CA1081232A - 5-(3-substituted-2-hydroxypropoxy)-8-substituted-carbostyril and 3,4-dihydrocarbostyril compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Carbostyril derivatives represented by the formula (I)

Description

108~232 1 BACKGROUND OF T~IE INVENTION

1. Field of the Invention -This invention relates to carbostyril deriva~ives and a process for preparing the same. More particularly, this invention relates to carbostyril derivatives represented by the formula (I) hereinafter described, the pharmaceutically acceptable acid addition salts thereof/ and a process for preparing the carbostyril derivatives of the formula (I)~

lO 2. Description of the Prior Art ~

It is well known that certain carbostyril derivatives ~`
exhibit useful pharmaceutical activities Representative compounds of this type have been disclosed in Journal of Medical Chemistry, Vol. 15, No. 3r pp. 260-266 tl972), Japanese Patent Publication No. 38789/1971 and Chemical Abstracts, 62, 16212e (1965), etc. However, these prior art references do not teach that the compounds having a wide variety of sub-stituents at the 1-, 5- and/or 8-position of the carbostyril or 3,4-dihydrocarbostyril moiety possess an excellent adreno-receptor blocking activity.
Hitherto, various carbostyril compounds have been disclosed as having a ~-adrenoreceptor blocking a-ctivity~
For example, U.S. Patents 3,340,266, 3,910,924 and 3,953,456, and German Patent Application DT 2,549,889 disclose that carbo-styril or 3,4-dihydrocarbostyril derivatives having a (2-hydroxy-3-substituted-amino)propoxy group at the 5-, 6-, 7~ or 8-position of the carbostyril or 3,4-dihydrocarbostyril nucleus possess a ~-adrenoreceptor blocking activity.
However, these ~-adrenoreceptor blocking agents, i.e., ~-blockers, are usuallv contraindication to subject suffering _ .

~L08~ J~
1 from bronchial asthma and, thereEo~e, it ha~ been desired to develop B-blockers having a high cardioselectivity.
Recently, carbostyril compounds haviny a (2-hyd.roxy-3-substitute~-~mino)propoxy yroup at the 5-position of the carbostyril nucleus were found to have a cardioselective ~
adrenoreceptor bloc~ing activity, as disclosed in German Patent Applica-tion DT ~,615,406. SUch cardioselective ~-blockers would be very useful for treatment of cardiac disorders such as angina pectoris, heart arrhythmia and hypertension. The :
10 compounds of the present .invention were also found to have .::
excellent cardioselectivity better than that of these ~nown compounds and are useful in treatm~nt or prophylaxis of cardiac disorders in subjects suffering also from chronic obstructive lung disease such as bronchial asthma.

DETAILED DESCRIPTION OF T~IE INVENTION
As a result of extensive studies, it was found that the carbostyril derivatives having the formula (I) OH
~CH2-CHCH2N ~ 3 . :~

2~ \ R : .:
~ ~ 4 '' Rl wherein Rl represents a hydrogen at.o~, an alkyl group or a phenylalkyl group, R2 represents a hydrogen atom, an alkyl ~:
group, a phenylalkyl group, an alkenyl group, an alkoxyalkyl yroup, a hydroxyalkyl group, a carboxyalkyl group, an alkyl-carbonyl group, a cycloalkylcarbonyl group, an alkylcarbonyl~
: . :
alkyl group, an alkoxycarbonylalkyl group, an alkynyl group or a carbamoylalkyl group, R3 and R~, which may be the same ~; .
~ -2-~
.

3~ :

1 or di~ferent, each represen-ts ~ hyclro~en atom, an alkyl group, a cycloal~yl group, an alkoxyalkyl group, an alkenyl group, a phenylalkyl group, a phenoxyalkyl yroup, a heterocyclic alkyl group or a phenyl group, or R3 and R4 can form, when taken together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic ring which may contain a nitrogen atom or an oxygen atom as an additional hetero atom, the 3,4-bond of the carbostyril nucleus represents a single or double bond, with the proviso that, when one of R3 and R4 represents a hydrogen atom and the other represents an alkyl group, and Rl represents a hydrogen atom, then R~ cannot be a hydrogen atom, an alkyl group or a phenylalkyl group having no substituents on the phenyl moiety thereof, pharmaceutically acceptable acid addition salts thereof, possess an excellent cardioselective ~-blocking activity.
The term "alkyl" as used herein for Rl, R2, R3 and R4 means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl group and the like-The term "cycloalkyl" as used herein ~or R3 and R4 meansa cycloalkyl group having 3 to 7 carbon atoms, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group and the like.
The term "phenylalkyl" as used herein ~or Rl, R2, R3 and R4 means a monophenylalkyl or diphenylalkyl group having a -2a~

. i ~ ,.~

~08~

1 s-traight or br~nched chain alkyl ~roup having 1 -to 6 carbon atoms in the alkyl moiety and includes, for example, a ~enzyl, 2-phenylethyl, l-phenylethyl, 2-methyl-2-phenylpropyl, diphenyl-methyl, 2,2-diphenylethyl, ~-phenylbutyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-4-phenylbutyl, 2-methyl-3-phenylpropyl group and the like.
The term "alkenyl" as used herein for R2, R3 and R4 means a straight or branched chain alkenyl group having 2 to 6 carbon atoms and includes, for example, an ethylenyl, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 1-methyl-2-butenyl, 2-hexenyl, 4-hexenyl group and the like.
The term "alkoxyalkyl" as used herein for R2, R3 and R4 means an alkoxyalkyl group having a straight or branched chain alkoxy group of 1 to 6 carbon atoms in the alkoxy moiety thereof and a straight or branched chain alkylene group of 1 to 6 carbon atoms in the alkyl moiety thereof and includes an ethoxymethyl, 2-methoxyethyl, 2-isopropoxyethyl, 3-butoxypropyl, 5-sec-butoxy-pentyl, 4-hexyloxybutyl, 6-pentylo~yhexyl, 3-ethoxybutyl and the .-like.
The term "hydroxyalkyl" as used herein for R2 means a : : .
monohydroxyalkyl group having a straight or branched chain alkyl group of 1 to 6 carbon atoms and includes, for example, a hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,

4-hydroxybutyl, 3-hydroxybutyl, 2-methyl-3-hydroxypropyl,

5-hydroxypentyl, ~-hydroxypentyl, 2-methyl-4-hydroxybutyl, 2-methyl-3-hydroxybutyl, 6-hydroxyhexyl, 5-hydroxyhexyl, 2-methyl-5-hydroxypentyl, 2-methyl-4-hydroxypentyl group and the lilce.
The term "carboxyalkyl" as used herein for R2 means a :~
carboxyalkyl group having a straight or branched chaln alkylene group of 1 to 6 carbon atoms in the alkyl moiety thereof and ~ - 3 -1%~2 1 includes, for example, a carbo~ymethyl, 2-carbo~yethyl, 3 carboxypropyl, ~-carboxybutyl, 2-carboxyhexyl, 3-carboxy-2-methylbutyl yroup and the like.
The term "alkylcarbonyl" as used herein for R2 means an alkylcarbonyl group having a straight or branched chain alkyl group of 1 to 6 carbon atoms in the alkyl moiety thereof and includes, for example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl group and the like.
The term "cycloalkylcarbonyl" as used herein ~eans a ~ cycloalkylcarbonyl group having a cycloalkyl group of 3 to 7 carbon atoms in the cycloalkyl moiety thereof and includes, for example, a cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl- ;
carbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl group and the like.
The term "alkylcarbonylalkyl 1l as used herein for R2 means an alkylcarbonylalkyl group having a stxaight or branched chain alkylene group of 1 to 6 carbon atoms and the alkylcarbonyl group as defined above and includes, for example, a methyl-carbonylmethyl, ethylcarbonylmethyl, 2-ethylcarbonylethyl, 2-20 isopropylcarbonylethyl, 3-sec-butylcarbonylpropyl, 6- .
hexylcarbonylhexyl, 3-ethylcarbonyl-2-methylpropyl group and the like.
The term "alkoxycarbonylalkyl" as used herein for R2 means an alkoxycarbonylalkyl group having an alkoxycarbonyl moiety consisting of a straight or branched chain alkoxy group having 1 to 6 carbon atoms a-ttached to a carbonyl group and a straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety and includes, for example, a methoxy-carbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-sec-butoxycarbonylpropyl, 5-isobutoxy-- 3~-~81'~3i2 1 carbonylpentyl, 6-hexyloxycarbonylhexyl, ~-ethoxycarbonyl-2-methylbutyl group and the like.
The term "alkynyl" as used herein for R2 means a straight or branched chain alkynyl group having 2 to 7 carbon atoms and includes, for example, 2-propynyl, l-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1-methyl-3-butynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, l-methyl-3-pentynyl, 2-heptynyl, 3-heptynyl group and the like.

The term "carbamoylalkyl" as used herein for R2 means a carbamoylalkyl group having a straight or branched chain alkylene group of 1 to 6 carbon atoms in the alkyl moiety thereof.
and a carbamoyl group which may be substituted.on the nitrogen atom thereof with an alkyl group having 1 to 6 carbon atoms ~r a substituted or unsubstituted phenylalkyl group and includes, for example, a carbamoylmethyl, 3-carbamoylpropyl, 4-carbamoyl- :.
butyl, 6-carbamoylhexyl, 2-~N,N-diethylcarbamoyl)ethyl, N-(3,4 dimethoxyphenethyl)carbamoylmethyl group and the like. ~ ~
The term "phenoxyalkyl" as used herein means a phenoxy- ~ :
alkyl group having a straight or branched alkylene group of 1 to ;~

6 carbon atoms in the alkyl moiety thereof and includes, for example, a phenoxymethyl, 2-phenoxyethyl, l-phenoxyethyl, 2-methyl-2-phenoxypropyl, diphenoxymethyl, 2,2-diphenoxyethyl, 4-phenoxybutyl, 6-phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-4-phenoxybutyl, 2-methyl-3-phenoxypropyl group and the like.
The term "heterocyclic alkyl" as used herein for R3 and R4 means a heterocyclic alkyl group consisting of a straight or branched alkylene group of 1 to 6 carbon atoms and a 5- or 30 6-membered heterocyclic ring containing at least one nitrogen atom .
~, 10~31232 1 and, optionally, an additional nitrogen atom and/or an oxygen atom, the alk~lene ~roup being attached to the nitrogen atom of the heterocyclic ring. Examples of the heterocyclic alkyl yroup .
are a pyrrolidinomethyl, 2-piperazinoethyl, 3-morpholino-propyl, 2-piperazinopropyl, 2-imidazolidinoethyl, 3-piperazino-butyl, 6-morpholinohexyl group and the like.
The term "5- or 6-membered heterocyclic ring" as used herein means heterocyclic groups containing at least one nitrogen atom and, optionally, an oxygen atom as hetero atoms such as a piperidino, morpholino, pyrrolidino, piperazino, imidazolidino group and the like~
The above phenyl, phenylal~yl, phenoxyalkyl and heterocyclic alkyl groups and the heterocyclic ring may contain 1 to 3 substituents which may be the same or different.
Examples of such substituents include an alkyl group havlng 1 to 4 carbon atoms such as a methyl, ethyl, propyl, isopropyl, n-butyl, ter-butyl group and the like, an alkoxy group havin~
1 to 4 carbon atoms such as a methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy group and the likej a halogen atom such :
as a chlorine, bromine, iodine or fluorine atom, an alkylene-dioxy group having 1 to 2 carbon atoms such as a methylenedioxy or ethylenedioxy group and the like, a carbamoyl group, a substituted or unsubstituted phenyl group, etc.
Typical examples of groups having the above substituents are for example, 4-methoxyphenyl, 3-chlorophenyl, 3,4-methylenedioxy, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-chlorophenyl, 2-(4-fluorophenyl)ethyl, 2-(3,4-dibromophenyl)-ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,4,5-trimethoxyphenyl)-.
ethyl, 4-(3,4,5-triethoxyphenyl)butyl, 2-(3,4-methylenedioxyphenyl)-ethyl, 3-(3,5-dichlorophenyl)propyl, 2-(4-carbamoylphenyl)-.. ~ : . . .:
.

