JPH0135827B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril derivatives. The carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R is a hydrogen atom or the following group shows. In the above group, A is a lower alkylene group, R ³ is a lower alkyl group, a lower alkyl group having a hydroxyl group as a substituent, a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group, or a benzoyloxy lower alkyl group, R ⁴
is a lower alkyl group, a C _3-10 cycloalkyl group that may have a hydroxyl group as a substituent on the cycloalkyl ring, a lower alkyl group that has a C _3-10 cycloalkyl group as a substituent, phenyl group, phenyl ring A phenyl lower alkyl group which may have a lower alkoxy group as a substituent, a lower alkyl group having a hydroxyl group as a substituent, a pyridyl group or a thienyl group, a furyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyridyl group, or 3 , 4-dihydro-2H-pyranyl group as a substituent. this
R ³ and R ⁴ are bonded together with the nitrogen atom to which they are bonded to form a group.

[Formula] (where R ⁵ is a phenyl group, a C _3-10 cycloalkyl group or a phenyl lower alkyl group, and Z is a methine group or a nitrogen atom) may be formed. However, when R ³ represents a lower alkyl group, R ⁴ represents a lower alkyl group, a C _3-10 cycloalkyl group that may have a hydroxyl group as a substituent on the cycloalkyl ring, a phenyl group, or a lower alkyl group on the phenyl ring. It must not be a phenyl lower alkyl group that may have an alkoxy group as a substituent or a lower alkyl group that has a C _3-10 cycloalkyl group as a substituent. Also,
When R ¹ and R ² are hydrogen atoms, R ³ is a lower alkyl group substituted with one hydroxyl group, and R ⁴ is a C _3-10 cycloalkyl group, the side chain shall not be substituted at the 6-position of the carbostyryl skeleton. In addition, R ¹ is a hydrogen atom, a lower alkyl group,
Lower alkenyl group or phenyl lower alkyl group, R ² is hydrogen atom, lower alkyl group or the following group (A, R ³ and R ⁴ in the group are the same as above) are shown respectively. However, either R or R ² is a group. shall be shown. Furthermore, 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position represents a single bond or a double bond. ] The compound of the present invention represented by the above general formula (1) has excellent platelet aggregation inhibiting action, phosphodiesterase inhibiting action, cardiac contractility enhancing action (positive inotropic action),
It has anti-ulcer, anti-inflammatory, antihypertensive, cerebral blood flow increasing, platelet agglomeration, and thromboxane _A2 antagonistic effects. The characteristics of the compound of the present invention are:
It has a long duration of action and low toxicity,
Furthermore, side effects on the heart, such as increased heart rate, cardiovascular hypertrophy, and myocardial damage, are particularly weak. Furthermore, the compound of the present invention is well absorbed and easily transferred into the blood, and has a high concentration in the blood and is difficult to be degraded (metabolized). Therefore, the compound of the present invention can be used as a prophylactic or therapeutic agent for thrombosis such as stroke, cerebral infarction, or myocardial infarction, a cerebral circulation improving agent, an anti-inflammatory agent, an anti-asthmatic agent, a cardiotonic agent,
It can be suitably used as an antihypertensive agent and a phosphodiesterase inhibitor. In the above general formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵
Specifically, each group represented by and A is as follows. Lower alkylene group...methylene, ethylene, methylmethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-
Ethyltrimethylene, 1-methyltrimethylene, etc. Lower alkyl group...methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Lower alkyl group having hydroxyl group as a substituent...
Hydroxymethyl, 2-hydroxyethyl, 3-
Hydroxypropyl, 4-hydroxybutyl, 2
-Hydroxybutyl, 3-hydroxybutyl, 5
-Hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 1-methyl-2-hydroxyethyl, 2- Hydroxypropyl, 1,1-dimethyl-2-hydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl, 1,3
-dihydroxypropyl, 2,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1,4-dihydroxybutyl, 2,4-dihydroxybutyl, 3,4-dihydroxybutyl,
1,2-dihydroxybutyl, 2,3-dihydroxybutyl, 1,3-dihydroxybutyl, 2,
2-dihydroxybutyl, 1,2,3-trihydroxybutyl, 2,3,4-trihydroxybutyl, 2,3-dihydroxypentyl, 3,4-dihydroxypentyl, 3,5-dihydroxypentyl, 2,3, 4-trihydroxypentyl,
3,4,5-trihydroxypentyl, 2,4,
5-trihydroxypentyl, 2,3-dihydroxyhexyl, 2,5-dihydroxyhexyl,
2,6-dihydroxyhexyl, 3,4-dihydroxyhexyl, 4,5-dihydroxyhexyl, 4,6-dihydroxyhexyl, 5,6-dihydroxyhexyl, 2,3,4-trihydroxyhexyl, 3,4,5 -trihydroxyhexyl, 4,5,6-trihydroxyhexyl group, etc. Lower alkoxy lower alkyl group...methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, 1-methyl-2-methoxyethyl, 2-methoxypropyl, 1, 1-
Dimethyl-2-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, 1-methyl-2-ethoxyethyl, 2-ethoxypropyl, 1 ,1-
Dimethyl-2-ethoxyethyl, propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl, 5-propoxyhexyl, 2-propoxypropyl, 2-isopropoxyethyl, 2-butoxyethyl, 3-butoxypropyl , 4-butoxybutyl, 6-butoxyhexyl, 2-tert-butoxyethyl, 2-pentyloxyethyl, 5-pentyloxypentyl, 2-hexyloxyethyl, 6-hexyloxyhexyl group, etc. Lower alkanoyloxy lower alkyl group...2-
Formyloxyethyl, 3-formyloxypropyl, 4-formyloxybutyl, 2-formyloxypropyl, acetyloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl, 6-acetyloxyhexyl, 1
-Methyl-2-acetyloxyethyl, 2-acetyloxypropyl, 1,1-dimethyl-2-acetyloxyethyl, 2-propionyloxyethyl, 3-propionyloxypropyl, 4-propionyloxybutyl, 5-propionyloxypentyl , 6-propionyloxyhexyl,
2-propionyloxypropyl, 2-butyryloxyethyl, 3-butyryloxypropyl, 4
-Butyryloxybutyl, 2-butyryloxypropyl, 2-isobutyryloxyethyl, 4-isobutyryloxybutyl, 2-pentanoyloxyethyl, 5-pentanoyloxypentyl, 2
-tert-butylcarbonyloxyethyl, 2-hexanoyloxyethyl, 6-hexanoyloxyhexyl group, etc. Benzoyloxy lower alkyl group...benzoyloxymethyl, 2-benzoyloxyethyl, 3
-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl, 6
-benzoyloxyhexyl, 1-methyl-2-
Benzoyloxyethyl, 2-benzoyloxypropyl, 1,1-dimethyl-2-penzoyloxyethyl groups, etc. A _C3-10 cycloalkyl group that may have a hydroxyl group as a substituent on the cycloalkyl ring...cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 3-
Hydroxycyclopentyl, cyclohexyl, 2
-Hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl,
3,4-dihydroxycyclohexyl, 3,4,
5-trihydroxycyclohexyl, cycloheptyl, 2-hydroxycycloheptyl, 3-hydroxycycloheptyl, 4-hydroxycycloheptyl, cyclooctyl, 2-hydroxycyclooctyl, 3-hydroxycyclooctyl, 4-
Hydroxycyclooctyl, 5-hydroxycyclooctyl, cyclononanyl, 2-hydroxycyclononanyl, 3-hydroxycyclononanyl,
4-hydroxycyclononanyl, cyclodecanyl, 2-hydroxycyclodecanyl, 4-hydroxycyclodecanyl group, etc. Lower alkyl group having a C _3-10 cycloalkyl group as a substituent...4-cyclohexylbutyl,
Cyclopropylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, cyclopentylmethyl, 2-cyclohexylethyl, 2
-Cyclohexylpropyl, 2-cycloheptylethyl, 3-cyclobutylpropyl, 1,1-dimethyl-2-cyclohexylethyl, 1-methyl-2-cyclopentylethyl, 2-cyclooctylethyl, cyclononanylmethyl, 2-cyclo decanylethyl, 5-cyclohexylpentyl, 6
- Cyclohexylhexyl group, etc. Phenyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring...benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 2
-Methyl-3-phenylpropyl, 5-phenylpentyl, 6-phenylhexyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,
4,5-trimethoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl enyl)ethyl, 2-(3,4-diethoxyphenyl)ethyl, 2-(3,4-diisopropoxyphenyl)
Ethyl, 2-(3,4-dibutoxyphenyl)ethyl, 1-(3,4-dimethoxyphenyl)ethyl, 2-(3,4,5-trimethoxyphenyl)
Ethyl, 3-(3,4-dimethoxyphenyl)propyl, 4-(3,4-dimethoxyphenyl)butyl, 6-(3,4-dimethoxyphenyl)hexyl, 1,1-dimethyl-2-( 3,4-dimethoxyphenyl)ethyl, 2-(2,5-dimethoxyphenyl)ethyl groups, etc. Lower alkenyl group: vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl group, etc. Phenyl lower alkyl group...benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3 -Phenylpropyl, diphenylmethyl groups, etc. In addition, the lower alkyl group substituted with a thienyl group, furyl group, tetrahydrofuryl group, tetrahydropyranyl group, pyridyl group, or 3,4-dihydro-2H-pyranyl group refers to the above-mentioned thienyl group, furyl group,
Refers to a lower alkyl group to which a tetrahydrofuryl group, a tetrahydropyranyl group, a pyridyl group, or a 3,4-dihydro-2H-pyranyl group is bonded as a substituent, such as 3-pyridylmethyl, 2-pyridylmethyl, 4-pyridylmethyl. , 2-(3-pyridyl)ethyl, 3-(3-pyridyl)propyl, 4-(3-pyridyl)butyl, 2,2-dimethyl-2-(2-pyridyl)ethyl, 5-(4-
pyridyl)pentyl, 6-(4-pyridyl)hexyl, 1,1-dimethyl-2-(3-pyridyl)
Ethyl, 2-furylmethyl, 3-furylmethyl,
2-(3-furyl)ethyl, 4-(2-furyl)
Butyl, 2-tetrahydrofurylmethyl, 3-tetrahydrofurylmethyl, 2-(3-tetrahydrofuryl)ethyl, 5-(2-tetrahydrofuryl)pentyl, 2-2H-pyranylmethyl, 3-
2H-pyranylmethyl, 2-(3-2H-pyranyl)ethyl, 6-(2-2H-pyranyl)hexyl, 2-4H-pyranylmethyl, 2-(2-4H-
pyranyl)ethyl, 2-3,4-dihydro-2H
-pyranylmethyl, 4-3,4-dihydro-2H
-pyranylmethyl, 2-(3-3,4-dihydro-2H-pyranyl)ethyl, 4-(4-3,4-
dihydro-2H-pyranyl)butyl, 2-tetrahydropyranylmethyl, 2-(2-tetrahydropyranyl)ethyl, 3-(4-tetrahydropyranyl)propyl, 5-(3-tetrahydropyranyl)pentyl, 2- thienylmethyl, 2-(2-
thienyl)ethyl, 3-thienylmethyl, 4-
(3-thienyl)butyl, 2-tetrahydrothienylmethyl, 3-tetrahydrothienylmethyl,
etc. can be mentioned. Representative compounds of the present invention are listed below. Γ5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(4-hydroxybutyl)-
N-cyclooctylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(4-hydroxybutyl)-
N-cyclooctylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-cyclodecanylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-hydroxyethyl)-
N-cyclodecanylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{2-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]ethoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{6-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]hexyloxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{2-methyl-3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl [Propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{2,2-dimethyl-3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}- 3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonylmethoxy]-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{3-[N-(2-hydroxyethyl)-
N-(3-pyridyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-ethyl-N-(3-pyridyl)aminocarbonyl]propoxy }-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-methyl-N-(2-pyridyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-methyl-N-(4-pyridyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-butyl-N-(3-pyridyl)aminocarbonyl]propoxy}-3,4
-Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-pyridylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl [Propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ5-{3-[N-ethyl-N-(2-pyridylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenator Γ8-{3-[N-butyl-N-(4-pyridylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenation product Γ6-[3-{N-methyl-N-[4-(3-pyridyl)butyl]aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6 -{3-[N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy}-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-[3-{N-ethyl-N-[2-(3-furyl)ethyl]aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or Its 3,4-position dehydrogenation product Γ7-[3-{N-methyl-N-[4-(2-furyl)butyl]aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or 3,4-position dehydrogenation Form Γ6-{3-[N-methyl-N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N- (2-hydroxyethyl)-
N-(2-furylmethyl)aminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenase Γ5-{2-methyl-3-[N-methyl(3-tetrahydrofurylmethyl ) aminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{4-[N-ethyl-N-(2-tetrahydrofurylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbo Styryl or its 3,4-position dehydrogenate Γ6-[3-{N-methyl-N-[5-(2-tetrahydrofuryl)pentyloxy]aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or its 3 , 4-position dehydrogenation product Γ6-{3-[N-methyl-N-(2-2H-pyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ5-{ 3-[N-ethyl-N-(3-2H-pyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-ethyl-N- (2-4H-pyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-methyl-N-(2-3,4-
dihydro-2H-pyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-3,4-dihydro-2H-pyranylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-[3-{N-methyl-N-[2-(3-
3,4-dihydro-2H-pyranyl)ethyl]
aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-methyl-N-(4-3,4-
dihydro-2H-pyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl [Propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-ethyl-N-(4-tetethydropyranylmethyl)aminocarbonyl]propoxy}-3,4 -dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-methyl-N-(3-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3, 4-position dehydrogenation product Γ6-[3-{N-methyl-N-[3-(4-tetrahydropyranyl)propyl]aminocarbonyl}propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Body Γ5-{3-[N-ethyl-N-(3-thienylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-thienylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-methyl-N-(2-tetrahydrothienyl)aminocarbonyl ] propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{4-[N-methyl-N-(3-tetrahydrothienyl)aminocarbonyl]propoxy}-3,4-dihydrocarbo Styryl or its 3,4-position dehydrogenation Γ6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Element Γ5-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[ N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{4-[N-(2-hydroxyethyl )―
N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]propoxy} -3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Γ6-{3-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Form Γ6-{3-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[ N-(3,4-dihydroxybutyl)-N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2,3,4-trihydroxybutyl)-N-cyclohexylaminocarbonyl]propoxy}-3, 4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3 , 4-position dehydrogenated Γ6-{3-[N-(2,4-dihydroxybutyl)-N-cyclooctylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(3,4-dimethoxybenzyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]butyloxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(4-hydroxybutyl) ―
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl) ―
N-benzylaminocarbonyl]propoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(β-phenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ6-[4-{N-(2-hydroxyethyl)-
N-[4-(3,4-dimethoxyphenyl)butyl]aminocarbonyl}butoxy]-3,4
-Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-hydroxyethyl)-
N-(β-phenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ7-{3-[N-(2-hydroxyethyl)-
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-(2-hydroxyethyl) ―
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(4-hydroxybutyl) ―
N-6-phenylhexylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2,3-dihydroxypropyl)-N-(β-3,4-dimethoxyphenethyl) Aminocarbonyl]propoxy}-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(3,4-dihydroxybutyl)-N-(α-phenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbo Styryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl propoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(3-hydroxypropyl)
-N-phenylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-(2,3-dihydroxypropyl)-N-phenylaminocarbonyl ]Propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxypropyl)
-N-phenylaminocarbonyl]butoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{4-[N-(2-hydroxypropyl)
-N-phenylaminocarbonyl]butoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(4-hydroxybutyl)-
N-phenylaminocarbonyl propoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(4-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]
Butoxy-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl propoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl propoxy}
-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxypropyl)
-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxypropyl)
-N-(4-cyclohexylbutyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenant Γ5-{3-[N-(2-hydroxypropyl)
-N-(3-cyclohexylpropyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-[3-(N-methoxymethyl-N-cyclohexylaminocarbonyl)propoxy] ―
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{3-[N-(2-ethoxyethyl)-N
-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(4-butoxybutyl)-N
-cyclohexylaminocarbonylpropoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-cyclooctylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-cyclopropylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ5-{3-[N-(2-methoxyethyl)- N
-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{4-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ8-{3-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(3-acetyloxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-methoxyethyl)-N
-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-benzoyloxyethyl) -N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(6-benzoyloxyhexyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbo Styryl or its 3,4-position dehydrogenated product Γ6-{4-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6-{4-[N-(5-propionyloxyheptyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydro Carbostyryl or its 3,4-position dehydrogenator Γ6-{4-[N-(3-acetyloxypropyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(6-hexyloxyhexyl)-N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ6-{3-[N-(5-propionyloxyheptyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydro Carbostyryl or its 3,4-position dehydrogenate Γ7-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(6-hydroxyhexyl)
-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ6-{3-[N-(2-hydroxyethyl)-
N-(2-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenant Γ6-{3-[N-(2-hydroxyethyl)-
N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-methyl-N-(2-thienylmethyl)aminocarbonyl [Propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ5-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ5-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]- 3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Γ6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Element Γ6-[3-(4-benzyl-1-piperidinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6-[3-(4-phenyl-1- piperidinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ5-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Styryl or its 3,4-position dehydrogenation product Γ7-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ8-[3 -(4-phenyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ1-methyl-6-{3-[N-(2-hydroxyethyl) -N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ1-hexyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl ] propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ1-allyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3, 4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-[3-(4-benzyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogen Γ1-(2-hexenyl)-6-{3-[N-
(2-Hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ1-benzyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3 , 4-position dehydrogenated Γ1-(6-phenylhexyl)-6-{3-
[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenation product Γ1-methyl-5-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ1 -Benzyl-5-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-7-{ 3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-8-{3-[N-( 2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-6-{3-[N-methyl-N-
(4-pyridyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-6-[3-(4-phenyl-1-
piperazinylcarbonyl)propoxy]-3,
4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ1-benzyl-5-[3-(4-phenyl-1
-piperidylcarbonyl)propoxy]-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ4-methyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or Its 3,4-position dehydrogenation product Γ4-ethyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Element Γ4-hexyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-hydrocarbostyryl or its 3,4-position dehydrogenate Γ1,4- Dimethyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-hexyl-4-methyl- 7-{3-[N-
(2-Hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-benzyl-4-methyl-8-{3-[N-
(2-Hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-ethylaminocarbonylpropoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{3-[N,N-di-(2-hydroxyethyl)aminocarbonyl]propoxy}-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]
Propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{4-(N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-ethoxyethyl)-N
-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-Phenylaminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenate Γ6-{4-(2-ethoxyethyl)-N-(2
-hydroxyethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-ethylaminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ6-{4-[N-(2-methoxyethyl)-N
-(β-phenethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-{3-[N-(2-hydroxyethyl) ―
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl) ―
N-(β-3,4-diethoxyphenethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl )―
N-(β-3,4,5-trimethoxyphenethyl)aminocarbonyl]propoxy}-3,4
-Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{5-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]pentyloxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-[3-[N-(2-hydroxyethyl)-
N-(β-4-methoxyphenethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]
Propoxy}-3,4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ6-{3-[N-(2-hydroxyethyl)-
N-cyclooctylmethylaminocarbonyl]
Propoxy}-3,4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ6-{4-(N-(2-hydroxyethyl)-
N-cyclodecanylmethylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydro Carbostyryl or its 3,4-position dehydrogenated product Γ6-{4-[N-(2-benzoyloxyethyl)-N-phenylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position Dehydrogenated Γ6-{3-[N-(2-benzoyloxyethyl)-N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-benzoyloxyethyl)-N-(2-hydroxyethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-{3-[N-(2-acetyloxyethyl)-N-cyclohexylaminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-acetyloxyethyl)-N-cyclohexylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-propionyloxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbo Styryl or its 3,4-position dehydrogenated product Γ5-{4-[N-(2-acetyloxyethyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6-{4-[N-(2-acetyloxyethyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydro Carbostyryl or its 3,4-position dehydrogenator Γ6-{3-[N-(2-acetyloxyethyl)-N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-acetyloxyethyl)-N-phenylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3, 4-position dehydrogenated Γ6-{4-[N-(2-acetyloxyethyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-N-(2-methoxyethyl)-N-
(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-(N-(2-benzoyloxyethyl)-N-(2 -tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4
-Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(3-hydroxypropyl)
-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenator Γ6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-(2-tetrahydropyranyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-acetyloxyethyl)-N-(2 -tetrahydropyranyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-2,3-dihydroxypropyl)-N-(2-tetrahydropyrani (methyl)aminocarbonyl]propoxy}-3,4
-Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(4-hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2,3-dihydroxypropyl)-N-( 3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2,3-dihydroxypropyl)-N-(3-hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4-
Dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-methoxyethyl)-N
-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-acetyloxyethyl)-N-(3- hydroxycyclohexyl)
aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-benzoyloxyethyl)-N-(3-hydroxycyclohexyl)
Aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(3,4-dihydroxycyclohexyl)
Aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{3-[N-(2-hydroxyethyl)-
N-(3,4,5-trihydroxycyclohexyl)aminocarbonyl]propoxy}-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(4-hydroxycyclooctyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenant Γ6-[3-(4-cyclooctyl-1-piperazinylcarbonyl)propoxy ]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-[4-(4-phenyl-1-piperazinylcarbonyl)butoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate position dehydrogenation product Γ6-[4-(4-cyclohexyl-1-piperazinylcarbonyl)butoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ6-[4-(4-β- Phenethyl-1-piperazinylcarbonyl)butoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ5-[4-(4-phenyl-1-piperazinylcarbonyl)butoxy]-3, 4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ6- [4-(4-phenyl-1-piperidylcarbonyl)butoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ5-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]- 3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-[3-(4-cyclohexyl-1-piperidylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogen Γ6-[3-(4-benzyl-1-piperidylcarbonyl)propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation Γ6-[3-(4-β-phenethyl-1-piperidylcarbonyl) ) propoxy]-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-methyl-6-{3-(N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3, 4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-methyl-6-{3-[N-(2-hydroxyethyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenator Γ4-methyl-6-{4-[N-(2-hydroxyethyl)-N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenator Γ4-methyl-6-{3-[N-(2-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-Methyl-5-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-methyl-6- {4-[N-(3-hydroxypropyl)-N-phenylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-methyl-6-[3-(4 -Phenyl-1-
piperazinylcarbonyl)propoxy]-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-methyl-6-{3-[N-(2-methoxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or Its 3,4-position dehydrogenator Γ4-methyl-6-{4-[N-(2-acetyloxyethyl)-N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position Dehydrogenated product Γ4-methyl-6-{3-(N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ4- Methyl-6-{3-[N-(2-hydroxyethyl)-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,
4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ4-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-hydroxyethyl)-
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{3-[N-(2-hydroxyethyl) ―
N-(2-tetrahydropyranylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenated Γ4-{3-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-methoxyethyl)-N
-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{3-[N-(2-methoxyethyl)-N
-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-methoxyethyl)-N
-(3-hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ4-{3-[N-(2-acetyloxyethyl)-N-cyclohexyl)amino carbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenated product Γ4-{4-[N-(2-acetyloxyethyl)-N-(3-hydroxycyclohexyl)
aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{3-[N-(2-acetyloxyethyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl ]Propoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ4-{4-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-dehydrogenated product Γ4-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-6-{3-[N-(2-hydroxyethyl)- N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenation product Γ1-methyl-6-{4-[N-(2-methoxyethyl)-N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenation product Γ1 -Methyl-6-{4-[N-(2-hydroxyethyl)-N-(3-hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4
-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-benzyl-6-{4-[N-(2-acetyloxyethyl)-N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or Its 3,4-position dehydrogenator Γ1-allyl-6-{3-[N-(2-hydroxyethyl)-N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]propoxy}-
3,4-dihydrocarbostyryl or 3,
4-position dehydrogenator Γ1-methyl-6-{3-[N-(2-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-methyl-6-{4-[N-(2-hydroxyethyl)-N-phenylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ1-benzyl-6-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3, 4-dihydrocarbostyryl or its 3,4-position dehydrogenate Γ6-{4-[N-(2-hydroxyethyl)-
N-(4-Hydroxycyclohexyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl or its 3,4-position dehydrogenate The compound of the present invention can be produced by various methods, but a preferred example thereof is as follows: For example, it is produced by the method shown in the following reaction scheme-1. [In the formula, R ² ' represents a hydrogen atom or a lower alkyl group.
R ¹ , R ³ , R ⁴ , A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] The method shown in Reaction Scheme-1 is a method in which a carboxyalkoxycarbostyryl derivative represented by general formula (2) and an amine represented by general formula (3) are reacted in a conventional amide bond-forming reaction. In the present invention, a compound whose carboxyl group is activated may be used instead of the compound of general formula (2). As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. for example
(a) Mixed acid anhydride method, which is a method in which carboxylic acid 2 is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with amine 3; (b) Active ester method, which is a method in which carboxylic acid 2 is reacted with p-nitrocarboxylic acid 2. Phenyl ester, N-hydroxysuccinimide ester, 1
- A method in which an activated ester such as hydroxybenzotriazole ester is reacted with amine 3; (3) Carbodiimide method, that is, condensation of amine 3 with carboxylic acid 2 in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole. Method (d) Other methods include carboxylic acid 2
A method of converting carboxylic acid anhydride into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride and reacting it with amine 3, a method of reacting amine 3 with an ester of carboxylic acid 2 and a lower alcohol under high pressure and high temperature, and an acid halide of carboxylic acid 2 That is, a method of reacting carboxylic acid halide with amine 3, etc. can be mentioned. Among these, the mixed acid anhydride method is preferred. The alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate,
Examples include ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound of the present invention is produced by reacting it with the amine 3 without isolation. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]nonene-5( DBN), 1,5-diazabicyclo[5,
4,0] undecene-5 (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO)
organic bases such as potassium carbonate, sodium carbonate,
Examples include inorganic bases such as potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is carried out at -20 to 100°C, preferably 0 to 50°C, and the reaction time is from 5 minutes to
It is carried out for 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine 3 is -20 to 150
The reaction time is preferably 5 minutes to 10 hours, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, and specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The ratio of carboxylic acid 2, alkylhalocarboxylic acid, and amine 3 used in this method is usually equimolar amounts;
The alkylhalocarboxylic acid and the amine 3 may be used in an amount of 1 to 1.5 times the mole of the carboxylic acid 2. Thus, in the compound of the present invention represented by general formula (1), R is a group.

