JPS6019295B2 - Carbostyryl derivatives and their production method - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel carbostyril derivatives.

The compound of the present invention is a new compound, and has the general formula [wherein R,
represents a lower alkynyl group, hydroxyalkyl group, carbamoylalkyl group, carboxyalkyl group, alkylcarbonylalkyl group or alkoxycarbonylalkyl group.

R2 and R3 are the same or different and represent a hydrogen atom, a lower alkyl group, a cyclohexyl group, an alkoxyalkyl group, a lower alkenyl group, a phenylalkyl group, a phenoxyalkyl group, a morpholinoalkyl group, or a phenyl group.
Further, R2 and R3 may be bonded to each other with or without the nitrogen atom or oxygen atom to form a five- or six-membered multi-ring. Furthermore, the bonds at the 3rd and 4th positions of the carbostyryl skeleton represent a single bond or a double bond. ] and its acid addition salts. The compound of the present invention has a 3-adrenergic inhibitory effect and is extremely useful as a B-flocker agent that selectively acts on 8,1-receptors, and can treat arrhythmia,
It is useful as a drug for heart diseases such as angina pectoris, and as an antihypertensive drug.
In the above general formula (1), the lower alkynyl group represented by R can include straight chain or branched alkynyl groups having 2 to 7 carbon atoms, and specifically, 2-propynyl, 1 -propynyl, 2-butynyl, 3-butynyl, 2
-bentinyl, 3-bentinyl, 4-bentinyl, 2-methyl-3-butynyl, 1-methyl-3-butynyl, 2
Examples include -hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-4-bentinyl, 1-methyl-4-bentinyl, 2-methyl-3-bentinyl, 1-methyl-3-bentinyl, 2-heptynyl, and 3-heptynyl groups.

Examples of the hydroxyalkyl group include groups in which a linear or branched alkylene group having 1 to 6 carbon atoms and a hydroxyl group are bonded, and specifically, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-methyl-3-hydroxypropyl, 5-hydroxybentyl, 4-hydroxybentyl, 2-methyl-4-hydroxybutyl, 2-methyl-3-hydroxy Examples include butyl, 6-hydroxyhexyl, 5-hydroxyhexyl, 2-methyl-5-hydroxybentyl, 2-methyl-4-hydroxybentyl, and the like. Examples of the carbamoyl alkyl group include a group in which a linear or branched alkylene group having 1 to 6 carbon atoms and a substituted or unsubstituted carbamoyl group are bonded to the nitrogen atom thereof, and specifically, Carbamoylmethyl, 3-carbamoylpropyl, 4-carbamoylbutyl, 6-carbamoylhexyl, 2-(N.N-diethylcarbamoyl)ethyl, N-(8-3.4-dimethoxyphenethyl)
Examples include carbamoylmethyl group. Examples of the carboxyalkyl group include groups in which a linear or branched alkylene group having 1 to 6 carbon atoms and a carboxy group are bonded, and specific examples include carboxymethyl, 2-carboxyethyl, and 3-carbon groups. Luboxif. Examples include lopyl, 4-carboxybutyl, 6-carpoxyhexyl, and 3-carboxy-2-methylbutyl groups. Examples of the alkylcarbonylalkyl group include groups in which a linear or branched alkylene group having 1 to 6 carbon atoms and a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms are bonded to each other. Specifically, methylcarbonylmethyl,
Examples include ethylcarbonylmethyl, 2-ethylcarbonylethyl, 2-isopropylcarbonylethyl, 3-sec-butylcarbonylpropyl, 6-hexylcarbonylhexyl, 3-ethylcarbonyl-2-methylpropyl, and butylcarbonylmethyl groups. The alkoxycarbonylalkyl group is a group in which a straight chain or branched alkoxy group having 1 to 6 carbon atoms is bonded to a carbonyl group, and this is further bonded to a straight chain or branched alkylene group having 1 to 6 carbon atoms. Specifically, methoxycarbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-sec-butoxycarbonylpropyl,
5-isobutoxycarbonylbentyl, 6-hexyloxycarbonylhexyl, 3-ethoxycarbonyl-2
-Methylbutyl group, etc. can be exemplified. Examples of the lower alkyl group represented by R2 and R3 include straight chain or branched alkyl groups having 1 to 6 carbon atoms, specifically methyl, ethyl, propyl, and isop. pill, butyl,
Examples include isobutyl, sec-butyl, te-butyl, bentyl, hexyl, and the like. Examples of the alkoxyalkyl group include groups in which a straight chain or branched alkoxy group having 1 to 6 carbon atoms and a straight chain or branched alkylene group having 1 to 6 carbon atoms are bonded; Examples include 2-methoxyethyl, 2-ethoxyethyl, 3-ethoxypropyl, 3-ethoxybutyl, 2-isopropoxyethyl, and 6-hexyloxyhexyl groups. Examples of the lower alkenyl group include straight or branched alkenyl groups having 2 to 6 carbon atoms, and specific examples include ethylenyl, 2-probenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, and 1-methyl-2m-butenyl. , 2-hexenyl, 4-hexenyl stems, etc. Examples of the phenylalkyl group include groups in which a linear or branched alkylene group having 1 to 6 carbon atoms and a phenyl group are bonded, and specifically, penzyl, 2-phenylethyl, 1-phenylethyl, 2-methyl- 2-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl,
4-phenyl phthyl, 6-phenylhexyl, 1,1-
Examples include dimethyl-2-phenylethyl, 2-methyl-4-phenylbutyl, and 2-methyl-3-phenylpropyl groups. The phenoxyalkyl group has 1 or more carbon atoms.
Examples include groups in which a linear or branched alkylene group and a phenoxy group are bonded, and specific examples include phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, and 2-methyl-2-phenoxylene groups. Sibropyr, diphenoxymethyl, 2,2-diphenoxyethyl, 4-phenoxybutyl, 6-phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-4-phenoxybutyl, 2- Examples include methyl-3-phenoxypropyl group. Morpholinoalkyl group has 1 or more carbon atoms
Examples include groups in which the linear or branched alkylene group of 6 is bonded to the nitrogen atom of a morpholine ring, and specific examples include 3-morpholinopropyl and 6-morpholinohexyl groups. The five- or six-membered heterocycle formed by R2 and R3 bonding to each other with or without a nitrogen atom or an oxygen atom includes piverizine, morpholine, thiomorpholine, pyrrolidine, piperazine, imidazo. Examples include lysine. R
The phenylalkyl group, phenoxyalkyl group, morpho IJ noalkyl group, phenyl group represented by 2 and R3, and the Enomoto ring group formed by bonding R2 and R3 to each other, have 1 to 3 on the phenyl or multihata ring. They may have the same or different substituents. Such substituents include methyl, ethyl, and phthalate. o-pyl, isopropyl, butyl, rt
-lower alkyl groups such as butyl groups, methoxy, ethoxy,
Lower alkoxy groups such as isopropoxy, butoxy, and rt-butoxy groups, halogen atoms such as chlorine atom, bromine atom, iodine atom, and fluorine atom, lower alkylene dioxy groups such as methylenedioxy and ethylenedioxy groups, carbamoyl groups, In addition to hydroxy groups and amino groups, phenyl groups with or without these groups as substituents can be exemplified. Examples of the phenylalkyl group, phenoxyalkyl group, morpholinoalkyl group, phenyl group and the heterocyclic group formed by bonding R2 and R3 with each other having such a substituent include 4-methoxyphenyl, 3-chlorophenyl, 3・4-methylenedioxyphenyl, 304-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
4-Chlorphenyl, 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)butyl. Pill, 2-(4-carbamoylphenyl)ethyl, 2-(4-chloro-3,5-dimethoxyphenyl)ethyl, 2-(2-isopropoxyphenyl)
Ethyl, 2-(4-methoxyphenyl)ethyl, 2-(
3,4-dimethoxyphenoxy)ethyl, 2-(3,5
-dimethoxyphe/xy)ethyl, 4-(3,4,5-
triethoxyphenoxy)butyl, 2-(3,4-ethylenedioxyphenoxy)ethyl, 2-(4-fluorophenoxy)ethyl, 2-(4-tert-butoxyphenoxy)ethyl, 3-(315-dichlorophenoxy)
Propyl, 2-(4-carbamoylphenoxy)ethyl, 2-(4-chloro-3,5-dimethoxyphenoxy)
Ethyl, 2-(4-methoxyphenoxy)ethyl, 4-phenylpiverazino, 4-(4-methoxyphenyl)piverazino, 4-(3-chlorophenyl)piverazi/, 4
-(4-kolphenyl)piverazino, 4-ethylpiverazino, 4-(tert-butyl)piverazino, 4-(
2-methoxyphenyl)piverazino, 3-methyl-4-(4-chlorophenyl)piverazino, 3-isopropylpiberazino, 4-(3,4-methylenedioxyphenyl)piverazino, 2-chloropiberazino, 4-( 3,4-dimethoxyphenyl)piverazino, 4-(2-methylphenyl)piverazino, 2-(2-chloromorpholino)ethyl, 4-fluoropiveridino, 3-ethylpiberidino,
2-isopropylpyrrolidi/, 2-(3,4-dihydroxyphenyl)ethyl, 2-(3,4-dihydroxyphenoxy)ethyl, 2-(4-hydroxyphenyl)ethyl, 2-(4-) hydroxyphenoxy)ethyl, 2-
Examples include (2-hydroxyphenyl)ethyl, 2-(4-aminophenoxy)ethyl, and 2-(4-aminophenyl)ethyl groups. Representative compounds of the present invention are listed below.