1~81;~3~

1 e-thyl, 2-(~-chloro-3,5-dime~hoxyphenyl)ethyl, 2-(2-isopropoxy phenyl~ethyl, 2-(3,~-dimethoxyphenoxy)ethyl, 2-(3,5-dimethoxy-phenoxy)ethyl, ~-(3,4,5--triethoxyphenoxy)butyl, 2-(3,~-ethylenedioxyphenoxy)ethyl, 2-(4-fluorophenoxy)ethyl, 2-(4-tert-butoxyphenoxy)ethyl, 3-(3,5-dichlorophenoxy)prop~l, 2-(4-carbamoylphenoxy)ethyl, 2-(~-chloro-3,5-dimethoxyphenoxy)ethyl, 2-(4-methoxyphenoxy)ethyl, 4-phenylpiperazino, 4-(4-methoxy-phenyl)piperazino, ~-(3-chlorophenyl)piperazino, 4-(4-chlorophenyl)piperazino, 4-ethylpiperazino, ~-(tert-butyl)-tO piperazino, 4-(2-methoxyphenyl)piperazino, 3-methyl-~-(4-chlorophenyl)piperazino, 3-isopropylpiperazino, 4-(3,4-methylenedio~yphenyl)piperazino, 2-chloropiperazino, 4-(3,4-dimethoxyphenyl)piperazino, 4-(2-methylphenyl)piperazino, 3-(~-ethylpiperazino)propyl, 2-~2-chloromorpholino)ethyl, 4-fluoropiperidino~ 3-ethylpiperidino, 2-isopropylpyrrolidino and the like.
The term "pharmaceutically acceptable acid addit1on salts" as used herein means those formed with pharmaceutically acceptable inorganic and organic acids which are well known in the art such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methane-sulLonic acid, benzoic acid and the like.
The chemical structure representing carbostyril com-pounds of the present invention used throughout the specifi-cation and claims of this invention, i.e., the partial structure having the formula:

~08~2~2 1 includes both carbos-tyril ancl 3,4-dihydrocarbostyril of the partial structure:

~ ~ and ~ ~

respectively. ;
The carbos-tyril derivatives represented by the formula (I) can be prepared by reacting a carbostyril compound of the formula ~II), i.e., a 2,3-epoxypropoxycarbostyril compound of the formula ~IIa) or a 2-hydroxy-3-halopropoxycarbostyril compound of the formula (IIb), with an amine compound of the formula (III), as i]lustrated by the following reaction scheme:
~CH2CH - CH2 O ~ ~R~

O-CH2Y ~ N /R3 R20 ~1 HN~ (III) ~ I o R2 ~ Rl l (IIa) ! ~ (I) (II) 1O-CH2CHCH2X
~0 R20 Rl (IIb) wherein Rl, R2, R3 and R4 are as defined above, and Y represents a -CH - CH2 group or a -CHCH2X group wherein X represents a halogen atom.
More specifically, -the starting matexial, carbostyril .. . .
. ~ . .~. :

1~31Z3Z

1 compounds of the formuJa (XI), can be either an epoxy Eorm haviny -the formul~ (IIa), a 2-hydroxy-3-halopropoxy form having the formula (IIb) or a mixture thereof.
The reaction between a 2,3-epoxypropoxycarbostyril compound of the formula ~IIa) and an amine of the formula (III) can be carried out in the absence of solvents, but is preferably conducted in ~he presence of a solvent, for example, ethers ;
such as dioxane, tetrahydrofuran and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, water, dimethylformamide, etc., more preferably in a polar solvent such as methanol, ethanol, isopropanol and the like.
The reaction can be carried out at a temperature of about 0C to 100C,preferably 0C to 70C, using an approxi-mately equimolar amount to a molar excess, preferably 3 to 8 mols, of the amine of the formula (III) per mol of the 2,3-epoxypropoxycarbostyril compound of the formula (IIa).
The reaction between a 2-hydroxy-3-halopropoxy-carbostyril of the formula (IIb) and an amine of the formula (III) can be advantageously carried out in the presence of a base, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, preferably sodium carbonate or potassium carbonate, but the reaction can be carried out in the absence of such base.
The reaction can be carried out at a temperature of about 0 to about 100C, preferably 20 to 80C, in the absence of solvents, but advantageously carried out in the presence of solvents, e.g., alcohols such as methanol, ethanol, propanol, isopropanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, water, etc., preferably alcohols such as methanol, ethanol, isopropanol and the like.

~. :

~O~LZ~

1 In the above reac-tion, the amine of the formula (III) is used in a molar excess, preferably 3 to 8 mols, per mol of the 2-hydroxy-3-halopropoxycarbostyril compound of the formula (IIb).
The reaction between a mixture of the carbostyril compounds of the formulae (IIa) and (IIb) and an amine compound of the formula (III) can be carried out in the presence or absence of the base set forth above at a temperature of about 0C to about 100C, preferably 50 to 80C. The type of solvents and the amount of the amine of the formula (III) which can be used in this reaction are the same as those set forth above for the reac-tion of the compound of the formula (IIa)or (IIb) with the amine of the formula (III).
` The time required for completing the reaction of the carbostyril compound of the formula (IIa), (IIb) or a mixture thereof with an amine varies depending upon the temperature used, but is generally about 0.5 to about 30 hours, more ~ :
generally, 2 to 14 hours.
The starting material of the formula (II) are novel compounds and can be derived from corresponding 5,8-dihydroxy-carbostyril compounds of the formula (IV) via various routes, as illustrated by Reaction Scheme 1 below.

. _ 9 _ .. . - : ~ .

1(~8~23~

Reactlon Scheme 1 ::
:~;

~ ~0 H H _ / \
/ I (IV) \~H - C~2 (v) ~:
R2 'xl (VI) (B) or (C) Rl'X2 (X~ ~

R2 ' \ ~\

VII` --~ jC112 (V) (C) ~) . ~
~0 ~o I I ~
Rl ' O Rl ' R2 . :~
(XIII) (IX) .

3~
- 10 - ''';''' '"

., .

lOBlZ;~

[From (IX) ] [Fr m (VII) ]

1 RI X2 (X) ~From ( IV) ]
[~ rom (XIII) ] ,~ (C) : .

HX3 (XIV) ~

~/ R2 ' l Rl (XI ) ~H ~!, H ( C ) H~XIV~

HO Rl (IV~ 2 ~ Rl ¦ ¦

\(D) XCH2CH - CH2 (V) (V) \ ~ (C) , ",)J

~OCH2Y
~0 (II) 1~)8~32 1 Representative proced~lres for the preparation of the starting ma-terials of -the formula (II) are as follows:

Method A
The carbostyr.il compounds of the formula (II~ wherein Rl and R2 both represent hydrogen atoms can be prepared by reacting a known dihydroxycarbostyril compound of the formula (IV) with an epihalohydrin of the formula (V) in the presence of a base.
ethod B
1 0 ' The carbostyril compounds of the formula (II) wherein Rl represents a hydrogen atom and R2 represents R2' which represents a group as defined by R2 except for a hydrogen atom, :
can be prepared by reacting a known compound of the formula (IV) with a halide of the formula R2'Xl wherein R2' is as defined above and Xl represents a halogen atom, in the presence of a base to produce a hydroxycarbostyril compound of the formula (VII) and then reacting.the thus obtained hydroxycarbostyril :
compound of the formula (VII) with an epihalohydrin of the :~
formula (V) in the presence of a base. -`

Method C
The carbostyril compounds of the ormula (II) wherein Rl represents Rl' which represents a group as defined by Rl except for a hydrogen atom and R2 represents R2' which is as defined above, can be prepared by reacting a compound of the~ :~
formula (VII) with a 2,3-dihydropyran of the formula (VIII) to produce a tetrahydropyranyl compound of the formula (TX) ::
wherein the hydroxyl group at the S-position is protected with a tetrahydropyranyl group, reacting the thus obtained compound of the formula (IX) with a halide of the formula (X) [Rl'X2] in the presence of a base to produce a carbostyril compound of the .. ~ :.

~ ' - , . . , ~ - .

~ Z 3Z

1 formula (XI), hydrolyz.ing the compound of the formula (XI) to produce a correspond.ing hydroxycarbostyri.l compound of the formula (XII) and reactiny the thus obtained hydroxycarbostyril compound of the formula (XXI) with an epihalohydrin of the formula (V) in the presence of a base. Alternatively, the compound of the ~ormula (XII) can be derived from the compound of the formula (XV).

Method D
. .
The carbostyril compounds of the formula (II) wherein Rl represents Rl' which is as defined above and R2 represents a hydrogen atom can be prepared by reacting a compound of the formula (IV) with a halide of the formula (X) [Rl'X2] in the presence of a base to produce a carbostyril compound of the formula (XIII), hydrolyzing the compound of the formula (XIII) to produce a compound of the formula (XV) and then reactiny the thus obtained compound of the formula (XV) with an epi-halohydrin of the formula (V) in the presence of a base.
Alternatively, the compound of the formula (XV) can ~ ;

be prepared from the corresponding compound of the formula (XI) or (XII) by hydrolysis.
The carbostyril derivatives represented by the formula (II) include the compounds of the formulae (IIa), (IIb), (IIc) and (IId), as illustrated in Reaction Scheme 2 below, and the compounds can be converted interchangeably as shown by arrow lines.
:

- 13 - :

3%

Rea c tion ~S cheme 2 I C~12Y I CH2Y

B > ~ Rl ' X2 (X) > ~ A~ C

H
OR2 ~
(IIb) j71 (IIc) . o R2 Xl T ~x2 (x) 1 ~ R2 xl (v OCH2Y OC 2Y :~

A ~ ~ ~ O ~;

(IIa) (IId) The processes for preparing the starting compound of the formula (II) of the present invention are further :
illustrated hereina~ter in greater detail. ;
The reaction between the compound of the formula (IV), ::
~VII), (XII) or (XV) and an epihalohydrin of the formula (V) can be carried out in the presence of a base at a temperature of about 0 to about 150C, preferably 50 to 100C, in the ;~ ;
absence or, preferably, in the presence of a solvent.

Suitable examples of bases which can be used in the : ~
above reaction are inorganic bases, for example, alkali metal :
hydroxides such as sodium hydroxide, potassium hydroxide and 3~ the like, alkali metal carbonates such as sodium carbonate, ;
potassium carbonate and the like, alkali metals such as sodium, ,' - 1~ - .

, . . . . .

8~32 1 potassi~ and the like, or organi.c bases such as pyridine, piperidine, piperazine and the like~
Suitable examples of solvents which can be used in the above reaction are lower alcohols such as methanol, ethanol, isopropanol and the like, ketones such as acetone, methyl ethyl ketone and the like, ethers such as diethyl ether, dioxane and the like, and aromatic hydrocarhons such as benzene, toluene, xylene and the like, preferably methanol and ethanol.
The epihalohydrin of the formula (V) can be epi-chlorohydrin, epibromohydrin or epiiodohydrin and can beused in an amount of about 1 to about 3 mols, preferably 1 to 1.5 mols, per mol of the compound of the formula (IV) or (XV) and in an approximately equimolar amount to a molar excess amount, preferably 5 to 10 mols, per mol o the compound of the formula (VII) or (XII).
In the above reaction, the hydroxyl group attached to the 5-position of the compounds of the formulae (IV?, (VII), (XII) and (XV) is converted into a (2,3-epoxy)propoxy group or a 3-halo-2-hydroxypropoxy group and the resulting reaction product is usually a mixture of corresponding 5-(2,3-epoxy)-propoxy compound and 5-(3-halo-2-hydroxypropoxy) compound.
The mixture ~ se thus obtained is usually used for the subsequent reaction with an amine of the formula (III) without isolating each of the compounds, but, if desired, each of the compounds can be isolated and purified by conventional procedures, for example, by fractional crystall.ization, column chromatography and then reacted with an amine of the formula (III).
The reaction between the compound of the formula ~IIa), (IIb), (IX) or (IV) and a compound of the formula (X) [Rl'X2]

~0~3lZ3'~ ;

1 can be carried out by first converting the compound of the Eormula (IIa), (IIb), (IX) or tIV) into an alkali me-tal salt thereoE by reacting the compound with a base such as an alkali metal or an alkali metal compound, for example, sodium hydride, potassium hydride, sodium amide, sodium potassium and the like.
The conversion of the compound having the formula (IIa), ~IIb), (IX) or (IV) into an alkali metal salt thereof can be conducted at a temperature of about 0 to about 200C, pre-ferably room temperature to 50C in a solvent, for example, :
1~ aromatic solvents such as benzene, toluene, xylene and the like, n-hexane, cyclohexane, ethers such as diethyl ether, :
1,2-dimethoxyethane, dioxane and the like, non-protonic polar solvents such as dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide and the like, preferably non-. .
protonic polar solvents.
The alkali metal or the alkali metal compound can be used in an amount of about 1 to about 5 mols, preferably 1 to 3 mols, per mol of the compound of the formula (IIa), or (IX), ~ . .
and in an amount of about 2 to about 10 mols, preferably 3 to .~
~ 5 mols, per mol of the compound of the formula (IIb) or (IV). ~ ;`
The resulting alkali metal salts o~ the compounds of the formulae (IIa), (IIb), (IX) and (IV) can then be reacted : :
with a halide of the formula ~X). This reaction proceeds .
smoothly in a solvent such as dimethylformamide, dimethyl sulfoxide and the like at room temperature (about 15 to 30C).
The halide (X) can be used in an amount of about 1 to about 5 mols, preferably 1 to 3 mols, per mol of the compound .
of the formula (IIa) or (IX), and in an amount of about 2 to about 10 mols, preferably 3 to 5 mols, per mol of the compound of the formula (IIb) or (IV).
~.

