JPH05194405A - Carbostyril derivative and platelet aggregation suppressing agent - Google Patents

Abstract

PURPOSE:To provide a new compound having long-acting platelet aggregation suppressing action, phosphodiesterase inhibiting action, positively inotropic action, etc., and low toxicity. CONSTITUTION:The compound of formula I [A is alkylene; R is NR<1>R<2>, SO2NR<3> R<4> or Y-NR<5>R<6>; W is O or S; R<1> is group of formula II ((l) and (m) are 0 or 1; B is alkylene; R<7> and R<8> are H, alkyl, alkanoyl, etc.) or substituted alkyl; R<2> is H, cycloalkylalkyl, cycloalkyl, phenyl, etc.; R<3> is H, (substituted)alkyl, etc.; R<4> is H, cycloalkyl, phenyl, etc.; Y is NHCO, NHCS or CS; R<5> and R' are H, alkyl, cycloalkyl, etc.] or its salt, e.g. 6-[3-{N-benzyl-N-[2-(4-hydroxy-1- piperidinyl)ethyl]amino}butoxy]carbostyril. The compound can be produced by reacting a compound of formula III with a compound of the formula X-A-R (X is halogen, alkanesulfonyloxy, etc.) preferably in the presence of a dehydrohalogenation agent in a proper solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carbostyril derivative and a platelet aggregation inhibitor.

[0002]

DISCLOSURE OF THE INVENTION The carbostyril derivative of the present invention is represented by the following general formula (1).

[0003]

[Chemical 3]

[In the formula, A represents a lower alkylene group. R
Is a group —NR ¹ R ² , a group —SO ₂ NR ³ R ⁴ or a group —Y
-NR ⁵ shows the R ^6. R ¹ is a group-(CO) l-B- (C
O) m-NR ⁷ R ⁸ (wherein l and m represent 0 or 1; B represents a lower alkylene group; R ⁷ and R ⁸ may be the same or different and each may have a hydrogen atom or a hydroxyl group). A lower alkyl group or a lower alkanoyl group, R ⁷ and R ⁸ are a 5- or 6-membered saturated group bonded to each other with or without a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded; And a lower alkyl group which may have a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkyl group which may have a hydroxyl group, an amino group which may have a lower alkyl group as a substituent, or a lower alkoxy group. 1 to 3 groups selected from the group consisting of a lower alkoxy group, an oxo group and an aminocarbonyl group which may have a lower alkyl group as a substituent may be substituted. A lower alkylenedioxy group may be substituted on the heterocycle.); Lower alkoxycarbonyl group substituted lower alkyl group; Carboxy group substituted lower alkyl group; Aminocarbonyl group substituted with a lower alkyl group as a substituent Lower alkyl group; lower alkyl group having hydroxyl group; imidazolyl-substituted lower alkyl group; pyridyl-substituted lower alkyl group; a group selected from the group consisting of lower alkyl group, lower alkoxy lower alkoxy group and hydroxyl group on the pyrrolidine ring ~ 3 pyrrolidinyl lower alkyl groups which may have; or a group -S
O ₂ -D-R ⁹ (D represents a lower alkylene group. R
⁹ is 5 having 1 to 3 halogen atoms or nitrogen atoms
Or a 6-membered saturated or unsaturated heterocyclic residue. The heterocycle may have a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group as a substituent. ) Is shown. R ²
Is a hydrogen atom; a cycloalkyl lower alkyl group; a cycloalkyl group; a phenyl group; a group selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group on the phenyl ring as a substituent. ~ 3
A phenyl lower alkyl group which may have one; a pyridyl substituted lower alkyl group; a thienyl substituted lower alkyl group; a cycloalkylcarbonyl group; a benzoyl group; a tetrahydropyranyl substituted lower alkyl group; a phenyl lower alkylsulfonyl group; a phenylsulfonyl group; An alkyl lower alkylsulfonyl group is shown. R ¹ and R ² are
A pyrrolidinyl group may be formed with the nitrogen atom to which they are attached. On the pyrrolidinyl group, a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group, a lower alkoxycarbonyl group, a piperidinylcarbonyl group, and a cycloalkyl lower alkyl group as a substituent. And 1 to 2 groups selected from the group consisting of aminocarbonyl groups which may have R ³ is a lower alkyl group which may have a hydrogen atom or a hydroxyl group; a carboxy-substituted lower alkyl group; a lower alkoxycarbonyl group-substituted lower alkyl group; a group -E- (CO) n-NR ¹⁰ R
¹¹ (Here, E represents a lower alkylene group which may have a hydroxyl group. N represents 0 or 1. R ¹⁰ and R ¹¹ are the same or different and each is a hydrogen atom; a lower alkyl group which may have a hydroxyl group. Or a lower alkanoyl group, and R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom, an oxygen atom or a sulfur atom. On the heterocycle, a hydroxyl group; an oxo group; a lower alkoxy lower alkoxy group; a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group; and an amino group which may have a lower alkyl group as a substituent. 1 to 3 groups selected from the group consisting of groups may be substituted, and a lower alkylenedioxy group may be substituted on the heterocycle.); Lower alkyl group as a substituent on the Roridin ring shows a pyrrolidinyl lower alkyl group which may have 1 to 3 groups selected from lower alkoxy-lower alkoxy group and a hydroxyl group becomes a group. R ⁴ may have a hydrogen atom; a cycloalkyl group; a cycloalkyl lower alkyl group; 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. Phenyl lower alkyl group; phenyl group; thienyl substituted lower alkyl group; pyridyl substituted lower alkyl group; imidazolyl substituted lower alkyl group; or tetrahydropyranyl substituted lower alkyl group. Y is a group -NHCO-, a group -NHC (= S)-, or a group -C (=
S) -indicates. R ⁵ and R ⁶ are the same or different and each is a hydrogen atom; a lower alkyl group; a cycloalkyl group; a cycloalkyl lower alkyl group; or a piperidinyl which may have a lower alkoxy lower alkoxy group or a hydroxyl group as a substituent on the piperidinyl ring. A lower alkyl group is shown. W
Represents an oxygen atom or a sulfur atom. The carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton represents a single bond or a double bond. Among the carbostyril derivatives represented by the above general formula (1), the compound represented by the following general formula (1A) is a novel compound not described in the literature.

