BE852556A - CARBOSTYRILE DERIVATIVES AND THEIR PREPARATION PROCESS - Google Patents

Description

       

  "Carbostyril derivatives and their preparation process"

  
The present invention relates to carbostyril derivatives, as well as their preparation process. More particularly, the invention relates to carbostyril derivatives corresponding to

  
 <EMI ID = 1.1>

  
maceutically acceptable, as well as a method of preparing the

  
carbostyril derivatives of formula (I).

  
Certain carbostyril derivatives are known to exert useful pharmaceutical activities. Representative compounds of this type have been described in "Journal of Medical Chemistry.

  
 <EMI ID = 2.1> <EMI ID = 3.1>

  
16212th (1965), etc. However, these prior art references do not state that compounds having a wide variety of substituents in the 1, 5, and / or 8 positions of the carbostyril or 3,4-dihydrocarbostyril moiety exhibit excellent β-blocking activity. ; -adrenoreceptors.

  
Heretofore, various carbostyril compounds have been described which exert β-adrenoreceptor blocking activity. For example, in the United States of America Patents

  
 <EMI ID = 4.1>

  
Patent Application 2,549,889 filed in the Federal Republic of Germany, it is stipulated that carbostyril or 3,4dihydrocarbostyril derivatives having a (2-hydroxy-3-substituted amino) -propoxy group in position 5, 6, 7 or 8 of the carbostyril or 3,4-dihydrocarbostyril have P-adrenoreceptor blocking activity.

  
However, these &#65533; -adrenoreceptor blockers

  
 <EMI ID = 5.1>

  
indicated for subjects with bronchial asthma and, therefore, it has been desirable to develop O-blockers with high cardioselectivity.

  
Recently, it has been found that carbostyril compounds having a (2-hydroxy-3-substituted amino) -propoxy group at the 5-position of the carbostyril ring exert cardioselective activité -adrenoreceptor blocking activity (see Patent Application 2.615. .406 registered in the Federal Republic of Germany). Of

  
 <EMI ID = 6.1>

  
treatment of heart conditions such as angina, cardiac arrhythmia and hypertension. Likewise, the compounds of the present invention have been found to exert excellent cardioselectivity superior to that of these known compounds, while they are useful for the treatment or prophylaxis of cardiac disorders in subjects also suffering from chronic diseases of the heart. obstruction of the lungs such as bronchial asthma.

  
Following extensive studies, it was found that the carbostyril derivatives of formula (I) above, as well as their pharmaceutically acceptable acid addition salts, exerted excellent cardioselective activity of blocking β-adrenoreceptors. .

  
The term "alkyl group" as used herein

  
 <EMI ID = 7.1>

  
a straight or branched chain alkyl group containing 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group ., a pentyl group or a hexyl group and the like.

  
The term "cycloalkyl group" as used in

  
 <EMI ID = 8.1>

  
cycloalkyl group containing 3 to 7 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.

  
The expression phenylalkyl group ", used in

  
 <EMI ID = 9.1>

  
denotes a monophenylalkyl group or a diphenylalkyl group having a straight or branched chain alkyl group containing

  
1 to 6 carbon atoms in the alkyl moiety, for example, benzyl group, 2-phenylethyl group, 1-phenylethyl group, 2-methyl-2-phenylpropyl group, diphenylmethyl group, 2,2- group diphenylethyl, a 4-phenylbutyl group, a group

  
 <EMI ID = 10.1>

  
2-methyl-4-phenylbutyl, a 2-methyl-3-phenylpropyl group and the like.

  
The term "alkenyl group" as used in

  
 <EMI ID = 11.1>

  
a straight or branched chain alkenyl group containing 2 to 6 carbon atoms, for example, an ethylenyl group, a 2-propenyl group, a 2-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a group 1 -methyl-2-butenyl, a 2hexenyl group, a 4-hexenyl group and the like.

  
The term "alkoxyalkyl group" used in

  
 <EMI ID = 12.1>

  
an alkoxyalkyl group containing a straight or branched chain alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety, as well as a straight or branched chain alkylene group containing 1 to 6 carbon atoms in the alkyl moiety, for example , an ethoxymethyl group, a 2-methoxyethyl group, a 2-isopropoxyethyl group, a 3-butoxypropyl group, a 5-sec-butoxypentyl group, a 4-hexyloxybutyl group, a 6pentyloxyhexyl group, a 3-ethoxybutyl group and the like.

  
The term "hydroxyalkyl group" used in

  
 <EMI ID = 13.1>

  
monohydroxyalkyl having a straight or branched chain alkyl group containing 1 to 6 carbon atoms, for example, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group, 2-methyl-3-hydroxypropyl group, 5-hydroxypentyl group, 4-hydroxypentyl group, 2-methyl-4-hydroxybutyl group, 2-methyl-3-hydroxybutyl group, 6-group -hydroxyhexyl, a 5-hydroxyhexyl group, a 2- group

  
 <EMI ID = 14.1>

  
analogues.

  
The term "carboxyalkyl group" used in

  
 <EMI ID = 15.1>

  
for example, a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 2-carboxyhexyl group, a 3-carboxy-2-methylbutyl group and the like.

  
The term "alkylcarbonyl group" used in

  
 <EMI ID = 16.1>

  
alkylcarbonyl having a straight or branched chain alkyl group containing 1 to 6 carbon atoms in the alkyl moiety, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pentanoyl group, a hexanoyl group and analogues.

  
The term "cycloalkylcarbonyl group" as used in this specification refers to a cycloalkylcarbonyl group having a cycloalkyl group containing 3 to 7 carbon atoms in the cycloalkyl moiety, for example, a cyclopropylcarbonyl group &#65533; a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cycloheptylcarbonyl group and the like.

  
 <EMI ID = 17.1>

  
alkylcarbonylalkyl group comprising a straight or branched chain alkylene group containing 1 to 6 carbon atoms, as well as an alkylcarbonyl group of the type defined above, for example, a methylcarbonylmethyl group, an ethylcarbonylmethyl group, a 2-ethylcarbonylethyl group, a 2-isopropylcarbonylethyl group, a 3-sec-butylcarbonylpropyl group, a 6-hexylcarbonylhexyl group, a 3-ethylcarbonyl-2-methylpropyl group and the like.

  
The term "alkoxycarbonylalkyl group" as used

  
 <EMI ID = 18.1>

  
alkoxycarbonylalkyl group having an alkoxycarbonyl moiety consisting of a straight or branched chain alkoxy group containing 1 to 6 carbon atoms and attached to a carbonyl group, as well as a straight or branched chain alkyl group containing 1 to 6 carbon atoms , for example, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, an isopropoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 3-sec-butoxycarbonylpropyl group, a 5-isobutoxycarbonylpentyl group, a 6-hexyloxycarbonyl 2- 3-ethyl group, a methylbutyl and the like.

  
The term "alkynyl group" as used in

  
 <EMI ID = 19.1>

  
straight or branched chain alkynyl containing 2 to 7 carbon atoms, for example, 2-propynyl group, 1-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group, 3-group -pentynyl, a 4-pentynyl group, a 2-methyl3-butynyl group, a 1-methyl-3-butynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group , a 2-methyl-4-pentynyl group, a 1-methyl-4-pentynyl group,

  
a 2-methyl-3-pentynyl group, a 1-methyl-3-pentynyl group, a 2-heptynyl group, a 3-heptynyl group and the like.

  
The term "carbamoylalkyl group" as used

  
 <EMI ID = 20.1>

  
carbamoylalkyl group having a straight or branched chain alkylene group containing 1 to 6 carbon atoms in the alkyl moiety, as well as a carbamoyl group which may be substituted on the nitrogen atom by an alkyl group containing 1 to

  
6 carbon atoms or a substituted or unsubstituted phenylalkyl group, for example, a carbamoylmethyl group, a 3-carbamoylpropyl group, a 4-carbamoylbutyl group, a 6-carbamoylhexyl group, a 2- (N, N-diethylcarbamoyl) -ethyl group , N- (3,4-di-methoxyphenethyl) -carbamoylmethyl group and the like.