o8-(2-propynyloxy)-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2-propynyloxy)
-5-(2-hydroxy-3-hexylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-(2-hydroxy-3-methylaminopropoxy)-3,4-dihydro Carbostyryl o8-(2-propynyloxy)-5-(2-hydroxy-3-rt-butylaminopropoxy)-13,4-dihydrocarbostyryl o8-(2-propynyloxy)-51[2-hydroxy- 3-(2-methylbutylamino)propoxy]-3,4-dihydrocarpostyryl o8-(2-propynyloxy)-5-1[2-hydroxy-3-(2-butenylamino)propoxy]-3,4
-dihydrocarpostyryl o8-(2-propynyloxy)-5-[2-hydroxy-3-(3-heptenylamino)propoxy]-3,4-dihydrocarpostyryl o8-(2-propynyloxy)-5-[2 -hydrooxy3-(2-methyl-4-bentenylamino)propoxy]-304-dihydrocarbostyryl o8-(2-
propynyloxy)-5-[2-hydroxy-3-3-phenethylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[3
-(8-4-rubamoylphenethylamino)-2-hydroxyp.

poxy]-3,4-dihydrocarbostyryl o8-(2
-propynyloxy)-5-[3-(3,4-dimethoxyphenylmethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[3-( 8-4-chlorophenethylamine/)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(2-propynyloxy)
-5-[2-hydroxy-3-(8-4-methoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[2-
Hydroxy-3-(8-4-hydroxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl o
8-(2-propynyloxy)-5-[2-hydro.

xy-3-(3-4-hydroxy-3-methoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-bropynyloxy)-5-[3-(
8-3,5-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-{3-[1,1
-dimethyl-2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-
5-{2-hydroxy-3-[1-methyl-2-(3.
4-dimethoxyphenyl)ethylaminopropoxy}
-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[3-(8-3,4,5-trimethoxyphenethylamino)-2-hydroxypropoxy]
-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[2-hydroxy-3-(4n phenylbutylamino)propoxy]-3,4-dihydrocarbostyryl'leo8-(2- propynyloxy)-5-{2-hydroxy-3-[6m(4-methoxyphenyl)hexylamino]propoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-{
3-[2-(3,4-dimethoxyphenoxy)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5
1 [3-(4-hydroxyphenylmethylamino)-2
monohydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[2-hydroxy-3-(3-phenoxybutylamino)propoxy]-3,4-dihydrocarbostyryl o8 One (2-
propynyloxy)-5-{3-[3-(3,4-methylenedioxyphenoxyphenoxy)propylamide/]
-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-{3
-[4-(4-hydroxyphenoxy)butylamino]
-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-{2
-Hydroxy-3-[2-(4-methoxyphenoxy)
ethylamino]proboxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-51[3-
(2-methoxyethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-
propynyloxy)-5-[3-(2-isopropoxyethylamino)-21-hydroxypropoxy]-3,4
-dihydrocarbostyryl o8-(2-hydroxyethoxy)-51 [3-(2-ethoxyethylamino)-2
-Hydroxyproboxy]-3,4-dihyde.

