3-carboxy-5-carboxylate 
were dissolved in 10 ml of hexamethylphosphoramide and 1.2 ml of 
30%--sodium hydroxide aqueous solution, then 1.4 ml of epibromohydrin were 
added thereto and the mixture was stirred at room temperature overnight. 
To the reaction mixture was added water and the mixture was extracted with 
ethyl acetate. The organic layer was washed with water, dried, then the 
solvent was removed by distillation, and the residue obtained was 
crystallized from diethyl ether to yield 2.6 g of methyl 
.beta.,.alpha.-epoxypropyl 
2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylate. 
REFERENCE EXAMPLE 11 
10 Grams of 3-nitrobenzaldehyde and 11 g of 2-chloroethyl acetoacetate were 
dissolved in 100 ml of toluene, then under an ice-cooled condition, 
hydrogen chloride gas was introduced into the solution for 2 hours. The 
reaction mixture was allowed to stand at room temperature for 2 days, and 
was concentrated. The residue obtained was extracted with chloroform, then 
the chloroform layer was washed with a saturated sodium chloride aqueous 
solution and with a saturated sodium hydrogen carbonate aqueous solution 
and dried with anhydrous magnesium sulfate. Chloroform was removed by 
distillation and the residue was recrystallized from isopropanol to yield 
10 g of 2-chloroethyl 2-(3-nitrobenzyliden)acetoacetate in the form of 
colorless needle-like crystals. 
Melting point: 95.degree.-97.degree. C. 
REFERENCE EXAMPLE 12 
25 Grams of 2-chloroethyl 2-(3-nitrobenzyliden)acetoacetate which was 
prepared by a method similar to that described in Reference Example 11, 
and 10 g of methyl 3-aminocrotonate were added to 100 ml of methanol and 
the whole mixture was refluxed for 4 hours, then allowed to stand 
overnight. The precipitates formed were collected by filtration, and were 
recrystallized from isopropanol to yield 22.7 g of 2-chloroethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate in the 
form of yellowish prism-like crystals. Melting Point: 
144.degree.-145.degree. C. 
REFERENCE EXAMPLE 13 
4 Grams of 2-chloroethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate and 6 
ml of cyclohexylamine were added to 70 ml of toluene and the mixture was 
refluxed for 10 hours. After cooling the reaction mixture, the 
precipitates thus formed were removed by filtration, the filtrate was 
concentrated, and the residue was extracted with chloroform. The 
chloroform layer was washed with 5%-hydrochloric acid aqueous solution, 
2%-sodium hydroxide aqueous solution and a saturated sodium chloride 
aqueous solution, and dried with anhydrous magnesium sulfate, then was 
concentrated. The concentrate was purified by a silica gel column 
chromatography (eluant: chloroform/methanol=20/1) to yield 1.0 g of 
N-cyclohexylaminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate in the 
form of yellowish needle-like crystals. Melting point: 
84.degree.-87.degree. C. 
REFERENCE EXAMPLE 14 
To 100 ml of dimethylformamide, there were added 7.45 g of 
N-cyclohexyl-N-(2-hydroxyethyl)-4-(6-carbostyriloxy)butyramide and 0.5 ml 
of triethylamine, then the whole mixture was heated at 80.degree. to 
90.degree. C. on an oil bath. Next, 1.8 g of diketene were added dropwise 
to the reaction mixture, then the mixture was stirred for 1 hour at the 
same temperature. The reaction mixture was concentrated then was purified 
by a silica gel column chromatography (eluant: chloroform/methanol=50/1), 
and the solvent was removed by distillation under reduced pressure to 
yield 6.33 g of 
N-(2-acetoacetoxyethyl)N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the 
form of a brownish oily substance. 
NMR (CDCl.sub.3).delta. (ppm) 0.8-1.9 (10H, m), 1.95-2.35 (2H, m), 2.20 
(3H, s), 2.40-2.67 (2H, m); 3.33 (2H, s), 3.40 (2H, t, J=6.6 Hz), 
3.40-3.70 (1H, m), 3.97 (2H, t, J=6.5 Hz), 4.13 (2H, t, J=6.6 Hz), 6.60 
(1H, d, J=9.6 Hz), 6.89 (1H, d, J=2 Hz), 7.03 (1H, dd, J.sub.1 =9.0 Hz, 
J.sub.2 =2 Hz), 1.27 (1H, d, J=9.0 Hz), 7.60 (1H, d, J=9.6 Hz), 12.5 (1H, 
bs). 