  
The term "phenoxyalkyl group" used in

  
this specification denotes a phenoxyalkyl group having a straight or branched chain alkylene group containing 1 to

  
6 carbon atoms in its alkyl moiety, for example, a group

  
 <EMI ID = 21.1>

  
a 2-methyl-2-phenoxypropyl group, a diphenoxymethyl group,

  
2,2-diphenoxyethyl group, 4-phenoxybutyl group, 6-phenoxyhexyl group, 1,1-dimethyl-2-phenoxyethyl group, 2-methyl-4-phenoxybutyl group, 2-methyl-3- group phenoxypropyl and the like.

  
The term "heterocyclic alkyl group" as used

  
 <EMI ID = 22.1>

  
a heterocyclic alkyl group comprising a straight or branched chain alkylene group containing 1 to 6 carbon atoms and a 5 or 6 membered heterocyclic ring containing at least

  
a nitrogen atom, as well as possibly an additional nitrogen atom and / or an oxygen atom, the alkylene group being attached

  
to the nitrogen atom of the heterocyclic ring. Among the heterocyclic alkyl groups, there is, for example, a pyrrolidinomethyl group, a 2-piperazinoethyl group, a 3-morpholinopropyl group, a 2-piperazinopropyl group, a 2-imidazolidinoethyl group,

  
a 3-piperazinobutyl group, a 6-morpholinohexyl group and the like.

  
The term "five-membered or six-membered heterocyclic ring" used in the present specification denotes a heterocyclic group containing at least one nitrogen atom and optionally one oxygen atom as hetero atoms, for example, a piperidino group, a group morpholino, a pyrrolidino group, a piperazino group, an imidazolidino group and the like.

  
The phenyl, phenylalkyl, phenoxyalkyl and heterocyclic alkyl groups, as well as the above heterocyclic ring may contain 1 to 3 substituents which may be the same or different. Among these substituents, there is, for example, an alkyl group containing 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a tert-group. butyl and the like, an alkoxy group containing 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group and the like, a halogen atom such than a chlorine atom, a bromine atom, an iodine atom or an atom

  
fluorine, an alkylene-dioxy group containing 1 or 2 carbon atoms such as a methylene-dioxy group or an ethylenedioxy group and the like, a carbamoyl group, a substituted or unsubstituted phenyl group, etc.

  
Among the groups having the above substituents, there are specifically, for example, 4-methoxyphenyl group, 3-chlorophenyl group, 3,4-methylene-dioxy group, 3,4-dimethoxyphenyl group, group 3, 4,5-trimethoxyphenyl, 4-chlorophenyl group, 2- (4-fluorophenyl) -ethyl group,

  
2- (3,4-dibromophenyl) -ethyl group, 2- (3,4-dimethoxyphenyl) -ethyl group, 2- (3,4,5-trimethoxyphenyl) -ethyl group, 4- (3 , 4,5-triethoxyphenyl) -butyl, 2- (3,4-methylenedioxyphenyl) -ethyl group, 3- (3,5-dichlorophenyl) -propyl group, 2- (4-carbamoylphenyl) -ethyl group, 2- (4-chloro-3,5dimethoxyphenyl) -ethyl group, 2- (2-isopropoxyphenyl) -ethyl group, 2- (3,4-dimethoxyphenoxy) -ethyl group, 2- (3,5dimethoxyphenoxy) group ) -ethyl, group 4- (3,4,5-triethoxyphenoxy) -

  
 <EMI ID = 23.1>

  
2- (4-fluorophenoxy) -ethyl, 2- (4-tert-butoxyphenoxy) ethyl group, 3- (3,5-dichlorophenoxy) -propyl group, 2- (4carbamoylphenoxy) -ethyl group, group 2 - (4-chloro-3,5-dimethoxy-phenoxy) -ethyl &#65533; 2- (4-methoxyphenoxy) -ethyl group, group

  
 <EMI ID = 24.1>

  
4- (3-chlorophenyl) -piperazino group, 4- (4-chlorophenyl) piperazino group, 4-ethylpiperazino group, 4- (tert-butyl) piperazino group, 4- (2-methoxyphenyl) -piperazino group , 3-methyl-4- (4-chlorophenyl) -piperazino group, 3-isopropylpiperazino group, 4- (3 &#65533; 4-methylene-dioxyphenyl) -piperazino &#65533;

  
2-chloropiperazino group, 4- (3,4-dimethoxyphenyl) piperazino group, 4- (2-methylphenyl) -piperazino group, 3- (4-ethylpiperazino) -propyl group, 2- (2- chloromorpholino) -

  
 <EMI ID = 25.1>

  
the 2-isopropylpyrrolidino group and the like.

  
The term "pharmaceutically acceptable acid addition salts" as used in this specification refers to salts formed with pharmaceutically acceptable organic and inorganic acids well known in the art, 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, l malic acid, mandelic acid, methanesulfonic acid, benzoic acid and the like.

  
The chemical structure representing the carbostyril compounds of the present invention used in the present specification and the claims hereafter, that is, the partial structure of formula:

  

 <EMI ID = 26.1>
 

  
includes both carbostyril and 3,4-dihydrocarbostyril

  
 <EMI ID = 27.1>

  

 <EMI ID = 28.1>


  
respectively.

  
The carbostyril derivatives of formula (I) can be prepared by reacting a carbostyril compound of formula (II), i.e. a 2 2 3-epoxypropoxycarbostyril compound of formula (IIa) or a 2-hydroxy-3-halopropoxycarbostyril compound of formula (IIb) with an amino compound of formula (III) as. illustrated by the following reaction scheme:

  

 <EMI ID = 29.1>
 

  
 <EMI ID = 30.1>

  
where X represents a halogen atom.

  
More specifically, the starting material, namely the carbostyril compounds of formula (II), can be an epoxy form of formula (IIa), a 2-hydroxy-3-halopropoxy form of formula (IIb) or a mixture of these. shapes.

  
The reaction between a 2,3-epoxypropoxycarbostyril compound of formula (IIa) and an amine of formula (III) can be carried out in the absence of solvents but, preferably, it is carried out in the 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

  
 <EMI ID = 31.1>

  
using an approximately equimolar amount to a molar excess, preferably 3 to 8 moles of the amine of formula (III) per mole of the 2,3-epoxypropoxycarbostyril compound of formula (IIa).

  
The reaction between a 2-hydroxy-3-halopropoxycarbostyril of formula (IIb) and an amine of formula (III) can advantageously be 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; however, this reaction can also be carried out in the absence of this base.

  
The reaction can be carried out at a temperature of between about 0 and about 100 [deg.] C, preferably between

  
 <EMI ID = 32.1>

  
in the presence of solvents, for example, alcohols such as methanol, ethanol, propanol, isopropanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, water, etc. but preferably in the presence of alcohols such as methanol, ethanol, isopropanol and the like.

  
In the above reaction, the amine of formula (III) is used in a molar excess, preferably in an amount of 3 to 8 moles per mole of the 2-hydroxy-3-halopropoxycarbostyril compound of formula (IIb) .

  
The reaction between a mixture of the carbostyril compounds of formulas (IIa) and (IIb) and an amino compound of formula (III) can be carried out in the presence or absence of the base indicated above at a temperature between about

  
 <EMI ID = 33.1>

  
solvents and the amount of amine of formula (III) which can be used in this reaction, are the same as those given above for the reaction of a compound of formula (IIa) or (IIb) with amine of formula (III).

  
The time required to complete the reaction of the carbostyril compound of formula (IIa) and / or (IIb) with an amine varies depending on the temperature adopted but, as a rule, it is

  
 <EMI ID = 34.1>

  
between 2 and 2 p.m .:

  
The starting materials of formula (II) are novel compounds which can be derived from corresponding 5,8-dihydroxycarbostyril compounds of formula (IV) by various methods as indicated by reaction scheme 1 below.

  
Reaction scheme 1
 <EMI ID = 35.1>
 
 <EMI ID = 36.1>
 Representative methods will be given below.