Carbostyryl o8-(2-propynyloxy)-5-
[3-(2-methoxyethylamino)-2-hydroxypropoxy]carbostyryl o8-(2-propynyloxy)-5-[2-hydroxy-3-(Q-3,4-dimethoxyphenethylamino)propoxy]- 3,4-dihydrocarbostyryl o8-(2-propynyloxy)
-5-[3-(Q-4-chlorophenethylamino)-2
Monohydroxypropoxy]-13,4-dihydrocarbostyryl o8-(2-propynyloxy)-151[2-hydroxy-3-(4-chlorophenylamino)propoxy]-13,4-dihydrocarbostyryl'leo8 -(2-propynyloxy)-5-[2-hydroxy-3-(4
-Methoxyphenylamino/)propoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)
-5-[2-Hydroxy-3-(3,4-dimethoxyphenylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[2-
Hydroxy-3-(3,4,5-trimethoxyphenylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-[3-(2,
5-dimethoxyphenylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2
-propynyloxy)-15-[3-(4-hydroxypyrrolidino)-2-hydroxypropoxy]-314-dihydrocarbostyryl o8-(2-propynyloxy)
-5-[3-(N-ethylpiverazino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8
-(2-propynyloxy)-5-[2-hydroxy-3-(2-methylmorpholy/)propoxy]-3,4-dihydrocarpostyryl o8-(2-butynyloxy)
-5-[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-butynyloxy)-5-(
3-cyclohexylamino-2-hydroxyph.

ropoxy)-3,4-dihydrocarbostyryl o8-(
2-butynyloxy)-5-[3-(N/N-dimethylamino)-21-hydroxypropoxy]-13,4-dihydrocarbostyl/shio8-(3-butynyloxy)-
5-(2-hydroxy-3-te-9-butylaminopropoxy)-13,4-dihydrocarbostyryl o8-(3
-butynyloxy)-5-{2-hydroxy-3-[3
-(4-methoxyphenoxy)propylamino]propoxy}-3,4-dihydrocarbostyryl o8-(3-
(butynyloxy)-5-[2-hydroxy-3-(3-morpholinopropylamino)propoxy]-3,4-dihydrocarbostyryl o8-(3-butynyloxy)-
5-(3-cyclohexylamino-2-hydro.

(xypropoxy)-3,4-dihydrocarbostyryl o
8-(2-bentinyloxy)-5-[3-(8-3.
4,5-trimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o
8-(2-bentinyloxy)-5-[3-(8-3.
4-dimethoxyphenethylamino)-21-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(
2-bennchyloxy)-5-[3-(8-3,4-dihydroxyphenethylamino)-22-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(3-
Bentinyloxy)-5-[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]
-3,4-dihydrocarbostyryl o8-(4-bentinyloxy)-51 [3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3.
4-dihydrocarbostyryl o8-(4-bentinyloxy)-5-1 [2-hydroxy-3-(3-3,4-ethylenedioxyphenethylamino)propoxy]-3.
4-dihydrocarbostyryl o8-(4-bentinyloxy)-5-(2-hydroxy-3-rt-butylaminopropoxy)-3,4-dihydrocarbostyryl o
8-(2-methyl-3-butynyloxy)-51 [3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(1-methyl (13-butynyloxy)151 [
3-(8-3,4-dimethoxypheneteramino)-2
-Hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(1-methyl-3-butynyloxy)-5
-(2-hydroxy m3 -tert-butylaminof.

ropoxy) 13,41 dihydrocarbostili/shio8-
(2-hexynyloxy)-5-1 [3-(8-3,4-dimethoxyphenethylamino)-2-hydroxyp.

poxy]-3,4-dihydrocarbostyryl o8-(3
-hexynyloxy)-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyryl o8-(5-hexynyloxy)-5-[3
-(8-3.5-dimethoxyphenethylamino)-2-
Hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-hydro.

xyethoxy)-5-(3-ethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl o
8-(2-hydroxyethoxy)-5-(2-hydroxy-3-butylaminopucopoxy)-13,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5-(2-hydroxy-3- hexylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2
-Hydroxyethoxy)-15-1 (3-isopropylamino/hydroxypropoxy)-13,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-15-1 [2-hydroxy-3-(2-brobenylamino)propoxy] -3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy) -51 [2-hydroxy-3-(4-bentenylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy) 15-
(2-Hydroxy-3-8-phenethylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-15-[3-(3-p-chlorophenylpropylamino)-2-hydroxy Propoxy]-
3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5-[2-hydroxy-3-(8-3.
4-methylenedioxyphenethylamino)propoxy]
-3,4-dihydrocarbostyryl o8 -(2-hydroxyethoxy)-5-{2-hydroxy-3-[5-(
2-methoxyphenyl)bentylamino]propoxy}
-3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5-[2-hydroxy-3-(4-furomophenoxymethylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-hydroxy ethoxy)-5-{3-[2-(3,4-dimethoxyphenoxy)ethylamino]-2-hydroxyph.

ropoxy}-3,4-dihydrocarbostyryl o8-(
2-hydroxyethoxy)-5-{2-hydroxy-3
-[2-Methyl-3-(3,4-methylenedioxyphenoxy)propylamino]propoxy}-3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)
-5-[2-hydroxy-3-(3-morpholinopropylamino)propoxy]-3,4-dihydrocarbostyryl o8-(2-hydroxy-3-phenylaminopropoxy)-3,4-dihydrocarbostyryl o8-(2
-hydroxyethoxy)-5-(3-cyclohexylamino-12-hydroxypropoxy)-3,4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5
-(2-hydroxy-3-morpholinopropoxy) -3
・4-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5-(3-piveridino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl o8-(
2-hydroxyethoxy)-5-[3-(N-phenylpiveradi/)-2-hydroxypropoxy)-3,4-
Dihydrocarbostyryl o8-(2-hydroxyethoxy)-15-1(3-pyrrolidino-2-hydroxypropoxy)-13,4-dihydrocarbostyryl o8-(3-hydropropoxy)-151(2-hydroxy-3 1-butylaminopropoxy)-3,4-dihydrocarbostyryl o8-(3-hydroxybropoxy)-5-
[2-Hydroxy-3-(4-pentenylamino)propoxy]-3,4-dihydrocarbostylinoleo8-(
3-hydroxypropoxy)-5-[3-(8-3.4
-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(3
-hydroxypropoxy)-5-{3-[3-(4-chlorophenyl)propylamino]-2-hydroxypropoxy}-3,4-dihydrocarpostyryl o8-(3
monohydroxybropoxy)-5-{3-[2-(3.4
monodimethoxyphenoxy)ethylamino]-2-hydroxyproboxy}-3,4-dihyde.