REFERENCE EXAMPLE 15 
To 10 ml of pyridine were added 0.9 g of 3-nitrobenzaldehyde and 2.7 g of 
N-(2-acetoacetoxyethyl)-N-cyclohexyl-4-(6-carbostyriloxy)butyramide, and 
the mixture was heated at 90.degree.-100.degree. C. for 20 hours. After 
cooling the reaction mixture was extracted with chloroform, and the 
chloroform layer was washed with a saturated aqueous solution of potassium 
hydrogensulfate and with a saturated aqueous solution of sodium chloride, 
then was dried with anhydrous magnesium sulfate. After being concentrated, 
the residue was purified by a silica gen column chromatography (eluant: 
chloroform/methanol=100/1), then the eluate was dried under vacuum 
condition to yield 0.2 g of 
N-{2-[2-(3-nitrobenzyliden)acetoacetoxy]ethyl}-N-cyclohexyl-4-(6-carbostyr 
iloxy)butyramide in the form a brown oily substance. 
NMR (CDCl.sub.3).delta. (ppm) 0.8-1.9 (10H, m), 1.95-2.35 (2H, m), 
2.40-2.67 (2H, m), 2.43 (3H, s), 3.45 (2H, t, J=6.5 Hz), 3.40-3.70 (1H, 
m), 3.97 (2H, t, J=6.5 Hz), 4.33 (2H, t, J-6.5 Hz), 6.60 (1H, d, J=9.6 
Hz), 6.89 (1H, d, J-2.0 Hz), 7.03 (1H, dd, J.sub.1 =9.0 Hz, J.sub.2 =2 
Hz), 7.27 (1H, d, J=9.0 Hz), 7.50 (1H, s), 7.45-7.83 (3H, m), 8.10-8.33 
(2H, m), 12.5 (1H, bs). 
REFERENCE EXAMPLE 16 
1 Gram of 2-cyclohexlaminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate was 
added to 20 ml of acetone, then 0.34 g of potassium carbonate and 1 ml of 
water were added thereto. Under an ice-cooled condition with stirring, an 
acetone solution containing 0.35 g of 4-chlorobutyl chloride was added 
dropwise thereto, then the reaction mixture was stirred under an 
ice-cooled condition for 1 hour, and further stirred at room temperature 
for 3 hours. The reaction mixture was concentrated, and the residue was 
extracted with chloroform, then the chloroform layer was washed with 
0.5N-sodium hydroxide aqueous solution, then with a saturated sodium 
chloride aqueous solution, and dried with anhydrous magnesium sulfate. The 
dried chloroform extract was concentrated and the residue obtained was 
purified by a silica gel column chromatography (eluant: chloroform), then 
the eluate was dried under vacuum to yield 0.5 g of 
2-[N-(4-chlorobutyl)-N-cyclohexyl]aminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate in the 
form a yellowish oily substance. 
NMR (CDCl.sub.3).delta. (ppm) 0.8-1.90 (10H, m), 1.90-2.20 (2H, m), 2.27 
(6H, s), 2.40 (2H, t, J=6.0 Hz), 3.20-3.70 (5H, m), 3.55 (3H, s), 4.03 
(2H, t, J-6.9 Hz), 5.00 (1H, s), 6.65 (1H, bs), 7.25 (1H, t, J=7.2 Hz), 
7.53 (1H, dd, J.sub.1 =7.2 Hz, J.sub.2 =2.0 Hz), 7.87 (1H, dd, J.sub.1 
=7.2 Hz, J.sub.2 =2.0 Hz), 7.98 (1H, t, J=2.0 Hz). 
EXAMPLE 1 
1.6 Grams of 8-hydroxy-3,4-dihydrocarbostyril and 1.5 g of potassium 
carbonate were added to 30 ml of dimethylformamide, then this mixture was 
heated to 80.degree.-90.degree. C., and 30 ml of dimethylformamide 
solution containing 5 g of 3-iodopropylmethyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate were 
added dropwise thereto. The reaction mixture was stirred at the same 
temperature for 5 hours, and the reaction mixture was concentrated, then 
the residue obtained was extracted with chloroform, the chloroform layer 
was washed with water, 0.5N-sodium hydroxide aqueous solution, 
5%-hydrochloric acid aqueous solution and a saturated sodium chloride 
aqueous solution, then was dried with anhydrous magnesium sulfate. The 
dried chloroform extract was concentrated and purified by a silica gel 
column chromatography (eluant: chloroform/methanol=100/1). The eluate was 
recrystallized from methanol containing water to yield 2.9 g of 
8-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-3,4-dihydrocarbostyril in the form of yellowish 
plate-like crystals. 
Melting point: 167.degree.-167.5.degree. C. 
EXAMPLES 2-48 
By a method similar to that described in Example 1, there were prepared 
compounds represented by the following general formula as shown in Table 6 
below. 