"

`8~Z3Z

1 The reaction between the compound of the formula (IIa), (IId), (IV) or (XV) and a halide of the formula (VI) [R2'Xl]
can be carried out in the presence of a base without using a solvent, but a solvent, e.~., ethers, such as dioxane, diethyl ether, tetrahydro~uran and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ketones such as acetone, methyl ethyl ketone, acetophenone and the like, dimethylformamide, ace~onitrile, methanol, ethanol, etc. can be used.
Suitable examples of bases which can be used in the above reaction are inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like, alkali metals such as sodium, potassium and the like, or organic bases such as pyridine, piperidine, piperazine and the like.
The reaction between the compound of the formula (IV) or tXV) and the halide (VI) can be conducted using about 1 mol to about 3 mols, preferably 1 to 1.5 mol, of the halide per mol of the compound of the formula (IV) or tXV) at a temperature of about 0C to about 100C, preferably at 50 to 8ac.
The reaction of a compound of the formula (VII) with a 2,3-dihydropyran can be conducted in a solvent in the presence of a catalyst at a temperature of about 0C to a boiling point of the solvent used, preferably at room temperature to 50C.
Suitable examples of solvents which can be used in the above reaction are aromatic solvents such as benzene, toluene, xylene and the like, n-hexane, cyclohexane, ethers such as diethyl ether, 1,2-dimethoxyethane, dioxane and the like, 1 chloroEorm, dime-thylform~mide, hexamethylphosphoric triamide, dimethyl sulfoxide and the like.
Suitable examples of catalysts which can be used in the above reaction are inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and the like, organic acids such as acetic acid, p-toluenesul~onic ~ ;
acid, methanesulfonic acid and the like, Lewis acids such as aluminum chloride, zinc chloride, boron trifluoride and the like, thionyl chloride, etc., in an amount of about 0.1% to about 5~, preerably 0.5% to 3~, by weight based on the weight of the compound of the formula (VII).
The removal of the tetrahydropyranyl yroup -from the .
compound of the formula (IX) can be achieved by using an acid in a solvent, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, n-hexane, cyclohexane, e-thers such as diethyl ether, 1,2-dimethoxyethane, dioxane . .
and the like, hydrated solvents for example, alcohols such as methanol, ethanol,propanol and the like, chloroform, dimethyl- - ;.~ .
formamide, hexamethylphosphoric triamide, dimethyl sulfoxide ~ ;
and the like, at a temperature of about room temperature to a boiling point of the solvent used, preferably room temperature to 50C. . .
Suitable examples of acids which can be used in the removal o~ tetrahydropyranyl group are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic .
acid and the like, and organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, : particularly preferred acids are weakly acidic inorganic and organic acids, for example, phosphoric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. The .

, 1 amount of acids used is no-t critical and can be a large excess relative to the compound of the Eormula (IX).
The hydrolysis reaction of the compound of the formula (XI), (XII) or (XIII) can be carri.ed out using a hydrogen halide such as hydrogen bromide, hydrogen chloride, hydrogen iodide. Generally, the hydrogen halide is used together with an appropriate solvent, in particular, with an aqueous medium, in the form of a hydrohalie acid. A particularly preferred example of the hydrogen halide is hydrogen bromide which is usually used as an aqueous solution having a concentration of about 10 to 50%, preferably 47%. The hydrogen halide can be used in an approximately 1 mol to a molar excess, preferably in a large exeess amount, relative to the eompound of the formula (XI), (XII) or (XIII).
The hydrolysis ean be advantageously earried out under heating at a temperature of about 100 to about 150C.
The compounds of the present invention having the formula (I) can be eonverted interehangeably into different types of eompounds within the formula (I), as illustrated by Reaetion Seheme 3 below.

Reaetion Seheme 3 N~R3 ~N ~ 3 OH Rl R O R
(Ib) ~ 2 1 (Ie) 2 ~ R = o~ 2N \

N o R O

(Ia) (Id) ~08~Z3'~
1 The conversi.Qn of a compound havlng a -OR2 g~oup at the 8-position into a corresponding compound having a -OH group at the 8-position can be achieved by catalytic reduction or hydro~enation u~ing a reducing agent, or alkali hydrolysis or mild acid hydrolysis. Examples of R2 ~roups which can easily be removed by the above procedures are aralkyl groups such as a benzyl group, an ~-methylbenxyl group and the like, and acyl yroups For example, the compounds of the formulae (Id) and (Ic) having a benzyl group as R2 can be catalytically reduced in the presence of a catalyst which is generally used for catalytic reduction, for example, Raney nickel, palladium-carbon, palladium black, platinum oxide and the like to produce a corresponding compound of the formulae (Ia) and (Ib), respectively.
The above catalytic reduction can be carried out in a solvent, for example, lower alcohols such as methanol, ethanol, isopropanol and the like, acetic acid, water, etc. The reaction -conditions which can be used in the catalytic reduction are not critical and generally the reduction proceeds under atmospheric ~O pressure at room temperature.
The thus obtained compounds of the formula (I) can be converted into their pharmaceutically acceptable acid addition salts thereof as previously described by conventional procedures which are well known in the art.
The compounds of the present invention as well as the intermediates therefor previously described can be isolated from the reaction mixture obtained in each step in conventional manners, for example, by distilling off the solvent used. If necessary, the resulting compounds can be purified by conventional 3~ procedures such as frictional crystallization, column chroma-tography and the like.

Z3~

1 As is apparent to one skilled in the art, the carbostyril compounds of the formula (I) can be prepared through various routes. Representative routes which can be used are shown in Reaction Scheme 4 below.

Reaction Scheme 4 OH

~ ~ (IVj X4cH2cHcH2oH (XVI

CH2 - CHCH20H / . 1 2 \ R
(XVIII) /
/ (XVI) ~ ~ (VII) .

- 21 - ~ ~

~Q8~'Z32 [Yrom (IV)] [From (VII)] [From (VII)] [From (VII)] [From (IV)]

XVII) OH
(XVIII) ~

OCH CHCH2OH / ~ ¦ ~R3 or ) 2 Rl ~ YlC 2 ~R4 ~N O (XIX) ~R3 (XVI) R O R O YCH2N~ . ~ ;

50 X ~XVII) \ ~ ~ Y I M~R3 ~;0502R5 1 ~R3 XVI) R20 1 R3 OCH2CHCH2N .

~XXI) ~ , R~

R ~

wherein ~1 represents Y or OS02R5 wherein R5 represents a lower alkyl group or a phenyl group, and X4 and X5 each represents a halogen atom. : :
Further, the present invention includes, in its scope, optical isomers of the carbostyril compounds of the formula (I).
The carbostyril compounds of the present invention of the formula (~) can be easily converted into oxazolidine~
30 carbostyril derivatives which can be produced by condensing a ~O~lZ3~

1 carbostyril compound oE the formula (I) havlng a side chain o~ -OCH2CEI(OH)C~12NH- with an aldehyde compound, ancl acylcarbo-styril derivatives which can be procluced by acylating the hydroxyl group present in the above side chain with a wide variety of acrylating agents by conventional acylating procedures. These oxazolidine and acylcarbostyril derivatives were also found to have an excellent cardioselective ~-blocking activity.
Representative compounds of the present invention having the ~ormula (I) are:

l-benzyl-8-benzyloxy-5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, l-isopropyl-8-hydroxy-5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, l-ethyl-8-hydroxy-5-(3-hexylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-hydroxy-5-(3-phenethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-hydroxy-5-[3-(4-carbamoylphenethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, l-benzyl-5-[3-(4-chlorophenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-hydroxy-5-~3-(3,4-methylenedioxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-hydroxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, l-methyl-8-hydroxy-5-(3-tert-butylamino-2-hydroxy-30propoxy)carbostyril, 108~

1 1-ben~yl-8-benzyloxy-5-(3-tert-butylamino-2-hydroxy- : :
propoxy)carbostyril, l-ethyl-8-hydroxy-5-(3-hexylamino-2-hydroxypropoxy)- ~: :
carbostyril, 8-hydroxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-hydroxy-5-[3-(4-carbamoylphenethylamino)-2-hydroxy-propoxy]carbostyril, 8-hydroxy-5-[3-(3,4-methylenedioxyphenethylamino)-2-hydroxypropoxy~carbostyril, 8-hydroxy-5-(3-phenoxyethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-hydroxy-5-[3-(3,4-dimethoxyphenoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarb~styril, 8-hydroxy-5[3-(4-carbamoylphenoxyethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, 8-hydroxy-5-[3-(3,4-methylenedioxyphenoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-hydroxy-5-{2-hydroxy-3-[1-methyl-2-(3,4-dimethoxyphenoxy~-ethylamino]propoxy}-3,4-dihydrocarbostyril, 8-hydroxy-5-[3~~3,4,5-trimethoxyphenoxyethylamino-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-allyloxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-allyloxy-1-methyl-5-[2-hydroxy-3-(3,4-dimethoxy-phenethylamino)propoxy]-3,4-dihydrocarbostyril, .

.,~ ' ' ~ '.

:. .

~013~;~3Z

1 8-allyloxy-1-benzyl-5-[3-~4-carbamoylphenoxyethylamino)-2-hydro~ypropoxy]-3,4-dihyclrocarbostyril, 8-allyloxy-1-ethyl-5-[3-(4-methoxyphenoxyethylamino)~
2-hydroxypropoxy]-3,4-dihydroc~rbostyril, 8-acetoxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-acetoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, 8-acetoxy-1-methyl-5-~3-(4-carbamoylphenoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-cyclohexylcarbonyloxy-1-ethyl-5-[3-(4-methoxyphenoxy-ethylamino-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-isobutyryloxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-methoxyethoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-methoxyethoxy-5-(3-tert-butylamino-2-hydroxypropoxy)-20~ 3,4-dihydrocarbostyril, ~;

8-ethoxyethoxy-5-[3-(1,1-dimethylphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-butoxymethoxy-1-butyl-5-(2-hydroxy-3-isopropylamino-propoxy)-3,4-dihydrocarbostyril, 8-methylcarbonylmethoxy-5-[3-(3,4-dimethoxyphenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, `~ :

8-methylcarbonylmethoxy-1-ethyl-5-[3-(4-carbamoyl-phenoxyethylamino)-2-hydroxypropoxy~.-3,4-dihydrocarbostyril, 8-ethylcarbonylmethoxy-5-(2-hydroxy-3-isopropylamino- : ~
propoxy)-3,4-dihydrocarbostyril, ~ .

~ . :
;

18-ethylcarbonylethoxy-s-[3-(4-methoxyphenoxyethylamino) 2-hydroxypropoxy]-3,~-d.ihydrocarbostyril, 8-methylcarbonylmethoxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-butylcarbonylme~hoxy-1-isopropyl-5-(3-ethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-isopropylcarbonylbutoxy-5-[3-(3,4-methylenedioxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 108-hexylcarbonylhexyloxy-5-[3-(3,4-dimethoxyphenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-methylcarbonylmethoxy-(3-N,N-diethylamino-2-hydroxy- :
propoxy)-3,4-dihydrocarbostyril, 8-methylcarbonylmethoxy-S-(3-cyclohexylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, 8-methylcarbonylmethoxy-5-(3-allylamino-2-hydroxy~
propoxy)-3,4-dihydrocarbostyril, :~

8-methoxycarbonylmethoxy-5-[2-hydroxy-3-(3,4-dimethoxy-phenethylamino)propoxy]-3,4-dihydrocarbostyril, 8-ethoxycarbonylmethoxy-5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, 8-methoxycarbonylethoxy-5-[3-(3,4,5-trimethoxyphenethyl- .

amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-hydroxy-5-[3-(3,4-dimethoxyphenoxyethylamino)-2- ~ `
hydroxypropoxy]carbostyril, 8-hydroxy-5-[3-(4-carbamoylphenoxyethylamino~-2~
hydroxypropoxy]carbostyril, : ::

8~hydroxy-5-[3-(3,4-methylenedioxyphenoxyethylamino)- :
2-hydroxypropoxy]carbostyril, ~ 3Z

1 8-allyloxy-5-(3-tert-hutylamino-2-hydroxyprOpoxY)-carbostyril, 8-allyloxy-l-methyl-5-[2-hydroxy-3-(3,4-dimethoxy-phenethylamino)propoxy]carbostyril, 8-acetoxy-5-(3-tert-butylamino-2-hydroxypropoxy) carbostyril, 8-acetoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]carbostyril, l~ 8-cyclohexylcarbonyloxy-5-(3-isopropylamino-2-hydroxy-propoxy)carbostyril, 8-isobutyryloxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-methoxyethoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-methoxyethoxy-5-(3-tert-butylamino-2-hydroxypropoxy)- ;
carbostyril, 8-methylcarbonylmethoxy-5-(3-tert-butylamino)-2-hydroxypropoxy)carbostyril, 8-methylcarbonylmethoxy-S-[3-(3,4-dimethoxyphenethyl-amino)-2-hydroxypropoxy]carbostyril, 8-ethylcarbonylethoxy-1-benzyl-5-[3-(4-metlloxyphenQxy- : ~

ethylamino)-2-hydroxypropoxy]carbostyril, ~:

8-isopropylcarbonylbutoxy-5-[3-(3,4-methylenedioxy- :: :
phenethylamino)-2-hydroxypropoxy~carbostyril, 8-ethoxycarbonylmethoxy-5-(3-tert-butylamino-2-hydroxypropoxy)carbostyril, .

. .