Carbostyryl o8-(3-hydroxypropoxy)-5-[2-hydroxy-3-(41-p-methoxyphenoxybutylamino)propoxy]-3,4-dihydrocarbostyryl o8-(3-hydroxybropoxy)- 5
-(2-hydroxy-3-phenylaminopropoxy)
-3,4-dihydrocarpostyryl o8-(21-hydroxypropoxy)-5-(2-hydroxy-3-te-9-butylaminopropoxy)-3,4-dihydrocarpostyryl o8-(21-hydroxypropoxy)-5 one〔
3-(8-3,4-dimethoxyphenethylamino)-2
monohydroxypropoxy]-3,4-dihydrocarbostyryl o8-(2-hydroxypropoxy)-5-[3
-(3-4-ethoxyphenethylamino)-22-hydroxypropoxy]-3,4-dihydrocarbostyryl o
8-(4-hydroxypropoxy)-5-[3-(8-
3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8
1 (3-hydroxybutoxy) 151 [31 (813.
4-dimethoxyphenethylamino)-21-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(
2-methyl-3-hydroxypropoxy)-5-[3-
(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(2-methyl-3-hydroxypropoxy)-151 [2-hydroxy-3-(3- Morpholinopropylamino)bropoxy]-3,4-dihydrocarbostyryl o8-(2-methyl-3-hydroxybropoxy)-151 3,4-dihydrocarbostyryl o8-(5-hydroxybentyloxy)-5
-[3-(8-3,4-dimethoxyphenethylamino)
-2-hydroxybropoxy]-3,4-dihydrocarbostyryl o8-(5-hydroxybentyloxy)-
(2-Hydroxy-3-te-9-butylaminopropoxy)-3,4-dihydrocarbostyryl o8-(3-hydroxybentyloxy)-5-[3-(8-3,4-dimethoxyphenethylamino) 121-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(4-hydroxybentyloxy)-5-[2-hydroxy-3-(3-p-methoxyphenylpropylamino)propoxy]-3,4- Dihydrocarbostyryl o8-(2
-methyl-4-hydroxybutoxy)-5-[3-(8
-3,4-dimethoxyphenethylamine/)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o
8-(2-methyl-4-hydroxybutoxy)-5-[
31(N-phenylpiverazino)121hydroxypropoxy]13,4-dihydrocarpostyryl o8-(6
-Hydroxyhexyloxy) 151 [31 (813・
4-dimethoxyphenethylamino)-2-hydroxybropoxy]-3,4-dihydrocarbostyryl o8-(
5-Hydroxyhexyloxy)-5-(3-cyclobentylamino-12-hydroxypropoxy)-3,4-dihydrocarpostyl-(2-methyl-5-hydroxybentyloxy)-5-[ 3-(8-3,4-dimethoxyphenethylamino)-2-hydroxyp.

poxy]-3,4-dihydrocarbostyryl o8-(2
-methyl-4-hydroxybutoxy)-5-[2-hydroxy. C3-(4-p-chlorophenylbutyramide/
) propoxy]-3,4-dihydrocarbostyryl o8
-(2-heptynyloxy)-5-[3-(8-3・4
-dimethoxyphenethylamine/)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(5
-methyl-2-hexynyloxy)-5-[3-(8-
(3,4-dimethoxyphenethylamino)-21-hydroxypropoxy]-3,4-dihydrocarbostyryl o
8-(6-hydroxyhexyloxy)-5-1[3-(
8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(1-methyl-2-hydroxyethoxy)-51[3-(3-3,4- dimethoxyphenethylamino)-
2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(5-methyl-2-hexynyloxy)
-5-[3-(P-304-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyryl o8
1(6-hydroxyhexyloxy)151[31(8
-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyryl o8-(2-hydroxyethoxy)-15-[3-(Q-3,4-dimethoxyphenethylamino)-2-hydroxy Propoxy〕13・
4-dihydrocarbostyryl o8-(2-propynyloxy)-15-1 (2-hydroxy-3- and rt-butylaminof).

carbostyril o8-(2-propynyloxy)-5-(2-hydroxy-3-isopropylaminopropoxy) carbostyril o8-(2-propynyloxy)-5-(2-hydroxy-3-allylaminopropoxy) carbostyryl o8- (2-propynyloxy)-5-1(2-hydroxy-3-6-phenethylaminopropoxy)-rubostyryl o8-(2-propynyloxy)-5-[3-(8-4-rubamoylphenethyl) Amino)-2-hydroxypropoxy]carbostyryl o8-(2-propynyloxy)-5-[3-(8-chlorophenethylamide/)-2-hydroxypropoxy]
Carbostyryl o8-(2-propynyloxy)-51 [2-hydroxy-3-(8-4-hydroxy-3-methoxyphenethylamino)propoxy] Carbostyryl o8-(2-propynyloxy)-151 [3- (8-3
・5-dimethoxyphenethylamine/)-2-hydroxypropoxy]carbostyryl o8-(2-propynyloxy)-5-1 {3-[1,1-dimethyl-2-(3,4)
-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy}carbostyryl o8-(2-provinyloxy)-15-[3-(8-3,4,5-trimethoxyphenethylamino)-2- hydroxypropoxy]carbostyryl o8-(2-propynyloxy)-151 {3
-[2-(3,4-dimethoxyphenoxy)ethylamide/]-2-hydroxypropoxy]carbostyryl o8
-(2-propynyloxy)-51[2-hydroxy-
3-(4-phenoxybutyrami/)propoxy]carbostyryl o8-(2-propynyloxy)-5-{3
1[3-(3,4-methylenedioxyphenoxy)propylamino]12-hydroxypropoxy}rubostyryl o8-(2-propynyloxy)-151[2-hydroxy-31(N.N-methylphenoxy) enylamino)propoxy]carbostyryl o8-(2-propynyloxy)
-5-(3-cyclohexylamino-2-hydroxypropoxy)carbostyryl o8-(2-propynyloxy)-5-(2-hydroxy-3-morpholinof).

carbostyryl o8-(2-propynyloxy)-5-(2-hydroxy-N-methylpiberazinopropoxy)carbostyryl o8-(2-butynyloxy)-51[3-(B-3,4-dimethoxyf) enethylami/)-2-hydroxypropoxy]carbostyryl o
8-(2-propynyloxy)-5-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)
Carbostyryl o8-(3-benzenyloxy)-5-
[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyryl o8-(4
-bentinyloxy)-5-[2-hydroxy-3-(
6-3,4-ethylenedioxyphenethylamino)propoxy]carpostyryl o8-(2-methyl-3-butynyloxy)-5-[3-[8-3,4-dimethoxyphenethylamino-2-hydroxypropoxy] ] Rubostyril o8-(propynyloxy)-5-[2-hydroxy-31-(4-phenylpiverazino)propoxy] Lupostyryl o8-(1-methyl-3-butynyloxy)-5-(2-hydroxy-3-tert-butylaminoproxy) .