##STR51## 
wherein R is a side-chain of the formula, 
##STR52## 
TABLE 6 
__________________________________________________________________________ 
Substituted 
position of 
Example 
the side- 
No. chain or R 
R R.sup.1 R.sup.2 
R.sup.3 
R.sup.4 
R.sup.5 
(R.sup.6).sub.m 
__________________________________________________________________________ 
2 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
3 5 Side-chain 
OCH.sub.2 CHCH.sub.2 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
4 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
5 7 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
6 8 H Side-chain 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
7 4 H H Side-chain 
CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
8 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
9 5 Side-chain 
OCH.sub.2 CCH 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
10 5 Side-chain 
O(CH.sub.2).sub.2 CH.sub.3 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
11 4 H H Side-chain 
CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
12 6 Side-chain 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
13 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
14 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
15 5 Side-chain 
OCH.sub.2 CHCH.sub.2 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
16 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
17 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
18 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
19 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
20 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
21 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
22 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
23 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-NO.sub.2 
24 5 Side-chain 
OCH.sub.2 CHCH.sub.2 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
25 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
26 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
27 5 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
28 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
29 7 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
30 5 Side-chain 
2-Tetrahydro- 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
pyranyloxy 
31 5 Side-chain 
OH H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
32 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
33 8 H Side-chain 
H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
34 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
35 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
36 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
37 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3-NO.sub.2 
38 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-CF.sub.3 
39 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-CF.sub.3 
40 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-SCH.sub.3 
41 6 Side-chain 
H H CH.sub. 3 
CH.sub.3 
CH.sub.3 
2-Cl 
42 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
H 
43 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-CH.sub.3 
44 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2,4-(Cl).sub.2 
45 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3,4-(OCH.sub.3).sub.2 
46 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
3,4,5-(OCH.sub.3).sub.3 
47 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
2-COOCH.sub.3 
48 6 Side-chain 
H H CH.sub.3 
CH.sub.3 
CH.sub.3 
H 
__________________________________________________________________________ 
Carbon-carbon 
bond between 
Example 3- and 4- 
Crystal form 
No. A positions 
(Recrystallization solvent) 
Melting point (.degree.C.) 
__________________________________________________________________________ 
2 (CH.sub.2).sub.2 
Double bond 
Light yellowish powdery crystals 
271-272 
(Dimethylformamide-methanol) 
3 (CH.sub.2).sub.2 
Single bond 
Yellowish needle-like crystals 
135-137 
(Methanol) 
4 (CH.sub.2).sub.2 
Double bond 
Light yellowish powdery crystals 
246-249 
(Dimethylformamide-methanol) 
5 (CH.sub.2).sub.2 
Single bond 
Yellowish prism-like crystals 