[0005]

[Chemical 4]

[In the formula, the bonds at the 3 and 4 positions of A, W and the carbostyril skeleton are the same as described above. ^RA is a group -NR
¹ R ² , a group —SO ₂ NR ³ R ⁴ or a group —Y—NR ⁵ R ⁶
Indicates. R ¹ is a group-(CO) l-B- (CO) m-NR
⁷ R ⁸ (wherein, 1 and m are 0 or 1; B is a lower alkylene group; R ⁷ and R ⁸ are the same or different and are a lower alkyl group which may have a hydrogen atom or a hydroxyl group; or A lower alkanoyl group, R ⁷ and R ⁸
May be bonded to each other through a nitrogen atom, an oxygen atom, or a sulfur atom together with the nitrogen atom to which they are bonded to form a 5- or 6-membered saturated heterocycle. The heterocycle includes a hydroxyl group, a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group, an amino group which may have a lower alkyl group as a substituent, a lower alkoxy lower alkoxy group, an oxo group and a substituent group. 1 to 3 groups selected from the group consisting of an aminocarbonyl group which may have a lower alkyl group may be substituted. Further, a lower alkylenedioxy group may be substituted on the heterocycle. ); Lower alkoxycarbonyl group-substituted lower alkyl group; Carboxy group-substituted lower alkyl group; Aminocarbonyl group-substituted lower alkyl group which may have a lower alkyl group as a substituent; Lower hydroxyl group-containing lower alkyl group; imidazolyl-substituted lower alkyl group; Pyridyl-substituted lower alkyl group; pyrrolidinyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of lower alkyl group, lower alkoxy lower alkoxy group and hydroxyl group on the pyrrolidine ring; or group -SO ₂ -DR
⁹ (D represents a lower alkylene group. R ⁹ represents a 5- or 6-membered saturated or unsaturated heterocyclic residue having 1 to 3 halogen atoms or nitrogen atoms. Represents a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxy lower alkoxy group, or a lower alkyl group which may have a hydroxyl group. R ² is a hydrogen atom; a cycloalkyl lower alkyl group; a cycloalkyl group; a phenyl group; a group selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group as a substituent on the phenyl ring. 1 to 3 phenyl lower alkyl groups; pyridyl substituted lower alkyl groups; thienyl substituted lower alkyl groups; cycloalkylcarbonyl groups; benzoyl groups; tetrahydropyranyl substituted lower alkyl groups; phenyl lower alkylsulfonyl groups; phenylsulfonyl Or a cycloalkyl lower alkylsulfonyl group. R ¹ and R ² may form a pyrrolidinyl group together with the nitrogen atom to which they are attached. On the pyrrolidinyl group, a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy group or a lower alkyl group having a hydroxyl group, a lower alkoxycarbonyl group,
One or two groups selected from the group consisting of a piperidinylcarbonyl group and an aminocarbonyl group which may have a cycloalkyl lower alkyl group as a substituent are substituted. R ³ is a lower alkyl group which may have a hydrogen atom or a hydroxyl group; a carboxy-substituted lower alkyl group; a lower alkoxycarbonyl group-substituted lower alkyl group;
^{- (CO) n-NR 10} R 11 (.R 10 and R ¹¹ .n is 0 or 1 indicating a lower alkylene group which may where E having a hydroxyl group are the same or different, a hydrogen atom; A lower alkyl group which may have a hydroxyl group; or a lower alkanoyl group, and R ¹⁰ and R ¹¹ are 5- or 6-membered with or without a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded. On the heterocycle, a hydroxyl group; an oxo group; a lower alkoxy lower alkoxy group; a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group; and a substituent 1 to 3 groups selected from the group consisting of an amino group which may have a lower alkyl group may be substituted, and a lower alkylenedioxy group is substituted on the heterocycle. It may be);. Or pyrrolidine ring on the lower alkyl group as a substituent, a group selected from lower alkoxy-lower alkoxy group and a hydroxyl group consisting 1
A pyrrolidinyl lower alkyl group which may have 3 is shown. R ⁴ may have a hydrogen atom; a cycloalkyl group; a cycloalkyl lower alkyl group; 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. Phenyl lower alkyl group; phenyl group; thienyl substituted lower alkyl group; pyridyl substituted lower alkyl group; imidazolyl substituted lower alkyl group; or tetrahydropyranyl substituted lower alkyl group. Y is a group —NHCO—, a group —NHC (=
S)-, or a group -C (= S)-. R ⁵ and R
⁶ is the same or different and is a hydrogen atom; a lower alkyl group;
A cycloalkyl group; a cycloalkyl lower alkyl group; or a piperidinyl lower alkyl group which may have a lower alkoxy lower alkoxy group or a hydroxyl group as a substituent on the piperidinyl ring. However, when W is an oxygen atom and R ¹ is a lower alkyl group having a hydroxyl group, R ² is a hydrogen atom, a cycloalkyl group, or a group selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent on the phenyl ring. Must not be a phenyl lower alkyl group which may have 1 to 3 Further, when R ¹ and R ² form a pyrrolidinyl group, the pyrrolidinyl group is not a pyrrolidinyl group in which one hydroxyl group or a lower alkyl group having a hydroxyl group is substituted. According to the studies by the present inventors, the carbostyril derivative represented by the above general formula (1) or a salt thereof has an excellent platelet aggregation inhibitory action, phosphodiesterase inhibitory action, cardiac contractile force enhancing action (positive inotropic action). ,
It has anti-ulcer action, anti-inflammatory action, cerebral and peripheral blood flow increasing action, platelet mass dissociation action, thromboxane A ₂ antagonistic action and the like. The compound of the present invention is characterized by a long duration of the above-mentioned action and low toxicity (particularly weak toxicity to the heart such as cardiovascular thickening and myocardial damage), heart rate increasing action, blood pressure lowering action and the like. The circulation effect is also very weak. Further, the compound of the present invention has an advantage that it is well absorbed in the intestinal tract and is easily transferred into blood. Therefore, the compound of the present invention, a stroke, cerebral infarction, a prophylactic and therapeutic agent for thrombosis such as myocardial infarction,
It can be optimally used as a peripheral circulation improving agent, cerebral circulation improving agent, anti-inflammatory agent, anti-asthma agent, preventive and therapeutic agent for diabetic complications (neuropathy, nephropathy, etc.), cardiotonic agent and phosphodiesterase inhibitor.