poxy)carbostyryl o8-(2-hexynyloxy)-5-1[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyryl o
8-(3-hexynyloxy)-5-(2-hydroxy-3-isopropylaminopropoxy) carbostyryl o8-(2-hydroxyethoxy)-5-(2-hydroxy-3-butylaminopropoxy) o8-(2-hydroxyethoxy)-15-(2-hydroxy-3-allylaminopropoxy) carbostyril o8-(2-hydroxyethoxy)-15-(2-hydroxy-3-8-phenethylaminopropoxy) carbostyryl o8- (2-hydroxyethoxy)-5-[
2-Hydroxy-3-(8-3.4-methylenedioxyphenethylami/)propoxy]carbostyryl o8-(2-hydroxyethoxy)-5-{3-[2-(3.
4-dimethoxyphenoxy)ethylamino]12-hydroxypropoxy}carbostyryl o8-(2-hydroxyethoxy)-5-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)carbostyryl o8-(2 -hydroxyethoxy)-5-(3-cyclohexylamino-2-hydroxypropoxy)-rubostyryl o8-(2-hydroxyethoxy)-5-(3-
piberidi/-2-hydroxypropoxy)carbostyryl o8-(2-hydroxyethoxy)-51[31(N
-Phenylpiverazino)-2-hydroxypropoxy]
carbostyryl o8-(3-hydroxypropoxy)-5-(2-hydroxy-3-te-butylaminopropoxy) -Dimethoxyphenethylamino)-2-hydroxypropoxy]carbostyryl o8-(5-hydroxybentyloxy)-(2-hydroxy-31-butylaminopropoxy)-carbostyryl o8-(6-hydroxyhexyloxy) 15
-[3-(8-3,4-dimethoxyphenethylamino)
-2-Hydroxybropoxy] Rubostyril o8- (
5-hydroxyhexyloxy)-5-1 [3-(P-4
-carbamoylphenethylamino)-2-hydroxypropoxy] Rubostyryl o8-(2-methyl-5-hydroxybentyloxy)-151 [3-(B-13,4-methylenedioxyphenethylamino)-12 monohydroxypropoxy] -(2-propynyloxy)-5-{2-hydroxy-3-[4-(4-methoxyphenyl)piverazino)propoxy}-3,4-dihydrocarbostyryl o8-(2- propynyloxy)
-5-{2-hydroxy-3-[4-(2-methylphenyl)piverazino]propoxy}-3,4-dihydrocarbostyryl o8-(2-propynyloxy)-5-{
2-Hydroxy-3-[4-(4-chlorophenyl)piverazino]propoxy}-3,4-dihydro Rubostyryl o8-(2-propynyloxy)-5-(diphenylmethylamino-2-hydroxypropoxy)-3,4
-dihydrocarbostyryl o8-(2-hydroxyethoxy)-5-{2-hydroxy-3-[4-(4-methoxyphenyl)piverazino]propoxy}-13,4-dihydrocarbostyryl o8-(2-hydroxy ethoxy)-5-{2-hydroxy-3-[4-(4-chlorophenyl)piverazino]propoxy}-3,4-dihydrocarbostyryl08-methylcarbonylmethoxy-5-[3-(8-phenethylamino)- 2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-methylcarbonylmethoxy5-[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbo Styryl 08-methylcarbonylmethoxy5-{3-[2-(4-rubamoylphenoxy)ethylamino]121-hydroxypropoxy}-13,4-dihydrocarbostyryl o8-ethylcarbonylmethoxy5- (2-Hydroxy-3-isopropylaminopropoxy)-13,4-dihydrocarbostyryl o8-(2-ethylcarbonylethoxy)-151 {3-[2-(4-methoxyphenoxy)ethylamino]-121 hydroxy propoxy}-3,4-dihydrocarbostyryl o8-methylcarbonylmethoxy5-(
3 pt-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl o8-butylcarbonylmethoxy-5-[3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-1 3
・4-dihydrocarbostyryl o8-(6-hexylcarbonylhexyloxy)-5-1 [3-(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8 -(4-isopropylcarbonylptoxy)-5-[3-(P-13,4-methylenedioxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-methylcarbonylmethoxy C51 (3-cyclohexylamino-2-hydroxypropoxy)-3.4
-dihydrocarbostyryl o8-methylcarbonylmethoxy5-(3-allylamino-2-hydroxypropoxy)-3,4-dihydrocarpostyryl o8-isopropylcarbonylmethoxy5-[3-(8-3-4-dimethoxyphene) thylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(3-isopropylcarbonylbutoxy)-5-[3-(8-
3,4-dimethoxyphenethylamine/)-121-hydroxypropoxy]-3,4-dihydrocarbostyryl o8
-Methylcarbonylmethoxy 51 (31 to rt-butylamino-2-hydroxypropoxy) Rubostyryl 08 - Methylcarbonylmethoxy51 [31 (8-3
・4-Dimethoxyphenethylamino)-21-hydroxypropoxy] Rubostyril o8-(2-ethylcarbonylethoxy)-51 {3-[2-(4-methoxyphenoxy)ethylamino]-2-hydroxy Propoxy}
carbostyryl o8-(4-isopropylcarbonylbutoxy)-5-[3-(8-3,4-methylenedioxyphenethylamino)-2-hydroxypropoxy] carbostyril 08-ethylcarbonylmethoxy-5-{3
1 [1-methyl-3-(3,4-dimethoxyphenyl)
Propylamino〕121 Hydroxypropoxy〝13.
4-dihydrocarbostyryl o8-methylcarbonylmethoxy5-{3-[111-dimethyl-4-(314
-dimethoxyphenyl)butylamine/]-2-hydroxypropoxy}-3,41-dihydrocarbostyrene
81 (3-ethylcarbonylptoxy)151 {31
5-(3,4-dimethoxyphenyl)bentylamino]
-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o8-methylcarbonylmethoxy-5-{3
-[1-Methyl-2-(4-methoxyphenoxy)ethylamino]-12-hydroxypropoxy}-13,4-dihydrocarbostyryl o8-methylcarbonylmethoxy5-[3-(B-13,4- dichlorophenethylamino)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl 08-methylcarbonylmethoxy5-[
3-(8-4-methoxyphenethylamino)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(2-methylcarponylethoxy)-5-[3-(8-3,5-dimethoxy) phenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-methylcarbonylmethoxy5-[3-(8-
3,4,5-trimethoxyphenethylami/)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-methylcarbonylmethoxy-5-{3-[4-methoxyphenyl)piverazino ]-2-hydroxyproboxy}-3,4-dihydrocarbostyryl 08
-ethylcarbonylmethoxy5-(2-hydroxy-3-morpholinopropoxy)-3,4-dihydrocarpostyryl o8-(2-methylcarbonylethoxy)-5
-[3-(4-phenylpiveradi/)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl 08-
Methylcarbonylmethoxy-5-[3-(3-morpholinopropylamino)-2-hydroxypropoxy]-3
・4-dihydrocarpostyryl 08-methylcarbonylmethoxy-5-[3-(Q-3.4-dimethoxyphenethylamino)-2-hydroxybropoxy]-3.4-
Dihydrocarbostyryl 08-methoxycarbonylmethoxy 5-[2-hydroxy-3-(8-3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl o8-ethoxycarbonylmethoxy 5-[3- cert-butylamino-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(
2-methoxycarbonylethoxy)-5-[3-(B-
3,4,5-trimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarpostyryl o8-ethoxycarbonylmethoxy5-[3-(8
-3,4-dimethoxyphenethylamino) -21hydroxybropoxy] -3,4-dihydrocarbostyryl o
8-(3-ethoxycarbonyl-2-methylbutoxy)
-5-1 [3-(8-3,5-dimethoxyphenethylami/)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(6-hexyloxycarbonylhexyloxy)-5-[3 -(8-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(3-sec-
hydroxycarponylpropoxy)-[3-(4-phenylbutylamino)-22-hydroxypropoxy]-3.
4-dihydrocarbostyryl o8-(3-propoxycarbonylpropoxy)-{3-[2-(4-methoxyphenoxy)ethylamino]-2-hydroxyproboxy}-3,4-dihydrocarbostyryl o8-ethoxy Carbonylmethoxy-5-[3-(8-3,4-dimethoxyphenethylami/)-2-hydroxypropoxy]carbostyryl o8-ethoxycarbonylmethoxy-5-(3-rt-butylamino-2-hydroxypropoxy) Carbostyryl 08-ethoxycarbonylmethoxy-5-[3-(Q-3,4-dimethoxyphenethylamino)-12-hydroxybropoxy]-3,4-dihydrocarbostyryl 08-carboxymethoxy-5-[3 -(B-3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl
t-butylamino-2-hydroxypropoxy)-3.
4-dihydrocarbostyryl o8-(4-carpoxybutoxy)-5-(3-8-phenethylamino-2-hydroxybropoxy)-3,4-dihydrocarbostyryl o8-(3-carboxypropoxy)-5 1 {3-[2
-(4-Methoxyphenoxy)ethylamide/]-2-hydroxypropoxy}--3,4-dihydrocarbostyryl o8-(3-carboxy-2-methylbutoxy)-5
1 [3-1 (6-3,4-dimethoxyphenethylamino)
-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-(6-lupoxyhexyloxy)-51 (3-allylamino-2-hydroxybropoxy)
-3,4-dihydrocarbostyryl o8-carboxymethoxy-5-[3-(8-3,4-dimethoxyphenethylamino)-12-hydroxybropoxy]carbostyryl o8-(3-carboxypropoxy)-5- {3-[2
1(4-methoxyphenoxy)ethylamino]12-hydroxypropoxy}carbostyryl o8-(3-carboxy2-methylbutoxy)151[31(813.
4-dimethoxyphenethylamino)-2-hydroxypropoxy] carbostyryl 3-piveridino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl 08-hydroxymethoxy5-{3-[4-(2-methylphenyl)
Piverazino]-2-hydroxypropoxy}-3,4-
Dihydrocarbostyryl o8-ethoxycarbonylmethoxy-5-[3-(4-phenylpiberazino)-2-hydroxypropoxy]-13,41 dihydrocarbostyryl 08-carboxymethoxy-5-1[3 One (Q-3・
4-dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl 08-rubamoylmethoxy5-[3-(8-3,4-dimethoxyphenethylamino)-2- Hydroxypropoxy]
Rubostyril O8- Rubamoylmethoxy-5-[3
-(8-3,4-dimethoxyphenethylamino)-2-
Hydroxypropoxy]-3,4-dihydrocarbostyryl o8-[N-(B-3,4-dimethoxyphenethyl)rubamoylmethoxy]-51[3-(B-3,4-dimethoxyphenethyl) amino)-121-hydroxypropoxy]-3,4-dihydrocarbostyryl o8-N・N
-diethylcarbamoylmethoxy5-[3-(8-3
・4-dimethoxyphenethylamino)-21-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-
(3-carbamoylpropoxy)-15-1 [3-1 (P-13
・4-dimethoxyphenethylamino)-21-hydroxypropoxy]-13,4-dihydrocarbostyryl o8-(2-carbamoylethoxy)-151 {3-[2-1(3
・4-dimethoxyphenoxy)ethylamino]-12-hydroxypropoxy}-13,4-dihydrocarbostyryl o8-(6-carbamoylhexyloxy)-5-(
3-tere-butylamino-2-hydroxypropoxy]13,41-dihydrocarbostyrene The above general formula (1
) The compound of the present invention represented by formula (0) can be produced by various methods.
It is manufactured using the compound as a starting material.