178-180 
(Methanol) 
6 (CH.sub.2).sub.2 
Single bond 
Light yellowish needle-like crystals 
176-177 
(Water-containing methanol) 
7 (CH.sub.2).sub.2 
Double bond 
Yellowish needle-like crystals 
169-171 
(Methanol) 
8 (CH.sub.2).sub.3 
Double bond 
Light yellowish powdery crystals 
244-245 
(Dimethylformamide-methanol) 
9 (CH.sub.2).sub.3 
Single bond 
Yellowish prism-like crystals 
183.5-184.5 
(Methanol) 
10 (CH.sub.2).sub.3 
Single bond 
Light yellowish prism-like crystals 
150.5-152 
(Methanol) 
11 (CH.sub.2).sub.3 
Double bond 
Light yellowish powdery crystals 
148-149.5 
(Water-containing methanol) 
12 (CH.sub.2).sub.3 
Double bond 
Light yellowish powdery crystals 
211-212 
(Dimethylformamide-methanol) 
13 (CH.sub.2).sub.4 
Single bond 
Light yellowish powdery crystals 
246-248 
(Dimethylformamide-methanol) 
14 (CH.sub.2).sub.4 
Double bond 
Light yellowish powdery crystals 
252-254 
(Dimethylformamide-methanol) 
15 (CH.sub.2).sub.4 
Single bond 
Yellowish powdery crystals 
168-169.5 
(Methanol) 
16 (CH.sub.2).sub.4 
Single bond 
Light yellowish powdery crystals 
153-155 
(Chloroform-methanol) 
17 (CH.sub.2).sub.4 
Double bond 
Yellow-orange powdery crystals 
229-230.5 
(Chloroform-methanol) 
18 (CH.sub.2).sub.2 
Double bond 
Yellowish powdery crystals 
255-258 
(Dimethylformamide-methanol) 
19 (CH.sub.2).sub.3 
Double bond 
Yellowish powdery crystals 
246-247 
(Dimethylformamide-methanol) 
20 (CH.sub.2).sub.4 
Double bond 
Yellowish powdery crystals 
222-224 
(Dimethylformamide-methanol) 
21 (CH.sub.2).sub.2 
Single bond 
Yellowish powdery crystals 
235-236 
(Dimethylformamide-methanol) 
22 (CH.sub.2).sub.3 
Single bond 
Yellowish prism-like crystals 
182-184 
(Methanol) 
23 (CH.sub.2).sub.4 
Single bond 
Yellowish needle-like crystals 
152-154 
(Methanol) 
24 (CH.sub.2).sub.3 
Single bond 
Yellowish powdery crystals 
156-157.5 
(Chloroform-n-hexane) 
25 (CH.sub.2).sub.2 
Single bond 
Yellowish powdery crystals 
262-263.5 
(Chloroform-isopropyl ether) 
26 (CH.sub.2).sub.2 
Single bond 
Light yellowish powdery crystals 
172.5-174 
(Chloroform-ether) 
27 (CH.sub.2).sub.3 
Single bond 
Yellowish prism-like crystals 
173-176 
(Methanol) 
28 (CH.sub.2).sub.3 
Single bond 
Light yellowish needle-like crystals 
180-181 
(Methanol) 
29 (CH.sub.2).sub.3 
Single bond 
Light yellowish powdery crystals 
137-139 
(Water-containing methanol) 
30 (CH.sub.2).sub.3 
Single bond 
Yellow-brown oily substance 
NMR.sup.1 (cf. Note 1) 
31 (CH.sub.2).sub.3 
Single bond 
Yellowish prism-like crystals 
193.5-194 
(Water-containing methanol) 
32 (CH.sub.2).sub.3 
Double bond 
Light brownish powdery crystals 
227-227.5 
(Water-containing methanol) 
33 (CH.sub.2).sub.3 
Single bond 
Yellowish plate-like crystals 
167-167.5 
(Water-containing methanol) 
34 
Single bond 
Yellowish powdery substance (Chloroform-isopropyl 
ether) NMR.sup.2 & IR data-1 (cf. Note 
2) 
35 
##STR53## 
Single bond 
Yellowish powdery substance (Chloroform-isopropyl 
ether) NMR.sup.3 & IR data-2 (cf. Note 
3) 
36 
##STR54## 
Double bond 
Yellowish powdery substance (Isopropanol-isopropyl 
ether) NMR.sup.4 & IR data-3 (cf. Note 
4) 
37 
##STR55## 
Double bond 
Yellowish powdery substance (Chloroform-isopropyl 
ether) NMR.sup.5 & IR data-4 (cf. Note 
5) 
38 (CH.sub.2).sub.4 
Double bond 
Colorless needle-like crystals 
138-141 
(Methanol) 
39 (CH.sub.2).sub.4 
Single bond 
Colorless needle-like crystals 
103-105 
(Methanol) 
40 (CH.sub.2).sub.4 
Single bond 
Light yellowish needle-like crystals 
90-92 
(Water-containing methanol) 
41 (CH.sub.2).sub.4 
Single bond 
Light yellowish amorphous crystals 
135 
(Methanol) 
42 (CH.sub.2).sub.4 
Single bond 
Colorless flake-like crystals 
119 
(Methanol) 
43 (CH.sub.2).sub.4 
Single bond 
Colorless amorphous crystals 
93-95 
(Methanol) 
44 (CH.sub.2).sub.4 
Single bond 
Light yellowish amorphous crystals 
138.5-140 
(Methanol) 
45 (CH.sub.2).sub.4 
Single bond 
Colorless amorphous crystals 
149-150 
(Methanol) 
46 (CH.sub.2).sub.4 
Single bond 
Colorless amorphous crystals 
121-123 
(Methanol) 
47 (CH.sub.2).sub.4 
Single bond 
Light yellowish amorphous crystals 