Further, the compound of the present invention has a platelet adhesion inhibitory action, and is a therapeutic and prophylactic agent for arteriosclerosis, ischemic heart disease, chronic arterial occlusion, acute or chronic nephritis, etc., percutaneous coronary artery. It can be used as a preventive and therapeutic agent for coronary artery reocclusion by intravascular management such as dilatation (PCTA) or indwelling of a stent, or during artificial dialysis or artificial organ implantation.

Each group represented by the above general formula (1) is as follows.

As the lower alkylene group, for example, methylene, ethylene, methylmethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-
Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms such as ethyltrimethylene and 1-methyltrimethylene groups.

Lower alkoxy A lower alkoxy group or a lower alkyl group which may have a hydroxyl group includes methyl, ethyl, propyl, isopropyl, butyl and tert-
Butyl, pentyl, hexyl, methoxymethoxymethyl, 2-methoxymethoxyethyl, 3-methoxymethoxypropyl, 2,3-dimethoxymethoxypropyl, 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-dihydroxy-butyl, 1,
3-hydroxybutyl, 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,
Alkoxy moieties such as 5,6-dihydroxyhexyl, 2,3,4-trihydroxyhexyl, 3,4,5-trihydroxyhexyl and 4,5,6-trihydroxyhexyl groups are straight-chain with 1 to 6 carbon atoms. Alternatively, a branched alkoxy group having an alkoxyalkoxy group or a hydroxyl group of 1 to
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms which may have three.

Examples of the lower alkanoyl group include straight-chain or branched-chain alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups. it can.

The amino group which may have a lower alkyl group as a substituent includes, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino and dimethylamino. , Diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N
Examples of the substituent such as -butylamino, N-methyl-N-hexylamino group and the like include an amino group which may have 1 or 2 linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the aminocarbonyl group which may have a lower alkyl group as a substituent include aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, tert-butylaminocarbonyl, Pentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-ethyl-N-propylamino Carbon number as a substituent of carbonyl, N-methyl-N-butylaminocarbonyl, N-methyl-N-hexylaminocarbonyl group, etc. The aminocarbonyl group which may have 1-2 linear or branched alkyl groups of ~ 6 can be mentioned.

As the lower alkylenedioxy group, for example, methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy group and the like having 1 to 4 carbon atoms.
The straight chain or branched chain alkylenedioxy group can be mentioned.

As the lower alkyl group substituted with a lower alkoxycarbonyl group, for example, methoxycarbonylmethyl, 3
-Methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,1-dimethyl-
Carbon in which the alkyl moiety such as 2-butoxycarbonylethyl, 2-methyl-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl group is a linear or molecular chain alkyl group having 1 to 6 carbon atoms. Mention may be made of straight-chain or branched-chain alkoxycarbonylalkyl groups of the formulas 1 to 6.