or (in the above formula, X represents a halogen atom.

R,, R2, R3 and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above), that is, the 518-dihydroxycarbostyryl derivative of general formula (b) is reacted with a halogen compound represented by R and X to form the general formula A novel carbostyryl derivative of (m) is obtained, and it is isolated and purified or reacted with epihalogenohydrin without purification.
, (V) is obtained. Next, the compound of general formula (1) is produced by isolating and purifying it or reacting it with an amine of general formula (W) without purification. 5,8-dihydride represented by formula (b).

Xycarbostyryl derivative and R. The reaction with the halogen compound represented by
In the presence of a basic compound such as calcium hydride, preferably sodium carbonate or potassium carbonate, soot or lower alcohols such as methanol, ethanol, propanol, isopropanol, ketones such as acetone, methyl ethyl ketone, ether, dioxane, tetrahydrofuran. ethers such as benzene, toluene, xylene, aromatic hydrocarbons such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, water, etc. in a solvent, preferably acetone, methanol, ethanol or water. It is better. When 2-halogeno-1-ethanol is used as the halogen compound, it is preferable to protect the hydroxyl group before using it in the reaction. As such a protecting group, a tetrahydrofuranyl group, a benzyl group, etc. are used. The amounts of the halogen compounds represented by R and
Preferably, it is used in an equimolar to 1.5-fold molar amount.
The reaction temperature is not particularly limited and may be carried out under cooling or heating, but is usually 0 to 150 qo, preferably 50 to 150 qo.
It is preferable to carry out the reaction at 80°C. The reaction between the carbostyryl derivative represented by the general formula (m) and iphalogen/hydrin can be carried out using a suitable basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
In the presence of an inorganic base such as sodium metal, potassium metal, or sodium hydride, or an organic base such as pyridine, piverizine, pyrrolidine, or piperazine, without a solvent or with lower alcohols such as methanol, ethanol, propanol, and isopropanol, acetone, and methyl ethyl ketone. Ketones such as ethers, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, and solvents such as water, preferably methanol, ethanol and isopropanol. Good.