A compound represented by the formula (compound of general formula (1a)) can be obtained. Among the compounds of the present invention represented by general formula (1), R ²
is the basis

[Formula] Compounds also have the general formula [In the formula, R ¹ , A, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. It can be produced similarly according to the above reaction scheme-1 using the compound represented by ] as a raw material. Carboxylic acids 2 and 2' are known compounds,
Also, amine 3 is a known compound or a new compound. Amine 3 is produced, for example, by the method shown in Reaction Scheme 2 or 3 below. [In each of the above reaction schemes, R ³ and R ⁴ are the same as above. X represents a halogen atom. ] According to reaction scheme-2, the amine represented by the general formula (3) is obtained by combining the known amine represented by the general formula (4) and the known halogen compound represented by the general formula (5) into a basic compound. It is easily produced by reacting in the presence of Also, according to the reaction equation-3, the general formula
The amine represented by (3) can be easily produced by reacting a known amine represented by general formula (6) with a known halogen compound represented by general formula (7) in the presence of a basic compound. This reaction is carried out using a basic compound as a deoxidizing agent. A wide range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, sodium methylate, sodium ethyl Examples include alcoholates such as alcoholates, triethylamine, pyridine, and organic bases such as N,N-dimethylaniline. The reaction is carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol; Ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, N,N-dimethyl Examples include aprotic polar solvents such as formamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide. The reaction is also advantageously carried out in the presence of a metal iodide such as sodium iodide and potassium iodide. The ratio of compound (5) or compound (7) to compound (4) or compound (6) in the above method is not particularly limited and is appropriately selected from a wide range. In cases where the latter is usually used in large excess relative to the former, in cases where the process is carried out in a solvent, the latter is usually used in equimolar to 5 to 5 molar amounts relative to the former.
It is desirable to use twice the molar amount, preferably equimolar to twice the molar amount. The reaction temperature is also not particularly limited, but is usually room temperature to 200°C, preferably
It is carried out at 50-160°C. Reaction time is usually 1-30
time, preferably 5 to 15 hours. The compound of the present invention can also be produced by the method shown in Reaction Scheme-4 below. [In the formula, X' represents a halogen atom, alkanesulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy group. R ¹ , R ² ′, R ³ ,
R ⁴ , A, and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] That is, when a hydroxycarbostyryl derivative represented by general formula (8) is reacted with a haloalkanamide derivative represented by general formula (9) in the presence of a basic compound, a compound represented by general formula (1a) is obtained. The reaction conditions of reaction scheme 2 or 3 above can be applied to this reaction. Specific examples of the alkanesulfonyloxy group represented by Examples include sulfonyloxy and hexanesulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4
-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α- or β-naphthylsulfonyloxy groups, etc. Examples include substituted or unsubstituted arylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, and 4-phenylethylsulfonyloxy.
Phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-
Alternatively, a substituted or unsubstituted aralkylsulsunyloxy group such as a β-naphthylmethylsulfonyloxy group can be exemplified. Among the compounds of the present invention represented by general formula (1), R ²
is the basis

[Formula] Compounds also have the general formula [In the formula, R ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. It can be produced similarly according to the above reaction scheme-4 using the compound represented by ] as a raw material. The compound of general formula (8) or (8)' which is the starting material is a known compound, and the compound of general formula (9) which is the other raw material
The compounds include known or novel compounds.
The compound of general formula (9) can be easily produced, for example, by the method shown in Reaction Scheme-5. [In the formula, R ³ , R ⁴ , A and X' are the same as above. ] That is, the compound of general formula (9) can be obtained by reacting the compound of general formula (10) with the compound of general formula (3) according to a usual amide bond forming reaction. The conditions for the amide bond-forming reaction in the above-mentioned reaction scheme-1 can be applied to the amide bond-forming reaction. The compound of the present invention can also be produced by the method shown in Reaction Scheme-6 below. [In the formula, B represents an unsaturated lower alkylene group.
R ¹ , R ² ', R ³ , R ⁴ , A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] That is, the compound of the present invention of general formula (1a) has general formula (11)
It is produced by ring-forming a carbostyryl derivative represented by For the reduction of the compound of general formula (11), a wide range of conditions can be adopted that normally reduce an unsaturated alkane compound to a saturated alkane compound. Among these methods, it is especially advantageous to employ a method using catalytic reduction. Catalytic reduction is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method. Catalysts that can be used include platinum catalysts such as platinum black, platinum oxide, and colloidal platinum; palladium catalysts such as palladium black, palladium carbon, and colloidal palladium;
Conventional catalysts for nuclear hydrogenation reactions are used, such as rhodium catalysts such as rhodium with asbestos and rhodium alumina, ruthenium catalysts, nickel catalysts such as Raney nickel and nickel oxide, and cobalt catalysts. Solvents used include lower alcohols (methanol, ethanol, isopropanol, etc.), water, acetic acid,
Examples include acetic acid ester, ethylene glycol, ethers (tetrahydrofuran, dioxane, etc.), and cycloalkanes (cyclohexane, cyclopentane, etc.). The reaction is carried out in a hydrogen stream under normal pressure or increased pressure, preferably under normal pressure. The reaction is usually carried out at room temperature to about 100°C, preferably room temperature to 50°C, and is generally completed in about 1 to 10 hours. Furthermore, under the conditions of the above reduction reaction,
The lower alkenyl group represented by R ¹ , some of the groups represented by R ³ and R ⁴ , and the double bonds at the 3- and 4-positions of the carbostyryl skeleton may be reduced at the same time. Among the compounds of the present invention represented by general formula (1), R ²
is the basis

[Formula] Compounds also have the general formula [In the formula, R ¹ , R ³ , R ⁴ , B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ]
It can be produced similarly according to the above reaction scheme-6 using the compound represented by as a raw material. The compound of general formula (11), which is the raw material compound in the above reaction, is a new compound, and the compound is produced, for example, by the method shown in the following reaction scheme-7. Reaction equation-7 [In the formula, R ¹ , R ² ', R ³ , R ⁴ , B, X' and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (8) and the compound of general formula (12) is carried out in the same manner as the reaction in the reaction scheme-4 above, and the reaction between the compound of general formula (13) and the compound of general formula (3) is performed. The reactions can be carried out in the same manner as in the reaction scheme-1 above. Here, the compound of the general formula (12) is a compound represented by the general formula It is easily produced according to the reaction in Reaction Scheme-5 above. In addition, the compound of general formula (11)′ is the compound of general formula (8)′ or the compound of general formula [In the formula, R ¹ , B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. It is produced by the same reaction as above using the compound represented by ] as a starting material. In the compound of the present invention represented by general formula (1), R is a group

Compounds having the formula and R ³ representing a lower alkanoyloxy lower alkyl group or a benzoyloxy lower alkyl group (general formula (1c)
compound) is prepared by the method shown in the following reaction scheme-8, where R is a group.

It is produced from a compound (compound of general formula (1b)) having the formula and R ³ representing a lower alkyl group having a hydroxyl group as a substituent. [In the formula, R ⁵ is a lower alkyl group having a hydroxyl group as a substituent, R ⁶ is a lower alkanoyloxy lower alkyl group or benzoyloxy lower alkyl group, R ⁷ is a lower alkyl group or a phenyl group, and X is a halogen atom, respectively. show. R ¹ , R ² ′, R ⁴ ,
A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] General ester production reactions can be widely applied to the reaction of synthesizing the compound of general formula (1c) from the compound of general formula (1b). For example, the compound of general formula (15), (16) A compound of general formula (1c) is produced by reacting the compound of formula (1c). When using a compound of general formula (16) or (17), Schotten-Baumann reaction conditions can be applied.
This reaction is carried out without a solvent or in a solvent. As the solvent used, any solvent commonly used in the Schotten-Baumann reaction can be used, such as halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and tetrahydrofuran, acetic acid, fatty acids such as propionic acid,
Examples include aromatic hydrocarbons such as benzene and toluene, aprotic polar solvents such as dimethylformamide, hexamethylphosphoric acid triamide, and acetonitrile. In addition, in this reaction,
Inorganic bases such as sodium acetate, potassium carbonate, sodium hydrogen carbonate, organic bases such as triethylamine, pyridine, N-methylmorpholine, 4-dimethylaminopyridine, DBU, protonic acids such as p-toluenesulfonic acid, sulfuric acid, aluminum chloride, Lewis acids such as boron trifluoride and zinc chloride may be present in the reaction system. The amount of the compound of general formula (16) or (17) to be used is not particularly limited, but it is usually an equimolar to 5 times the molar amount, preferably an equimolar to 2 times the molar amount of the compound of the general formula (1b). Good to use. The reaction temperature in this reaction may be appropriately selected and is not particularly limited, but is usually about -10 to 100°C.
It is preferable to carry out the heating at a temperature of about 0 to 50°C. Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in about 10 minutes to 10 hours. When using the compound of general formula (15), conditions for the usual dehydration reaction between a hydroxy compound and a carboxylic acid can be applied. This reaction is usually carried out in the presence of a catalyst. As the catalyst used in this case, a wide variety of catalysts that are used in ordinary esterification reactions can be used. Typical examples include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, and p-tosylic acid. , organic acids such as benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as catalysts in the present invention. The amount of the catalyst to be used is not particularly limited and may be used in a normal amount. The reaction proceeds either without a solvent or in a solvent. As the solvent used at this time, solvents used in ordinary esterification reactions can be effectively used, and specifically, benzene,
Examples include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. There is no particular limitation on the amount of the compound of general formula (15) used, but usually general formula (1b)
It is preferable to use an equimolar to 5-fold molar amount of the compound. The reaction temperature in this reaction may be appropriately selected and is not particularly limited, but is usually about -20 to 200°C.
It is best to carry out the temperature within a range of about 0 to 150 degrees Celsius.
It is preferable to do this in moderation. Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in about 10 minutes to 20 hours. In this reaction, anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate,
It is also possible to further increase the production rate by removing produced water from the reaction system using a desiccant such as phosphorus pentoxide. Among the compounds of the present invention represented by general formula (1), R ²
is the basis