As the carboxy lower alkyl group, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 1,1-dimethyl-2-carboxyethyl, 5-carboxypentyl, 6 Examples thereof include a carboxyalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as -carboxyhexyl and 2-methyl-3-carboxypropyl group.

Aminocarbonyl group which may have a lower alkyl group as a substituent. Examples of the substituted lower alkyl group include aminocarbonylmethyl, 1-aminocarbonylethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl and 4-aminocarbonyl. Butyl, 5-aminocarbonylpentyl, 6-aminocarbonylhexyl, 1,1-dimethyl-2-aminocarbonylethyl,
2-methyl-3-aminocarbonylpropyl, methylaminocarbonylmethyl, ethylaminocarbonylmethyl, propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, butylaminocarbonylmethyl, tert-butylaminocarbonylmethyl, pentylaminocarbonylmethyl, hexylaminocarbonyl Methyl, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, dipropylaminocarbonylmethyl, dibutylaminocarbonylmethyl, dipentylaminocarbonylmethyl, dihexylaminocarbonylmethyl, N-methyl-N-ethylaminocarbonylmethyl,
N-ethyl-N-propylaminocarbonylmethyl, N
-Methyl-N-butylaminocarbonylmethyl, N-methyl-N-hexylaminocarbonylmethyl, 2-methylaminocarbonylethyl, 1-ethylaminocarbonylethyl, 3-propylaminocarbonylpropyl, 4
-Butylaminocarbonylbutyl, 1,1-dimethyl-
2-pentylaminocarbonylethyl, 5-hexylaminocarbonylpentyl, 6-dimethylaminocarbonylhexyl, 2-diethylaminocarbonylethyl, 1
-(N-methyl-N-hexylamino) carbonylethyl, 3-dihexylaminocarbonylpropyl, 4-dibutylaminocarbonylbutyl, 2- (N-methyl-N
-Pentylamino) carbonylethyl group and the like having 1 to 1 carbon atoms
Mention may be made of a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, which has an aminocarbonyl group which may have 1 to 2 straight-chain or branched-chain alkyl groups of 6 as a substituent.

As the lower alkyl group having a hydroxyl group,
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. A linear or branched alkyl group having 1 to 6 carbon atoms and having 1 to 3 hydroxyl groups can be exemplified.

Examples of the imidazolyl-substituted lower alkyl group include (2-imidazolyl) methyl, 2- (1-imidazolyl) ethyl, 1- (4-imidazolyl) ethyl, 3- (5-imidazolyl) propyl, 4- (2 -Imidazolyl) butyl, 1,1-dimethyl-2- (4-imidazolyl) ethyl, 5- (1-imidazolyl) pentyl, 6- (5-imidazolyl) hexyl, 2-methyl-
Examples thereof include an imidazolylalkyl group in which an alkyl moiety such as a 3- (1-imidazolyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

As the pyridyl-substituted lower alkyl group,
(2-pyridyl) methyl, 2- (3-pyridyl) ethyl, 1- (4-pyridyl) ethyl, 3- (4-pyridyl) propyl, 4- (2-pyridyl) butyl, 1,1-
Dimethyl-2- (3-pyridyl) ethyl, 5- (4-pyridyl) pentyl, 6- (2-pyridyl) hexyl, 2
Examples thereof include a pyridyl-substituted alkyl group in which the alkyl moiety such as -methyl-3- (3-pyridyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

The pyrrolidinyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy lower alkoxy group and a hydroxyl group on the pyrrolidine ring is (2-pyrrolidinyl) methyl. , 2- (3-pyrrolidinyl) ethyl, 1- (2-pyrrolidinyl) ethyl, 3- (2-pyrrolidinyl) propyl, 4- (3-pyrrolidinyl) butyl, 5- (3-pyrrolidinyl) pentyl, 6- (2 -Pyrrolidinyl) hexyl, (3-methoxymethoxy-1-ethoxy-2-pyrrolidinyl) methyl, (1,3-dimethyl-4-ethoxymethoxy-2-pyrrolidinyl) methyl, 2- (3-propoxymethoxy-1-pyrrolidinyl ) Ethyl, 1,1-
Dimethyl-2- (2-pyrrolidinyl) ethyl, 2-methyl-3- (3-pyrrolidinyl) propyl, (1-ethyl-4-hydroxy-2-pyrrolidinyl) methyl, 2-
(1-Methyl-3-pyrrolidinyl) ethyl, 1- (1-
Propyl-2-pyrrolidinyl) ethyl, 3- (1-butyl-4-hydroxy-2-pyrrolidinyl) propyl, 4
-(1-Pentyl-3,4-dihydroxy-3-pyrrolidinyl) butyl, 5- (1-hexyl-3-pyrrolidinyl) pentyl, 6- (1-methyl-2-pyrrolidinyl)
Hexyl, (1,3-dimethyl-4-hydroxy-2-
As a substituent on the pyrrolidine ring such as pyrrolidinyl) methyl, 2- (3-hydroxy-2-pyrrolidinyl) ethyl, (4-hydroxy-2-pyrrolidinyl) methyl, and 3- (5-hydroxy-2-pyrrolidinyl) propyl. 1 to 3 carbon atoms which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms and hydroxyl groups
The pyrrolidinylalkyl group which is a linear or branched alkyl group of ~ 6 can be illustrated.