  
 <EMI ID = 37.1>

  
Method A

  
The carbostyril compounds can be prepared from

  
 <EMI ID = 38.1>

  
of hydrogen, by reacting a known compound of dihydroxycarbostyril of formula (IV) with an epihalohydrin of formula (V) in the presence of a base *

  
Method B

  
The carbostyril compounds can be prepared from

  
 <EMI ID = 39.1>

  
base to form a hydroxycarbostyril compound of formula (VII), then reacting the hydroxycarbostyril compound thus

  
 <EMI ID = 40.1>

  
in the presence of a base. Method C

  
The carbostyril compounds can be prepared from '

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1> .with a 2,3-dihydropyran of formula (VIII) to form a tetrahydropyranyl compound of formula (IX) in which the hydroxy group in position 5 is protected by a tetrahydropyranyl group, by reacting the thus obtained compound of formula (IX) with an <EMI ID = 43.1> obtaining a carbostyril compound of formula (XI), by hydrolyzing the compound of formula (XI) to obtain a corresponding hydroxycarbostyril compound of formula (XII) and by reacting the hydroxycarbostyril compound thus obtained of formula (XII) with an epihalohydrin of formula (V) in the presence of a base. As a variant, the compound of formula (XII) can be derived from the compound of formula (XV).

  
Method D

  
The carbostyril compounds can be prepared from

  
 <EMI ID = 44.1>

  
carbostyril compound of formula (XIII), hydrolyzing the compound of formula (XIII) to obtain a compound of formula (XV), then reacting the compound thus obtained of formula (XV) with an epihalohydrin of formula (V) in presence of a base.

  
Alternatively, the compound of formula (XV) can be prepared from the corresponding compound of formula (XI) or (XII) by hydrolysis.

  
Among the carbostyril derivatives corresponding to formula (II), there are compounds corresponding to formulas (IIa),
(Ilb), (IIc) and (IId) as illustrated in the reaction scheme

  
2 below, it being possible for the compounds to be converted interchangeably as indicated by the arrows.

  
Reaction scheme 2

  

 <EMI ID = 45.1>


  
Methods of preparing the starting compound

  
of formula (II) of the present invention will be illustrated below in more detail.

  
The reaction between the compound of formula (IV), (VII), (XII) or (XV) and an epihalohydrin of formula (V) can be carried out in the presence of a base at a temperature between about 0 and about 150 [ deg.] C, preferably between 50 and 100 [deg.] C in the absence or, preferably, in the presence of a solvent.

  
Among the bases which can be used in the above reaction, there are, for example, inorganic bases such as alkali metal hydroxides, especially sodium hydroxide, potassium hydroxide and the like, metal carbonates alkalis, including 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.

  
Among the solvents which can be used in the above reaction, there are, for example, 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, as well as aromatic hydrocarbons such as benzene,

  
toluene, xylene and the like, preferably methanol and ethanol.

  
The epihalohydrin of formula (V) can be epichlor-

  
 <EMI ID = 46.1>

  
in an amount of about 1 to about 3 moles, preferably of

  
1 to 1.5 moles per mole of the compound of formula (IV) or (XV) and in an amount ranging between an approximately equimolar amount and a molar excess, preferably between 5 and 10 moles per mole of the compound of formula (VII) or (XII).

  
In the above reaction, the attached hydroxy group

  
 <EMI ID = 47.1>

  
(XII). And (XV) is converted into a (2,3-epoxy) -propoxy group or a 3-halo-2-hydroxypropoxy group and the reaction product obtained

  
 <EMI ID = 48.1>

  
epoxy) -propoxy and 5- (3-halo-2-hydroxypropoxy). The mixture thus obtained is usually used for the subsequent reaction with an amine of formula (III) without isolating each of the compounds, but each of the compounds can optionally be isolated and purified by conventional methods, for example, by fractional crystallization or by chromatography in column, to then react with an amine of formula (III).

  
The reaction can be carried out between the compound of formula (IIa), (IIb), (IX) or (IV) and a compound of formula (X)

  
 <EMI ID = 49.1>

  
(Ilb), (IX) or (IV) to an alkali metal salt by reacting the compound with a base such as an alkali metal or a compound of an alkali metal, for example, sodium hydride, l 'hydride

  
 <EMI ID = 50.1>

  
analogues.

  
The transformation of the compound of formula (IIa), (IIb),
(IX) or (IV) in an alkali metal salt can be carried out at a temperature of between about 0 and about 200 [deg.] C, preferably

  
 <EMI ID = 51.1>

  
example, 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, polar solvents non-protonics such as dimethylformamide, hexamethylphosphoric triamide, dimethylsulfoxide and the like, preferably, polar non-proton solvents.

  
The alkali metal or the alkali metal compound can be used in an amount ranging from about 1 to about

  
5 moles, preferably between 1 and 3 moles per mole of the compound

  
of formula (IIa) or (IX) and in an amount of from about 2 to about
10 moles, preferably 3 to 5 moles per mole of the compound of formula (IIb) or (IV).

  
Subsequently, the alkali metal salts obtained from the compounds of formulas (IIa), (IIb), (IX) and
(IV) with a halide of formula (X). This reaction proceeds smoothly in a solvent such as dimethylformamide, dimethylsulfoxide and the like at room temperature (approx.

  
 <EMI ID = 52.1> The halide (X) can be used in an amount of about 1 to about 5 moles, preferably 1 to 3 moles per mole of the compound of formula (IIa) or (IX), thus than in an amount of about 2 to about 10 moles, preferably 3 to 5 moles per mole of the compound of formula (IIb) or (IV).

  
The reaction between the compound of formula (IIa), (IId),

  
 <EMI ID = 53.1>

  
carried out in the presence of a base without using a solvent, but

  
a solvent can be employed, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran 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, acetonitrile, methanol, ethanol, etc.

  
Among the bases which can be used in the above reaction, there are, for example, inorganic bases such as alkali metal hydroxides, especially sodium hydroxide, potassium hydroxide and the like, metal carbonates alkalis 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 formula (IV) or
(XV) and the halide (VI) can be carried out using about 1 to about 3 moles, preferably 1 to 1.5 moles of the halide per mole of the compound of formula (IV) or (XV) at a temperature of about 0 to about 100 [deg.] C, preferably at a temperature of

  
 <EMI ID = 54.1>

  
The reaction of a compound of formula (VII) with a 2,3-dihydropyran can be carried out in a solvent in the presence of a catalyst at a temperature between about 0 [deg.] C and the boiling point of solvent used, preferably at a temperature between room temperature and 50 [deg.] C.

  
Among the solvents which can be used in the above reaction, there are, for example, aromatic solvents such as benzene, toluene, xylene and the like, n-hexane, cyclohexane, ethers such as l diethyl ether, 1,2-dimethoxyethane, dioxane and the like, chloroform, dimethylformamide, hexamethylphosphoric triamide, dimethylsulfoxide and the like.

  
Among the catalysts which can be used in the above reaction, there are, for example, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and the like, organic acids such as acetic acid, p-toluenesulfonic acid, acid

  
 <EMI ID = 55.1>

  
aluminum chloride, zinc chloride, boron trifluoride and the like, thionyl chloride, etc., in an amount such as

  
 <EMI ID = 56.1>

  
3% by weight, calculated on the weight of the compound of formula (VII).

  
The tetrahydropyranyl group can be removed from the compound of formula (IX) using an acid in a solvent, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, n-hexane, cyclohexane, ethers 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, dimethylformamide, triamide hexamethylphosphoric acid, dimethylsulfoxide and the like, at a temperature approximately between room temperature and the boiling point of the solvent used, preferably at a temperature

  
 <EMI ID = 57.1>

  
1 Among the acids which can be used for the removal of the tetrahydropyranyl group, there are, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like,

  
as well as organic acids such as acetic acid,

  
i p-toluenesulfonic acid, methanesulfonic acid and the like.

  
Particularly preferred acids are weakly acidic organic and inorganic acids, for example, phosphoric acid, acetic acid, p-toluenesulphonic acid, methanesulphonic acid and the like. The amount of acids used is not critical and can be a large excess with respect to the compound of formula (IX).

  
The hydrolysis reaction of the compound can be carried out

  
 <EMI ID = 58.1>

  
hydrogen nide with a suitable solvent, in particular, with

  
an aqueous medium in the form of a halogenated hydracid. A particularly preferred example of a hydrogen halide is hydrogen bromide which is usually used in the form of an aqueous solution at a concentration of about 10 to 50%, preferably 47%. Hydrogen halide can be used in

  
an amount between approximately 1 mole and a molar excess,

  
preferably, in a large excess with respect to the compound of formula (XI), (XII) or (XIII).