~C~8~3Z

1 8-methoxycarbonylmethoxy-5-[2-hydroxy-3-(3,4-dimethoxy-phenethylamino)propoxy~carbostyril, 8-(2-propinyloxy)-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-(2-hydroxy-3-tert-butylaminopropoxy)-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[2-hydroxy-3-(2-butenylamino)-propoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-(2-hydroxy-3-phenethylaminopropoxy)-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[3-(4-carbamoylphenethylamino)-2- :
hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-~3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[3-(4-chlorophenethylamino)-2- ~ -hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[2-hydroxy-3-(4-methoxyphenethyl-amino)propoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-~3-t3,5-dimethoxyphenethylamino)-2-hydroxypropoxy]~3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-{3-[1,1-dimethyl-2-~3,4-dimethoxy-phenyl)ethylamino~2-hydroxypropoxy}-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-{2-hydroxy-3-[1-methyl-2-(3,4-dimethoxyphenyl)ethylamino]propoxy}-3,4-dihydrocarbostyril, ~`

8-(2-propinyloxy)-5-~3-(3,4,5-trimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-{-2-hydroxy-3-16-(4-methoxyphenyl)-hexylamino]propoxy}-3,4-dihydrocarbostyril, , :

-.' , 3~

1 8-(2-propinyloxy)-5-{3-[2-(3,4-dimethoxyphenoxy)ethyl-amino]-2-hydroxypropoxy}-3,4~dihydrocarbostyril, 8-(2-propinyloxy)-5~[2-hydroxy-3-(3-phenoxybutylamino)-propoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-{3-[3-(3,4-methylene~ioxyphenoxy)-propylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[3-(2-pyrrolidinoethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbo~tyril, 8-(2-propinyloxy)-5-{2-hydroxy-3-[2-(N-methylpiperazino)-ethylamino]propoxy}-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[3-(4-piperizinobutylamino)-2-hydroxypropoxy)]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)~5-[3-(2-pyrazolidinoethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-~2-butynyloxy)-5-{2-hydroxy-3-[2-(4-methoxyphenoxy)- : :
ethylamino]propoxy3-3,4-dihydrocarbostyril, . 8-(2-propinyloxy)-5-[2-hydroxy-3-(4-chlorophenylamino)-propoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-~2-hydroxy-3-~4-methoxyphenylamino)- ~ :~
propoxy~-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[2-hydroxy-3-~3,4-dimethoxyphenyl-amino)propoxy]-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[3-(N-ethylpiperazino)-2-hydroxy- .
propoxyl-3,4-dihydrocarbostyril, 8-(2-propinyloxy)-5-[2-hydroxy-3-(2-methylmorpholino)-propoxy]-3,4-dihydrocarbo~tyril, .

~8~'~3Z
1 8-(2-butynyloxy)-5-(3-isopropylamino-2-hydroxypropoxy)-3,~-dihydrocarbostyril, 8-(2-buty~yloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-butynyloxy)-5-(3-cyclohexylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-(2-butynyloxy)-5-[3-(N,N-dimethylamino)-2-hydroxy- ~ :~
propoxy]-3,4-dihydrocarbostyril, 8-(3-butynyloxy)-5-{-2-hydroxy-3-~3-(4-methoxyphenoxy)- ~ -propylamino]propoxy}-3~4-dihydrocarbostyril, 8-(3-butynyloxy)-5-[2-hydroxy-3-(3-morpholinopropyl- . .
amino)propoxy]-3,4-dihydrocarbostyril, 8-(2-pentynyloxy~-5-[3-(3,4~dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(3-pentynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(4-pentynyloxy)-5-[2-hydroxy-3-~3,4-ethylenedioxy-phenethylamino)propoxy]-3,4-dihydrocarbostyril, 8-(4-pentynyloxy)-5-(2-hydroxy-3-tert-butylaminopropoxy)-3,4-dihydrocarbostyril, 8-(2-methyl-3-butynyloxy)-5-~3-t3,4-dimethoxyphenethyl-amino-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-~2-methyl-3-butynyloxy)-5-{2-hydrOxY-3-r3-(4-phenylpiperazino)ethylamino]propoxy}-3,4-dihydrbcarbostyril, 8-(1-methyl-3-butynyloxy)-5-[3-(3,4-dimethoxyphenethyl)-amino-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-hexynyloxy)-5-[3-(3,4-dimethoxyphenethylamino-2-hydroxypropoxy]-3,4-dihydrocarbostyril, ~ - 30 -Z~

1 8-(3-hexynyloxy)-5-(2-hydroxy-3-isopropylam.inopropoxy)-3,~-dihydrocarbostyril, 8-(5-hexynyloxy)-5-[3-(3,5-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-(2-hydrQxy-3-tert-butylamino-propoxy)-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-(3-isopropylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, 8-t2-hydroxyethoxy)-5-(2-hydroxy-3-hexylaminopropoxy)-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-~2-hydroxy~3-(2-propenylamino)~ ::
propoxy]-3,4-dihydrocarbostyril, ~ ~ ;

8-(2-hydroxyethoxy)-5-~2-hydroxy-3~phenethylamino- .
propoxy)-3,4-dihydrocarbostyril, ~ ~.

8-(2-hydroxyethoxy)-5-[3-(3-p-chlorophenylpropylamino)- ~ ~.
2-hydroxypropoxy]-3,4-dihydrocarbostyril, . .

8-(2-hydroxyethoxy)-5-[2-hydroxy-3-(3,4-methylenedioxy-20 phenethylamino)propoxyl-3,4-dihydrocarbostyril, . :

8-(2-hydroxyethoxy)-5-[2-hydroxy-3-~4-bromophenoxy-butylamino)propoxy]-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-E3-(3,4-dimethoxyphenoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-{2-hydroxy-3-[2-methyl-(3,4- ~-methylenedioxyphenoxy)propylamino]propoxy}-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5~[2-hydroxy-3-(3-morpholinopropyl-amino~propoxy]-3,4-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-(2-hydroxy-3-rnorpholinopropoxy)-3,4-dihydrocarbostyril, _ 31 - ~.

~L08~LZ3'~

8- (2-hyclroxyethoxy) -5- (3-piper:idino-2-hyclroxypropoxy) ~
3, ~-clihydrocarbostyril, 8- (2-hyclroxyethoxy)-5- [~3- (N-phenylpiperazino)-2-hydroxy-propoxy] -3, 4 -dihydrocarbos tyril, 8- (2-hydroxyethoxy-5- (3-pyrrolidino-2-hydroxypropoxy) -3, 4-dihydrocarbostyril, 8- (3-hydroxypropoxy)-5 (2-hydroxy-3-tert-butylamino- ~ :.
propoxy) -3, 4-dihydrocarbostyril, 1 0 8 - ( 3 -hydroxypropoxy ) - 5 - E 3 - ( 3, ~ -d imethoxyphenethyl amino ) -2-hydroxypropoxy~ -3, 4-dihydrocarbostyril, 8- (3-hydroxypropoxy~-5- [3- (3,4-dimethoxyphenoxyethyl~
amino) -2-hydroxypropoxy] -3, 4-dihydrocarbostyril, 8- (3~hydroxypropoxy) -5- [2-hydroxy-3- (4-p-methoxyphenoxy-butylamino) propoxy] -3, 4 -dihydrocarbostyril, 8- (3-hydroxypropoxy) -5- [3- (3-pyrrolidinopropylamino) -2-hydroxypropoxy] -3, 4 -dihydrocarbostyril, 8- (3-hydroxypropoxy) -5- (2-hydroxy-3-phenylaminopropoxy)- .
20 3, 4-dihydrocarbostyr~

8- (3-hydroxypropoxy)-5- (3-cyclohexylamino-2-hydroxy-propoxy) -3, 4-dihydrocarbostyril, 8 - (propynyloxy) -1-benzyl-5- [2-hydroxy- (3, 4-dimethoxy- ~ :

phenethylamino ) propoxy] ~3, 4 -dihydrocarbos tyril, 8 - (propynyloxy) -l-ethyl -5- [ 2 -hydroxy- ( 3, 4 -dimethoxy-phenethylamino) propoxy] -3, 4-dihydrocarbostyril, 8- ~2-hydroxypropoxy) -5- ~2-hydroxy-3-tert-butylamino-propoxy) -3, 4 -dihydrocarbostyril, 8- (2-hydroxypropoxy) -5-1 3- (3 , 4-dimethoxyphenethylamino) - ~;
2-hydroxypropoxy] -3 ,4-dihydrocarbostyril, :
.

" ~08~'~3~

1 8-(4-hydroxybu-toxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydro~ypropoxy]-3,4-dihydrocarbostyr.il, 8-(3-hydroxybutoxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-methyl~3-hydroxypropoxy)-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(2-methyl-3-hydroxypropoxy)-5-[3-(4-p-chlorophenyl- ::
butylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(5-hydroxypentyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(5-hydroxypentyloxy)-5-(2-hydroxy-3-tert-butylamino-propoxy)-3,4-dihydrocarbostyril, 8-(3~hydroxypentyloxy)-5-[3-(3,4-dimet~oxyphenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(4-hydroxypentyloxy)-5-~2-hydroxy--3-(3~p-methoxyphenyl-propylamino)propoxy}-3,4-dihydrocarbostyril, 8-(2-methyl-4-hydroxybutoxy)-5-[3-(3,4-dimethoxyphenethyl- ` :
amino)-2-hydroxypropoxy]-3,4 dihydrocarbostyril, 8-(2-methyl-4-hydroxybutoxy)-5-[3-(N-phenylpiperazino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(6-hydroxyhexyloxy)-5-[3-(3,4-dimethoxyphenethylamino)- ?
2-hydroxypropoxyl-3,4-dihydrocarbostyril, 8-(2-methyl-5-hydroxypentyloxy)-5-~3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3l4-dihydrocarbostyri 8-(2-methyl-4-hydroxybutoxy)-5-[2-hydroxy-3-(4-p-chloro-phenylbutylamino)propoxy]~3,4-dihydrocarbostyril, .
8-(2-heptynyloxy)-5-[3-~3,4-dimethoxyphenethylamino)- :
2-hydroxypropoxy]-3,4-dihydrocarbostyril, - 33 ~

- , :, .: .

10~ 23Z

1 8-(5-methyl-2-hexynyloxv)-5-[-(3,~-dimethoxyphenethyl-amino)-2-hydroxypropoxy] 3,4-dihydrocarbostyril, 8-(6-hydroxyhexyloxy)-5-[3-(3,4-climethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(1-methyl-2-hydroxyethoxy)-5-[3-(3,4-dimethoxyphenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-(5-methyl-2-hexynyloxy)-5-[3 t3,4-dlmethox~phenethyl-amino)-2-hydroxypropoxy]carbostyril, 8-(6-hydroxyhexyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-(2-propynyloxy)-5-~2-hydroxy-3-tert-butylaminopropoxy)- :
carbostyril, 8-(2-propynyloxy)-5-(2-hydroxy-3-allylaminopropoxy)-carbostyril, 8-(2-propynyloxy)-5-~3-(4-carbamoylphenethylamino)-2-hydroxypropoxy]carbostyril, :

8-(2-propynyloxy)-5-[3-(3,4-dimethoxyphenylmethylamino)- :
2-hydroxypropoxy]carbostyril, 8-~2-propynyloxy)-5-[3-(~-chlorophenethylamino)-2-hydroxypropoxy~carbostyril, 8-~2-propynyloxy)-5-~3-~3,5-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-(2-propynyloxy)-5-{3-~1,1-dimethyl-2-~3,4-dimethoxy-phenyl)ethylamin ~ 2-hydroxypropoxy}carbostyril, 8-~2-propynyloxy)-5-[3-~3,4,5-trimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, .
8-(2-propynyloxy)-5-[3-(3,4-dimethoxyphenoxyethylamino)-2-hydroxypropoxy]carbostyril, '~

. :, , ~ , :

10~3123Z

1 8-(2-propynyloxy)-5-{3-[3-(3,4-methylenedioxyphenoxy)-propylamino]-2-hydroxypropoxy}carbos-tyril, 8-(2-propynyloxy)-5-[3-(4-piperizinobutylamino)-2- :

hydroxypropoxy]carbostyril, ~ .
8-(2-p.ropynyloxy)-5-(3-cyclohexylamino-2-hydroxypropoxy)-carbostyril, 8-(2-propynyloxy)-5-(2-hydroxy-3-morpholinopropoxy)-carbostyril, 8-(2-propynyloxy)-5-(2~hydroxy-N-methylpiperazinopropoxy)-carbostyril, 8-(2-butynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyril, 8-(2-propynyloxy)-5-[2-hydroxy-3-(3-morpholinopropylamino)-propoxy~carbostyril, 8-(3-pentynyloxy-5-[3-(3,4-dimeth~xyphenethylamino)-2-hydroxypropoxy~carbostyril, :
.. , <
8-(2-methyl-3-butynyloxy)-5-~3-(3,4-dimethoxyphenethyl- ~:
20 amino-2-hydroxypropoxy]carbostyril, 8-(2-propynyloxy)-5-[2-hydroxy-3-(4-phenylpiperazino)-propoxy]carbostyril, 8-(1-methyl-3-butynyloxy)-5-(2-hydroxy-3-tert-butylamino-propoxy]carbostyril, 8-(2-hexynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)- ~ :
2-hydroxypropoxy]carbostyril, 8-(2-hydroxyethoxy)-5-(2-hydroxy-3-tert-butylamino-propoxy)carbostyril, :

- 35 - . ".~
.: , .