Compounds represented by the general formula and R ³ represents a lower alkanoyloxy lower alkyl group or a benzoyloxy lower alkyl group also have the general formula Using the compound represented by [in the formula, R ¹ , R ⁴ , R ⁵ , A, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above] as a raw material, the reaction scheme 8 was similarly carried out. Can be manufactured. Among the compounds of the general formula (1) of the present invention, the compound in which the carbon-carbon bond at the 3- and 4-positions of carbostyril is a double bond is a lactam-lactim type tautomer as shown in the following reaction scheme-9. Gender [(1d) and (1e)]
can be taken. Reaction equation-9 [In the formula, R and R ² are the same as above. ] Furthermore, as shown in Reaction Scheme-10, the compound of the present invention is a compound (1f) in which the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are a single bond, and a compound (1g) in which the carbon bonds at the 3- and 4-positions are reduced. They can be mutually converted by reaction and dehydrogenation. Reaction equation-10 [In the formula, R, R ¹ and R ² are the same as above] Among the compounds represented by the general formula (1), a compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Specific examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide, and alkali metal alcoholates such as sodium methylate and potassium ethylate. Further, among the compounds represented by the general formula (1), those having a basic group can form a salt with a pharmacologically acceptable acid. Specifically, such acids include sulfuric acid,
Examples include inorganic acids such as nitric acid, hydrochloric acid, and hydrobromic acid. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation methods, extraction methods, recrystallization methods, column chromatography, preparative thin layer chromatography, and the like. The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers.
The dosage unit form is not particularly limited and can be appropriately selected and used as required. Examples of such dosage unit forms include tablets, granules, oral preparations such as oral solutions, and parenteral preparations such as injections. The amount of the active ingredient to be administered is not particularly limited and can be appropriately selected from a wide range, but in order to achieve the desired effect, it is preferably 0.06 to 10 mg per kg of body weight per day. Also, the active ingredient may be contained in the dosage unit form from 1 to 1.
It is recommended to contain 500 mg. In the present invention, oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. Syrups or elixirs contain the compound of the present invention, sweeteners such as sucrose, methyl
and preservatives and colorants such as propylparabens,
Manufactured by mixing with seasonings, etc. Moreover, parenteral preparations are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline.
Solutions having the desired clarity, stability and suitability for parenteral use are prepared by dissolving about 1 to 500 mg of the active ingredient in water and organic solvents and in polyethylene glycol having a molecular weight of 200 to 5000. .
Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol. Furthermore, the above solution contains bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, and if necessary, sucrose,
Isotonic agents such as sodium chloride, local anesthetics, stabilizers, buffers, and the like may also be included. To further increase stability, parenterally administered drugs may be frozen after filling and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use. Preparation of capsules 10 mg each of 6-{4-[N-(2-hydroxyethyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4
-1000 two-piece hard gelatin capsules for oral use containing dihydrocarbostyril are prepared according to the following formulation. Blend amount (g) 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl 10 Lactose (Japanese Pharmacopoeia) 80 Starch (Japanese Pharmacopoeia) 30 Talc (Japanese Pharmacopoeia) 5 Magnesium stearate (Japanese Pharmacopoeia product)
1. The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions. Preparation of capsules 10 mg each of 6-[3-(4-phenyl-1)
- Piperazinylcarbonyl)propoxy] 1000 pieces 2 for oral use containing carbostyril
Single-piece hard gelatin capsules are prepared according to the following recipe. Blend amount (g) 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyryl 10 Lactose (Japanese Pharmacopoeia product) 80 Starch (Japanese Pharmacopoeia product) 30 Talcstone (Japanese Pharmacopoeia product) 5 Magnesium stearate (Japanese Pharmacopoeia product)
1. The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions. Preparation of capsules 10 mg each of 6-{3-[N-methyl-N-
1000 two-piece hard gelatin capsules for oral use containing (3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl are prepared according to the following formulation. Blend amount (g) 6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl 10 Lactose (Japanese Pharmacopoeia product) 80 Starch (Japanese Pharmacopoeia product) 30 Talcum (Japanese Pharmacopoeia product) 5 Magnesium stearate (Japanese Pharmacopoeia product)
1. The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions. Preparation of capsules 10 mg each of 6-{3-[N-ethyl-N-
(2-pyridyl)aminocarbonyl]propoxy}
1000 for oral use containing carbostyril
Two-piece hard gelatin capsules are prepared according to the following recipe. Blend amount (g) 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl 10 Lactose (Japanese Pharmacopoeia product) 80 Starch (Japanese Pharmacopoeia product) 30 Stone (Japanese Pharmacopoeia) 5 Magnesium stearate (Japanese Pharmacopoeia)
1. The above ingredients are finely powdered, thoroughly stirred to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions. The results of pharmacological tests on the compounds of the present invention are listed below. <Pharmacological test 1> The platelet aggregation inhibitory effect was measured using an AC-type aggregometer (Bryston Manufacturing Company).
Manufactured by Manufacturing Co.). The blood sample collected from the rabbit is a mixture of sodium citrate and whole blood, with a mixing ratio of 1:9 (volume ratio).
It is. The sample was centrifuged at 1000 rpm for 10 minutes to obtain platelet rich serum.
plasma (PRP)]. The resulting PRP was separated and the remaining blood sample was further centrifuged at 3000 rpm for 15 minutes to obtain platelet-poor serum.
poor plasma (PPP)]. The number of platelets contained in the PRP was determined using the Brecher-Clonkite method.
PRP containing 300,000/ ^mm2 platelets was measured using PPP method, diluted with PPP, and subjected to adenosine diphosphate (ADP)-induced aggregation test.
Prepare samples and prepare PRP samples containing 450,000 platelets/mm ² for collagen-induced aggregation testing. Add 0.6 ml of the PRP sample prepared above to 0.01 ml of a solution containing the compound to be tested at a predetermined concentration, and place the mixture in a constant temperature bath at 37° C. for 1 minute. Then add 0.07 ml of ADP or collagen solution to the mixture. Measure the permeability of this mixture,
The change in permeability is measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. In this test ADP
Or use Oren Veronal buffer (PH7.35) to prepare a solution of collagen. the above
The ADP solution was prepared to have a concentration of 7.5×10 ^-5 M.
A collagen solution is prepared by adding 5 ml of the above buffer solution to 100 mg of collagen, grinding the mixture, and using the supernatant as a collagen inducer. Acetylsalicylic acid is used as a control substance. The platelet aggregation inhibitory effect is measured as inhibition rate (%) with respect to the control aggregation rate. The aggregation rate is calculated according to the formula below. Aggregation rate = c-a/b-a x 100 where a: Permeability of PRP b: Permeability of PRP containing test compound and aggregation inducing agent c: Permeability of PPP For collagen-induced rabbit platelet aggregation The inhibitory effect is shown in Table 1, and the inhibitory effect on rabbit platelet aggregation induced by ADP is shown in Table 2. The test compounds are as follows. Test compound No.1 6-{3-[N-ethyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl No.2 6-{3-[N-ethyl-N-(2-pyridyl) ) aminocarbonyl [propoxy]
Carbostyril No. 3 6-{3-[N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy} Carbostyril No. 4 6-{3-[N-methyl-N-(2-thienylmethyl )Aminocarbonyl]propoxy}carbostyryl No.5 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl No.6 6-{4-[N-( 2-Hydroxybutyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl No. 7 6-{4-[N-(4-hydroxybutyl)-N-cyclohexylmethylaminocarbonyl]butoxy} -3,4-dihydrocarbostyryl No. 8 6-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylaminocarbonyl]propoxy} Carbostyryl No. 9 6-{4-[N-(2 -Hydroxyethyl)-N-phenylaminocarbonyl]
butoxy}-3,4-dihydrocarbostyryl No.10 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyryl No.11 6-[3-(4-benzyl-1-pipe Radinylcarbonyl)propoxy]-3,4
-Dihydrocarbostyryl No.12 6-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]Carbostyryl No.13 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]-3 ,4
-Dihydrocarbostyryl No.14 6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]-
3,4-dihydrocarbostyryl No.15 6-{3-[N-(2-hydroxyethyl)-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}carbostyryl No.16 6-{4-[N -(2-Hydroxyethyl)-N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}carbostyryl No.17 6-{4-[N-(3-acetyloxypropyl)-N- (2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl No.18 6-{4-[N-(2-hydroxyethyl)-N-benzylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl No.19 6-{4-[N-(2-methoxyethyl)
-N-cyclohexylaminocarbonyl]butoxy}carbostyryl No.20 Acetylsalicylic acid (aspirin) No.21 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclooctylmethylaminocarbonyl]butoxy}carbo Styryl No.22 6-{3-[N-(2-methoxyethyl)
-N-cyclohexylaminocarbonyl]propoxy}carbostyryl No.23 6-{3-[N-(4-hydroxybutyl)-N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl No.24 6 -{4-[N-(5-propionyloxypentyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,
4-Dihydrocarbostyryl No.25 6-{4-[N-(5-hydroxypentyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl No.26 6-{5-[N -(5-hydroxypentyl)-N-cyclohexylmethylaminocarbonyl]pentyloxy}-3,4
-Dihydrocarbostyryl No.27 6-{4-[N-(3-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl No.28 6-[3-(4- Cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyryl No.29 6-{4-[N-(2-hydroxyethyl)-N-benzylaminocarbonyl]
Butoxy}carbostyryl No.30 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl No.31 6-{3-[N -Methyl-N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}carbostyryl No.32 6-{3-[N-methyl-N-(2-3,
4-dihydro-2H-pyranylmethyl)
Aminocarbonyl]propoxy}carbostyryl No.33 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]
Propoxy} Carbostyril (Unexamined Japanese Patent Publication No. 1983)
No. 34 6-[3-(N-cyclohexyl-N-benzylaminocarbonyl)propoxy ]
Carbostyril (compound of Example 48 described in JP-A-54-115383, JP-A-54-115383)
No. 35 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril (Example described in JP-A-54-5981) Compound No. 2, JP-A-1987-
Compound of Example 2 described in Publication No. 163825)

【table】

[Table] <Pharmacological test 2> Inhibitory effect on cyclic adenosine monophosphate phosphodiesterase (C-AMP-PDE) This test was conducted by Biochimica et Biophysica Acta
Volume 429, pages 485-497 (1976) and
It is carried out according to the activity assay method described in Biochemical Medicine, Vol. 10, pp. 301-311 (1974). That is, first, to the precipitated platelets obtained by centrifuging rabbit PRP at 3000 rpm for 10 minutes, 10 ml of a solution of 1 mmol MgCl ₂ added to 50 mmol Tris-HCl buffer (pH 7.4) was added. Float the platelets, grind them with a Teflon potter type homogenizer, repeat freezing and thawing twice, and then
Apply Watsuto's ultrasonic wave for 300 seconds and destroy it at 100,000G.
Ultracentrifuge for 60 minutes and use the supernatant as a crude enzyme solution. Preliminary 50 mmol-Tris acetate buffer (PH6.0)
Pass 10 ml of the crude enzyme solution prepared above through a 1.5 x 20 cm DEAE-cellulose column buffered with
Wash and elute with 30 ml of 50 mmol Tris acetate buffer, and elute by applying a linear gradient to this buffer with 0 to 1 M sodium acetate-Tris acetate buffer (total eluate volume: about 300 ml). The flow rate is
The flow rate was 0.5 ml/min, and 5 ml of each fraction was collected. By the above operation, 100 μmol of high C-
It has weak activity at AMP substrate concentrations below 2 nmol/ml/min and at low C-AMP substrate concentrations of 0.4 μmol.
Collect fractions with strong activity greater than 100 pmol/ml/min. Let this be C-AMP-PDE. 0.1 ml of test compound aqueous solution of each concentration was determined in advance.
A total of 0.2 ml of a mixture containing 0.4 μmol of C-AMP (tritium C-AMP) at pH 8.0 and 40 mmol Tris-HCl buffer (containing 50 μg of bovine serum albumin and 4 mmol of MgCl ₂ ) was added to the substrate solution. and add the C-AMP-PDE solution of a certain concentration prepared above to this.
Add 0.2 ml and react at 30°C for 20 minutes to generate tritium 5'-AMP from tritium C-AMP. Next, after immersing in boiling water for 2 minutes to stop the reaction, the reaction solution was cooled in ice water, 0.05 ml of snake venom (1 mg/ml) was added as 5'-nucleotidase, and the reaction was allowed to proceed for 10 minutes at 30°C. Converts 5′-AMP to tritium adenosine. The entire amount of the reaction solution obtained was transferred to a cation exchange resin [AG.50W×4,
200 to 400 mesh (Bio-Rad product), column size 0.5 x 1.5 cm] to bind only tritiated adenosine, washed with 6 ml of distilled water, and eluted with 1.5 ml of 3N-ammonia water. PDE activity is measured by adding 10 ml of a triton-toluene type scintillator to the entire volume of this eluate and measuring the tritiated adenosine produced using a liquid scintillation counter. PDE of each test compound measured according to the above method
The PDE inhibition rate (%) is calculated from the activity value (V _s ) and the control value (V _c ) (water not containing the test compound) using the following formula. PDE inhibition rate (%)=V _c −V _s /V _c ×100 The concentration of the test compound inhibiting 50% (IC ₅₀ value) was determined, and the results are shown in Table 3 below. Table 3 also shows the results of a similar test using the known 1-methyl-3-isobutylxanthene as a control compound.

[Table] <Pharmacological test 3> Method by Hashimoto et al. [M. Endoh & K. Hashimoto,
Am.J.Physiol, 218, 1459-1463 (1970)]
The positive muscle inotropic effects of the compounds of the present invention are investigated according to the following methods.
First, an adult male and female mixed breed dog weighing 8 to 12 kg is anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. heparin sodium salt
After intravenous administration at a rate of 1000u/Kg, the patient was killed by exsanguination.
The heart is removed into lock solution and the papillary artery muscle is excised along with the intercardial septum. The septal artery is dissected, a polyethylene cannula is inserted, and it is ligated with thread. The septal artery attached to other than the papillary muscle is ligated with thread. The body weight was then anesthetized with pentobarbital sodium salt (30 mg/Kg, intravenous administration) and treated with heparin (1000 u/Kg, intravenous administration).
Blood from the carotid artery of a ~27 kg adult mongrel dog is directed via a peristaltic pump to a polyethylene cannula inserted into the septal artery to perfuse the papillary muscles.
The perfusion pressure is a constant pressure of 100 mmHg. Papillary muscle movement was performed under a resting tension of 2 g, using an electron tube stimulator, using a bipolar electrode sewn into the intercardiac septum at 2× (minimum value for effect) 2 _Hz , duration of 2 ms. is electrically stimulated, and the generated tension is measured via a force displacement transducer. Coronary artery blood flow is measured by measuring the blood flow led to the septal artery via an electromagnetic flowmeter. Record all data on an ink recorder. The test compound is injected into the artery in a volume of 10-30μ through a rubber tube connected closely to a polyethylene cannula inserted into the septal artery. The results obtained are shown in Table 4 below. The % increase in contractile force in Table 4 is expressed as a % change in the tension generated before administration of the test compound.