  
The hydrolysis can advantageously be carried out by heating to a temperature between about 100 and about

  
 <EMI ID = 59.1>

  
The compounds of the present invention corresponding to formula (I) can be converted interchangeably into different types of compounds of formula (I) as illustrated by reaction scheme 3 below.

  
Reaction scheme 3
 <EMI ID = 60.1>
 The transformation of a compound comprising a group
-OR "in position 8 in a corresponding compound comprising a group
-OH in position 8 can be carried out by hydrogenation or catalytic reduction using a reducing agent, or by-hydrolysis <EMI ID = 61.1>

  
To be easily removed by the above methods, there are, for example, aralkyl groups such as benzyl group, α-methyl-benzyl group and the like, as well as acyl groups.

For example, compounds corresponding to the formulas

  
 <EMI ID = 62.1>

  
can be subjected to catalytic reduction in the presence of a catalyst which is generally used for catalytic reduction, for example, Raney nickel, palladium on carbon, palladium black, platinum oxide and the like, in order to 'obtain a corresponding compound corresponding to formulas (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 adopted during the catalytic reduction are not critical and, in general, the reduction takes place at atmospheric pressure and at room temperature.

  
The compounds thus obtained of formula (I) can be converted into their pharmaceutically acceptable acid addition salts as described above by conventional methods well known in the art.

  
The compounds of the present invention, as well as their intermediates described above, can be isolated from the reaction mixture obtained in each step by conventional methods, for example, by separating the solvent used by distillation. If necessary, the obtained compounds can be purified by conventional methods such as fractional crystallization, column chromatography and the like.

  
As will be understood by those skilled in the art, the carbostyril compounds of formula (I) can be prepared by various methods. Methods which may be adopted are illustrated in Reaction Scheme 4 below.

  
Reaction scheme 4
 <EMI ID = 63.1>
 
 <EMI ID = 64.1>
 <EMI ID = 65.1>

  
each a halogen atom.

  
Furthermore, the scope of the present invention encompasses the optical isomers of the carbostyril compounds of formula (I).

  
The carbostyril compounds of formula (I) according to the present invention can be easily converted into oxazolidine-carbostyril derivatives which can be prepared by condensing a carbostyril compound of formula (I) having a chain

  
 <EMI ID = 66.1>

  
as acylcarbostyril derivatives which can be prepared by acylating the hydroxy group present in the above side chain with a wide variety of acylating agents by conventional acylation methods. These oxazolidine and acylcarbostyril derivatives were also found to exert excellent cardioselective β-adrenoreceptor blocking activity.

  
A list of compounds represented below will be given below.

  
 <EMI ID = 67.1>

  
propoxy) -3,4-dihydrocarbostyril.,

  
1-isopropyl-8-hydroxy-S- (3-tert-butylamino-2-hydroxypropoxy) -3,4-dihydrocarbostyril,

  
 <EMI ID = 68.1>

  
3,4-dihydrocarbostyril,

  
8-hydroxy-S- [3- (3,4-methylenedioxyphenethylamino) -2hydroxypropoxy] -3,4-dihydrocarbostyril,

  
 <EMI ID = 69.1>

  
 <EMI ID = 70.1>

  
8-hydroxy-5- [3- (3,4-methylcnedioxyphenethylamino) -2hydroxypropoxy) carbostyril;

  
 <EMI ID = 71.1>

  
hydroxypropoxy] -3,4-dihydrocarbostyril,

  
8-hydroxy-5- (2-hydroxy-3- [1-methyl-2- (3,4-dimethoxyphenoxy) -

  
 <EMI ID = 72.1>

  
2-hydroxypropoxy] -3,4-dihydrocarbostyril &#65533;

  
8-acetoxy-5- (3-tert-butylamino-2-hydroxypropoxy) -3,4dihydrocarbostyril,

  
 <EMI ID = 73.1> <EMI ID = 74.1>

  
hydroxypropoxy] carbostyril, <EMI ID = 75.1>

  
2-hydroxypropoxy] carbostyril,

  
8-allyloxy-5- (3-tert-butylamino-2-hydroxypropoxy) carbostyril,

  
 <EMI ID = 76.1>

  
ethylamino) -2-hydroxypropoxy] carbostyril, <EMI ID = 77.1> <EMI ID = 78.1>

  
8- (2-propinyloxy) -S- [3- (3,4,5-trimethoxyphenethylamino) - 2-hydroxypropoxy] -3,4-dihydrocarbostyril,

  
8- (2-prbpinyloxy) -5- {2-hydroxy-3- [6- (4-methoxyphenyl) -

  
 <EMI ID = 79.1>

  
propoxy] -3,4-dihydrocarbostyril,

  
8- (2-propinyloxy) -S- [2-hydroxy-3- (4-methoxyphenylamino) propoxy] -3,4-dihydrocarbostyril, <EMI ID = 80.1>

  
3,4-dihydrocarbostyril e,

  
8- (2-Butynyloxy) -S- [3- (3,4-dimethoxyphenethylamino) -

  
 <EMI ID = 81.1>

  
8- (3-butynyloxy) -5- [2-hydroxy-3- (3-morpholinopropylamino) propoxy] -3,4-dihydrocarbostyril,

  
 <EMI ID = 82.1>

  
8- (4-pentynyloxy) -S- (2-hydroxy-3-tert-butylaminopropoxy) 3,4-dihydrocarbostyril, <EMI ID = 83.1>

  
hydroxypropoxy] -3,4-dihydrocarbostyril,

  
8- (3-hexynyloxy) -5- (2-hydroxy-3-isopropylaminopropoxy) 3,4-dihydrocarbostyril,

  
 <EMI ID = 84.1> <EMI ID = 85.1>

  
propoxy] -3,4-dihydrocarbostyril.,.

  
8- (2-hydroxyethoxy) -5- (3-pyrrolidirio-2-hydroxypropoxy) 3,4-dihydrocarbostyril,

  
 <EMI ID = 86.1>

  
butylamino) propoxy] -3,4-dihydrocarbostyril,

  
8- (3-hydroxypropoxy) -S- [3- (3-pyrrolidinopropylamino) -

  
 <EMI ID = 87.1> <EMI ID = 88.1> <EMI ID = 89.1>

  
8- (2-propynyloxy) -5- (2-hydroxy-3-tert-butylaminopropoxy) carbostyril e,. 8- (2-propynyloxy) -5- (2-hydroxy-3-allylaminopropoxy) .carbostyril, 8- (2-propynyloxy) -S- [3- (4-carbamoylphenethylamino) -2hydroxypropoxy] carbostyril,

  
 <EMI ID = 90.1>

  
carbostyril e, <EMI ID = 91.1>

  
amino) propoxy] carbostyril &#65533;

  
 <EMI ID = 92.1>

  
8- (5-hydroxypentyloxy) - (2-hydroxy-3-tert-butylaminopropoxy] carbostyril,

  
 <EMI ID = 93.1>

  
propoxy &#65533; -3,4-dihydrocarbostyril &#65533;

  
 <EMI ID = 94.1>

  
hydroxypropoxy] -3,4-dihydrocarbostyril,

  
8- (2-propynyloxy) -S- (3- (2-methoxyethylamino) -2-hydroxypropoxy] carbostyril,

  
 <EMI ID = 95.1>

  
propoxy] -3,4-dihydrocarbostyril, <EMI ID = 96.1>

  
hydroxypropoxy] -3,4-dihydrocarbostyril,

  
8- (3-carboxypropoxy) -S- (3-tert-butylamino-2-hydroxypropoxy) 3,4-dihydrocarbostyril,

  
 <EMI ID = 97.1>

  
8-carbamoylmethoxy-S- [3- (3,4-dimethoxyphenethylamino) -2hydroxypropoxy] -3,4-dihydrocarbostyril,

  
 <EMI ID = 98.1>

  
logues.

  
The present invention is illustrated in more detail by the following examples which are given only by way of illustration and without any limiting nature * Reference example 1

  
 <EMI ID = 99.1>

  
drocarbostyril in 100 ml of anhydrous tetrahydrofuran and, to the solution thus obtained, 100 mg of p-toluenesulfonic acid is added. 10 g of dihydropyran are slowly added dropwise thereto at room temperature with stirring.