Epihalogenohydrins include epichlorohydrin and epib. Examples include mohydrin and epiodohydrin. The amount of epihalogenohydrin to be used is not particularly limited and is appropriately selected from a wide range, but it is usually used in an equimolar to excess amount, preferably 5 to 1 pmol to the compound of the general formula (dish). good. The reaction proceeds at 0 to 150 qo, but it is generally preferred to carry out at 50 to 100 qo. In the above reaction, epihalogenohydrin becomes a (2,3-epoxy)propoxy group or a 3-halogeno-2-hydroxypropoxy group, so that the reaction product is obtained as a mixture. These reaction mixtures can be separated and purified by commonly used purification methods such as fractional crystallization and column chromatography. However, in order to produce the object of the present invention, the mixture may be reacted with amine without any particular separation and purification. Next, the general formula (W)
, (V) and the general formula (
In the reaction with the amine represented by W), isolated and purified (W
), it can be carried out without a solvent, but for example, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, xylene, etc.
It is preferable to conduct the reaction in a polar solvent such as water, dimethylformamide, and more preferably methanol, ethanol, and isopropanol. The amines are used in equimolar to excess amounts relative to the epoxy compound represented by the general formula (W), but 3 to
It is preferable to use 8 times the molar amount. This reaction is 0~100oo
However, it is preferable to proceed at a range of 0 to 7.
Further, when using the 2-hydroxy-3-halogen/propoxy compound represented by the general formula (V), the reaction is carried out in the presence or absence of a suitable base. Examples of such bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. Among these, sodium carbonate and potassium carbonate are preferred. The reaction may be carried out without solvent or in lower alcohols such as methanol, ethanol, propanol, isopropanol, ether,
The reaction is preferably carried out in an ether such as dioxane or tetrahydrofuran, an aromatic hydrocarbon such as benzene, toluene or xylene, a solvent such as water, or preferably an alcohol such as methanol, ethanol or isopropanol. The amines are used in excess of the 2-hydroxy-3-halogenopropoxy compound represented by the general formula (V), preferably in an amount of 3 to 8 times the molar amount. This reaction is 0-1
It progresses at 000○, but it is better to do it at 20-8000. When using a mixture of (W) and (V), the same base as above may or may not be used, and the amounts of solvent and amine are the same as above.The reaction temperature is 0 to 100 qo. However, it is preferable to carry out the reaction at a concentration of 50 to 80 oo.The thus obtained compound of the present invention can be made into an acid addition salt by reacting with a pharmacologically acceptable acid.

Such acids include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid, propionic acid,
Examples include organic acids such as oxalic acid, maleic acid, succinic acid, tartaric acid, fumaric acid, malic acid, ethane sulfonic acid, and p-toluenesulfonic acid. After completion of the reaction, the compound of the present invention is isolated from the reaction mixture according to conventional methods.

For example, it is purified by conventional means such as fractional recrystallization, column chromatography, and thin layer chromatography. In order to further clarify the present invention, reference examples and examples are listed below.

Reference Example 1 2 parts of acetone and 500 parts of water were added to 1509 parts of 5,8-dihydroxy-3,4-dihydrocarbostyryl, and then 138 parts of potassium carbonate and 15 parts of propargyl bromide were added.
Add 0.0 ml of water and heat under reflux on a water bath for 3 hours.

After the reaction is complete, acetone and propargyl bromide are removed under reduced pressure, and concentrated hydrochloric acid is added to the residue to make it acidic, followed by extraction with chloroform. After washing with water, dry the chloroform with anhydrous sodium sulfate. Remove the chloroform under reduced pressure. Recrystallize the residual crystals with isopropanol ether to obtain mp141-142.
8-(2-propynyloxy)-5-hydroxy-
110 ml of 3,4-dihydrocarbostyryl is obtained. Reference example 28-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyryl 78 times, epichlorohydrin 102 times, potassium carbonate 60 times, methanol 6 times
2.00ml of mixture on a water bath. Heat to reflux for an hour.

After the reaction is completed, methanol is removed under reduced pressure. Add water to the residual light and extract with chloroform, wash with water, dry over anhydrous sodium sulfate, and remove the chloroform under reduced pressure. The afterglow crystals were recrystallized from isopropanol to give 8 of mp142-143.5qo.
1(2-propynyloxy)-15-1(2,3-epoxypropoxy)-3,4-dihydrocarbostyryl 67 is obtained. Example 15-(2,3-epoxypropoxy)-18-(2-propynyloxy)-3,4-dihydrocarbostyryl was dissolved in 15 parts of methanol, and
Add 2.6 g of t-butylamine and leave to stand at 15-20°C for 1 hour.

After the reaction is completed, rt-butylamine is distilled off using methanol. The residual crude oil was converted into a hydrochloride with hydrochloric acid and ethanol, and the solvent was removed under reduced pressure to obtain crude crystals. The obtained crude crystals are dissolved in water and washed with chloroform to remove impurities. The aqueous layer was made alkaline with caustic soda and extracted with chloroform. After washing with water, it is dried over anhydrous sodium sulfate, and chloroform is distilled off under reduced pressure to obtain colorless crystals. The crystals are converted into hydrochloride with HCI and ethanol. The solvent was removed under reduced pressure, and the remaining crystals were recrystallized from isopropanol.
182-18300 of 8-(2-propynyloxy)-51[3-(ten-butylamino)-12-hydroxypropoxy]-13,4-dihydrocarbostyryl hydrochloride was obtained. Example 2 8-(2-propynyloxy)-5-1(3-koo-2
-Hydroxybroboxy)-3,4-dihydrocarbostyryl (1.0%) was dissolved in 30% methanol (28%).
NKOHO. Add the solution from step 5 and heat the mixture at 70°C for 10 hours.

Methanol and NH40H are distilled off under reduced pressure, and the liquid is acidified with hydrochloric acid and washed with ethyl acetate. After separating the aqueous layer, it is made alkaline with caustic soda and then extracted with chloroform. After washing with water, dry with anhydrous sodium sulfate. Chloroform is removed under reduced pressure and the residue is separated using silica chromium. Next, methanol-hydrochloric acid is added to form a hydrochloride. Recrystallized from methanol ether, mpl 96.5-1 group. 0.5 of 8-(2-propynyloxy)-15-(3-amino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl hydrochloride is obtained. Example 3 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyryl1.
One hour was dissolved in methanol for 30 minutes, 2-methoxyethylamine was added for 1.5 hours, and the mixture was left at 10 to 10 hours for two periods.