178-181 
(Methanol) 
48 (CH.sub.2).sub.3 
Single bond 
Colorless amorphous crystals 
218-220 
(Methanol) 
__________________________________________________________________________ 
Note 1: 
NMR.sup.1 .delta. (in CDCl.sub.3) 1.30-21.5 (8H, m), 2.30 (6H, s), 
2.33-2.55 (2H, m), 2.70-3.00 (2H, m), 3.23 (2H, t, J=7Hz), 3.53 (3H, s), 
3.75 (2H, t, J=6.5Hz), 4.03 (2H, t, J=7Hz), 4.10-4.30 (1H, m), 5.00 (1H, 
s), 6.10 (1H, bs), 6.20 (1H, d, J=9Hz), 6.83 (1H, d, J=9Hz), 7.10-8.05 
(5H, m) 
Note 2: 
NMR.sup.2 .delta. (in CDCl.sub.3) 2.25 (3H, s), 2.29 (3H, s), 2.30-2.90 
(4H, m), 3.53 (3H, s), 3.50-3.90 (2H, m), 3.90-4.30 (3H, m), 5.00 (1H, s) 
6.50 (3H, bs), 6.70 (1H, bs), 7.00-8.00 (4H, m), 8.81 (1H, bs) 
IR data1 .nu..sub.KBr cm.sup.-1 : 3340 (M), 3100 (W), 2950 (W), 1690 (SH) 
1680 (S), 1630 (SH), 1530 (S), 1510 (S), 1350 (S) 
Note 3: 
NMR.sup.3 .delta. (in CDCl.sub.3) 2.00 (3H, s), 2.27 (3H, s), 2.30 (3H, 
s), 2.50 (2H, t, J=7Hz), 8.84 (2H, t, J-7Hz), 3.89 (3H, s), 3.83 (2H, t, 
J=6Hz), 4.23 (2H, t, J=5Hz), 5.00 (1H, s), 5.10-5.30 (1H, m), 6.40-6.70 
(3H, m), 6.74 (1H, bs), 7.10-8.00 (4H, m), 8.96 (1H, bs) 
IR data2 .nu..sub.KBr cm.sup.-1 : 3350 (M), 3100 (W), 2980 (W), 2960 (W), 
1745 (M), 1690 (S), 1680 (S), 1630 (SH), 1530 (S), 1510 (S), 1350 (S) 
Note 4: 
NMR.sup.4 .delta. (in CDCl.sub.3) 2.25 (3H, s), 2.27 (3H, s), 3.47 (3H, 
s), 3.70-4.10 (5H, m), 4.93 (1H, s), 6.41 (1H, d, J=9Hz), 6.90-8.00 (8H, 
m), 8.97 (1H, bs) 
IR data3 .nu..sub.KBr cm.sup.-1 : 3350 (M), 3100 (W), 2980 (W), 1690 (SH) 
1660 (S), 1620 (S), 1530 (S), 1350 (S) 
Note 5: 
NMR.sup.5 .delta. (in CDCl.sub.3) 2.27, 2.30 (3H, each s), 2.27 (3H, s), 
2.30 (3H, s), 3.55 (3H, s), 3.90 (2H, t, J=5Hz), 4.25 (2H, t, J-5Hz), 5.9 
(1H, s), 5.10-5.30 (1H, m), 6.35 (1H, bs), 6.61 (1H, d, J=9Hz), 6.70-8.00 
(8H, m), 12.33 (1H, bs) 
IR data4 .nu..sub.KBr cm.sup.-1 : 3340 (W), 3100 (W), 2980 (W), 1745 (M), 
2690 (SH), 1670 (S), 1635 (S), 1530 (S), 1350 (S) 
EXAMPLE 49 
2.0 Grams of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril, 3.3 g of 
5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3-carb 
oxylic acid and 2.1 g of dicyclohexylcarbodiimide were added to 50 ml of 
dimethylformamide, and the mixture was heated at 80.degree.-90.degree. C. 
for 5 hours. After cooling the reaction mixture, the precipitate was 
removed by filtration, and the filtrate was concentrated, then the residue 
was extracted with chloroform. The chloroform layer was washed with 
1N-sodium hydroxyde aqueous solution and with a saturated sodium chloride 
aqueous solution, then dried with anhydrous magnesium sulfate. The dried 
chloroform extract was concentrated and was purified by a silica gel 
column chromatography (eluant: chloroform/methanol=50/1). The elute was 
recrystallized from chloroform-isopropyl ether to yield 0.5 g of 
5-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethoxy}-3,4-dihydrocarbostyril in the form of yellowish powdery 
crystals. 
Melting point: 262.degree.-263.5.degree. C. 
EXAMPLE 50 
By a method similar to that described in Example 49, there were prepared 
compounds of Examples 2, 4-8, 11-14, 16, 24, 26-29, 32 and 33-48. 
EXAMPLE 51 
1.3 Grams of 
6-{2-[2-(3-nitrobenzyliden)acetoacetoxy]ethoxy}-3,4-dihydrocarbostyril and 
0.5 g of methyl 3-aminocrotonate were added to 10 ml of pyridine and the 
mixture was refluxed for 8 hours. The reaction mixture was concentrated, 
then the residue was extracted with chloroform, washed with a saturated 
aqueous solution of potassium hydrogensulfate and with a saturated aqueous 
solution of sodium chloride, and dried with anhydrous magnesium sulfate. 
The dried extract was concentrated and the residue was purified by a 
silica gel column chromatography (eluant: chloroform/methanol=100/1), then 
was recrystallized from chloroform-ether to yield 0.92 g of 
6-{2-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]ethoxy}-3,4-dihydrocarbostyril in the form of light yellowish 
powdery crystals. 
Melting point: 172.5.degree.-174.degree. C. 
EXAMPLE 52 
By a method similar to that described in Example 51, there were prepared 
compounds of Examples 1-25 and 27-48. 