  
After the addition is complete, the mixture is stirred at room temperature for 12 hours, poured into a large volume of a saturated aqueous solution of sodium chloride, and then extracted with chloroform. The extract is washed successively with a 5% aqueous solution of sodium hydroxide and water, then the chloroform layer is dried over anhydrous potassium carbonate. The chloroform is evaporated off under reduced pressure and the residue is crystallized from petroleum ether. By recrystallization from a mixture of ethanol and water, 9.5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl (IV) ether are obtained in the form of colorless needle crystals.

  
 <EMI ID = 100.1>

  
Reference example 2

  
5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether (IV) is dissolved in 100 ml of anhydrous dimethylformamide and, while stirring, 810 mg of sodium hydride is slowly added to the solution. , then we shake

  
at room temperature for one hour. Another 1.05 ml of methyl iodide was added dropwise thereto, followed by stirring at the same temperature for 2 hours. The reaction mixture is 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 is evaporated off under reduced pressure and the residue is recrystallized from ligrolne to obtain 1.42 g.

  
 <EMI ID = 101.1> hydropyranyl in the form of colorless needle crystals

  
 <EMI ID = 102.1>

  
By following the same processes as those described above, 1-benzyl-8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether is obtained.

  
Nuclear Magnetic Resonance Spectrum: 60 MHz in Dimethylsulfoxide-d6 3.3-4.1 (m. 2H), 4.87 (s. 2H), 5.37

  
(s. 2H) parts per million.

  
Reference example 3

  
14 g of 1-methyl-8-benzyloxy-3,4dihydrocarbostyril-5-ol-tetrahydropyranyl ether are added to 280 ml of methanol containing 80 ml of concentrated hydrochloric acid, followed by stirring at room temperature for 10 minutes. The reaction mixture is basified with sodium hydroxide, then the methanol is evaporated off under reduced pressure. The precipitated crystals are extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate, then the chloroform is evaporated under reduced pressure. The residue is recrystallized from ethanol to obtain 8.1 g of

  
 <EMI ID = 103.1>

  
form colorless needle crystals having a melting point of 196-197 [deg.] C.

  
Reference example 4

  
5.5 g of 1-methyl-5-hydroxy-8-benzyloxy3,4-dihydrocarbostyril is added to 15 g of epichlorohydrin, then 12 drops of piperidine are added thereto and then stirred at 90-100 [deg.] C for 3 hours, under reduced pressure, the piperidine and the unreacted epichlorohydrin are evaporated off, the residue is dissolved in chloroform, washed successively with a 5% aqueous solution of sodium hydroxide and water, then dried over anhydrous potassium carbonate. The chloroform is evaporated off under reduced pressure and the mixture is purified.

  
residue by chromatography on silica gel and then recrystallized from ethanol to obtain 3.5 g of 1-methyl-

  
 <EMI ID = 104.1>

  
Reference example 5

  
2 g of 5,3- (3,4-dimethoxyphenethylamino) -2hydroxypropoxy-8-benzyloxy-3,4-dihydrocarbostyril are suspended in 50 ml of methanol and, to the suspension thus obtained, an ethanolic solution containing hydrogen chloride until the mixture becomes acidic. When the mixture has become homogeneous, 0.7 g of palladium on carbon is added thereto.

  
 <EMI ID = 105.1>

  
atmospheric so as to absorb hydrogen. The reaction is complete when the absorption of hydrogen ceases. The catalyst is removed by filtration and the methanol is evaporated off. A small amount of ethanol is added to the residue to crystallize the product. By recrystallization from ethanol, one obtains

  
 <EMI ID = 106.1>

  
colorless powder crystals with a melting point of
171-173 [deg.] C.

  
Reference example 6

  
 <EMI ID = 107.1>

  
styril and 19.9 g of potassium carbonate to a mixture comprising 480 ml of acetone and 120 ml of water, then the resulting mixture is stirred with heating under reflux for 30 minutes. Then we

  
76 g of 2-methoxyethyl bromide are added thereto, followed by stirring with heating under reflux for 8 hours. The solvent is evaporated off and to the residue is added water. The mixture is extracted with diethyl ether. The aqueous layer is acidified with hydrochloric acid, then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the chloroform evaporated to give 15 g of 5-hydroxy-8- (2-methoxyethoxy) -3,4-dihydrocarbostyril as a black oily substance.

  
Reference example 7

  
 <EMI ID = 108.1>

  
3,4-dihydrocarbostyril in 50 ml of dimethylsulfoxide and, to

  
the solution thus obtained, 1.3 g of sodium hydride are added

  
at 50%, then stirred at room temperature for 30 minutes. 2.9 g of methyl iodide dissolved in 10 ml of dimethyl sulfoxide are added dropwise thereto and the resulting mixture is stirred

  
at room temperature for 2 hours. To the reaction mixture is added 200 ml of a saturated aqueous solution of ammonium chloride, followed by extraction with chloroform. The chloroform layer is washed with water and then dried.

  
over anhydrous sodium sulfate. The chloroform is evaporated

  
under reduced pressure and the residue is purified by chromatography in a column of silica gel, then recrystallized! in ethanol to obtain 1.7 g of 1-methyl-5- (2,3-epoxypronoxy) -8-benzYloxY-3., 4-dihydrocarbostyr] * Lle as

  
 <EMI ID = 109.1>

  
Reference example 8

  
0.7 g of 8-hydroxy-5- (3-t-butylamino-2-

  
 <EMI ID = 110.1>

  
acetone and, to the suspension obtained, 3 ml of NaOH are added

  
 <EMI ID = 111.1>

  
ice and with stirring, to the solution obtained was added dropwise 0.2 g of acetyl chloride dissolved in a small amount of acetone. After allowing the mixture to stand while cooling in ice for 30 minutes, 2 ml of IN hydrochloric acid are added thereto, then the solvent is evaporated off under reduced pressure. The residue is purified by chromatography in

  
a column of silica gel using a mixture of chloroform and methanol (8: 1 by volume) as eluent. We evaporate

  
the solvent and the residue is recrystallized from a mixture of methanol and diethyl ether to obtain 0.4 g of hydrochloride

  
 <EMI ID = 112.1>

  
carbostyril in the form of colorless flake crystals with a melting point of 247-248 [deg.] C (with decomposition).

  
Reference example 9 0.66 g of 8-hydroxy-5- (2-hydroxy-3-isopropyl-aminopropoxy) -3,4-dihydrocarbostyril is suspended in 10 ml

  
 <EMI ID = 113.1>

  
form a homogeneous solution. To the obtained solution was added dropwise 0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone while ice-cooling and stirring. After allowing the reaction mixture to stand under ice-cooling for 30 minutes, the mixture is

  
 <EMI ID = 114.1>

  
The solvent is evaporated off and the residue is dissolved in water,

  
 <EMI ID = 115.1>

  
aqueous to dryness under reduced pressure, then subjected

  
the residue was chromatographed on silica gel using a mixture of chloroform and methanol (8: 1 by volume) as the eluent. The solvent is evaporated off and the residue is recrystallized from a mixture of methanol and diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyloxy-5- (2-hydroxy- hydrochloride).

  
 <EMI ID = 116.1>

  
colorless flake crystals having a melting point of
227-228 [deg.] C.

  
Reference example 10

  
1.5 g of 5- (3-t-butylamino-2-hydroxypropoxy) -

  
 <EMI ID = 117.1>

  
stir the mixture with heating under reflux for 4 hours. The solvent is evaporated and the residue is extracted with chloroform. The chloroform is evaporated from the extract and the residue is reoristallized in a mixture of methanol and diethyl ether containing hydrogen chloride for. obtain .0.9 g of hydrochloride

  
 <EMI ID = 118.1>

  
Example reference 11

  
0.75 g of 1-benzyl-8-hydroxy- hydrofluoride is added.

  
 <EMI ID = 119.1>

  
suspension in 10 ml of acetone and 3.3 ml of 1N sodium hydroxide are added thereto to form a homogeneous solution. Then, to this solution, while ice-cooling and stirring, 0.15 g of acetyl chloride is added, and the mixture is then allowed to stand for 20 minutes. The mixture is adjusted to a pH of 3

  
with IN hydrochloric acid, 'then the acetone is evaporated off.