[Table] <Pharmacological test 4> Cerebral blood flow increasing effect Cerebral blood flow increasing effect of the compound of the present invention was investigated in the Journal of Surgical Research (J.ofS.
Surgical Research), Volume 8, No. 10, 475~
It was measured according to the method described on page 481 (1968). That is, using a mixed dog (male, weight 12-20 kg),
The animal was fixed in a prone position under bentobarbital sodium anesthesia, and forced respiration was performed at 20 ml/Kg and 20 times/min. The skull is exposed and removed with a grinder to expose the superior sagittal sinus, and venous blood is guided externally by cannulation. The amount of blood flowing out was measured using electromagnetic statistics, and then the number of drops per 10 seconds was measured using a drop counter. The rate of increase was calculated by comparing the number of drops in 30 seconds at the peak of increase before and after drug administration. Drugs were dissolved in dimethylformamide, diluted with saline, and administered via a cannula inserted into the femoral vein. Papaverine was also used as a control drug. The results obtained are shown in Table 5.

[Table] <Pharmacological Test 5> Hypotensive Effect The antihypertensive effect of the compounds of the present invention was examined by non-invasively measuring systolic blood pressure under anesthesia by the Tail Cuff method. The experiment was conducted using the following two types of rats. (1) Gold blatt direnal hypertensive rats (RHR): Male Wistar rats weighing 160 to 180 g were placed under ether anesthesia with a silver clip with an internal diameter of 0.2 mm attached to the left renal artery, and the right kidney was is left intact. Four weeks after surgery, subjects with systolic blood pressure of 150 mmHg or higher were fasted overnight and subjected to experiments. (2) Deoxycorticosterone acetate (DOCA)/salt hypertensive rats (DHR); body weight
The left kidney of a male Wistar rat weighing 150 to 170 g was removed under ether anesthesia, and DOCA 10 mg/Kg was subcutaneously administered once a week from the first week after surgery, and 1% saline was given as drinking water. Five weeks after surgery, subjects with systolic blood pressure of 150 mmHg or higher were fasted overnight and subjected to experiments. Drugs were administered orally, and blood pressure was measured before drug administration and at 1, 2, 4, 6, and 8 hours after drug administration.
Blood pressure measurement is performed using a recorder (Reclihoriz type 8S,
San-ei instrument) and electrorosthygmomanometer
PE-300 (Narco bio-Systems, houston) was used. The results obtained are shown in Table 6.

[Table] <Pharmacological test 6> Measurement of heart rate The electrocardiogram obtained from lead 2 of male Wistar rats (weight 180-230 g) that has been fasted for 24 hours is recorded on an oscilloscope. After the heart rate stabilizes,
Take a 10-second record from any location (several locations) on the electrocardiogram, find the average heart rate per 10 seconds, and calculate the heart rate per minute. Next, 5 ml/Kg (30 mg/Kg of the test compound) of a suspension of the test compound to which gum arabic has been added is administered into the stomach of the rat using an oral probe. 60 minutes after administration,
Calculate the heart rate per minute in the same way as above,
Find the increase in heart rate per minute. The results are shown in Table 7 below. The heart rate of a normal male Wistar rat is approximately 320 per minute.

[Table] <Pharmacological test 7> Acute toxicity test Each test compound is orally administered to male mice to determine its acute toxicity (LD ₅₀ mg/Kg). The results are shown in Table 8.

[Table] <Pharmacological Test 8> In the above pharmacological test 1, human blood was used instead of rabbit blood, and the same test was conducted to determine the IC50 value. The results are shown in Table 9.

【table】

[Table] <Pharmacological test 9> Mongrel dogs of both sexes weighing 10 to 18 kg were anesthetized by intravenous administration of pentobarbital sodium 30 mg/Kg.
Fixed in dorsal position. Forced breathing was performed under conditions of 20 ml/Kg and 18 times/min. Blood pressure was measured via a pressure transducer (Sanei Scientific, MPU-05) through a cannula introduced into the left common carotid artery, and heart rate was measured by driving a tachometer (Data Graph T-149) based on the brain waves. Medication was administered through a cannula introduced into the right femoral vein, and pentobarbital sodium was administered at 4 mg/dose to maintain anesthesia during the test.
Heparin sodium was infused intravenously into the saphenous vein at a rate of 100 units/Kg/hr to prevent blood coagulation. The test compound was dissolved in dimethylformamide, and the concentration was adjusted so that the amount of solvent administered was 0.5 ml or less, except for 1 mg/Kg. Papaverine hydrochloride (Dainippon Pharmaceutical) was used after being diluted with 0.9% physiological saline. In addition, as a follow-up, 3ml
0.9% saline was administered. The results are shown in Table 10 below. The values in the table are the number of heart rate increases per minute.

[Table] <Pharmacological test 10> Male Wistar rats (weight 200-280 g)
They were fasted for 18 to 24 hours and used in the test. The heart rate was determined by writing the electrocardiogram in ink on a recording paper and counting the electrocardiogram 3 to 6 times at 10 second intervals.
After the heart rate became constant at no more than 20 beats per minute, the test compound suspended in gum arabic was orally administered at a dose of 30 mg/Kg. The heart rate after minutes was measured and the effect of the maximum response of the test compound was examined. The results are shown below.
Shown in Table 11.