After the reaction is complete, methanol and excess amine are distilled off under reduced pressure, and the residue is acidified with hydrochloric acid and washed with ethyl acetate. The aqueous layer is made alkaline with caustic soda and extracted with chloroform. After washing with water and drying over anhydrous sodium sulfate, chloroform was removed under reduced pressure. The residue was poured into methanol and methanol-hydrochloric acid was added to obtain a hydrochloride, which was then recrystallized from isopropanol to give 8-(2-propynyloxy) with mp171-17 ○.
-5-[2-hydroxy-3-(2-methoxyethylami/)propoxy]-3,4-dihydrocarpostyryl hydrochloride 0.8 g was obtained. Example 48-(2-propynyloxy)-5-(3-chloro-2-hydroxyph).

Dissolve 1.0 mol of 3,4-dihydrocarpostyril in 30 methanol and add 0.5 mol of anhydrous potassium carbonate and 1.4 mol of 2-(3,5-dimethoxyphenoxy)ethylamine. Time pseudo Azusa reflux. Methanol is removed under reduced pressure, and the residue is acidified with hydrochloric acid and washed with ethyl acetate.
Separate the hydrochloric acid layer and extract with chloroform. After washing with water, wash with anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure and the residue was recrystallized from methanol-ether to give mp187-1.
89o○ of 8-(2-propynyloxy)-51 {3-[2-(3,5-dimethoxyphenoxy)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl hydrochloride Get 0.4 evenings. Example 58-(
2-propynyloxy)-15-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyryl. 0.0 ml was dissolved in 20 methanol, and 0.5 ml of anhydrous potassium carbonate and 1.6 ml of 3,4-dimethoxyphenethylamine were added. Insect Time Kanryu Toyo.

After the reaction is completed, methanol is removed under reduced pressure. After dissolving the residue in chloroform and washing with water, the chloroform layer is dried over anhydrous sodium sulfate. The chloroform is removed under reduced pressure, and the residual oil is converted into a hydrochloride with hydrochloric acid and extracted with chloroform. After washing with water, dry with anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure, and the remaining groove was recrystallized from methanol-ether to obtain mp160
8-(2-propynyloxy)-5-[3 at ~162°C
-(8-3,4-dimethoxyphenethylamino)-2-
1.1 hydroxypropoxy]-3,4-dihydrocarbostyryl hydrochloride was obtained. Example 6 8-(2-hydroxyethoxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyryl 1
．． Dissolve 0 ml in 20 ml of methanol and add 1.5 ml of 8-3,4-dimethoxyphenethylamine to make 10 to 15 ml.
Leave it alone for an hour at C.

After the reaction is complete, methanol is distilled off under reduced pressure, and the residual oil is dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate.
Chloroform was removed under reduced pressure, and the residual oil was decanted and washed with ether, and then converted into a hydrochloride with hydrochloric acid-methanol. Recrystallized from methanol river ether, mp204-20600 8
-(2-hydroxyethoxy)-5-[3-(8m3・
4-dimethoxyphenethylamino)-21-hydroxypropoxy]-3,4-dihydrocarbostyryl hydrochloride 0
．． Get 9 evenings. Example 7 8-(2-propynyloxy)-5-(3-kuro2
Dissolve 1.0 volume of 3,4-dihydrocarbostyryl (monohydroxypropoxy) in 20 parts of methanol, add 0.7 volume of anhydrous potassium carbonate, and 1.7 volume of morpholine.
Time reflux light azusa.

After the reaction is completed, methanol and morpholine are distilled off under reduced pressure, and the remaining hawk oil is converted into a hydrochloride with hydrochloric acid water and washed with chloroform. The aqueous layer is separated, made alkaline with caustic soda, and extracted with chloroform. After washing with water, dry with anhydrous sodium sulfate. Chloroform was removed under reduced pressure, the residue was made into a hydrochloride with ethanol-hydrochloric acid, and recrystallized from water-ethanol to obtain mp2.
8-(2-propynyloxy) of 34.5-235qC
-5-(2-hydroxy-3-morpholinopropoxy)
-3,4-dihydrocarbostyril hydrochloride 0.8 g is obtained. Example 88-(2-propynyloxy)-15-(
2,3-Epoxypropoxy)-3,4-dihydrocarbostyryl (2) was dissolved in 30M methanol, 2.6% of pyrrolidine was added, and the mixture was left at a temperature of 10 to 1,530 ℃ for 12 hours.

After the reaction is complete, methanol and Pillow Jine are removed under reduced pressure.
The residual oil was converted to hydrochloride with hydrochloric acid and ethanol. Recrystallization from methanol yields 0.9 g of 8-(2-propynyloxy)-15-(3-pyrrolidino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl hydrochloride having a mp of 225-226°C. Examples 9 to 51 The compounds in the table below are obtained in the same manner as in Example 8.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a lower alkynyl group, a hydroxyalkyl group, a carbamoyl alkyl group, a carboxyalkyl group,
Indicates an alkylcarbonylalkyl group or an alkoxycarbonylalkyl group. R_2 and R_3 are the same or different and represent a hydrogen atom, a lower alkyl group, a cyclohexyl group, an alkoxyalkyl group, a lower alkenyl group, a phenylalkyl group, a phenoxyalkyl group, a morpholinoalkyl group, or a phenyl group. Further, R_2 and R_3 may be bonded to each other with or without the nitrogen atom or oxygen atom to form a five- or six-membered heterocycle. Furthermore, the bonds at the 3rd and 4th positions of the carbostyryl skeleton represent a single bond or a double bond. ) and its acid addition salts. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a lower alkynyl group, a hydroxyalkyl group, a carbamoyl alkyl group, a carboxyalkyl group,
Indicates an alkylcarbonylalkyl group or an alkoxycarbonylalkyl group. Y- indicates ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (X is a halogen atom). Furthermore, the bonds at the 3rd and 4th positions of the carbostyryl skeleton represent a single bond or a double bond. ] Carbostyryl derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. It represents a phenylalkyl group, a phenoxyalkyl group, a morpholinoalkyl group, or a phenyl group. Further, R_2 and R_3 may be bonded to each other with or without the nitrogen atom or oxygen atom to form a five- or six-membered heterocycle.
▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3 and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above.] A method for producing a carbostyryl derivative and an acid addition salt thereof.