108~1LZ3'~

1 8-(2-hydroxye-thoxy)-5-(2-hydroxy-3-allylaminopropoxy)-carbostyril, 8-(2-hydroxyethoxy)-5-(2-hydroxy-3-phenethylam.inopropoxy)-carbos-tyril, 8-(2-hydroxyethoxy)-5-[2-hydroxy-3-(3,4-methylenedioxy-phenethylaminopropoxy]carbostyril, 8-(2-hydroxyethoxy)-5-{3-[2~(3,4-dimethoxyphenoxy)ethyl-amino]-2-hydroxypropoxy}carbos-tyril, 8-(2-hydroxyethoxy)-5-[2-hydroxy-3-~3-morpholinopropyl-amino)propoxy]carbostyril, 8-(2-hydroxyethoxy)-5-[3-(N-phenylpiperazino) 2- ,:
hydroxypropoxy]carbostyril, .

8-(4-hydroxybutoxy)-5-~3-t3,4-dimethoxyphenethylamino)~
2-hydroxypropoxy]carbostyril, 8-(5-hydroxypentyloxy)-~2-hydroxy-3-tert-butylamino-propoxy]carbostyril, 8-(6-hydroxyhexyloxy)-5-[3-~3,4-dimethoxyphenethylamino)-2~ 2-hydroxypropoxy]carbostyril, .

8-(5-hydroxyhexyloxy)-5-[3-(4-carbamoylphenethylamino)-2-hydroxypropoxy]carbostyxil, 8-(2-methyl-5-hydroxypentyloxy)-5-[3-~3,4-methylene-d.ioxy-phenethylamino)-2-hydroxypropoxy]carbostyril, 8-(2-propynyloxy)-5-{2-hydroxy-3-[4-~4-methoxyphenyl)-piperazino]propoxy}-3,4-dihydrocarbostyril, 8-(2-propynyloxy)-5-{2-hydroxy-3-[4-(2-methylphenyl)-piperazino]propoxy}-3,4-dihydrocarbostyril, . 8-~2-propynyloxy)-5-{2-hydroxy-3-[4-~4-chlorophenyl)- :
piperazino]propoxy}-3,4-dihydrocarbostyril, ::- 36 .. .. . .
. : : .

81~232 1 8-(2~propynyloxy)-5-(diphenylrnethylamino-2-hyclroxy~
propoxy)-3,~-dihydrocarbostyril, 8-(2-hydroxyethoxy)-5-{2-hydroxy-3-[4-(4-methoxyphenyl)-piperazino]propoxy}-3,4-dihydrocarbos-tyril, 8-(2-hydroxyethoxy)-5-{2-hydroxy-3-[4-(4-chlorophenyl)-piperazino]propoxy}-3,4-dihydrocarbostyril, 8-benzyloxy-5-{2-hydroxy-3-[4-~4-methoxyphenyl)piperazino]-propoxy}-3,4-dihydrocarbostyril, .

$~hydroxy-5-[2-hydroxy-3-(4-phenylpiperazino)propoxy]-carbostyril, 8-hydroxy-5-(3-diphenylmethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril, 8-(2-methoxyethoxy)-5-{2-hydroxy-3-[4-~4-methoxyphenyl)-piperazino]propoxy}-3,4-dihydrocarbostyril, 8-acetoxy-5-{2-hydroxy-3-[4-(3-chloxophenyl)piperazino~
propoxy}-3,4-dihydrocarbostyril, .

8-(2-propynyloxy)-5-[3-(2-methoxyethylamino)-2-hydroxy- .~.
20 propoxy]-3,4-dihydrocarbostyril, ~ :

8-(2-propynyloxy)-5- E3- ~2-isopropoxyethylamino)-2-hydroxy-propoxy-2-hydroxypropoxyJ-3,4-dihydrocarbostyril!

8-(2-hydroxyethoxy)-5-~3-~2-ethoxyethylamino)-2- ;~ :

hydroxypropoxy]-3,4-dihydrocarbostyxil, 8-(2-propynyloxy)-5-(3-(2-methoxyethylamino)-2-hydroxy- .
propoxy]carbostyril, ~

8-(methylcarbonylmethoxy)-5-[3-(2-ethoxyethylamino)-2- .,;~;.. ;
hydroxypropoxy]-3,4-dihydrocarbostyril, .`~

8-(2-methoxyethoxy)-5-~3-(2-methoxyethylamino)-2- ~ .
hydroxypropoxy]-3,4-dihydrocarbostyril, . : ;- .

- 37 ~

~ 32 1 8-(methylcarbonylmethoxy)-5~[3-(2-ethoxyethylamino)-2-hydroxypropoxy]carbostyril, 8-carboxymethoxy-5-[3-(2-ethoxyethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, 8-propoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyril, 8-butoxy-5-{3-[2-~4-methoxyphenoxy-ethylamino)-2-hydroxy-propoxy]}-3,4-dihydrocarbostyril, 8-butoxy-5-[3-(1,1-dimethyl-2-phenylethylamino)-2-hydroxy-propoxy]-3,4-dihydrocarbostyxil, 8-propoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy-propoxy]carbostyril, 8-carboxymethoxy-5-[3-~3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-~3-carboxypropoxy)-5-~3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril, 8-~3-carboxy-2-methylbutoxy)-5-[3-(3,4-dimethoxyphen-ethylamino)~2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-~2-carboxyethoxy)-5-[3-(3,4-methylenedioxyphenethyl-amino)-2-hydroxypropoxy]carbostyril, 8-(2-carbamoylethoxy)-5-[3-(3,4-dimethoxyphenethylamino-2-hydroxypropoxy]carbostyril, 8-(2-hydroxyethoxy)-5-~3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, 8-carbamoylmethoxy-5-E3-~3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, , . . .

.

:1~8~23~

1 8-(3-carhamoylpropoxy)-5-~3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy~-3,4-dihydrocarbostyril, 8-(N,N-diethylcarbamoylmethoxy)-5-[3-(3,4-methylenedioxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril, and the like.

The present invention is further illustrated by the following Examples, but these examples are given for illustrative ~
purposes only and not to be construed as limitin~ the present -10 invention. Unless otherwise indicated, all parts, percents, - ?
ratios and the like are by weight.

Reference Example 1 ~. ~
1~ g of 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril was dissolved in 100 ml of anhydrous tetrahydrofuran, and 100 mg . .
of p-toluenesulfonic acid was added to the solution. 10 g of dihydropyran was slowly added dropwise thereto at room tem- ;~
perature while stirring. After completion of the addition, the mixture was stirred at room temperature for 12 hours, poured into a large volùme of a saturated aqueous solution of sodium chloride and then extracted with chloroform. The extract was washed successively with a 5~ aqueous solution of sodium -hydroxide and water, and the chloroform layer dried over anhydrous potassium carbonate. The chloroform was evaporated ~ ;;
under reduced prèssure, and the residue was crystallized from petroleum ether. Recrystalliæation from ethanol-water aforded 9.5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydro-pyranyl ether ~IV) as colorless needle-like crystals having a melting point of 113.5 - 114C.

Reference Example 2 5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydro-~81Z32 1 pyranyl ether (IV) was dissolved in 100 ml of anhydrous dimethyl-formamide, and 810 g of sodium hydride was slowly added to the solution while stirring, followed by stirring at room temperature for 1 hour. 1.05 ml of methyl iodide was further added dropwise thereto followed by stirring at the same temperature for 2 hours.
The reaction mixture was poured into a large volume of a saturated aqueous solution of sodium chloride, extracted with chloroform, washed with water and dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was recrystallized from ligroin to obtain 1.42 g of 1-methyl-8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether as colorless needle-like crystals having a melting point of 110.5 - 111.5C.
Following the same procedure as described above, 1-benzyl-8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether was obtained.
NMR Spectrum: 60MHz in dlmethyl sulfoxide-d6 3.33-4.1 ~m.2H), 4.87 ~s.2H), 5.37 (s. 2H)i ppm Reference Example 3 14.0 g of l methyl-8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether was added to 280 ml of methanol con-taining 80 ml o~ concentrated hydrochloric acid followed by stirring at room temperature for 10 minutes. The reaction mixture was rendered alkaline with sodium hydroxide, and the methanol evaporated under reduced pressure. The precipitated crystals were extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the chloroform was evaporated under reduced pressure. The residue was recrystallized from ethanol to afford 8.1 g of 1-methyl-5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril as colorless needle-':

. . , 10~

1 like crystals having a melting point oE 196 - 197C.

Reference Example 4 5.5 g of 1-methyl-5-hydroxy-8-benzyloxy-3,4-dihyaro-carbostyril was added to 15 g of epichlorohydrin, and 12 drops of piperidine were then added thereto followed by stirring at 90 to 100C for 3 hours. The unreacted epichlorohydrin and piperi-dine were evaporated under reduced pressure, and the residue was dissolved in chloroform, washed successively with a 5% aqueous solution of sodium hydroxide and water and dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was purifiea by silica gel chromatography and then recrystallized from ethanol to afford 3.5 g of 1-methyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,~-dihydro-carbostyril as yellow needle-like cry~tals having a melting point of 111 - 112.5C.

Reference Example 5 2.0 g of 5-3-~3,4-dimethoxyphenethylamino)-2-hydroxy- ~
propoxy-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml ~;
of methanol, and an ethanol solution containing hydrogen chloride was added to the suspension until the mixture showed acidity.
After the mixture became homogeneous,0.7 g of 1~ palladium ;
carbon was added therato followed by stirring at room temperature and at atmospheric pressure thereby absorbing hydrogen. The reaction completed when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated.
A small amount of ethanol was added to the residue to crystallize the product. Recrystallization rom ethanol gave 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171 - 173C.

~. ' : - .. ' ' . . . :-.., ~8~3'~

1 efere e_E m le 6 21.6 g of 5,8-dihydroxy-3,4-dihydrocarbostyril and 19.9 g of potassium carbonate were added to a mixture comprising 480 ml of acetone and 120 ml of water, and the resulting mixture was stirred while refluxing for 30 minutes. 76 g of 2-me~hoxye-thyl bromide was then added thereto followed by stirring while refluxing for 8 hours. The solvent was evaporated, and water ~as added to the residueO The mixture was extracted with diethyl ether. The aqueous layer was rendered acidic with hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfa-te, and the chloroform evaporated to obtain 15 g of 5-hydroxy-8-(2-methoxyethoxy)-3,4-dihydrocarbostyril as a black oily substance.
Reference Example 7 3.3 g of 5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydro-carbostyril was dissolved in 50 ml of dimethyl sulfoxide, and 1.3 g of 50% sodium hydride was added to the solution followed by stirring at room temperature for 30 minutes. 2.9 g of methyl iodide dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. 200 ml of a saturated aqueous solution of ammonium chloride was added to the reaction mixture followed by extracting with chloroform. The chloroform layer was washed with water and then dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethanol to obtain 1.7 g of l-methyl-5-(2,3-epoxypropoxy)-8~benzyloxy-3,4-dihydrocarbostyril as 3~ yellow needle-like crystals having a melting point of 111 - 112.5C.

~08~'~3~

Re~erenc~ Example 8 0.7 g of 8-hydroxy-5-t3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of lN NaOH was added to the suspension to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under ice-cooling and stirring. After the mixture was allowed ~o stand under ice-cooling for 30 minutes, 2 ml of lN ;
hydrochloric aci~ was added to the mixture, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloro~orm: methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized rom methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-~3-t-~utylamino-2-hydroxypropoxy)~
3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247 - 248C (with decomposition).

Reference Example 9 0.66 g of 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril was suspended in 10 ml o-f acetone,and 3.0 ml of lN sodium hydroxide was added thereto to form a homo-geneous solution. To the resulting solution was added dropwise `
0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone under ice-cooling and stirring. After the reaction mixture was allowed to stand under ice-cooling for 30 minutes, the mixture was adjusted to a pH of 3 with lN
hydrochloric acid. The solvent was evaporated, and the residue was dissolved in water and then extracted with chloroform.

The aqueous layer was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromato~
graphy using chloroform-methanol ~8:1 by volume) as an eluent.

, ~0~ 3'~ ~

1 The solvent was evaporated, and the residue was recr~stallized from methanol-diethyl ether to obtain 0.45 g of 8 cyclohexylcar-bonyloxy-5-~2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydro-carbosytril hydrochloride as colorless flake-like crystals having a melting point of 227 - 228C.