[Table] Production examples of raw material compounds for synthesizing the compounds of the present invention are listed below as reference examples, and production examples of the compounds of the present invention are listed below as examples. Reference Example 1 Add 41 g of ethylene chlorohydrin to 100 g of cyclohexylamine and stir at about 160°C for 10 hours. After cooling, add 100 ml of 10N-NaOH water to the reaction solution to separate the layers, and dry the organic layer with KOH. The KOH is removed and the mother liquor is distilled under reduced pressure. 48 g of N-(2-hydroxyethyl)cyclohexylamine are obtained as a colorless oil. mp132-135°C (18 mmHg) Compounds of Reference Examples 2-19 are obtained in the same manner as in Reference Example 1. Reference example 2 N-(3-hydroxypropyl)-N-cyclohexylamine Colorless plate-like crystals mp68.5-69.5℃ Reference example 3 N-(4-hydroxybutyl)-N-cyclohexylamine Colorless crystals bp158-163℃/ 18mmHg Reference example 4 N-(2-hydroxypropyl)-N-cyclohexylamine Colorless crystal bp117-119℃/17mmHg Reference example 5 N-(2-hydroxyethyl)-N-cyclooctylamine Colorless liquid bp98-103℃/0.1 mmHg Reference example 6 N-(2-hydroxyethyl)-N-cyclohexylmethylamine Colorless crystal bp131-133℃/12mmHg Reference example 7 N-(3-hydroxypropyl)-N-cyclohexylmethylamine Colorless liquid bp135-142℃/ 10mmHg Reference example 8 N-(4-hydroxybutyl)-N-cyclohexylmethylamine Colorless liquid bp158-160℃/12mmHg Reference example 9 N-(2-hydroxypropyl)-N-cyclohexylmethylamine Colorless liquid bp138-145℃/ 10mmHg Reference example 10 N-(1-methyl-2-hydroxypropyl)
-N-Cyclohexylmethylamine Colorless crystal bp120-126℃/10mmHg Reference example 11 N-(5-hydroxypentyl)-N-cyclohexylmethylamine Colorless liquid bp139-142℃/2mmHg Reference example 12 N-Ethyl-N-(2 -Tetrahydropyranylmethyl)amine Colorless liquid bp69~71℃/10mmHg Reference example 13 N-propyl-N-(2-tetrahydropyranylmethyl)amine Colorless liquid bp78~80℃/9mmHg Reference example 14 N-Butyl-N- (2-Tetrahydropyranylmethyl)amine Colorless liquid bp96-98℃/10mmHg Reference example 15 N-(2-hydroxyethyl)-N-(2-tetrahydropyranylmethyl)amine Colorless crystal bp136-138℃/11mmHg Reference example 16 N-(3-hydroxypropyl)-N-(2-
Tetrahydropyranylmethyl)amine Colorless liquid bp150-155℃/11mmHg Reference example 17 3-[N-(2-hydroxyethyl)aminomethyl]-pyridine Pale yellow liquid bp134-142℃/0.2mmHg Reference example 18 N-(2 ,3-dihydroxypropyl)-N-
Cyclohexylamine Colorless liquid bp114~118℃/0.4mmHg Reference example 19 N-(2-hydroxybutyl)-N-cyclohexylamine Colorless crystal bp122~125℃/12mmHg Reference example 20 Add 19g of γ-bromocrotonyl chloride to 100ml of diethyl ether Add N under stirring at 0 to 10°C.
- Add 25 g of (2-hydroxyethyl)cyclohexylamine dropwise. After the dropwise addition, the solution was stirred at the same temperature for 3 hours, and the ether solution was washed with 2N hydrochloric acid, diluted NaHCO ₃ water saturated with NaCl, and water in this order. organic layer
After drying with Na ₂ SO ₄ , the solvent is distilled off. 17.5 g of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide is obtained as a colorless oil. The structure is confirmed by NMR spectrum and elemental analysis values. Reference example 21 200ml of N,N-dimethylformamide and 50ml of water
6-hydroxycarbostyril 16g per ml,
17 g of K ₂ CO ₃ was added, and 31 g of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide was added dropwise while stirring at room temperature. After dropping, stir for 3 hours and concentrate. Add 500 ml of chloroform to the residue, wash with water, dilute NaOH water, and water, and concentrate.
The residue was recrystallized from MeOH-water to give colorless needle crystals of 6-{3-[N-(2-hydroxyethyl)-N
27 g of cyclohexylaminocarbonyl]-2-propenyloxy}carbostyryl was obtained. The structure is confirmed by NMR spectrum and elemental analysis values. Reference example 22 6-(3-carboxypropoxy)-3,4-dihydrocarbostyryl in 100ml of chloroform
2.5g and 1,8-diazabicyclo[5,4,0]
Add 1.65 g of Undecene-7 and dropwise add 1.5 ml of isobutyl chloroformate while stirring while externally cooling with ice. After the dropwise addition, the mixture was stirred for 30 minutes, and 2.0 g of N-(2-hydroxyethyl)cyclohexylamine was added thereto, followed by stirring at room temperature for 2 hours. After the reaction, dilute the chloroform solution.
Wash with _NaHCO3 water, dilute hydrochloric acid water, and dry _{with Na2SO4} . The chloroform was distilled off and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-
{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-
2.1 g of 3,4-dihydrocarbostyryl is obtained. Melting point: 139-141.5°C Compounds of Examples 1-4 were obtained in the same manner as in Reference Example 22 using appropriate raw materials. Example 1 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 2 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5-113.5℃ Example 3 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
butoxy}carbostyryl Colorless needle crystals mp138-140℃ Example 4 7-{3-[N-(3-hydroxypropyl)
-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp140-142℃ Example 5 Add 9.9 g of 6-(3-carboxypropoxy) carbostyril and 6.5 ml of DBU to 300 ml of chloroform. Isobutyl chloroformate under external ice-cooled stirring
Drop 5.7ml. After dropping, stir at room temperature for 1 hour.
Add 5.4 g of ethylaminopyridine dropwise. Stir for 5 hours after addition. Dilute the reaction solution with dilute NaHCO ₃ water, H ₂ O
Wash and concentrate. The residue was subjected to silica gel column chromatography (solvent: chloroform).
MeOH=20:1). The eluate is concentrated and then recrystallized from methanol. Colorless needle crystal 6-{3
4.5 g of [N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl is obtained. mp148-149℃ NMR (CDCl ₃ ) δppm: 1.56 (3H, t), 2.13 (2H, q) 2.41 (2H, t), 3.90 (2H, q) 4.01 (2H, t), 6.69 (1H, d) 6.95 (1H, d), 7.20-7.35 (4H, m), 7.60-7.80 (2H, m), 8.45-8.55 (1H, m), 11.40 (1H, s) Same as Example 5 using appropriate raw materials Compounds of Examples 6 to 26 are obtained. Example 6 6-{3-[N-ethyl-N-(3-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ Example 7 6-{3-[N-methyl-N- (3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp169.5-171℃ Example 8 6-{3-[N-ethyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbo Styryl Colorless needle crystals mp145~147℃ Example 9 6-{3-[N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp125.5~127.5℃ Example 10 6-{3-[N-methyl-N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp123-125℃ Example 11 6-{3-[N-methyl-N-( 2-thienylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp133.5-135℃ Example 12 6-{3-[N-methyl-N-(2-3,4-
Dihydro-2H-pyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp133.5-135℃ Example 13 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy }Carbostyryl colorless granular crystals mp150-151.5℃ Example 14 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl colorless ridge-like crystals mp121.5～123.5℃ Example 15 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 16 6-[N-ethyl-N-(3-pyridylmethyl)aminocarbonylmethoxy]-3,4 -Dihydrocarbostyryl Colorless needle crystals mp82-84℃ Example 17 6-{5-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]pentyloxy}carbostyryl Colorless needle crystals mp81-83 °C Example 18 8-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp115.5-117℃ Example 19 6-{4-[ N-Ethyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp87-88.5℃ Example 20 6-{4-[N-propyl-N- (2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp77-79.5℃ Example 21 6-{4-[N-butyl-N-(2-tetrahydropyranyl) Methyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp93.5-95.5℃ Example 22 6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 23 6-{4-[N-(2-hydroxyethyl)-
N-(3-pyridylmethyl)aminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp80-82.5℃ Example 24 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 25 6-{4-[N-(3-hydroxypropyl)
-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp98.5-100℃ Example 26 6-{4-[N-(4-hydroxybutyl) )―
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116°C Example 27 1-benzyl- in 100 ml of dimethylformamide
3.1 g of 6-(4-carboxybutoxy)-3,4-dihydrocarbostyryl and triethylamine
Add 1.7 ml of isobutyl chloroformate and dropwise add 1.4 ml of isobutyl chloroformate under external ice-cooling and stirring. After the dropwise addition, the mixture was stirred for 30 minutes, and 1.75 g of N-ethyl-N-(2-tetrahydropyranylmethyl)amine was added thereto, followed by stirring at room temperature for 3 hours. After the reaction, the solvent was distilled off and the residue was dissolved in chloroform.
Extract with 300 ml and wash with dilute _NaHCO3 water, water, dilute hydrochloric acid, and water. The residue was subjected to silica gel column chromatography [eluent CHCl ₃ :MeOH (20:
1)]. Colorless syrupy 1-benzyl-6-{4
-[N-(2-tetrahydropyranylmethyl)-
N-ethylaminocarbonyl]butoxy}-3,
2.3 g of 4-dihydrocarbostyril is obtained. IR νcm ^-1 (neat) 1620 1690 Elemental analysis value (%) Calculated value C; 75.29 H; 8.28 N; 6.06 Actual value C; 75.36 H; 8.13 N; 5.84 Example 28 6-(4-carboxybutoxy) in 100 ml of chloroform )-3,4-dihydrocarbostyryl 5g
and 3.2 g of DBU were added, and 2.8 g of isobutyl chloroformate was added dropwise under external ice-cooling and stirring, and the mixture was stirred for 30 minutes. Add N-(3-hydroxypropyl)-N-cyclohexylmethylamine to this at room temperature.
Add 3.9g and react for 3 hours. The reaction solution was washed with 1N-NaOH water, 10% HCl, and H ₂ O in this order, and dried with Na ₂ SO ₄ . After removing the desiccant, it is concentrated and the residue is subjected to silica gel column chromatography. Eluate: Chloroform:methanol (40:1) The eluate was concentrated and recrystallized from ethyl acetate-petroleum ether. 4.0 g of 6-{4-[N-cyclohexylmethyl-N-(3-hydroxypropyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl is obtained. Melting point: 95-97°C Colorless needle crystals Compounds of Examples 29-52 are obtained in the same manner as in Example 28 using appropriate raw materials. Example 29 6-[N-(2-hydroxyethyl)-N-phenylaminocarbonylmethoxy)carbostyryl Colorless powder crystals mp162-165℃ Example 30 6-{3-[N-(2-methoxyethyl) -N
-Cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless granular crystals mp142.5-143.5℃ Example 31 6-{3-[N-(2-hydroxy-1-methylpropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}carbo Styryl Colorless needle crystals mp179.5-181.5℃ Example 32 6-{3-[N-(2-hydroxyethyl)-
N-butylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp153~154℃ Example 33 6-{3-[N-di-(2-hydroxyethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp122~ 123.5℃ Example 34 6-{4-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl]butoxy}-
3,4 dihydrocarbostyryl Colorless needle crystals mp113-116℃ Example 35 6-{4-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl Colorless powder crystal mp91.5-93℃ Example 36 6-{4-[N-(2-hydroxyethyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate crystals mp123-125℃ Example 37 6-{4-[N-(4-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp119-120.5℃ Example 38 6-{4-[N-(2-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp123-125℃ Example 39 6-{4-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]butoxy}
- Carbostyril Colorless needle crystals mp107~109℃ Example 40 6-{5-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]pentyloxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp93.5-95.5℃ Example 41 6-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylamino Carbonyl]propoxy}-carbostyryl Colorless needle crystals mp94~97℃ Example 42 6-{4-[N-(5-hydroxypentyl)
-N-cyclohexylmethylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp113.5-115℃ Example 43 6-{3-[N-(4-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp109-111℃ Example 44 6-{4-[N-(5-propionyloxypentyl)-N-cyclohexylmethylaminocarbonyl ]Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp60~62℃ Example 45 6-{4-[N-(2-hydroxyethyl)-
N-(B-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}carbostyryl Colorless needle crystals mp78-81℃ Example 46 6-{4-[N-(3-acetyloxypropyl)-N- (2-tetrahydropyranylmethyl)
Aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp64.5-66.5℃ Example 47 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl] Butoxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp112-114℃ Example 48 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-carbostyryl Colorless powder crystal mp125-128℃ Example 49 6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-carbostyryl Colorless powdery crystals mp220-224℃ Example 50 4-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp176-178℃ Example 51 4-Methyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp171-173℃ Example 52 1-Ethyl-6-{4-[N-(4-hydroxybutyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless syrup IR νcm ^-1 (neat) 1620 1670 Elemental analysis value (%) Calculated value C; 73.26 H; 9.56 N; 6.33 Actual value C; 73.41 H; 9.38 N; 6.10 Example 53 1-allyl-6-(3-carboxypropoxy ) Add 5.9 g of carbostyril and 3.2 g of DBU to 200 ml of chloroform, and dropwise add 2.8 g of isobutyl chloroformate while stirring on ice. After stirring for 1 hour, 3.7 g of N-cyclohexylpiperazine was added dropwise at room temperature, and the mixture was allowed to react for 5 hours. The reaction solution was washed with 1% NaOH water, water, and diluted with Na ₂ SO ₄
Dry with. After removing the desiccant and concentrating the mother liquor, the residue is subjected to silica gel column chromatography. Eluent Chloroform:methanol (30:
1). 4.2 g of 1-allyl-6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyryl is obtained as a colorless oil. IR νcm ^-1 (neat) 1645 1680 Elemental analysis value (%) Calculated value C; 71.04 H; 8.48 N; 9.56 Actual value C; 70.95 H; 8.61 N; 9.72 Example 54 6-(3-carboxypropoxy) carbostyril Add 5g and 3.2g of DBU to 200ml of chloroform and add 2.8g of isobutyl chloroformate while stirring on ice.
Drop g. After stirring for 1 hour, 3.7 g of N-cyclohexylpiperazine was added dropwise at room temperature, and the mixture was allowed to react for 5 hours. The reaction solution was washed with 1% NaOH water, water, and diluted with Na ₂ SO ₄
Dry with. After removing the desiccant and concentrating the mother liquor, the residue was subjected to silica gel column chromatography [eluent: chloroform:methanol (30:
1)]. After concentrating the eluate, the residue is recrystallized from aqueous methanol to obtain 4 g of 6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyryl in the form of colorless needles. mp184.5-186°C Compounds of Examples 55-60 are obtained in the same manner as in Example 54 using appropriate starting materials. Example 55 6-[3-(4-phenyl-1-piperanylcarbonyl)propoxy]carbostyryl Colorless needle crystals mp202.5-203.5℃ Example 56 6-[3-(4-phenyl-1-piperanylcarbonyl)propoxy] Radinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle-like crystals mp182.5-183.5℃ Example 57 6-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]-carbostyryl Colorless needle-like crystals Crystal mp190-191℃ Example 58 6-[3-(4-benzyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless edge-like crystals mp174.5-175.5℃ Example 59 6-[3-(4-) Cyclohexyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle crystals mp133-134℃ Example 60 6-[3-(4-benzyl-1-piperidylcarbonyl)propoxy]-carbostyryl Colorless needle crystals mp145-146℃ Reference example 23 Add 2.5 g of 6-(3-carboxy)propoxycarbostyryl and 1.3 g of N-(2-hydroxyethyl)cyclohexylamine to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride. N,N'-dicyclohexylcarbodiimide under external ice cooling and stirring
A solution of 2.1 g dissolved in 5 ml of methylene chloride is added to
Drop while keeping at 20℃. After dropping, stir at the same temperature for 3.5 hours. The precipitated crystals were removed, and the liquid was concentrated to dryness under reduced pressure. The resulting residue was dissolved in methylene chloride.
Dissolve the organic layer in 100ml of 5% aqueous hydrochloric acid solution, 5%
After washing successively with an aqueous sodium bicarbonate solution and water, and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-{3-[ N-
(2-Hydroxyethyl)-N-cyclohexylaminocarbonyl)propoxy]carbostyril
Obtain 1.1g. Melting point: 165-166°C Compounds of Examples 61-77 are obtained in the same manner as in Reference Example 23. Example 61 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ NMR (CDCl ₃ ) δppm: 1.56 (3H, t), 2.13 (2H, q) 2.41 (2H, t), 3.90 (2H, q) 4.01 (2H, t), 6.69 (1H, d) 6.95 (1H, d), 7.20~7.35 (4H, m), 7.60~7.80 (2H, m), 8.45-8.55 (1H, m), 11.40 (1H, s) Example 62 6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless Needle-like crystals mp169.5-171℃ Example 63 6-{3-N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle-like crystals mp125.5-127.5℃ Example 64 6 -{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless granular crystals mp150-151.5℃ Example 65 6-{3-[N-methyl-N-(2 -thienylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp133.5-135℃ Example 66 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 67 6-{5-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl] Pentyloxy}carbostyryl Colorless needle crystals mp81-83℃ Example 68 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5-113.5℃ Example 69 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}carbostyryl Colorless needle crystals mp138-140℃ Example 70 6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 71 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 72 6-{4-[N-(4-hydroxybutyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116℃ Example 73 6-{3-[N-(2-methoxyethyl)-N
-Cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp142.5-143.5℃ Example 74 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3 ,4-dihydrocarbostyryl Colorless powder crystals mp112-114℃ Example 75 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyril Colorless needle-like crystals mp202.5-203.5℃ Example 76 6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-carbostyryl Colorless powdery crystals mp220-224℃ Example 77 6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp123-125℃ Reference example 24 2.4 g of 6-(3-carboxy-propoxy)carbostyryl was suspended in 200 ml of methylene chloride, and pyridine was added. After adding 2 ml, 1.4 g of thionyl chloride was added dropwise with stirring while maintaining the internal temperature at 0 to 20°C. After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and then 2 ml of N-(2-hydroxyethyl)cyclohexylamine was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. The reaction solution is thoroughly washed with an aqueous K ₂ CO ₃ solution, washed with water and diluted hydrochloric acid, and dried over Na ₂ SO ₄ , and then the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform:methanol (V/V) = 20:
After isolation and purification in step 1), recrystallization from chloroform-petroleum ether yields 6-{3-
1.2 g of [N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy] carbostyril is obtained. mp165-166°C Compounds of Examples 78-92 are obtained in the same manner as in Reference Example 24. Example 78 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ Example 79 6-{3-[N-methyl-N- (3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp169.5-171℃ Example 80 6-{3-[N-methyl-N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy} Carbostyril Colorless needle crystals 123-125℃ Example 81 6-{3-[N-methyl-N-(2-thienylmethyl)aminocarbonyl]propoxy} Carbostyril Colorless needle crystals mp133.5-135℃ Example 82 6-{3-[N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp125.5-127.5℃ Example 83 6-{3-[N-methyl-N -(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp121.5-123.5℃ Example 84 6-{4-[N-(2,3-dihydroxypropyl) )-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5-113.5℃ Example 85 6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 86 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 87 6-{4-[N-(4-hydroxybutyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116℃ Example 88 6-{3-[N-(2-methoxyethyl)-N
-Cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless granular crystals mp142.5-143.5℃ Example 89 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3, 4-Dihydrocarbostyryl Colorless powder crystals mp112-114℃ Example 90 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyril Colorless needle-like crystals mp202.5-203.5℃ Example 91 6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-carbostyryl Colorless powder crystals mp220-224℃ Example 92 6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp123-125℃ Reference example 25 6-[3-(p-nitrophenoxycarbonyl)propoxy]carbostyryl 3.8g was dissolved in dimethyl Dissolve in 40 ml of formamide, add 1.6 ml of N-(2-hydroxyethyl)cyclohexylamine, and stir at 60-70°C for 12 hours. After the reaction, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform: methanol (V/V) = 20:
After purification in step 1), the crude crystals were recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-{3-[N
1.3 g of carbostyril (2-hydroxyethyl)-N-cyclohexylaminocarbonylpropoxy is obtained. mp165-166°C Compounds of Examples 93-101 are obtained in the same manner as in Reference Example 25. Example 93 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ NMR (CDCl ₃ ) δppm: 1.56 (3H, t), 2.13 (2H, q) 2.41 (2H, t), 3.90 (2H, q) 4.01 (2H, t), 6.69 (1H, d) 6.95 (1H, d), 7.20~7.35 (4H, m), 7.60~7.80 (2H, m), 8.45-8.55 (1H, m), 11.40 (1H, s) Example 94 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbo Styryl Colorless granular crystals mp150-151.5℃ Example 95 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5~113.5℃ Example 96 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless needle-like crystals 202.5~ 203.5℃ Example 97 6-{4-[N-(2-hydroxyethyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate crystals mp123-125℃ Example 98 6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 99 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 100 6-{4-[N-(4-hydroxybutyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116℃ Example 101 6-{3-[N-(2-methoxyethyl)-N
-Cyclohexylaminocarbonyl]propoxy}carbostyril Colorless granular crystals mp142.5-143.5℃ Reference example 26 In 100 ml of ethanol, 2.7 g of 6-(3-ethoxycarbonylpropoxy) carbostyril, 0.5 g of sodium ethylate, and N-(2-hydroxy) Add 5 ml of (ethyl)cyclohexylamine and react in an autoclave at 110 atm and 140-150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 200 ml of chloroform, and 1% K ₂ CO ₃ was added.
After washing in the order of aqueous solution, dilute hydrochloric acid, and water,
After drying with Na ₂ SO ₄ , the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform: methanol (V/V) = 20:1). After that, the crude crystals were recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-{3-[N-(2-
Hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl 0.9g
get. mp165-166°C Compounds of Examples 102-104 are obtained in the same manner as in Reference Example 26 using appropriate starting materials. Example 102 6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp169.5-171℃ Example 103 6-{4-[N-( 2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 104 6-[3-(4-phenyl-1-piperazinylcarbonyl) ) Propoxy] carbostyril Colorless needle-like crystals mp202.5-203.5℃ Example 105 6-{3-[N-(2-
hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl 3.7g
Then, 1.8 ml of triethylamine was added, and 1.4 ml of benzoyl chloride was added dropwise while stirring under ice cooling. After dropping, the reaction mixture was allowed to react at room temperature for 1 hour, and the reaction solution was washed with 5% NaHCO ₃ water, diluted hydrochloric acid, and water, and dried over Na ₂ SO ₄ . After removing the desiccant, the mother liquor is concentrated and the residue is subjected to silica gel column chromatography. Eluate: The chloroform:methanol (30:1) eluate was recrystallized from chloroform-petroleum ether to give colorless needle-shaped crystals.
-{3-[N-(2-benzoyloxyethyl)
3.0 g of -N-cyclohexylaminocarbonyl]propoxy}carbostyryl was obtained. mp94-97°C Compounds of Examples 106-107 are obtained in the same manner as in Example 105 using appropriate starting materials. Example 106 6-{4-[N-(5-propionyloxypentyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp60-62℃ Example 107 6-{ 4-[N-(3-acetyloxypropyl)-N-(2-tetrahydropyranylmethyl)
Aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp64.5-66.5℃ Reference example 27 Add 1.73 g of 6-hydroxycarbostyryl, 1.8 g of K ₂ CO ₃ and 0.5 g of KI to 50 ml of dimethylformamide. 3.2 g of N-(2-hydroxyethyl)-N-(4-chlorobutyryl)cyclohexylamine was gradually added dropwise to the mixture at 60 to 70°C with stirring. After the dropwise addition, the mixture was stirred at the same temperature for 4 hours and the solvent was distilled off. Dissolve the residue in 200ml of chloroform and add diluted hydrochloric acid and 1% NaOH.
Wash with water, water and dry _{with Na2SO4} . After removing the drying agent, the mother liquor is concentrated and the residue is crystallized from petroleum ether. The obtained crystals were recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-{3-
0.5 g of [N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy] carbostyryl is obtained. Melting point: 165-166°C Compounds of Examples 108-131 are obtained in the same manner as in Reference Example 27 using appropriate raw materials. Example 108 6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp169.5-171℃ Example 109 6-{3-[N-ethyl -N-(3-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ Example 110 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy }-3,4-dihydrocarbostyryl colorless ridge-like crystals mp121.5-123.5℃ Example 111 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyryl colorless needle-like crystals mp123-125℃ Example 112 6-{3-[N-methyl-N-(2-thienylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp133.5-135℃ Example 113 6-{3- [N-methyl-N-(2-3,4-
Dihydro-2H-pyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp133.5-135℃ Example 114 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy }Carbostyril Colorless granular crystals mp150-151.5℃ Example 115 6-{3-[N-ethyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}Carbostyril Colorless needle-like crystals mp145-147℃ Example 116 6 -{3-[N-methyl-N-(2-furylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp125.5-127.5℃ Example 117 6-{3-[N-methyl-N-( 2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp123-125℃ Example 118 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 119 6-[N-ethyl-N-(3-pyridylmethyl)aminocarbonylmethoxy]-3,4 -Dihydrocarbostyryl Colorless needle crystals mp82-84℃ Example 120 6-{5-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]pentyloxy}carbostyryl Colorless needle crystals mp81-83 °C Example 121 8-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp115.5-117℃ Example 122 6-{4-[ N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5-113.5℃ Example 123 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}carbostyryl Colorless needle crystals mp138-140℃ Example 124 6-{4-[N-ethyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needles Crystals mp87-88.5℃ Example 125 6-{4-[N-propyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle-like crystals mp77-79.5℃ Example 126 6-{4-[N-butyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp93.5-95.5℃ Example 127 6 -{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 128 6-{4-[N-(2-hydroxyethyl)-
N-(3-pyridylmethyl)aminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp80-82.5℃ Example 129 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 130 6-{4-[N-(3-hydroxypropyl)
-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp98.5-100℃ Example 131 6-{4-[N-(4-hydroxybutyl) )―
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116°C Example 132 1-benzyl-6 in 50 ml of dimethylformamide
-Hydroxy-3,4-dihydrocarbostyryl
Add 1.90g, K ₂ CO ₃ 1.8g, KI 0.5g to 60-70
While stirring at °C, 3.4 g of N-ethyl-N-(2-tetrahydropyranylmethyl)-5-chloropentanoic acid amide was gradually added dropwise. 4 at the same temperature after dropping
Stir for an hour and evaporate the solvent. residue chloroform
Dissolve in 200 ml, wash with dilute hydrochloric acid, 1% NaOH water, and water, and dry with Na ₂ SO ₄ . After removing the desiccant, the mother liquor was concentrated and the residue was subjected to silica gel chromatography [eluent: CHCl ₃ :MeOH (20:1)]. Colorless syrupy 1-benzyl-6-{4-
[N-(2-tetrahydropyranylmethyl)-N
-ethylaminocarbonyl]butoxy}-3,4