As the lower alkoxycarbonyl group, for example, an alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group is a straight or branched chain having 1 to 6 carbon atoms. An alkoxycarbonyl group which is a branched alkoxy group can be mentioned.

As the cycloalkyl lower alkyl group,
For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl. , 6-cyclooctylhexyl, 2-
A cycloalkylalkyl group having 3 to 8 carbon atoms in which an alkyl moiety such as methyl-3-cyclohexylpropyl, 2-cyclohexylethyl, 1-cyclohexylethyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. Can be mentioned.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples thereof include cycloalkyl groups having 3 to 8 carbon atoms such as cycloheptyl, cyclooctyl, cyclononanyl and cyclodecanyl.

As the lower alkoxy group, for example, a straight or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group and the like. It can be illustrated.

Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl and tert-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl and hexyl groups.

As the phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group as a substituent on the phenyl ring, For example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-
Phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6
-Phenylhexyl, 2-methyl-3-phenylpropyl, 2-chlorobenzyl, 2- (3-chlorophenyl)
Ethyl, 1- (4-chlorophenyl) ethyl, 3- (2
-Fluorophenyl) propyl, 4- (3-fluorophenyl) butyl, 1,1-dimethyl-2- (4-fluorophenyl) ethyl, 5- (2-bromophenyl) pentyl, 6- (3-bromophenyl) Hexyl, 2-methyl-3- (4-bromophenyl) propyl, 4-fluorobenzyl, 3-iodobenzyl, 2- (4-iodophenyl) ethyl, 1- (3,5-dichlorophenyl) ethyl, 3,4 -Dichlorobenzyl, 2- (3,4-dichlorophenyl) ethyl, 3- (2,6-dichlorophenyl) propyl, 4- (3,4-dichlorophenyl) butyl, 1,1-dimethyl-2- (3,4- Difluorophenyl) ethyl, 5- (3,5-dibromophenyl) pentyl, 6- (3,4,5-trichlorophenyl) hexyl, 4-methylbe Jill, 2- (2-methylphenyl)
Ethyl, 1- (3-methylphenyl) ethyl, 3- (3
-Ethylphenyl) propyl, 4- (2-ethylphenyl) butyl, 5- (4-ethylphenyl) pentyl, 6
-(3-isopropylphenyl) hexyl, 2-methyl-3- (4-hexylphenyl) propyl, 2- (3,
4-dimethylphenyl) ethyl, 2- (2,5-dimethylphenyl) ethyl, 2- (3,4,5-trimethylphenyl) ethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5 -Trimethoxybenzyl,
1- (3-methoxyphenyl) ethyl, 2- (2-methoxyphenyl) ethyl, 3- (2-ethoxyphenyl)
Propyl, 4- (4-ethoxyphenyl) butyl, 5-
(3-Ethoxyphenyl) pentyl, 6- (4-isopropoxyphenyl) hexyl, 1,1-dimethyl-2-
(4-hexyloxyphenyl) ethyl, 2-methyl-
3- (3,4-dimethoxyphenyl) propyl, 2-
(3,4-dimethoxyphenyl) ethyl, 2- (3,4
-Diethoxyphenyl) ethyl, 2- (3,4,5-trimethoxyphenyl) ethyl, 1- (2,5-dimethoxyphenyl) ethyl, (2-chloro-4-methoxy) benzyl, 4-cyanobenzyl, 1- (3-cyanophenyl) ethyl, 1- (2-cyanophenyl) propyl, 1
-(2,3-dicyanophenyl) butyl, 1- (2,
3,4-tricyanophenyl) pentyl, 1- (2,4
-Dicyanophenyl) hexyl, 4-carboxybenzyl, 1- (3-carboxyphenyl) ethyl, 1- (2
-Carboxyphenyl) propyl, 1- (2,4-dicarboxyphenyl) butyl, 1- (2,4,6-tricarboxyphenyl) pentyl, 1- (2-chloro-4-)
Halogen atom as a substituent on a phenyl ring such as carboxyphenyl) hexyl, (3-methyl-4-cyano) benzyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, a carboxy group, a cyano group and 1 to 3 groups selected from the group consisting of linear or branched alkoxy groups having 1 to 6 carbon atoms
Examples thereof include a phenylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl portion which may be present.

Examples of the thienyl-substituted lower alkyl group include (2-thienyl) methyl, 2- (3-thienyl) ethyl, 1- (2-thienyl) ethyl, 3- (2-thienyl) propyl and 4- (3 -Thienyl) butyl, 1,1-
Dimethyl-2- (2-thienyl) ethyl, 5- (3-thienyl) pentyl, 6- (2-thienyl) hexyl, 2
Examples thereof include a thienyl-substituted alkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as -methyl-3- (3-thienyl) propyl group.

The cycloalkylcarbonyl group has, for example, 3 to 10 carbon atoms such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclononanylcarbonyl and cyclodecanylcarbonyl groups. The cycloalkylcarbonyl group of 8 can be illustrated.