Reference Exa~ple 10 1.5 g of 5-~3-t-butylamino-2-hydroxypropoxy)-8-hydroxy-3,4-dihydrocarbostyril was suspended in 20 ml of methanol, and 1~ 1.0 g of allyl bromide and 6 ml of lN sodium hydroxide were added thereto to form a homogeneous solution, followed by stirring the mixture while refluxing ~or 4 hours. The solvent was evaporated, and the residue extracted with chloroform.
The chloroform was evaporated from the extract, and the residue was recrystallized from methanol-diethyl ether containing hydrogen chloride to obtain 0.9 g of 8-allyloxy-5-~3-t-butyl-amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as white needle-like crystals having a melting point of 177 - 178C.
.
Reference Example 11 .
0.75 g of 1-benzyl-8-hydroxy-5-~3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrofluoride was suspended in 10 ml of acetone, and 3.3 ml of lN sodium hvdroxide was added thereto to form a homogeneous solution. 0.15 g of acetyl chloride was then added to the solution under ice-cooling and stirring followed by allowing the mixture to stand for 20 minutes. The mixture was adjusted to a pH of 3 with lN hydro- ;~
chloric acid, and the acetone was evaporated. The residue was extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The chloroform was evaporated leaving Z~

1 0.3 g of a colorless solid, which was found by NMR and IR
spectra to be l-benzyl 8-ace-tyloxy-5-(3-t-butyl~mino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril hyclrochloride.
NMR Spectrum: ~ppm) (in dimethyl sulfoxide d6) 5.03 singlet (2H), 2.33 singlet (3H) and 1.36 sin~let (9H) IR Spectrum: (KBr) 1760 cm and 1675 cm Reference Example 12 1 2 liters of acetone and 500 ml of water were added to 150 g of 5,8-dihydroxy-3,4-dihydrocarbostyril, and 138 g of potassium carbonate and 150 g of 2-propynyl bromide were further added thereto. The resulting mixture was heated while refluxing for 3 hours on a water bath. After completion of the reaction, the acetone and the 2-propynyl bromide were evaporated under reduced pressure, and the residue was made acidic with con- ;~
centrated hydrochloric acid. The mixture was extracted with chloroform, and the chloroform layer was washed with water and dr7ed over anhydrous sodium sulfate~ The chloroform was evaporated under reduced pressure,and the residual crystals were recrystallized from isopropanol-diethyl ether to obtain 110 g of 8-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyril having a melting point of 141 - 142C.

Reference Exam~le 13 To 78 g of 8-~2-propynyloxy)-5-hydroxy-3,4-dihydro-carbostyril were added 102 g of epichlorohydrin, 60 g of potassium carbonate and 600 ml of methanol, and the resulting mixture was heated whlle refluxing for 2.5 hours on a water bath. After completion of the reaction, the methanol was 3~ evaporated,and water was added to the residue followed by ~08~

1 extracting with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloro-form was evaporated under reduced pressure, and the residual crystals were recrystallized from isopropanol to obtain 67 g of 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbo-styril having a melting point of 142 - 143.5C.

1.7 g of 1-methyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril was dissolved in 20 ml of methanol, and ~.
1.6 ml of benzylamine was added thereto. The resulting mixture was stirred at 40 to 50C for 4 hours. The methanol and unreacted benzylamine were evaporated under reduced pressure,and the residue was purified by silica gel ~C-200, Tradename of Wako Junyaku Co., Japan) column chromatography using chloroform as an eluent. The product was converted to a hydrochloride thereof with a saturated ethanolic solution of hydrogen chloride. The ethanol was evaporated, and the residue was recrystallized from ethanol-ligroin to give l-methyl-5-(3-benzylamino-2-hydroxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril hydrochloride as colorless needle-like crystals having a melting point of 155 - 157C.

EX~PLE 2 In the same manner as described in Example 1 but using 1.23 g o~ 1-benzyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril, 20 ml of methanol and 4 ml of t-butylamine, 1.4 g of 1-benzyl-5-(3-t-butylamino-2-hydroxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril hydrochloride having a melti.ng point of 200 - 201C.

. 20 drops of piperidine were added to 4.5 g of 8-benzyloxy-.-;~

' ,. - '~

~8~Z3'~

1 5-hydroxy-3,4-dihydrocarbos-tyril and 5.0 g of epichlorohydrin, and the resulting mixture was stirred a-t 95 - 100 C for 4 hours.
The unreacted epichlorohydrin was evaporated under reduced pressure, and the residue was dissolved in 100 ml of chloroform.
The chloroform layer was washed successively with diluted sodium hydroxide and water, and then dried over anhydrous sodium sulfate. The chloroform was evaporated, and the residue dissolved in 30 ml of methanol. To the solution was added 1.5 g of 3,4-dimethoxyphenethylamine, and the resulting mixture was stirred at 50 to 55C for 4 hours. The methanol was e~aporated, and the residue was crystallized from diethyl ether. Recrystallization from acetone afforded l.l g of 5-l3-(3,4-dimethoxyPhenethylamino)-2-hydroxypropoxy]-8-~enzyloxy-3,4-dihydrocarbostyril as white powdery crystals having a melting point of 108 - 109.5C

EXAMPLES_4 to 33 In the same manner as described in Example l, the following compounds were prepared:
OH
OCH2lHCH2N 3 ~ ~

08J,Z3~h ou U~
C~ o ~ ~ oo ~ ~: l l l l l l l ~-~ o o~ l-- tn co ~ D
o ~ ~ u~ In ~I r~
~, ..

W

,, ~ P~ ~ W
p:~ ~) W ~) 0~3 0~

X ~ t~l W C.) ~ N ~1:
~ ~r U ~_) ~U L3 1:~; ~ ~ U - N \ / N W
z -~ m z , z 5 z~
Z I I I , .
~1 ;,; , N ~. .
W :
: C~

~ ' ~1 ~ C~
P~
o. = y E~ y W
~ , " '.
O ~ ~
~ O O
rl O h Q ~ R
tJI U~ ,5:1 ~1 o ~, ~ a ,C
~ ~ h O `~1 ~ r~ O
t`~ o ui 0 . ~ U~
:
~ I ~ ':
X Z ~ U) ~ I~ CO ~ O ' ' ' ~ .

., ~

: : :
:.
... . .. . - . ., ~, . , ~

o ~_ ~ ~ co ~ Ln n ~ Ln ~D ~ ~ ~
. .~ ~ Ll l -~ o L oo Ln 5 x ` ~
o o ~l ~
r--l W O O ~_) = C -- : ' ~ m 1 0 ": ~ :
~ ,.
~: . ,~ , ~ c~
u o o 1 v o x .

r~l er N ~3 N
~) X ~ ) c) Z J~; Z '' ;/ W ~ y m_w ~ ?

N N
m x ~ m ~ Y Y

m ' ': ~:
.~ : ` ~' o ~ ~ ~ .
--1 m w v ~ ~n o 5~ ~
O r~2 ~ r~
1 ) w _ _ _ :

3~ ~, .
~ Z, .
:
.

. . ~ .

-` ~ 083L%3~

~ ~ Ln o 1 ~ O I
CO ~ I~ 1-- 1~ 1 Ln .
o a~ Ln a) o ~ I~ I` ~O 1~ ~ ~ 1 ~U - =

0 .~ .
~m ~ ~ .
U O

U

~: U W' W
I U.......... U
~0 . ' ' .
' . .
.. '.
W
. : ' ~I
h ~
~-,~ ~ ~ , o '1 Q ~ R
O ~-1-) I C) ~ tJ`
O .. L~ .~J .,~ .
m ~ o ~ u~ ~
a) ' ~:' 3 0 R. ~ ~ :
Z ~ o ~ ~ ~) ~ Ln , X

_ 50 -- ~:

1~8~'Z3~

o t~ t~ .
o ~ ~ ~ o U~U~ ~, ~__ ~-1 1 ~ ~a, . o NIr) r-l~1 1~ ~1 a ~-~1 r~
~ N N -tr I C~
. `
:

~' a~ ~, C,) = ~ U

W r~
O , o ~ X ' ` ' U ~ )~

~ ~r N ~ N P ~
P; ~; ,z z m u , ~ ~ ~ ~C ) ~ N ~ ~
æ ~æ' ~z' m m U~ m u zm .,. ~
~J ~N
~1 C 3 P~ N N N ~ q m ~
m m P~ = m - u-u-u N
U C) U ~ t~, 2 0 I I N t~ U , `
. ' `, : - : : _ _ : ' ~1 . `
~ ~1 O ;~1 ~ ~ o ~o :, s R R R
o 5 1 R _ al ~ 40~ U~
.,~
a ~ O ~ I~ co ~ o ,~

~::

~08~3'~ ,, 1 ~XAMPL~ 3~

40 drops of piperidine were added to 10 g of 5-hydroxy-8-(2-methoxyethoxy)-3,4-dihydrocarbostyril and 13 g of epi-chlorohydrin, and the resulting mixture was stirred at 95 to 100C for 4 hours. After the unreacted epichlorohydrin was evaporated, the residue was d.issolved in chloroform, and the .
chloroform layer was washed successively with diluted sodium hydroxide and water and then dried over anhydrous sodium sulfate. :; .
The chloroform was evaporated, and the residue was dissolved in 100 ml of methanol. 20 g of t-butylamine was added to the solution, and the mixture refluxed for 8 hours. The unreacted amine and the solvent were evaporated, and the residue was dissolved in methanol containing hydrogen chloride. The residue obtained by evaporating the methanol was recrystallized from methanol-diethyl ether to obtain 6.8 g oE 5-~3-t-butylamino-2-hydroxypropoxy)-8-(2-methoxyethoxy)-3~,4-dihydrocarbos~yril hydro-chloride as white needle-like crystals having a melting point of 195-196 C. EXAMP~E 35 9.2 g of 8-benzyloxy-5-hydroxy-3,4-dihydrocarbostyril : .
and 18 g of epibromohydrin were dissolved in 120 ml of methanol, and 4.8 g of potassium carbonate was added to the solution followed by stirring while refluxing for 3 hours~ The methanol and the unreacted epibromoh~drin were evaporated under reduced pressure. The residue was dissolved in 100 ml of methanol, and ; ;
5.7 g of 4-methoxyphenoxyethylamine was added thereto followed by stirring while refluxing for 5 hours. The me~hanol was evaporated, and the residue was dissolved in chloro~orm. The solution was washed successively with lN hydrochloric acid, lN ~;~

30 sodium hydroxide and then water and dried over anhydrous ;~ -magnesium sulfate. The chloroform was evaporated, and the residue ~ ;~

- 52 - :

~ [)81'~3~ ( ~

1 ext.racted with ethyl acetate. The ethyl ~cctate was evaporated, and the rcsidue was recrystallized ~rom acetone-diethyl ether to obtain 5.6 g of 8-benzyloxy-5-[3-(4-methoxyphenoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril as colorless powdery -crystals having a melting point of 67 - 69C.

8.0 g of 5-~2~3-epoxypropoxy)-8-(2-methoxyethoxy)-3~4-dihydrocarbostyril and 2.0 g of 2-p-methoxyphenoxyethylamine were added to 100 ml of me~hanol followed by refluxing for 3 1~
hours. The methanol was evaporated, and the residue was purified by silica gel column chromatography using chloroform-methanol (40:1 by volume) as an eluent. The solvent was evaporated, and the residue was dissolved in methanol containing hydrogen chloride. The ethanol was evaporated, and the residue was re-crystallized from methanol-diethyl ether to obtain 1.5 g of :
8-(2-methoxyethoxy)-5-[3-t2-p-methoxyphenoxyethylamino)--2-hydroxypropoxy]-3,4-dihydrocarbostyril hydrochloride as white ~:
powdery crystals having a melting point of 78 - 80C.

. EXAMPLES 37 TO 78 In the samme manner as described in Example 36, the following compounds were prepared:

OCH~CHCH N ~ 3 R

N o . HA
2 Rl .
' .

- 53 ~ ;

~ :

~ 0~
~ ~ ~ 1` ~ O O ~1 ~ r,~ ~ o ~ ,1 ~co u u~ o I
a) o o P, ~ ~ ~ ~ I~ ~n ~ ~ . I

~ .
m ~ O

\ / ~- X~
u m :~ m ~o ~ o uu u ~ m m ~ m c~ ~q m Z ~ I U tl~ ~ ~ U
U O O ~ ~ U
~:
Z Z ~Z ~ Zi Z Z
Z; ~'~

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2 ~ of 5-(2,3-epoxypropoxy)~ 2-propynyloxy~-3,4-dihydrocarbostyril was dissolved in 15 ml of methanol, and 2.6 g of t-butylamine was added to the solution, followed by allowing the mixture to stand at 15 - 20C for 12 hours. After com-pletion of the reaction, the methanol and the t-butylamine were evaporated under reduced pressure, and the resulting crude oil was converted into the hydrochloride thereof using hydro-chloric acid and ethanol. The solvent was evaporated under reduced pressure, and the resulting crystals were dissolved in water and washed with chloroform to remove impurities. The aqueous layer was made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to obtain colorless crystals, which were converted into the hydrochloride thereo with hydro-chloric acid-ethanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from isopropanol to obtain 1.6 g of 8-~2-propynyloxy)-5-[3-(t-butylamino)-2-hydroxy-propoxy~-3,4-dihydrocarbostyril hydrochloride having a meltin~
point of 182 - 183C.

1.0 g of 8-~2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol, and 4.5 ml of 28~ ammonium hydroxide was added to the solution followed by heating at 70C for 10 hours. The methanol and the ammonium hydroxide were evaporated under reduced pressure, and the residue was made acidic with hydrochloric acid and washed ~ ~
30 with ethyl acetate. The aqueous layer was separated, made 7 alkaline with sodium hydroxide, extracted with chloroform, washed ;~

- 10~2~32 1 with water and then dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel chromatography, and the product was converted to the hydrochloride thereof by adding methanol-hydrochloric acid. Recrystallization frcm methanol-diethyl ether afforded 0.5 g of 8-(2-propynyloxy)-5-(3-amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride having a meltinq point of 196.5 - 198C.