- Obtain 0.6 g of dihydrocarbostyril. IR νcm ^-1 (neat) 1620 1690 Elemental analysis value (%) Calculated value C; 75.29 H; 8.23 N; 6.06 Actual value C; 75.41 H; 8.32 N; 6.21 Reference example 28 6-Hydroxy-3,4- in 50 ml of DMF Dihydrocarbostyril 1.6g, K ₂ CO ₃ 1.4g and KI 0.5g
and N-(3-hydroxypropyl)-N-(5-chlorovaleryl)- under stirring at 60 to 70°C.
Add 3.6 g of N-cyclohexylmethylamine in portions. After the addition, the mixture was allowed to react at the same temperature for 5 hours and the solvent was distilled off. Extract the residue with 100ml of chloroform,
Wash in the order of 1% NaOH water, dilute hydrochloric acid, and water.
Dry _{with Na2SO4} . After removing the desiccant and concentrating the mother liquor, the residue is subjected to silica gel column chromatography. Eluate:
The chloroform:methanol (40:1) eluate was concentrated and the residue was recrystallized from ethyl acetate-petroleum ether. Colorless needle crystals 6-{4-[N
-Cyclohexylmethyl-N-(3-hydroxypropyl)aminocarbonyl]butoxy}-3,
1.1 g of 4-dihydrocarbostyryl is obtained. mp95-97°C Compounds of Examples 133-153 are obtained in the same manner as in Reference Example 28 using appropriate raw materials. Example 133 6-[N-(2-hydroxyethyl)-N-phenylaminocarbonylmethoxy]carbostyril Colorless powder crystals mp162-165℃ Example 134 6-{3-[N-(2-methoxyethyl) -N
-Cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals 142.5-143.5℃ Example 135 6-{3-[N-(2-hydroxy-1-methylpropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp179.5-181.5℃ Example 136 6-{3-[N-(2-hydroxyethyl)-
N-butylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp153~154℃ Example 137 6-{3-[N-di-(2-hydroxyethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp122~ 123.5℃ Example 138 6-{4-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl Colorless needle crystals mp113-116℃ Example 139 6-{4-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl Colorless powder crystal mp91.5~93℃ Example 140 6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp123-125℃ Example 141 6-{4-[N-(4-hydroxybutyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp119-120.5℃ Example 142 6-{4-[N-(2-hydroxybutyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp123-125℃ Example 143 6-{4-[N-(5-hydroxypentyl)
-N-cyclohexylmethylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp113.5-115℃ Example 144 6-{3-[N-(4-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp109-111℃ Example 145 6-{4-[N-(5-propionyloxypentyl)-N-cyclohexylmethylaminocarbonyl ]Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp60-62℃ Example 146 6-{4-[N-(2-hydroxyethyl)-
N-(β-3,4-dimethoxyphenethyl)aminocarbonyl]butoxy}carbostyryl Colorless needle crystals mp78-81℃ Example 147 6-{4-[N-(3-acetyloxypropyl)-N- (2-tetrahydropyranylmethyl)
Aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp64.5-66.5℃ Example 148 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl] Butoxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp112-114℃ Example 149 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-carbostyryl Colorless powder crystal mp125-128℃ Example 150 6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}carbostyryl Colorless powder crystals mp220-224℃ Example 151 4-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp176-178℃ Example 152 4-Methyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp171-173℃ Example 153 1-Ethyl-6-{4-[N-(4-hydroxybutyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless syrup IR νcm ^-1 (neat) 1620 1670 Elemental analysis value (%) Calculated value C; 73.26 H; 9.56 N; 6.33 Actual value C; 73.42 H; 9.41 N; 6.21 Example 154 1-allyl-6-hydroxy- in 100 ml of isopropanol 3,4-dihydrocarbostyryl 2.0
g, 4-cyclohexyl-1-γ-bromobutyrylpiperazine by adding 1.8ml of DBU and stirring under reflux.
Add 4.2g. After the addition, stir under reflux for 8 hours and concentrate. Extract the residue with chloroform and 1N-
Wash with NaOH water, _H2O and treat _{with Na2SO4} . Remove the desiccant and concentrate the mother liquor. The residue is subjected to silica gel column chromatography. Eluent: Chloroform:methanol (20:1) 1-allyl-6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]-
3.5 g of 3,4-dihydrocarbostyryl are obtained. Colorless syrup IR νcm ^-1 (neat) 1645 1680 Elemental analysis value (%) Calculated value C; 71.04 H; 8.48 N; 9.56 Actual value C; 70.95 H; 8.61 N; 9.72 Example 155 6-Hydroxy-3 in 100 ml of isopropanol ，
Add 1.6 g of 4-dihydrocarbostyryl and 1.8 ml of DBU, and add 4-cyclohexyl-1-γ under reflux and stirring.
-Add 4.2g of bromobutyrylpiperazine.
After the addition, stir under reflux for 8 hours and concentrate. The residue was extracted with chloroform and washed with 1N-NaOH and _H2O .
Treat _{with Na2SO4} . Remove the desiccant and concentrate the mother liquor. The residue is subjected to silica gel column chromatography. Eluate: Chloroform:methanol (20:1) The eluate was concentrated and the residue was recrystallized from chloroform-ethyl acetate to give 6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]
2.8 g of -3,4-dihydrocarbostyryl is obtained. Colorless needle crystals mp 133-134°C Compounds of Examples 156-161 are obtained in the same manner as in Example 155 using appropriate starting materials. Example 156 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless needle crystals mp202.5-203.5℃ Example 157 6-[3-(4-phenyl-1-piperazinylcarbonyl)propoxy] Radinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle-like crystals mp182.5-183.5℃ Example 158 6-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]-carbostyryl Colorless needle-like crystals Crystal mp190-191℃ Example 159 6-[3-(4-benzyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless edge-like crystals mp174.5-175.5℃ Example 160 6-[3-(4-) Cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless needle crystals mp184.5-186.0℃ Example 161 6-[3-(4-Benzyl-1-piperidylcarbonyl)propoxy]-Carbostyril Colorless needle crystals mp145～146℃ Reference example 29 6-{3-[N-(2-hydroxyethyl)-
After dissolving 1.0 g of N-cyclohexylaminocarbonyl]-2-propenyloxy}carbostyryl in 50 ml of methanol, 0.1 g of 5% palladium-carbon was added and hydrogenated at room temperature and normal pressure for 5 hours.
After the reaction was completed, the catalyst was removed, the liquid was concentrated to dryness under reduced pressure, and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-{3-[N-
(2-Hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl
Obtain 0.8g. mp165-166°C Compounds of Examples 162-184 are obtained in the same manner as in Reference Example 29. Example 162 6-{3-[N-ethyl-N-(3-pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ Example 163 6-{3-[N-ethyl-N- (2-Pyridyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp148-149℃ NMR (CDCl ₃ ) δppm: 1.56 (3H, t), 2.13 (2H, q) 2.41 (2H, t), 3.90 (2H , q) 4.01 (2H, t), 6.09 (1H, d) 6.95 (1H, d), 7.20 ~ 7.35 (4H, m), 7.60 ~ 7.80 (2H, m), 8.45 ~ 8.55 (1H, m), 11.40 (1H, s) Example 164 6-{3-[N-methyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp169.5-171℃ Example 165 6-{ 3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless granular crystals mp150-151.5℃ Example 166 8-{3-[N-methyl-N-(2-tetrahydro Pyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp115.5-117℃ Example 167 6-{3-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}- 3,4-dihydrocarbostyryl Colorless edge-like crystals mp121.5-123.5℃ Example 168 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 169 6-[N-ethyl-N-(3-pyridylmethyl)aminocarbonylmethoxy}-3,4 -Dihydrocarbostyryl Colorless needle crystals mp82-84℃ Example 170 6-{5-[N-methyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]pentyloxy}carbostyryl Colorless needle crystals mp81-83 °C Example 171 6-{3-[N-ethyl-N-(3-pyridylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp145-147℃ Example 172 6-{3-[N-methyl- N-(2-tetrahydrofurylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp123-125℃ Example 173 5-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp130-131.5℃ Example 174 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless edge-like crystals mp112.5-113.5℃ Example 175 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylaminocarbonyl]
Butoxy}carbostyryl Colorless needle crystals mp138-140℃ Example 176 7-{3-[N-(3-hydroxypropyl)
-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp140-142℃ Example 177 6-{4-[N-ethyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl ]Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp87-88.5℃ Example 178 6-{4-[N-propyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3, 4-dihydrocarbostyryl Colorless needle crystals mp77-79.5℃ Example 179 6-{4-[N-butyl-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless Needle crystals mp93.5-95.5℃ Example 180 6-{3-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp175.5-177℃ Example 181 6-{4-[N-(2-hydroxyethyl)-
N-(3-pyridylmethyl)aminocarbonyl]
Butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp80-82.5℃ Example 182 6-{4-[N-(2-hydroxyethyl)-
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp117-118.5℃ Example 183 6-{4-[N-(3-hydroxypropyl)
-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp98.5-100℃ Example 184 6-{4-[N-(4-hydroxybutyl) )―
N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp114-116℃ Example 185 6-{4-[N-(2-hydroxyethyl) )-N-cyclohexylmethylaminocarbonyl]-2-butenyloxy}-3,
Add 5 g of 4-dihydrocarbostyryl and 1 g of 10% palladium on carbon, and catalytically reduce the mixture at room temperature under normal pressure for 5 hours. After removing the catalyst, the mother liquor was concentrated, and the residue was recrystallized from ethyl acetate-petroleum ether to give colorless plate-like crystals of 6-{4-[N-(2-hydroxyethyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl 4.2
get g. mp123-125°C Compounds of Examples 186-204 are obtained in the same manner as in Example 185 using appropriate raw materials. Example 186 6-[N-(2-hydroxyethyl)-N-phenylaminocarbonylmethoxy]carbostyryl Colorless powder crystals mp162-165℃ Example 187 6-{3-[N-(2-methoxyethyl) -N
-Cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless granular crystals mp142.5-143.5℃ Example 188 6-{3-[N-(2-hydroxy-1-methylpropyl)-N-cyclohexylmethylaminocarbonyl]propoxy}carbo Styril Colorless needle crystals mp179.5-181.5℃ Example 189 6-{3-[N-(2-hydroxyethyl)-
N-butylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp153~154℃ Example 190 6-{3-[N-di-(2-hydroxyethyl)aminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp122~ 123.5℃ Example 191 6-{4-[N-(2-hydroxyethyl)-
N-phenylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl Colorless needle crystals mp113-116℃ Example 192 6-{4-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl Colorless powder crystal mp91.5-93℃ Example 193 6-{4-[N-(2-hydroxyethyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp123-125℃ Example 194 6-{4-[N-(4-hydroxybutyl)-
N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp119-120.5℃ Example 195 6-{4-[N-(2-hydroxybutyl)-
N-Cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp123-125℃ Example 196 6-{4-[N-(2-methoxyethyl)-N
-cyclohexylaminocarbonyl]butoxy}
- Carbostyril Colorless needle crystals mp107~109℃ Example 197 6-{5-[N-(2-hydroxyethyl)-
N-benzylaminocarbonyl]pentyloxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp93.5-95.5℃ Example 198 6-{3-[N-(2-benzoyloxyethyl)-N-cyclohexylamino Carbonyl]propoxy}-carbostyryl Colorless needle crystals mp94-97℃ Example 199 6-{4-[N-(3-acetyloxypropyl)-N-(2-tetrahydropyranylmethyl)
Aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl Colorless needle crystals mp64.5-66.5℃ Example 200 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl] Butoxy}-3,4-dihydrocarbostyryl Colorless powder crystals mp112-114℃ Example 201 6-{4-[N-(2,3-dihydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-carbostyryl Colorless powder crystal mp125-128℃ Example 202 6-{3-[N-(2-hydroxyethyl)-
N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-carbostyryl Colorless powdery crystals mp220-224℃ Example 203 4-{3-[N-(2-hydroxyethyl)-
N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp176-178℃ Example 204 4-Methyl-6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyryl Colorless needle crystals mp171-173℃ Example 205 Dissolve 1.0 g of 6-[3-(4-phenyl-1-piperazinylcarbonyl)-2-propenyloxy]-carbostyril in 50 ml of methanol, and then dissolve 5% Add 0.1 g of palladium-carbon and hydrogenate at room temperature and normal pressure for 5 hours. After the reaction was completed, the catalyst was removed, the liquid was concentrated to dryness under reduced pressure, and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-[3-(4-phenyl-1-piperazinyl). carbonyl)propoxy}carbostyryl 0.75g
get. mp202.5-203.5°C Compounds of Examples 206-211 are obtained in the same manner as in Example 205 using appropriate raw materials. Example 206 6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless needle crystals mp184.5-186℃ Example 207 6-[3-(4-phenyl-1-pipe Radinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle-like crystals mp182.5-183.5℃ Example 208 6-[3-(4-phenyl-1-piperidylcarbonyl)propoxy]-carbostyril Colorless needle-like crystals Crystal mp190-191℃ Example 209 6-[3-(4-benzyl-1-piperazinylcarbonyl)propoxy]carbostyryl Colorless edge-like crystals mp174.5-175.5℃ Example 210 6-[3-(4-) Cyclohexyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle crystals mp133-134℃ Example 211 6-[3-(4-benzyl-1-piperidylcarbonyl)propoxy]-carbostyryl Colorless needle crystals mp145-146℃ Example 212 6-{4-[N-(2-
Acetyloxyethyl)-N-(2-tetrahydropyranylmethyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyryl is obtained. Colorless needle crystals mp65-67℃ Example 213 6-{4-[N-(1-
Methyl-2-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-
3,4-dihydrocarbostyryl is obtained. mp95-98°C Example 214 6-[4-(4-phenyl-1-piperazinylcarbonyl)butoxy]carbostyryl is obtained in the same manner as in Example 28. mp196.5-198℃ Example 215 6-[4-(4-phenyl-1-piperazinylcarbonyl)butoxy]-
3,4-dihydrocarbostyryl is obtained. mp188.5～190.5℃ Example 216 6-{5-[N-(5-
hydroxypentyl)-N-cyclohexylmethylaminocarbonyl]pentyloxy}-3,4
- Obtain dihydrocarbostyril. mp110~113℃ Example 217 6-{4-[N-(2-
hydroxyethyl)-N-benzylaminocarbonyl]butoxy}carbostyryl is obtained. mp101~104℃ Example 218 6-{4-[N-(2,
3-dihydroxypropyl)-N-cyclooctylmethylaminocarbonyl]butoxy}carbostyril is obtained. mp85~86℃