The tetrahydropyranyl-substituted lower alkyl group includes (2-tetrahydropyranyl) methyl and (3-
Tetrahydropyranyl) methyl, (4-tetrahydropyranyl) methyl, 2- (2-tetrahydropyranyl) ethyl, 2- (3-tetrahydropyranyl) ethyl, 2-
(4-tetrahydropyranyl) ethyl, 1- (2-tetrahydropyranyl) ethyl, 1- (3-tetrahydropyranyl) ethyl, 1- (4-tetrahydropyranyl) ethyl, 3- (2-tetrahydropyranyl) ) Propyl, 3
-(3-Tetrahydropyranyl) propyl, 3- (4-
Tetrahydropyranyl) propyl, 4- (2-tetrahydropyranyl) butyl, 4- (3-tetrahydropyranyl) butyl, 4- (4-tetrahydropyranyl) butyl, 1,1-dimethyl-2- (2- Tetrahydropyranyl) ethyl, 1,1-dimethyl-2- (3-tetrahydropyranyl) ethyl, 1,1-dimethyl-2- (4-tetrahydropyranyl) ethyl, 5- (2-tetrahydropyranyl) pentyl , 5- (3-tetrahydropyranyl) pentyl, 5- (4-tetrahydropyranyl) pentyl, 6- (2-tetrahydropyranyl) hexyl, 6
-(3-tetrahydropyranyl) hexyl, 6- (4-
Tetrahydropyranyl) hexyl, 2-methyl-3-
(2-Tetrahydropyranyl) propyl, 2-methyl-
Tetrahydropyranyl in which the alkyl moiety such as 3- (3-tetrahydropyranyl) propyl and 2-methyl-3- (4-tetrahydropyranyl) propyl is a linear or branched alkyl group having 1 to 6 carbon atoms A substituted alkyl group can be mentioned.

Examples of the phenyl lower alkylsulfonyl group include benzylsulfonyl, 2-phenylethylsulfonyl, 1-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl and 1,1-dimethyl-2-phenylethylsulfonyl. , 5-phenylpentylsulfonyl, 6-phenylhexylsulfonyl, 2-methyl-3-phenylpropylsulfonyl group, and the like, which is a phenylalkylsulfonyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety. Can be illustrated.

Examples of the cycloalkyl lower alkylsulfonyl group include cyclopropylmethylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl, cycloheptylmethylsulfonyl, cyclooctylmethylsulfonyl, 2-cyclopropylethylsulfonyl, 1- Cyclobutylethylsulfonyl, 3-cyclopentylpropylsulfonyl, 4-cyclohexylbutylsulfonyl,
5-cyclohexylpentylsulfonyl, 6-cyclooctylhexylsulfonyl, 2-methyl-3-cyclohexylpropylsulfonyl, 2-cyclohexylethylsulfonyl, 1-cyclohexylethylsulfonyl, etc., or a straight-chain alkyl group having 1 to 6 carbon atoms or A cycloalkylalkyl group having 3 to 8 carbon atoms, which is a branched chain alkyl group, can be mentioned.

Examples of the aminocarbonyl group which may have a cycloalkyl lower alkyl group as a substituent include, for example, aminocarbonyl, cyclohexylmethylaminocarbonyl, cyclopropylmethylaminocarbonyl, cyclobutylmethylaminocarbonyl, cyclopentylmethylaminocarbonyl and cycloheptyl. Methylaminocarbonyl, cyclooctylmethylaminocarbonyl,
(2-cyclopropylethyl) aminocarbonyl, (1
-Cyclobutylethyl) aminocarbonyl, (3-cyclopentylpropyl) aminocarbonyl, (4-cyclohexylbutyl) aminocarbonyl, (5-cycloheptylpentyl) aminocarbonyl, (6-cyclooctylhexyl) aminocarbonyl, (2-methyl -3-Cyclohexylpropyl) aminocarbonyl, (2-cyclohexylethyl) aminocarbonyl, (1-cyclohexylethyl) aminocarbonyl, dicyclohexylmethylaminocarbonyl, N-cyclohexylmethyl-N
-Having 1 or 2 cycloalkylalkyl groups having 3 to 8 carbon atoms, which are linear or branched alkyl groups having 1 to 6 carbon atoms in the alkyl portion, as substituents such as cycloheptylmethylaminocarbonyl group And an aminocarbonyl group having

As the lower alkylene group which may have a hydroxyl group, for example, in addition to the above lower alkylene group, 2
-Hydroxytrimethylene, 2-hydroxytetramethylene, 2,3-dihydroxytetramethylene, 3-hydroxypentamethylene, 3-hydroxytetramethylene, 5-hydroxyhexamethylene and the like, having a hydroxyl group as a substituent. Examples thereof include linear or branched alkylene groups of 1 to 6.