.
1.1 g of 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydro-carbostyril was dissolved in 30 ml of methanol, and 1.5 g of 2-methoxyethylamine was added thereto, followed by allowing the mixture to stand at 10 to 15C for 29 hours. After completion of the reaction, the methanol and the unreacted amine were evaporated under reduced pressure. The residue was rendered acidic with hydrochloric acid and washed with ethyl acetate.
The aqueous layer was made alkaline with sodium hydroxide, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was dissolved in methanol.
The product was formed into the hydrochloride thereo~ by adding methanol-hydrochloric acid and then recrystallized from iso-propanol to afford 0.8 g of 8-~2-propynyloxy)-5-~2-hydroxy-3-(2-methoxyethylamino)propoxy]-3,4-dihydrocarbostyril hydrochloride having a melting point of 171 - 172C.

1.0 g of 8-(2-propynyloxy)-$-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol. 0.5 g of anhydrous potassium carbonate and 1.4 g of 2-(3,5-dimethoxy-phenoxy)ethylamine were added to the solution, and the resulting 1(~8~'~3Z

1 ~ixture was refluxed while stirring for 8 hours. The methanol was evaporated under reduced pressure, and the residue was rendered acidic with hydrochloric acid followed by washing with ethyl acetate. The hydrochloric acid layer was separated, ~ ~
extracted with chloroform, washed with water and dried over ~ -anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-(2-propynyloxy)-5{3-[2-~3,5-dimethoxyphenoxy)-ethylamino~-2-hydroxypropoxy}-3,4-dihydrocarbo-styril hydrochloride having a melting point of 187 - lB9 C.

l.0 g oE 8-(2-propynyloxy)-5-~3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 20 ml of methanol. 0.5 g of anhydrous potassium carbonate and 1.6 g of 2-(3,4-dimethoxy-phenyl)ethylamine were added thereto, and the resulting mixture was stirred while refluxing for 2.5 hours. After co~pletion of the reaction, the methanol was evaporated under reduced pressure, and the residue was dissolved in chloroform and then washed with water. The chloroform layer was dried over anhydrous sodium sulfate, and the chloroorm evaporated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to obtain l.l g of 8-(2-propynyloxy)-5- 3 ~2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy -3,4-dihydro-carbostyril hydrochloride having a melting point of 160 - 162C.

l.0 g of 8-(2-hydroxyethoxy)-5-(2,3-epoxypropoxy)-3,4 dihydrocarbostyril was dissolved in 20 ml of methanol, and 1.5 g of 2-(3,4-dimethoxyphenyl)ethylamine was added thereto followed by allowing the mixture to stand at lO to 15 C for 12 hours. After ~;

3L~8~
1 the reaction, the methanol was evaporated under reduced pressure, and the residual oil was dissolved in chloroform, washed with water and dried over anhydrous sodlum sulfate. The chloroform was evaporated under reduced pressure, and the residual oil was washed with diethyl ether followed by decantation and then converted into a hydrochloride using hydrochloric acid-methanol. Recrystal-lization from methanol-diethyl ether gave 0.9 g of 8-(2-hydroxy-ethoxy)-5-{3-[2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxy-propoxy}-3,4-dihydrocarbostyril hydrochloride having a melting point of 204 - 206C.
Example 85 1.0 g of 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)~
3,4-dihydrocarbostyril was dissolved in 20 ml of methanol. Q.7 g of anhydrous potassium carbonate and 1.7 g of morpholine were then added to the solution followed by stirring while refluxing for 4 hours. After completion of the reactio~, the methanol and the unreacted morpholine were evaporated under reduced pressure, and the residual oil was converted into a hydrochloride with an aqueous hydrochloric acid, and washed with chloroform. The aqueous layer was separated, made alkaline with sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was converted into a hydro-chloride with ethanol-hydrochloric acid. Recrystallization from water-ethanol gave 0~8 g of 8-(2-propynyloxy)-5-(2-hydroxy-3-morpholinopropoxy)-3,4-dihydrocarbostyril hydrochloride having a melting point of 234.5 - 235C.
Example 86 2 g of 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydro-carbostyril was dissolved in 30 ml of methanol, and 2.6 g of 3~ pyrrolidine was added thereto, followea by allowing the mixture to 1~81Z3;~

1stand at 10 to 15C for 12 hours. ~fter the reaction, the methanol and the unre~cted pyrrolidine were evaporated under reduced pressure. The resldual oil was converted into a hydrochloride with hydrochloric acid-ethanol. Recrystallization from methanol gave 0.9 g of 8-(2-propynyloxy)-5-(3-pyrrolidino-2-hydroxy-propoxy)-3,4-dihydrocarbostyril hydrochloride having a melting point of 225 - 226C.

.
In the same manner as described in Example 86, the following compounds were prepared:

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3L08~3~ f 2.0 g of 5-[3-t3,4-dimethoxYPhenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and ethanol containing hydrogen chloride was added to the suspension until the suspension showed acidity ;
to form a homogeneous solution. 0.7 g of 10% palladium carbon ..
was added to the resulting solution, and the mixture was stirred at room temperature and at atmospheric pressure to absorb hydrogen. The reaction completed at the point when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. To the residue was added a small amount of ethanol to crystallize followed by ~ ;
recrystallization from ethanol to obtain 1.5 g of 5-13-(3,4- : ;
dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powderous : .
crystals having a melting point of 171 - 173C. .: . .

In the same manner as described in Example 125, the ;:~
following compounds were prepared~

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1 EX~MPLI. 129 0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,~-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of lN sodium hydroxide was added thereto to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under cooling with water, followed by allowing the mixture to stand under water-cooling for 30 minutes. 2 ml of lN hydro-chloric acid was added thereto, and the solvent evaporated 1~ under reduced pressure. The residue was purified by silica gel column chromatography using chloroform-methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,~
dihydrocarbostyril hydrochloride as eolorless flake-like erystals having a melting point of 247 - 248C (with decomposition).

0.66 g of 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy) 3,4-dihydrocarbostyril was suspended in 10 ml of acetone, and 3.0 ml of lN sodium hydroxide was added thereto to form a homogeneous solution. 0.35 g of eyclohexylearbonyl chloride dissolved in a sma~l amount of aeetone was added dropwise to the solution while iee-eooling and stirring. After the reaction mixture was allowed to stand under iee-eooling for 30 minutes, lN hydrochloric aeid was added thereto to adjust to a pH o~ 3. The solvent was evaporated under redueed pressure, and the residue was dissolved in water and extraeted with chloroform. The aqueous layer was eoncentrated to dryness under redueed pressure, and the residue was purified hy siliea gel ehromatography using ehloroform-methanol ~8:1 by volume) as an ~81Z3~

1 eluent. The solvent was evaporated, and the residue was recrystallized from methanol~diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyloxy-5-(2-hydroxy-3-isopropylamlnopropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 227 - 228C.

1.5 g of 5-(3-t-butylam no-2-hydroxypropoxy)-8-hydroxy-3,4-dihydrocarbostyril was suspended in 20 ml of methanol, and 6 ml of lN sodium hydroxide was added thereto to form a homogeneous solution. 1.0 g of allyl bromide was added to the solution followed by stirring while refluxing for 4 hours.
The solvent was evaporated, and the residue was extracted with chloroform. The chloroform was evaporated, and the residue was recrystallized from methanol-diethyl ether containing hydrogen chloride to obtain 0.9 g of 8-allyloxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as white needle-like crystals having a melting point of 177 - 178 C.

2~ 0.75 g of 1-benzyl-8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy-3,4-dihydrocarbostyril hydrochloride was suspended in 10 ml of acetone, and 3.3 ml of lN sodium hydroxide was added thereto to form a homogeneous solution. 0.15 g of acetyl chloride was added to the solution while ice-cooling and stirring, followed by allowing the mixture to stand for 20 minutes. The mixture was adjusted to a pH of 3 with lN hydro-chloric acid. The acetone was evaporated, and the residue was extracted with chloroform. The chloroform layer was washed once with a saturated aqueous solution of sodium chloride and dried 3~ over anhydrous magnesium sulfate. The chloroform was evaporated ~08~Z~ ( 1 leaving 0.3 g of a colorless solid as ~ residue. This product was conEirmed by N~R and IR spectra to be l-benzyl-8-acetyloxy-5-(3-t-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril ~
hydrochloride. ~ -NMR Spectrum: ~(ppm) in dimethylsulfoxide d6 5.03 singlet (2H), 2~33 singlet (3H) and 1.36 singlet (9H) ;

IR Spectrum: KBr -1760 cm 1 and 1675 cm 1 ~ ~ -Reference Example 14 The ~-adrenergic blocking activity of the compounds of this invention was determined as follows:
Male hybrid adult dogs, weighing 10 to 16 kg, were anesthesized ~
with sodium pentobarbital administered intravenously at a level ~ ~ ;
of 30 mg/kg of body weight, and a cannula was inserted into the trachea of each of the anesthesized dogs. In order to avoid blood coagulation, heparin was administered intravenously at a level of 1000 units and thereafter a cannula was inserted into the right femoral artery. The experiments were conducted under artificial respiration at a rate o 20 ml/kg, 18 r.p.m.
The blood pressure was determined using a pressure transducer ~MPU-0.5 Type, tradename of Nippon Koden Co., Japan) and the heart rate (HR) was determined from the pulse wave of blood pressure using an instantaneous heart rate tachometer (2130 Type, tradename of Sanei Sokki Co., Japan). The air-way resistance (AR) was determined according to the K~nzett-R~ssler Method ~K~nzett H. & R~ssler R., "Versuchsanordnug zu Unter~
suchungen an der Bronchial Moskolatur" Arch. Exp. Path., Pharmak, 3'~ ~ ~

1 195~ 71-74, 27-40 (1940) usin~ a low-pressure type pressure transducer (LPU-0.1, tradename of Nippon Koden Co., Japan).
The above parameters were continuously recorded on a polygraph (8S 28 Type, tradename of Sanei Sokki Co., J`apan), During the experiment, gallamine was administered intravenously at a dosage of 3 mg/kg at one-hour intervals to avoid fluctuation of air-way resistance.
The ~-adrenergic bloc]cing activity of each of the test compounds was evaluated in terms of antagonism (Inhibition ~) to the depression at the diastolic blood pressure (dBP) and to the increase in the heart rate induced by the intravenous administration of isoprenaline (1 ~g/kg) and in terms of antagonism (Inhibition %) to the depression by isoprenaline in increase of air-way resistance which was induced by iII-travenous administration of histamine (5 pg/kg). In this case, histamine was administered 45 seconds after the administration of isoprenaline.
The ~-adrenergic blocking activity of the test compounds was determined 10 minutes after the intravenous administration of the test compounds at a level of 300 ~g/kg and the results obtained are shown in Table 1 below, where PROCTOLOL

(CH3cNH ~ -OCH2CEICH2NHCH ~ and ATENOLOL

(H2NgCH2 ~ -OCH2CHCH2NH/ H ) were used as controls. ~ ~

1H 3 : :

3~ * Trade Marks 3~ ( ~ , llABI~E 1 ~ .
.

OCH2CHCE~2N -R2 1 ~ ' ' ' `
- / R3 InhibitiQn (%) No. 1 R2 N--R HA HR*ldBP 2 AR
_ _ .
~r-<CH3 H -OH ~NHCHCH ~ OCH HCl 100 84.170.8 2 " -OCH CH OCH " ÇHCOOH 45.5 28.325.0 2 2 3 ~HCOOH

3 " -CH2cH=cH2 " HCl 50.2 23.524.5 4 " ~OCH C-CH " (COOH)2 57.6 39.514.0 2 ` ~;
S " -OCH2cocH3 " HCl 44 . 615.1 2.7 6 " -CH2cH2cH2cH3 ~ HCl 54.1 16.8 9.7 ~20 7 -OCH2C---CH ~ NHC~cHH CE2 HCl 50.5 35.024.3 CH2c CH -NHC--~ HCl 100 94.547.6~

9 " " -NHCH ~ " 18.4 20.58.0 '"~¢~
" " -NHCH2CH2CH2N~ " 58.5 59.535.4 11 " -CH2cH2H -NUCH2CH2~0CH3 " 26.3 16.88.1 CH
12 " OCH2C----H -NHC-CHa " 61.7 75.741.3 13 " -CH2cH=cH2 -NHCH2C ~ " 25.8 20.43.5 14 2 -NHCH2cH2 OCH3 Free 50.047.1 9.4 , ;~ - 76 ~L9~ ' , ' . .. .- , Z3;2 R Inhibition (9~) Sample Rl E~2 ~R H~ HR~l dPP 2 AR~3 H -OCH2CONH2 -NHCH2 2~oCH3 HCl 57, 9 44 . 2 15 . 2 16 .. H -NHC-~-CH3 " 100 100 100 17 -NHCEI2CH2~OCH3 " 87.265.6 79.1 18 " OH -NHC-C-CH3 ~ 100 1~0 100 19 " OCH3 " " 82.183.7 80.2 2 0 " OCH2 ~ " 71 . 3 10 . 2 6 7 . 8 CH
21 --CH2 ~ --oCOCN 3 -NHC -C--CH 3 Cl HC OOH 8 5 . 2 7 7 . 5 5 9 . 3 2 2 H -OCO{> IH3 HCl 4 3 . 2 3 6 . 3 2 7 . 6 ~OCH
23 H -OCH2COOC2H5 --NHCH2 24~o 3 HHCo 10.2 8.5 2.7 24 ~ H -oCH24~ -N/~l~ HCl 25.720 .6 15 .5 Cl'~ `
4 H -OCH2c-cH-NIICH2CH2~ocEI3 HCl 55.340.9 13.7 26 Proctolol 44.61.7 36.2 27 Atenolol 52 . 3 26 . 9 9 . 8 *l HR=Heart Rate *2 dBP= Diastolic Blood Pressure 30 *3 AR--Air-Way Resistance *4 3, 4-double bond compound ~1i~1 . .
, , -, . - , . .. ~ , , , . ~ :