  
The residue was extracted with chloroform and the chloroform layer washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate. We evaporate;

  
1

  
 <EMI ID = 120.1>

  
as can be seen by magnetic resonance spectra

  
 <EMI ID = 121.1>

  
Nuclear Magnetic Resonance Spectrum: 6 (parts per million) (in d6-dimethylsulfoxide) 5.03 singlet (2H), 2.33 singlet (3H) and 1.36 singlet (9H).

  
 <EMI ID = 122.1>

  
Reference Example 12 2 liters of acetone and 500 ml of water are added to

  
 <EMI ID = 123.1>

  
Another 138 g of potassium carbonate and 150 g of 2-propynyl bromide. The resulting mixture is heated under reflux for 3 hours in a water bath. At the end of the reaction, the acetone and the 2-propynyl bromide are evaporated off under reduced pressure,

  
then the residue is acidified with concentrated hydrochloric acid. The mixture is extracted with chloroform, washed

  
the chloroform layer with water and dried over

  
anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residual crystals are recrystallized.

  
in a mixture of isopropanol and diethyl ether to obtain

  
 <EMI ID = 124.1>

  
with a melting point of 141-1420C,

  
Reference example 13

  
 <EMI ID = 125.1>

  
carbostyril, 102 g of epichlorohydrin, 60 g of potassium carbonate and 600 ml of methanol are added, then the mixture obtained is heated at reflux for 2.5 hours in a water bath. At the end of the reaction, the methanol is evaporated off, water is added to the residue, then extraction is carried out with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residual crystals are recrystallized from isopropanol to obtain 67 g of 8- (2-propynyloxy) -5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril having a point of fusion of

  
 <EMI ID = 126.1>

Example 1

  
1.7 g of 1-methyl-5- (2,3-epoxypropoxy) 8-benzyloxy-3,4-dihydrocarbostyril are dissolved in 20 ml of methariol and 1.6 ml of benzylamine are added thereto. The resulting mixture is stirred

  
 <EMI ID = 127.1>

  
methanol and unreacted benzylamine under reduced pressure, then the residue is purified by chromatography in a silica gel column ("C-200", trade name of "Wako

  
 <EMI ID = 128.1>

  
The product is converted into the hydrochloride with ethanol saturated with hydrogen chloride * The ethanol is evaporated off and the mixture

  
 <EMI ID = 129.1>

  
crystals in colorless needles with a melting point of
155-157 [deg.] C.

Example 2

  
In the same way as in Example 1, but using

  
 <EMI ID = 130.1>

  
dihydrocarbostyril, 20 ml of methanol and 4 ml of t-butylamine, 1.4 g of 1-benzyl-5- (3-t-butylamino- hydrochloride) are obtained.

  
 <EMI ID = 131.1>

  
of fusion of 200-201 [deg.] C.

Example 3

  
20 drops of piperidine are added to 4.5 g of 8-benzyloxy-5-hydroxy-3,4-dihydrocarbostyril and 5 g of epichlorohydrin, then the resulting mixture is stirred at a temperature

  
 <EMI ID = 132.1>

  
unreacted under reduced pressure and the residue dissolved in 100 ml of chloroform. The chloroform layer is washed successively with dilute sodium hydroxide and water, then dried over sodium sulfate. The chloroform is evaporated off and the residue is dissolved in 30 ml of methanol. To the obtained solution, 1.5 g of 3,4-dimethoxyphenethylamine is added and the resulting mixture is stirred at a temperature of 50 to 55 [deg.] C for 4 hours. The methanol is evaporated off and the residue is crystallized from diethyl ether. By recrystallization from acetone, 1.1 g of 5- [3- (3,4-dimethoxyphenethyl-

  
 <EMI ID = 133.1>

Examples 4 to 33

  
In the same way as in Example 1, the following compounds are prepared

  

 <EMI ID = 134.1>


  
Table 1
 <EMI ID = 135.1>
 Table 1 (continued)
 <EMI ID = 136.1>
 Table 1 (continued)

  

 <EMI ID = 137.1>
 

Example 34

  
40 drops of piperidine are added to 10 g of 5-hydroxy-8- (2-methoxyethoxy) -3,4-dihydrocarbostyril and 13 g of epichlorohydrin, then the resulting mixture is stirred at 95-100 [deg.] C for 4 hours. After evaporation of the unreacted epichlorohydrin, the residue is dissolved in chloroform and the chloroform layer is washed successively with dilute sodium hydroxide and water, then dried over anhydrous sodium sulfate. . The chloroform is evaporated off and the residue is dissolved in
100 ml of methanol. To the solution, 20 g of t-butylamine is added, then the mixture is heated under reflux for 8 hours. The solvent and the unreacted amine are evaporated off, then the residue is dissolved in methanol containing hydrogen chloride.

   The residue obtained by evaporating the methanol from a mixture of methanol and diethyl ether is recrystallized to obtain 6.8 g of 5- (3-t-butylamino-2-hydroxypropoxy) -8- (2-methoxyethoxy) 3 hydrochloride. , 4-dihydrocarbostyril as white needle crystals

  
 <EMI ID = 138.1>

Example 35

  
9.2 g of 8-benzyloxy-5-hydroxy-3,4dihydrocarbostyril and 18 g of epibromhydrin are dissolved in 120 ml of

  
 <EMI ID = 139.1>

  
potassium, then stirred at reflux for 3 hours. We evaporate

  
 <EMI ID = 140.1>

  
scaled down. The residue is dissolved in 100 ml of methanol and there is

  
 <EMI ID = 141.1>

  
heating at reflux for 5 hours. The methanol is evaporated off and the residue dissolved in chloroform. We wash successively

  
 <EMI ID = 142.1>

  
 <EMI ID = 143.1>

  
anhydrous. The chloroform is evaporated and the residue is extracted with ethyl acetate. The ethyl acetate is evaporated off and the residue is recrystallized from a mixture of acetone and diethyl ether to give 5.6 g of 8-benzyloxy-5- [3- (4-methoxyphenoxy-

  
 <EMI ID = 144.1>

  
colorless powder crystals with a melting point of 67-69 [deg.] C.

Example 36

  
 <EMI ID = 145.1>

  
during 3 hours. The methanol is evaporated off and the residue is purified by chromatography on a column of silica gel using a mixture of chloroform and methanol (40: 1 by volume) as eluent. The solvent is evaporated off and the residue dissolved in methanol containing hydrogen chloride. The ethanol is evaporated off and the residue is recrystallized from a mixture of methanol and

  
 <EMI ID = 146.1> Examples 37 to 78

  
 <EMI ID = 147.1>

  
 <EMI ID = 148.1>

  

 <EMI ID = 149.1>
 

  
Table 2 (continued)

  

 <EMI ID = 150.1>
 

  

 <EMI ID = 151.1>
 

  

 <EMI ID = 152.1>
 

  

 <EMI ID = 153.1>
 

  

 <EMI ID = 154.1>
 

Example 79

  
2 g of 5- (2,3-epoxypropoxy) -8- are dissolved
(2-propynyloxy) -3,4-dihydrocarbostyril in 15 ml of methanol and, to the solution obtained, 2.6 g of t-butylamine are added, then

  
 <EMI ID = 155.1>

  
At the end of the reaction, the methanol and t-butylamine are evaporated off under reduced pressure, then the crude oil obtained is converted into its hydrochloride salt using hydrochloric acid and ethanol.

  
The solvent is evaporated off under reduced pressure and the crystals obtained are dissolved in water, then washed with chloroform to remove the impurities. The aqueous layer is basified with sodium hydroxide, then extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure to obtain colorless crystals which are converted into the hydrochloride with a mixture of hydrochloric acid and ethanol. The solvent is evaporated off under reduced pressure and the residue is recrystallized from isopro-

  
 <EMI ID = 156.1>

Example 80

  
1 g of 8- (2-propynyloxy) -5- (3-

  
 <EMI ID = 157.1>

  
the methanol and ammonium hydroxide are evaporated off under reduced pressure and the residue is acidified with hydrochloric acid, then

  
washed with ethyl acetate. The aqueous layer is separated, basified with sodium hydroxide, extracted with chloroform, washed with water, then dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residue is purified by chromatography in a column of silica gel and the product is converted into its hydrochloride by adding a mixture of methanol and hydrochloric acid.