Examples of the phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group in the phenyl ring as a substituent include, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-
Phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2
-Methyl-3-phenylpropyl, 2-chlorobenzyl, 2- (3-chlorophenyl) ethyl, 1- (4-chlorophenyl) ethyl, 3- (2-fluorophenyl)
Propyl, 4- (3-fluorophenyl) butyl, 1,
1-dimethyl-2- (4-fluorophenyl) ethyl,
5- (2-bromophenyl) pentyl, 6- (3-bromophenyl) hexyl, 2-methyl-3- (4-bromophenyl) propyl, 4-fluorobenzyl, 3-iodobenzyl, 2- (4-iodo) Phenyl) ethyl, 1-
(3,5-Dichlorophenyl) ethyl, 3,4-dichlorobenzyl, 2- (3,4-dichlorophenyl) ethyl, 3- (2,6-dichlorophenyl) propyl, 4-
(3,4-dichlorophenyl) butyl, 1,1-dimethyl-2- (3,4-difluorophenyl) ethyl, 5-
(3,5-dibromophenyl) pentyl, 6- (3,3
4,5-Trichlorophenyl) hexyl, 4-methylbenzyl, 2- (2-methylphenyl) ethyl, 1- (3
-Methylphenyl) ethyl, 3- (3-ethylphenyl) propyl, 4- (2-ethylphenyl) butyl, 5
-(4-Ethylphenyl) pentyl, 6- (3-isopropylphenyl) hexyl, 2-methyl-3- (4-hexylphenyl) propyl, 2- (3,4-dimethylphenyl) ethyl, 2- (2,2 5-dimethylphenyl) ethyl, 2- (3,4,5-trimethylphenyl) ethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 1- (3-methoxyphenyl) ) Ethyl, 2- (2-methoxyphenyl) ethyl, 3- (2-ethoxyphenyl) propyl,
4- (4-ethoxyphenyl) butyl, 5- (3-ethoxyphenyl) pentyl, 6- (4-isopropoxyphenyl) hexyl, 1,1-dimethyl-2- (4-hexyloxyphenyl) ethyl, 2- Methyl-3- (3,3
4-dimethoxyphenyl) propyl, 2- (3,4-dimethoxyphenyl) ethyl, 2- (3,4-diethoxyphenyl) ethyl, 2- (3,4,5-trimethoxyphenyl) ethyl, 1- ( 2,5-dimethoxyphenyl)
On the phenyl ring such as ethyl and (2-chloro-4-methoxy) benzyl group, a halogen atom as a substituent and a carbon number of 1 to 1
1 is a group selected from the group consisting of a straight-chain or branched-chain alkyl group having 6 carbon atoms and a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms.
~ 1 to 6 carbon atoms of the alkyl portion that may have
Examples thereof include phenylalkyl groups which are linear or branched alkyl groups.

Examples of the piperidinyl lower alkyl group which may have a hydroxyl group or a lower alkoxy lower alkoxy group as a substituent on the piperidinyl ring include (4-hydroxy-1-piperidinyl) methyl and 2- (4-hydroxy-1-). Piperidinyl) ethyl, 1- (4-hydroxy-1-piperidinyl) ethyl, 3- (4-hydroxy-1-piperidinyl) propyl, 4- (4-hydroxy-1-piperidinyl) butyl, 5- (4-hydroxy- 1-piperidinyl) pentyl, 6- (4-hydroxy-1-piperidinyl) hexyl, 1,1-dimethyl-2
-(3-Hydroxy-1-piperidinyl) ethyl, 2-
Methyl-3- (2-hydroxy-1-piperidinyl) propyl, 2- (2,4-dihydroxy-1-piperidinyl) ethyl, 3- (2-hydroxy-4-piperidinyl) propyl, (2,4,6- Trihydroxy-1-piperidinyl) methyl, 1- (2-hydroxy-3-piperidinyl) ethyl, 4- (3-hydroxy-2-piperidinyl) butyl, 5- (3-hydroxy-4-piperidinyl) pentyl, 6- (2-Hydroxy-3-piperidinyl) hexyl, 2- (4-methoxymethoxy-1-piperidinyl) ethyl, 3- (4-ethoxymethoxy-1)
-Piperidinyl) propyl, 2- (2,4-dimethoxymethoxy-1-piperidinyl) ethyl group and other straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms in the hydroxyl or alkoxy moiety as a substituent on the piperidine ring Examples include piperidinylalkyl groups in which the alkyl moiety, which may have 1 to 3 alkoxyalkoxy groups, is a linear or branched alkyl group having 1 to 6 carbon atoms.

A 5- or 6-membered saturated heterocyclic group formed with or without a nitrogen atom, a sulfur atom or an oxygen atom together with the nitrogen atom to which R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ is bonded is Examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isothiazolidinyl, 3,4,5,6-tetrahydro-1,2-thiazinyl group and the like.