1 Further, the acute toxicity of the compounds of the presen~ invention having the formula (I) was determined by intravenous administration (i.v.) and oral admi.nistration (p.o.) in 5 to 6 group of rats (dd, strain; body weight, 18 to 22 g;
10 rats in each group) which have been fasted for 12 hours prior to the test. A typical compound of the present inventlon of the formula (I), 8-(2-methoxyethoxy)-5-[3-(3,4-dimethoxyphenethyl- ;
amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril maleate, was found to have the following LD50 (50~ lethal dose): .
i.v. -P--Rats (Male) 185 mg/kg 1550 mg/kg Rats (Female) 160 mg/kg 1450 mg/kg The other compounds of the formula (I) were also Eound to have low toxicity, i.,e., higher than about 130 mg/kg (i.v.) and higher than about 1200 mg/kg tp.o.).
The compounds of the present invention can be administered at a dosage level of from about 40 ~g to about 2 mg/kg/day by oral administration. Typical examples of suitable formulations are given. below, but it is to be noted that other dosage forms can also be prepared using other compounds of this invention as well as other excipients which are well known to one skilled in the art, according to the well-established pharmaceutical technlques.
Formulation 1 Tablets each containing the following components.were parepared from the following components:
Components Amount `

8-(2-Propynyloxy)-5-{3-[2-~3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy}-3,4-dihydro-30 carbostyril hydrochloride 5 mg : :
Corn Starch 142 mg Magnesium Stearate 18 mg Lactose 45 m~
Total 200 mg ~L~8 L;23~ ( 1 E~ormulation 2 Tablets each containing -the following components were prepared from the following components:
Components Amount -8-(2-Propynyloxy)-5- 3-[2-(3,4-dimethoxy-phenyl)ethylamino]-2-hydroxypropo~y -3,4-dihydrocarbostyril hydrochloride 10 mg Corn Starch 140 mg Magnesium Stearate 18 mg Lactose 42 mg 1~ _ Total 200 mg .

Claims (44)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a carbostyril derivative represented by the formula (I) (I) wherein R1 represents a member selected from the group consisting of a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, and a phenylalkyl group wherein the alkyl group contains 1 to 6 carbon atoms;
R2 represents a member selected from the group consisting of a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a phenylalkyl group wherein the alkyl group contains 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkoxyalkyl group wherein the. alkoxy group contains 1 to 6 carbon atoms and the alkyl group contains 1 to 6 carbon atoms, a hydroxyalkyl group wherein the alkyl group contains 1 to 6 carbon atoms, a carboxyalkyl group wherein the alkyl group contains 1 to 6 carbon atoms, an alkylcarbonyl group wherein the alkyl group contains 1 to 6 carbon atoms, Claim 1 continued:
a cycloalkylcarbonyl group wherein the cycloalkyl group contains 3 to 7 carbon atoms, an alkylcarbonylalkyl group wherein the alkyl-carbonyl group contains 3 to 12 carbon atoms and the alkyl group contains 1 to 6 carbon atoms, an alkoxycarbonylalkyl group wherein the alkoxy group contains 1 to 6 carbon atoms and the alkyl group contains 1 to 6 carbon atoms, an alkynyl group containing 2 to 7 carbon atoms, and a carbamoylalkyl group containing 2 to 7 carbon atoms;
R3 is a member selected from the group consisting of a hydrogen atom, and a methyl group;
R4 is a member selected from the group consisting of a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms;
an alkoxyalkyl group wherein the alkoxy group contains 1 to 6 carbon atoms and the alkyl group contains 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, a phenylalkyl group wherein the alkyl group contains 1 to 6 carbon atoms and may be substituted with the phenyl group and wherein the phenyl group may be substituted with a member selected from the group consisting of a halogen an alkoxy group containing 1 to 4 carbon atoms an alkylenedioxy group containing 1 to 2 carbon atoms Claim 1 continued:
a carbamoyl group, and an alkyl group containing 1 to 4 carbon atoms, a phenoxyalkyl group wherein the alkyl group contains 1 to 6 carbon atoms and the phenoxy group may be substituted with a member selected from the group consisting of:
a halogen atom, an alkoxy group containing 1 to 4 carbon atoms, an alkylenedioxy group containing 1 to 2 carbon atoms, a carbamoyl group, and an alkyl group containing 1 to 4 carbon atoms;
a phenyl group which may be substituted with a member selected from the group consisting of:
a halogen atom, an alkoxy group containing l to 4 carbon atoms, an alkylenedioxy group containing 1 to 2 carbon atoms, a carbamoyl group, and an alkyl group containing 1 to 4 carbon atoms;
a heterocyclic alkyl group wherein the alkyl group contains 1 to 6 carbon atoms and the heterocyclic group is a 5- or 6-membered heterocyclic ring contain-ing at least one nitrogen atom and which may contain one more nitrogen or oxygen atom as a replacement atom for one carbon atom in the ring, and wherein these heterocyclic rings may be substituted with alkyl groups containing 1 to 4 carbon atoms on their carbon atoms, and wherein the second nitrogen atom may be substituted with the phenyl group which may be substituted with a member selected from the group consisting of Claim 1 continued:
an alkyl group containing 1 to 4 carbon atoms, a halogen atom, and an alkoxy group containing 1 to 4 carbon atoms;
and R3 and R4, when taken together with the nitrogen atom to which they are attached, may represent a 5- or 6-membered heterocyclic ring which may contain one more nitrogen or oxygen atom as a replacement atom for one carbon atom in the ring and wherein the heterocyclic rings may be substituted with alkyl groups containing 1 to 4 carbon atoms on their carbon atoms and wherein the second nitrogen atom may be substituted with the phenyl group which may be substituted with a member selected from the group consisting of an alkyl group containing 1 to 4 carbon atoms, a halogen atom, and an alkoxy group containing 1 to 4 carbon atoms;
and the pharmaceutically acceptable acid addition salts thereof;
which comprises reacting a carbostyril compound of the formula (II) (II) wherein R1 and R2 are defined hereinbefore, and Y represents a group or a -?HCH2X group wherein Y represents a halogen atom, with an amine compound of the formula (III) (III)
1. Claim 1 continued:
   wherein R3 and R4 are defined hereinbefore, at a temperature of about O°C to about 100°C, or an obvious chemical equivalent thereof.
2. 2. A carbostyril derivative represented by the formula I
   as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process as claimed in claim 1, or an obvious chemical equivalent thereof.
3. 3. A process as claimed in claim 1 wherein the reaction is conducted in the presence of a base, when the group Y of the compound of formula (II) represents a group and X represents a halogen atom.
4. 4. A carbostyril derivative represented by the formula I
   and defined in claim 1, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process as claimed in claim 3, or an obvious chemical equivalent thereof.
5. 5. A process as claimed in claim 3 wherein said base is selected from the group consisting of sodium hydroxiae, potassium hydroxide, sodium carbonate and potassium carbonate.
6. 6. A carbostyril derivative represented by the formula I
   and defined in claim 1, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process as claimed in claim 5, or an obvious chemical equivalent thereof.
7. 7. A process as claimed in claim 1 wherein the reaction is carried out in the process of a solvent.
8. 8. A carbostyril derivative represented by the formula I
   and defined in claim 1, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process as claimed in claim 7, or an obvious chemical equivalent thereof.
9. 9. A process as claimed in claim 1 for preparing 8-(2-propynyloxy)-5-{3[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy) -3,4-dihydrocarbo-styril with 2-(3,4-dimethoxyphenyl)ethylamine or an obvious chemical equivalent thereof.
10. 10. 8-(2-Propynyloxy)-5-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. 11. A process as claimed in claim 1 for preparing 8-(2-hydroxyethoxy)-5-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy}3,4-dihydrocarhostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-hydroxyethoxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril with 2-(3,4-dimethoxyphenyl)ethylamine or an obvious chemical equivalent thereof.
12. 12. 8-(2-Hydroxyethoxy)-5-{3-[2-(3,4-dimethaxyphenyl)-ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. 13. A process as claimed in claim 1 for preparing 8-(2-heptynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-heptynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbo-styril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
14. 14. 8-(2-Heptynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. 15. A process as claimed in claim 1 for preparing 8-(5-methyl-2-hexynyloxy)-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(5-methyl-2-hexynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamlne or an ohvious chemical equivalent thereof.
16. 16. 8-(5-Methyl-2-hexynyloxy)-5-[3-(3,4-dimethoxyphenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceuti-cally acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. 17. A process as claimed in claim 1 for preparing 8 (2-hydroxyethoxy)-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]carbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-hydroxyethoxy)-5-(2,3-epoxypropoxy)carbostyril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
18. 18. 8-(2-Hydroxyethoxy)-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]carbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 17 or an obvious chemical equivalent thereof.
    
    19. A process as claimed in claim 1 for preparing 8-(2 methoxyethoxy)-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically
19. Claim 19 continued:
    acceptable acid addition salts thereof, which comprises reacting 8-(2-methoxyethoxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbo-styril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
20. 20. 8-(2-Methoxyethoxy)-5-[3-(3,4-dimethoxy-phenethyl-amino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. 21. A process as claimed in claim 1 for preparing 8-carbamoylmethoxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-carbamoylmethoxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyri1 with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
22. 22. 8-Carbamoylmethoxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically aceeptable acid addition salts thereof, whenever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. 23. A process as claimed in claim 1 for preparing 8-allyloxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-allyloxy -5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
24. 24, 8-Allyloxy-5-[3-(3,4-clime-thoxyphene-thylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. 25. A process as claimed in claim 1 for preparing 8-methylcarbonylmethoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-methylcarbonylmethoxy-5-(3-chloro-2-hydroxypropoxy) 3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamino or an obvious chemical equivalent thereof.
26. 26. 8-Methylcarbonylmethoxy-5-[3-(3,4-dimethoxyphenet amino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. 27. A process as claimed in claim 1 for preparing 8-butoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-butoxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
28. 28. 8-Butoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 27 or an obvious chemical equivalenk thereof.
29. 29. A process as claimed in claim 1 for preparing 8-(2-propynyloxy)-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 5-(2,3-epoxypropoxy)-8-(2-propynyloxy)-3,4-dihydrocarbostyril with t-butylamine or an obvious chemical equivalent thereof.
30. 30. 8-(2-Propynyloxy)-5-[3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. 31. A process as claimed in claim 1 for preparing 8-(2-propynyloxy)-5-[3-(1,1-dimethyl-2-phenylethylamino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3-4-dihydrocarbostyril with 1,1-dimethyl-2-phenylethylamine or an obvious chemical equivalent thereof.
32. 32. 8-(2-Propynyloxy-5-[3-(1,1-dimethyl-2-phenylethylamino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. 33. A process as claimed in claim 1 for preparing 8-allyloxy-5-[3-(2,2-diphenyletllylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof,which comprises reacting 8-allyloxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 2,2-diphenylethylamine or an obvious chemical equivalent thereof.
34. 34. 8-Allyloxy-5-[3-(2,2-diphenylethylamino)-2-hydroxypropoxy]-3,4dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. 35. A process as claimed in claim 1 for preparing 8-carboxymethoxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-carboxymethoxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamino or an obvious chemical equivalent thereof.
36. 36. 8-Carboxymethoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. 37. A process as claimed in claim l for preparing 8-cyclohexylcarbonyloxy-5-(3-isopropylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril with cyclohexylcarbonyl chloride or an obvious chemical equivalent thereof.
38. 38. 8-Cyclohexylcarbonyloxy-5-(3-isopropylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 37 or an obvious chemical equivalent thereof.
39. 39. A process as claimed in claim 1 for preparing 8-ethoxycarbonylmethoxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceuti-cally acceptable acid addition salts thereof, which comprises reacting 8-ethoxycarbonylmethoxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
40. 40. 8-Ethoxycarbonylmethoxy-5-[3-(3,4-dimethoxy-phenethylamino)-2-hydroxypropoxy)-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 39 or an obvious chemical equivalent thereof.
41. 41. A process as claimed in claim 1 for preparing 8-(2-propynyloxy)-5-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy }-carbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-carbostyril with 2-(3,4-dimethoxyphenyl)ethylamine or an obvious chemical equivalent thereof.
42. 42. 8-(2-Propynyloxy)-5-{3-[2-(3,a-dimethoxy-phenyl)-ethylamino]-2-hydroxypropoxy}-carbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 41 or an obvious chemical equivalent thereof.
43. 43. A process as claimed in claim 1 for preparing 8-hydroxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 8-hydroxy-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril with 3,4-dimethoxyphenethylamine or an obvious chemical equivalent thereof.
44. 44. 8-Hydroxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by process as claimed in claim 43 or an obvious chemical equivalent thereof.