  
By recrystallization from a mixture of methanol and diethyl ether, 0.5 g of 8- (2-propynyloxy) - hydrochloride is obtained -

  
 <EMI ID = 158.1>

  
fusion of 196.5-198 [deg.] C.

Example 81

  
1.1 g of 8- (2-propynyloxy) -5- (2,3-

  
 <EMI ID = 159.1>

  
1.5 g of 2-methoxyethylamine are added thereto, then the mixture is left to stand at 10-15 [deg.] C for 29 hours. At the end of the reaction, the methanol and the unreacted amine are evaporated off under reduced pressure. The residue is acidified with hydrochloric acid and washed with ethyl acetate. The aqueous layer is basified with sodium hydroxide, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residue is dissolved in methanol. The product is converted to its hydrochloride by adding a mixture of methanol and hydrochloric acid, then recrystallized from isopropanol to obtain 0.8 g of 8- (2-propy- hydrochloride).

  
 <EMI ID = 160.1>

  
.

Example 82

  
1 g of 8- (2-propynyloxy) -5- (3chloro-2-hydroxypropoxy) -3,4-dihydrocarbostyril is dissolved in 30 ml of methanol. 0.5 g of carbonate are added to the solution obtained

  
of anhydrous potassium and 1.4 g of 2- (3,5-dimethoxyphenoxy) -ethylamine, then the resulting mixture is heated to reflux while stirring for 8 hours. The methanol is evaporated off under reduced pressure and the residue is acidified with hydrochloric acid, then washed with ethyl acetate. The hydrochloric acid layer is separated, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residue is recrystallized from a mixture of methanol and diethyl ether to obtain

  
 <EMI ID = 161.1>

  
with a melting point of 187-189 [deg.] C.

Example 83

  
1 g of 8- (2-propynyloxy) -5- (3-chloro-

  
 <EMI ID = 162.1>

  
0.5 g of anhydrous potassium carbonate and 1.6 g of 2- (3,4-dimethoxyphenyl) -ethylamine are added thereto, then the resulting mixture is stirred with heating under reflux for 2.5 hours. At the end of the reaction, the methanol is evaporated off under reduced pressure and the residue is dissolved in chloroform, then washed with water. The chloroform layer is dried over anhydrous sodium sulfate, then the chloroform is evaporated off under reduced pressure. The residue is recrystallized from a mixture of methanol and diethyl ether.

  
 <EMI ID = 163.1>

  
dihydrocarbostyril with a melting point of 160-162 [deg.] C.

Example 84

  
1 g of 8- (2-hydroxyethoxy) -5- (2,3-

  
 <EMI ID = 164.1>

  
let the mixture stand at 10-15 [deg.] C for 12 hours. At the end of the reaction, the methanol is evaporated off under reduced pressure and the residual oil is dissolved in chloroform, followed by washing with water and drying over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residual oil is washed with diethyl ether, after which it is allowed to settle and is converted into a hydrochloride using a mixture of hydrochloric acid and methanol. By recrystallization from a mixture of methanol and diethyl ether, one obtains

  
 <EMI ID = 165.1>

  
a melting point of 204-206 [deg.] C.

Example 85

  
1 g of 8- (2-propynyloxy) -5- (3-

  
 <EMI ID = 166.1>

  
methanol. Next, 0.7 g of anhydrous potassium carbonate and 1.7 g of morpholine are added to the resulting solution, followed by stirring with heating under reflux for 4 hours. At the end of the reaction, the methanol and unreacted morpholine are evaporated off under reduced pressure, then the residual oil is converted into a hydrochloride with aqueous hydrochloric acid, after which it is washed with chloroform. The aqueous layer is separated, basified with sodium hydroxide and extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure and the residue is converted into a hydrochloride with a mixture of ethanol and hydrochloric acid. By recrystallization from a mixture of water and ethanol,

  
 <EMI ID = 167.1>

  
fusion of 234.5-235 [deg.] C.

Example 86

  
2 g of 8- (2-propynyloxy) -5- (2,3-

  
 <EMI ID = 168.1>

  
2.6 g of pyrrolidine are added thereto, then the mixture is left to stand at 10-15 [deg.] C for 12 hours. At the end of the reaction, we evaporate

  
 <EMI ID = 169.1>

  
pick. The residual oil is converted to a hydrochloride with a mixture of hydrochloric acid and ethanol. By recrystallisa-

  
 <EMI ID = 170.1>

  
In the same way as in Example 86, the following compounds are prepared:

  

 <EMI ID = 171.1>


  
Table 3
 <EMI ID = 172.1>
 tl Table 3 (continued)
 <EMI ID = 173.1>
 Table 3 (continued)
 <EMI ID = 174.1>
 Table 3 (continued)

  

 <EMI ID = 175.1>


  
Note: * Nuclear magnetic resonance spectrum: 0 parts

  
 <EMI ID = 176.1>

  
J = 5Hz).

Example 125

  
We put 2 g of 5- [3- (3,4-dimethoxyphenethylamino) -

  
 <EMI ID = 177.1>

  
mixture in 50 ml of methanol and, to the suspension obtained, ethanol containing hydrogen chloride is added until the

  
 <EMI ID = 178.1>

  
0.7 g of 10% palladium-carbon is added to the resulting solution and the mixture is stirred at room temperature and under normal pressure to absorb hydrogen. The reaction is terminated by -

  
 <EMI ID = 179.1>

  
seur by filtration and the methanol is evaporated off. To the residue, a small amount of ethanol is added to effect crystallization, after which it is recrystallized from ethanol to obtain

  
 <EMI ID = 180.1>

  
the following compounds:

  

 <EMI ID = 181.1>


  
Table 4

  

 <EMI ID = 182.1>


  
0.7 g of 8-hydroxy-5- (3-t-butylamino-2hydroxypropoxy) -3,4-dihydrocarbostyril is suspended in 20 ml

  
 <EMI ID = 183.1>

  
form a homogeneous solution. To the resulting solution is added dropwise 0.2 g of acetyl chloride dissolved in a small amount of acetone while cooling with water, after which the mixture is allowed to stand while cooling with water. during 30 minutes. 2 ml of hydrochloric acid are added to it.

  
 <EMI ID = 184.1>

  
purifies the residue by chromatography on a silica gel column using a mixture of chloroform and methanol

  
(8: 1 by volume) as eluent. The solvent is evaporated off and the residue is recrystallized from a mixture of methanol and diethyl ether.

  
 <EMI ID = 185.1>

  
of colorless flake crystals having a melting point of
247-248 [deg.] C (with decomposition).

Example 130

  
0.66 g of 8-hydroxy-5- (2-hydroxy-3-isopro-

  
 <EMI ID = 186.1>

  
10 ml of acetone and 3 ml of 1N sodium hydroxide are added thereto to form a homogeneous solution. To the solution obtained, while cooling in ice and with stirring, 0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone is added dropwise. After allowing the reaction mixture to stand for 30 minutes while cooling in ice, it is

  
1N hydrochloric acid is added to adjust pH to 3. The solvent is evaporated off under reduced pressure and the residue is dissolved in water, then extracted with chloroform. The aqueous layer is concentrated to dryness under reduced pressure and the residue is purified by chromatography in a column of silica gel using a mixture of chloroform and methanol.

  
(8: 1 by volume) as eluent. The solvent is evaporated off and the residue is recrystallized from a mixture of methanol and diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyl hydrochloride.

  
 <EMI ID = 187.1>

  
in the form of colorless flake crystals with a melting point of 227-228 [deg.] C.

Example 131

  
1.5 g of 5- (3-t-butylamino-2-hydroxy-

  
 <EMI ID = 188.1>

  
20 ml of methanol and 6 ml of 1N sodium hydroxide are added thereto to form a homogeneous solution. To this solution, we add

  
1 g of allyl bromide, then stirred with heating at reflux for 4 hours. The solvent is evaporated and the residue is extracted with chloroform. The chloroform is evaporated off and the residue is recrystallized from a mixture of methanol and diethyl ether containing hydrogen chloride to obtain 0.9 g of 8-allyloxy-5- (3-t-butylamino-2-hydroxypropoxy hydrochloride. ) 3,4-Dihydrocarbostyril as white needle crystals with a melting point of 177-178 [deg.] C.