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom or the following group shows. In the above group, A is a lower alkylene group, R ³ is a lower alkyl group, a lower alkyl group having a hydroxyl group as a substituent, a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group, or a benzoyloxy lower alkyl group, R ⁴
is a lower alkyl group, a C _3-10 cycloalkyl group that may have a hydroxyl group as a substituent on the cycloalkyl ring, a lower alkyl group that has a C _3-10 cycloalkyl group as a substituent, phenyl group, phenyl ring A phenyl lower alkyl group which may have a lower alkoxy group as a substituent, a lower alkyl group having a hydroxyl group as a substituent, a pyridyl group or a thienyl group, a furyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyridyl group, or 3 , 4-dihydro-2H-pyranyl group as a substituent. this
R ³ and R ⁴ are bonded together with the nitrogen atom to which they are bonded to form a group [Formula] (where R ⁵ is a phenyl group, a C _3-10 cycloalkyl group or a phenyl lower alkyl group, and Z is a methine group or nitrogen (indicates an atom) may also be formed. However, when R ³ represents a lower alkyl group, R ⁴ represents a lower alkyl group, a C _3-10 cycloalkyl group that may have a hydroxyl group as a substituent on the cycloalkyl ring, a phenyl group, or a lower alkyl group on the phenyl ring. It must not be a phenyl lower alkyl group that may have an alkoxy group as a substituent or a lower alkyl group that has a C _3-10 cycloalkyl group as a substituent. Also,
When R ¹ and R ² are hydrogen atoms, R ³ is a lower alkyl group substituted with one hydroxyl group, and R ⁴ is a C _3-10 cycloalkyl group, the side chain shall not be substituted at the 6-position of the carbostyril skeleton. In addition, R ¹ is a hydrogen atom, a lower alkyl group,
Lower alkenyl group or phenyl lower alkyl group, R ² is hydrogen atom, lower alkyl group or the following group (A, R ³ and R ⁴ in the group are the same as above). However, either R or R ² is a group. shall be shown. Furthermore, 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position represents a single bond or a double bond. ] A carbostyryl derivative represented by these and its salt. 2 General formula [In the formula, R is the following group shows. In the above group, A is a lower alkylene group, R ³ is a lower alkyl group having a hydroxyl group as a substituent, a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group, or a benzoyloxy lower alkyl group, and R ⁴ is a cycloalkyl ring. May have a hydroxyl group as a substituent on
C _3-10 cycloalkyl group, lower alkyl group having a C _3-10 cycloalkyl group as a substituent, phenyl group, phenyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring, or thienyl represents a lower alkyl group having a furyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyridyl group, or a 3,4-dihydro-2H-pyranyl group as a substituent. this
R ³ and R ⁴ are bonded together with the nitrogen atom to which they are bonded to form a group [Formula] (where R ⁵ is a phenyl group, a C _3-10 cycloalkyl group or a phenyl lower alkyl group, and Z is a methine group or nitrogen (indicates an atom) may also be formed. However, when R ³ represents a lower alkyl group substituted with one hydroxyl group,
R ⁴ is a C _3-10 cycloalkyl group or pyridyl group,
It must not be a lower alkyl group having a thienyl group, furyl group, or tetrahydropyranyl group as a substituent. Furthermore, the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond. ] A platelet aggregation inhibitor containing a carbostyril derivative or a salt thereof.