EXAMPLE 53 
15 Grams of 
5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-(2-tetrahydropyranoxy)-3,4-dihydrocarbostyril were 
added to a mixture of 100 ml of tetrahydrofuran and 30 ml of water, then 2 
ml of 10%-hydrochloric acid were added to the mixture which was stirred at 
room temperature overnight. The reaction mixture was concentrated and the 
residue was extracted with chloroform, then the chloroform extract was 
washed with a saturated aqueous solution of sodium chloride, and with a 
saturated aqueous solution of sodium hydrogencarbonate, then dried with 
anhydrous magnesium sulfate, and the dried extract was concentrated. To 
the residue obtained was added ether and the insoluble matter formed was 
collected by filtration, then recrystallized from water-containing 
methanol to yield 8.9 g of 
5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-hydroxy-3,4-dihydrocarbostyril in the form of 
yellowish prismatic crystals. Melting point: 193.5.degree.-194.degree. C. 
EXAMPLE 54 
2.7 Grams of 
5-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]propoxy}-8-hydroxy-3,4-dihydrocarbostyril, 0.7 g of potassium 
carbonate and 0.74 g propyl bromide were added to 30 ml of acetone and the 
whole mixture was refluxed for 3 hours. The reaction mixture was 
concentrated and the residue was extracted with chloroform, the extract 
was washed with 1N-sodium hydroxide aqueous solution, then the precipitate 
formed was removed by filtration. The organic layer was washed with a 
saturated sodium chloride aqueous solution, then dried with anhydrous 
magnesium sulfate and was concentrated. The residue obtained was purified 
by a silica gel column chromatography (eluant: chloroform/methanol=100/1), 
then the elute was concentrated and the residue was recrystallized from 
methanol to yield 0.8 g of 5-{3-[2,6-dimethyl-5-methoxy 
carbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3-carboxy]propoxy}-8-propoxy 
-3,4-dihydrocarbostyril in the form of light yellowish prism-like crystals. 
Melting point: 150.5.degree.-152.0.degree. C. 
EXAMPLE 55 
By a method similar to that described in Example 54, there were prepared 
compounds of Examples 3, 9, 15 and 24. 
EXAMPLE 56 
3.2 Grams of 6-(4-acetoacetoxybutoxy)-3,4-dihydrocarbosyril, 1.5 g of 
2-methylmercaptobenzaldehyde and 1.2 g of methyl 3-aminocrotonate were 
added to 20 ml of isopropanol, and the reaction mixture was refluxed for 8 
hours under heating. The reaction mixture was then concentrated, and the 
residue obtained was purified by a silica gel column chromatography 
(eluant: chloroform/methanol=50/1). The elute was concentrated, and to the 
residue obtained was added 50%-water-containing methanol and with stirring 
at room temperature for 2 days to precipitate crude crystals. The crude 
crystals were recrystallized from water-containing methanol to yield 1.2 g 
of 
6-{4-[2,6-dimethyl-5-methyl-5-methoxycarbonyl-4-(2-methylthiophenyl)-1,4-d 
ihydropyridin-3-carboxy]butoxy}-3,4-dihydrocarbostyril in the form of light 
yellowish needle-like crystals. 
Melting point: 90.degree.-92.degree. C. 
EXAMPLE 57 
3.0 Grams of methyl .beta.,.gamma.-epoxypropyl 
2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylate, 1.25 
g of 6-hydroxy-3,4-dihydrocarbostyril and 1.1 g of potassium carbonate in 
30 ml of dimethylformamide were heated at 100.degree.-120.degree. C. for 4 
hours with stirring. Dimethylformamide was removed from the reaction 
mixture by distillation, then to the residue obtained was added water then 
the mixture was extracted with chloroform. The chloroform extract was 
washed with water, dried and the solvent was removed by distillation. The 
residue obtained was purified by a silica gel column chromatography 
(eluant: chloroform, next with chloroform/methanol=50/1), and the eluate 
was recrystallized from chloroform-isopropyl ether to yield 1.2 g of 
6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-hydropropoxy}-3,4-dihydrocarbostyril in the form of yellowish 
powdery crystals. 
NMR .delta. (CDCl.sub.3); 2.25 (3H, s), 2.29 (3H, s), 2.30-2.90 (4H, m), 
3.53 (3H, s), 3.50-3.9 (2H, m), 3.90-4.30 (3H, m), 5.00 (1H, s), 6.50 (3H, 
bs), 6.70 (1H, bs), 7.00-8.00 (4H, m), 8.81 (1H, bs). 
EXAMPLE 58 
By a method similar to that described in Example 57, there was prepared the 
compound of Example 36, by using a suitable starting material. 