Example 132

  
0.75 g of 1-benzyl-8- hydrochloride is added

  
 <EMI ID = 189.1>

  
styril suspended in 10 ml of acetone and 3.3 ml of 1N sodium hydroxide are added thereto to form a homogeneous solution. To the obtained solution, 0.15 g of acetyl chloride is added while ice-cooling and stirring, after which the mixture is allowed to stand for 20 minutes. The mixture is adjusted to pH 3 with 1N hydrochloric acid. The acetone is evaporated off and the residue is extracted with chloroform. The chloroform layer was washed once with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The chloroform was evaporated to obtain 0.3 g of a colorless solid as a residue. Nuclear magnetic resonance and infrared ray absorption spectra confirm

  
 <EMI ID = 190.1>

  
(3-t-Butylamino-2-hydroxy) -propoxy-3, [hundred] -dihydrocarbostyril.

  
Nuclear Magnetic Resonance Spectrum: 0 (parts per million) in d6-dimethylsulfoxide

  
5.03 singlet (2H),

  
2.33 singlet (3H) and

  
1.36 singlet (9H)

  
Infrared ray absorption spectrum: KBr

  
 <EMI ID = 191.1>

  
Reference Example 14

  
The β-adrenoreceptor blocking activity exerted by the compounds of the present invention is determined as follows:

  
Male hybrid adult dogs weighing 10-16 kg were anesthetized with sodium pentobarbital administered intravenously at 30 mg / kg body weight and a cannula was inserted into the trachea of each of the anesthetized dogs. In order to prevent the blood from clotting, heparin is administered intravenously at the rate of 1,000 units, after which a cannula is inserted into the right femoral artery. The experiments are carried out under artificial respiration at a rate of 20 ml / kg, 18 revolutions / minute.

  
Blood pressure is determined using a pressure transducer (type "MPU-0.5", trade name of

  
 <EMI ID = 192.1>

  
heart rate pulse wave blood pressure using an instant heart rate tachometer (type 2130,

  
 <EMI ID = 193.1>

  
The parameters are saved continuously

  
 <EMI ID = 194.1>

  
Administer intravenous gallamine at 3 mg / kg at hourly intervals to avoid fluctuations in airflow resistance.

  
The β-adrenoreceptor blocking activity exerted by each of the test compounds was evaluated in terms of antagonism (percent inhibition) to depression at diastolic blood pressure, as well as to increased blood pressure. heart rate caused by intravenous administration of isoprenaline (1 ug / kg), as well as in terms of antagonism
(percent inhibition) to isoprenaline depression with increased resistance to the passage of air, caused

  
 <EMI ID = 195.1>

  
in this case, histamine is administered 45 seconds after the administration of isoprenaline.

  
The β-adrenoreceptor blocking activity of the test compounds is determined 10 minutes after intravenous administration of the latter at the rate of

  
 <EMI ID = 196.1>

  
below in which we use, as witnesses, Proctolol
 <EMI ID = 197.1>
 Table 5
 <EMI ID = 198.1>
 
 <EMI ID = 199.1>
 
 <EMI ID = 200.1>
 Further, the acute toxicity of the compounds of formula (I) of the present invention is determined by intravenous and oral administration in five to six groups of rats (dd family; body weight: 18 to 22 g; 10 rats in each group ) who were deprived of food 12 hours before the test. It is found that a specific compound of formula (I) according to the present invention, namely the 8- (2-

  
 <EMI ID = 201.1>

  
after (lethal dose at 50%):

  

 <EMI ID = 202.1>


  
It is also observed that the other compounds of formula (I) have a low toxicity, that is to say more than approximately 130 mg / kg
(intravenously) and more than about 1,200 mg / kg (oral).

  
The compounds of the present invention can

  
 <EMI ID = 203.1>

  
approximately 2 mg / kg / day by oral administration. Specific examples of suitable formulations are given below, but it should be noted that other dosage forms can also be prepared using other compounds of the present invention, as well as other well known excipients of the invention. those skilled in the art and in accordance with accepted pharmaceutical techniques.

  
Formulation 1

  
Tablets are prepared each containing the following components

  

 <EMI ID = 204.1>

Formulation 2

  
Tablets are prepared each containing the following components:

  

 <EMI ID = 205.1>



    

Claims (1)

1. Carbostyril derivative corresponding to formula (I): <EMI ID = 206.1> <EMI ID = 207.1> alkyl group, phenylalkyl group, alkenyl group, alkoxyalkyl group, hydroxyalkyl group, carboxyalkyl group, alkylcarbonyl group, cycloalkylcarbonyl group, an alkylcarbonylalkyl group, an alkoxycarbonylalkyl group, a <EMI ID = 208.1> be the same or different, each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyalkyl group, an alkenyl group, a phenylalkyl group, a group phenoxyalkyl, a heterocyclic alkyl group or a phenyl group or alternatively R3 and R4 can form, together with the atom nitrogen to which they are attached, a five-membered heterocyclic ring or hexagonal may contain a nitrogen atom or an oxygen atom as an additional hetero atom, the 3,4 bond of the ring carbostyril represents a single or double bond, provided <EMI ID = 209.1> a hydrogen atom, R2-cannot be a hydrogen atom, a an alkyl group or a phenylalkyl group having no substituent on the phenyl moiety, as well as the pharmaceutically acceptable acid addition salts of this derivative. <EMI ID = 210.1> claim 1. 5. 8- (5-Methyl-2-hexynyloxy) -5- [3- (3,4- <EMI ID = 211.1> phenethylamino) -2-hydroxypropoxy] -carbostyril according to claim 1. 7. 5- [3- (3,4-Dimethoxyphenethylamino) -2- <EMI ID = 212.1> claim 1. 8. 8- (2-Methoxyethoxy) -5- [3- (3,4-dimethoxy- <EMI ID = 213.1> according to claim 1. 12. 8-butoxy-5- [3- (3,4-dimethoxyphenethyl- <EMI ID = 214.1> claim 1. 13. 8- (2-Propynyloxy) -5- (3-tert-butylamino- <EMI ID = 215.1> tion 1. 14. 8- (2-Propynyloxy) -5- [3- (1,1-dimethyl-2- <EMI ID = 216.1> according to claim 1. 15. 8-allyloxy-5- [3- (2,2-diphenylethylamino) - <EMI ID = 217.1> claim 1. 20. Process for preparing a derivative of <EMI ID = 218.1> <EMI ID = 219.1> in which R. represents a hydrogen atom, an alkyl group <EMI ID = 220.1> alkyl group, a phenylalkyl group, an alkenyl group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyalkyl group, an alkylcarbonyl group, a cycloalkylcarbonyl group, an alkylcarbonylalkyl group, an alkoxycarbonylalkyl group, a group <EMI ID = 221.1> identical or different, each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxyalkyl group, an alkenyl group, a phenylalkyl group, a phenoxyalkyl group, a heterocyclic alkyl group or a phenyl group or else R3 and R4, taken together with the nitrogen atom to which they are attached, can form a 5-membered or 6-membered heterocyclic ring which may contain a nitrogen or oxygen atom as an additional hetero atom, the 3,4-bond of the ring carbostyril represents a single or double bond, provided that one of the <EMI ID = 222.1> cannot be a hydrogen atom, an alkyl group or a phenylalkyl group having no substituent on the phenyl moiety, as well as pharmaceutically acceptable acid addition salts of this derivative, characterized in that it consists in reacting a carbostyril compound of formula (II): <EMI ID = 223.1> <EMI ID = 224.1> <EMI ID = 225.1> 9am -CHCH2X where X represents a halogen atom, with an amino compound of formula (III): <EMI ID = 226.1> <EMI ID = 227.1> at a temperature between about 0 and about 100 [deg.] C. <EMI ID = 228.1> terized in that the reaction is carried out in the presence of a base when the Y group of the carbostyril compound of formula (II) <EMI ID = 229.1> represents a group -CHCH2X in which X represents a halogen atom. 22. The method of claim 21, characterized in that the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. <EMI ID = 230.1> terized in that the reaction is carried out in the presence of a solvent.