EXAMPLE 59 
To 3 ml of a pyridine solution containing 0.8 g of 
6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-hydroxypropoxy}-3,4-dihydrocarbostyril was added 0.3 ml of 
acetic anhydride and the mixture was stirred at room temperature 
overnight. Then water was added to the reaction mixture, and the mixture 
was extracted with ethyl acetate. The ethyl acetate extract was washed 
with water, dried, the solvent was removed by distillation, and the 
residue obtained was recrystallized from chloroform-isopropyl ether to 
yield 0.4 g of 
6-{3-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 
3-carboxy]-2-acetoxypropoxy}-3,4-dihydrocarbostyril in the form of a 
yellowish powdery substance. 
NMR .delta. (CDCl.sub.3); 2.00 (3H, s), 2.27 (3H, s), 2.30 (3H, s), 2.50 
(2H, t, J=7 Hz), 2.84 (2H, t, J=7 Hz), 3.89 (3H, s), 3.83 (2H, t, J=6 Hz), 
4.23 (2H, t, J=5 Hz), 5.00 (1H, s), 5.10-5.30 (1H, m), 6.40-6.70 (3H, m), 
6.70 (1H, bs), 7.10-8.00 (4H, m), 8.96 (1H, bs). 
EXAMPLE 60 
By a method similar to that described in Example 59, by using a suitable 
starting material, there was prepared a compound of Example 37. 
EXAMPLE 61 
In 20 ml of chloroform, 0.44 g of 1,5-diazabicyclo[5,4,0]undecene-5 (DBU) 
and 0.6 g of 4-(6-carbostyriloxybutyric acid were dissolved, then under an 
ice-cooled condition, 0.36 g of isobutyl chloroformate was added dropwise 
thereto. The reaction mixture was stirred at the same temperature for 2 
hours, next 1 g of N-cyclohexylaminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate was 
added to the reaction mixture which was stirred at room temperature 
overnight. The precipitate formed was removed by filtration, the filtrate 
was washed with 5%-hydrochloric acid aqueous solution, 2%-sodium hydroxide 
aqueous solution, then with a saturated sodium chloride aqueous solution, 
and dried with anhydrous magnesium sulfate. The organic layer was 
concentrated, and the residue was purified by a silica gel column 
chromatography (eluant: chloroform/methanol=50/1), then the eluate was 
recrystallized from water-containing methanol to yield 0.4 g of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridin 
-3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)-butyramide in the form 
of yellowish powdery crystals. 
______________________________________ 
Elementary analysis: as C.sub.37 H.sub.42 H.sub.4 O.sub.9 
C H N 
______________________________________ 
Calculated (%): 
64.71 6.16 8.16 
Found (%): 64.35 6.12 8.06 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 1. 
NMR (90 MHz, CDCl.sub.3, Zevo, Ref. TMS): As shown in FIG. 2. 
EXAMPLES 62-66 
By a method similar to that described in Exampel 61, there were prepared 
compounds of Examples 62-66 as follows: 
EXAMPLE 62 
N-{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3 
-carboxy]ethyl}-N-cyclohexyl-4-(3,4-dihydro-6-carbostyriloxy)butyramide. 
Yellowish powdery crystals (from chloroformisopropyl ether). 
______________________________________ 
Elementary analysis for C.sub.37 H.sub.44 N.sub.4 O.sub.9 : 
C H N 
______________________________________ 
Calculated (%): 
64.52 6.44 8.14 
Found (%): 64.25 6.35 8.04 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 3. PG,111 
NMR (90 MHz, CDCl.sub.3, Zevo, Ref. TMS): As shown in FIG. 4. 
EXAMPLE 63 
N-{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3 
-carboxy]ethyl}-N-cyclohexyl-4-(5-carbostyriloxy)butyramide. 
Yellowish powdery crystals (from chloroformisopropyl ether). 
______________________________________ 
Elementary analysis for C.sub.37 H.sub.42 N.sub.4 O.sub.9 : 
C H N 
______________________________________ 
Calculated (%): 
64.71 6.16 8.16 
Found (%): 64.45 6.08 7.95 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 5. 
NMR (90 MHz, CDCl.sub.3, Zevo Ref. TMS): As shown in FIG. 6 
EXAMPLE 64 
N-{2-[1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridin-3 
-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide. 
Yellowish powdery crystals (from chloroformisopropyl ether). 
______________________________________ 
Elementary analysis for C.sub.37 H.sub.42 N.sub.4 O.sub.9 : 
C H N 
______________________________________ 
Calculated (%): 
64.71 6.16 8.16 
Found (%): 64.33 6.04 8.12 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 7 
EXAMPLE 65 
N-[2-(1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridin-3-carboxy) 
ethyl]-N-cyclohexyl-4-(6-carbostyriloxy)butyramide. 
Colorless powdery crystals (from chloroformisopropyl ether). 
______________________________________ 
Elementary analysis for C.sub.37 H.sub.43 N.sub.3 O.sub.7 : 
C H N 
______________________________________ 
Calculated (%): 
69.24 6.75 6.55 
Found (%): 68.95 6.70 6.35 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 8. 
NMR (90 MHz, CDCl.sub.3, Zero Ref. TSM): As shown in FIG. 9. 
EXAMPLE 66 
N-[2-(1,4-Dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridin-3-carboxy) 
ethyl]-N-ethyl-4-(6-carbostyriloxy)butyramide. 
Colorless powdery crystals (from chloroformisopropyl ether). 
______________________________________ 
Elementary analysis for C.sub.33 H.sub.37 N.sub.3 O.sub.7 : 
C H N 
______________________________________ 
Calculated (%): 
67.44 6.35 7.15 
Found (%): 67.26 6.10 7.08 
______________________________________ 
Infrared absorption spectrum (KBr): As shown in FIG. 10. 
NMR (90 MHz, CDCl.sub.3, Zevo Ref. TMS): As shown in FIG. 11. 
EXAMPLE 67 
To 20 ml of dimethylformamide, were added 1.2 g of 
4-(-3,4-dihydro-6-carbostyriloxy)butyric acid, 2.0 g of 
2-cyclohexylaminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridin-3,5-dicarboxylate and 
1.1 g of dicyclohexylcarbodiimide, then the mixture was stirred at 
60.degree. C. for 4 hours. After cooling, the precipitates were removed by 
filtration and the filtrate was concentrated, then the residue was 
purified by a silica gel column chromatography (eluant: 
chloroform/methanol=50/1), and the eluate was recrystallized from 
chloroform-isopropyl ether to yield 0.4 g of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(3,4-dihydro-6-carbostyriloxy)butyramide. 
This substance shows the same physical properties of those of the compound 
prepared in Example 2. 
EXAMPLE 68 
By a method similar to that described in Example 67, there were prepared 
compounds of Examples 61 and 63-66. 
EXAMPLE 69 
1.6 Grams of 6-hydroxycarbostyril and 1.5 g of potassium carbonate were 
added to 30 ml of dimethylformamide and the mixture was heated at 
80.degree.-90.degree. C.; then to this reaction mixture was added dropwise 
a dimethylformamide solution containing 6 g of 
2-N-(4-chlorobutyryl)-N-cyclohexylaminoethyl methyl 
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine 3,5-dicarboxylate. Then 
the reaction mixture was stirred for 6 hours at the same temperature. The 
reaction mixture was concentrated, then the residue obtained was extracted 
with chloroform, and the chloroform extract was washed with water, 
0.5N-sodium hydroxide, 5%-hydrochloric acid and a saturated sodium 
chloride aqueous solution, then dried with anhydrous magnesium sulfate. 
The dried chloroform extract was concentrated, then the residue was 
purified by a silica gen column chromatography (eluant: 
chloroform/methanol=50/1), and recrystallized from a water-containing 
methanol to yield 0.3 g of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostryriloxy)butyramide. This 
substance shows physical properties the same as those of the compound of 
Example 61. 
EXAMPLE 70 
By a method similar to that described in Example 69, there were prepared 
compounds of Examples 62-66. 
Example 71 
3.0 Grams of 
1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridin-3-carb 
oxylic acid, 3.8 g of 
N-(2-hydroxyethyl)-N-cyclohexyl-4-(6-carbostyriloxy)butyramide and 2.1 g 
of dicyclohexylcarbodiimide were added to 30 ml of dimethylformamide, then 
the mixture was heated at 60.degree. C. for 2 hours. Then the reaction 
mixture was cooled, and filtered, the filtrate obtained was concentrated, 
and the residue obtained was purified by a silica gel column 
chromatography (eluant: chloroform/methanol=50/1). Recrystallization from 
chloroform-isopropyl ether yielded 0.3 g of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide. This 
substance shows the same physical properties as those of the compound of 
Example 64. 
EXAMPLE 72 
A method similar to that described in Example 71, there were prepared 
compounds of Examples 61-63, 65 and 66. 
EXAMPLE 73 
To 20 ml of methanol, were added 3 g of 
N-{2-[2-(3-nitrobenzyliden)acetoactoxy]ethyl}-N-cyclohexyl-4-(6-carbostyri 
loxy)butyramide and 0.6 g of methyl 3-aminocrotonate, then the mixture was 
refluxed for 15 hours. The reaction mixture was concentrated, and the 
residue obtained was purified by a silica gel column chromatography 
(eluant: chloroform/methanol=50/1). The elute was recrystallized from a 
water-containing methanol to yield 0.3 g of 
N-{2-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin- 
3-carboxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the form of 
yellowish powdery crystals. This product shows physical properties the 
same as those of the compound prepared in Example 61. 
EXAMPLE 74 
By a method similar to that described in Example 73, there were prepared 
compounds of Examples 62 and 63.