As a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group, an amino group which may have a lower alkyl group as a substituent, an oxo group and a substituent group. A group selected from the group consisting of an aminocarbonyl group which may have a lower alkyl group is 1 to 3
Examples of the above-mentioned heterocyclic group substituted with an individual or substituted with a lower alkylenedioxy group include 4-hydroxy-1-piperidinyl, 2,6-dimethyl-1-piperidinyl and 4
-Methylamino-1-piperidinyl, 4,4-ethylenedioxy-1-piperidinyl, 3,4-dihydroxy-
1-pyrrolidinyl, 2-methoxymethoxymethyl-1-
Pyrrolidinyl, 2-methoxymethoxymethyl-4-hydroxy-1-pyrrolidinyl, 5-methoxymethoxymethyl-2-oxo-1-pyrrolidinyl, 4- (2-methoxymethoxyethyl) -1-piperazinyl, 2-hydroxymethyl-1 -Pyrrolidinyl, 2-dimethylaminocarbonyl-1-pyrrolidinyl, 2-hydroxymethyl-4
-Hydroxy-1-pyrrolidinyl, 1,1-dioxo-
3,4,5,6-tetrahydro-1,2-thiazine-2
-Yl, 4- (2-hydroxyethyl) -1-piperazinyl, 4-dimethylamino-1-piperidinyl, 1,1
-Dioxo-2-isothiazolidinyl, 3-hydroxy-1-pyrrolidinyl, 2-dimethylamino-1-pyrrolidinyl, 4-methoxymethoxy-1-piperidinyl, 4
-(2-Ethoxyethoxy) -1-piperidinyl, 3-
Propoxypropoxy-1-pyrrolidinyl, 3- (4-
Butoxybutoxy) thiomorpholino, 2- (5-pentyloxypentyloxy) morpholino, 3- (6-hexyloxyhexyloxy) -3,4,5,6-tetrahydro-1,2-thiazin-2-yl, 2 -Oxo-5
-Hydroxymethyl-1-pyrrolidinyl, 4-methyl-
1-piperazinyl, 2,4,6-trimethyl-1-piperidinyl, 3-ethyl-1-pyrrolidinyl, 3-propyl-1-piperazinyl, 3-methylmorpholino, 5-butyl-2-thiomorpholino, 2-amino- 1-pyrrolidinyl, 4- (N-methyl-N-propylamino) -1-
Piperidinyl, 3-dibutylamino-1-piperazinyl, 3- (N-ethyl-N-pentylamino) morpholino, 2-dihexylaminothiomorpholino, 3-dimethylaminocarbonyl-1-pyrrolidinyl, 3-methylaminocarbonyl-1- Piperidinyl, 2-ethylaminocarbonylmorpholino, 3-propylaminocarbonyl-1-piperazinyl, 3-butylaminocarbonyl-2
-Thiomorpholino, 3-pentylaminocarbonyl-
3,4,5,6-tetrahydro-1,2-thiazine-2
-Yl, 3-hexylaminocarbonyl-2-isothiazolidinyl, 3-dibutylaminocarbonyl-1-piperazinyl, 4- (N-methyl-N-ethylaminocarbonyl) -1-piperidinyl, 4-hydroxy-2, 6-
Dimethyl-1-piperidinyl, 2-oxo-1-piperazinyl, 3-oxo-1-piperazinyl, 4,4-methylenedioxy-1-piperazinyl, etc. Or an alkoxyalkoxy group which is a branched alkoxy group, an alkoxyalkoxy group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy portion, or 1 to 3 hydroxyl groups as substituents. A linear or branched alkyl group having 1 to 6 carbon atoms, an amino group which may have 1 or 2 linear or branched alkyl group having 1 to 6 carbon atoms as a substituent, an oxo group And 1 to 3 carbon atoms substituted with 1 to 3 groups selected from the group consisting of an aminocarbonyl group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as a substituent. Straight or branched chain alkylenedioxy group can be exemplified the above heterocyclic group substituted.

Selected from the group consisting of a hydroxyl group, a lower alkoxy lower alkoxy group, an oxo group, a lower alkoxy lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group and an amino group which may have a lower alkyl group as a substituent. Examples of the above-mentioned heterocyclic group having 1 to 3 substituted groups or a lower alkylenedioxy group substituted are 4-hydroxy-1-piperidinyl,
2,6-dimethyl-1-piperidinyl, 4-methylamino-1-piperidinyl, 4,4-ethylenedioxy-1
-Piperidinyl, 3,4-dihydroxy-1-pyrrolidinyl, 2-methoxymethoxymethyl-1-pyrrolidinyl, 2-methoxymethoxymethyl-4-hydroxy-1
-Pyrrolidinyl, 5-methoxymethoxymethyl-2-oxo-1-pyrrolidinyl, 4- (2-methoxymethoxyethyl) -1-piperazinyl, 2-hydroxymethyl-
1-pyrrolidinyl, 2-hydroxymethyl-4-hydroxy-1-pyrrolidinyl, 1,1-dioxo-3,4
5,6-tetrahydro-1,2-thiazin-2-yl,
4- (2-hydroxyethyl) -1-piperazinyl, 4
-Dimethylamino-1-piperidinyl, 1,1-dioxo-2-isothiazolidinyl, 3-hydroxy-1-pyrrolidinyl, 2-dimethylamino-1-pyrrolidinyl,
4-methoxymethoxy-1-piperidinyl, 4- (2-
Ethoxyethoxy) -1-piperidinyl, 3-propoxypropoxy-1-pyrrolidinyl, 3- (4-butoxybutoxy) thiomorpholino, 2- (5-pentyloxypentyloxy) morpholino, 3- (6-hexyloxyhexyloxy) -3,4,5,6-tetrahydro-
1,2-thiazin-2-yl, 2-oxo-5-hydroxymethyl-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 2,4,6-trimethyl-1-piperidinyl, 3-ethyl-1-pyrrolidinyl , 3-propyl-1
-Piperazinyl, 3-methylmorpholino, 5-butyl-
2-thiomorpholino, 2-amino-1-pyrrolidinyl,
4- (N-methyl-N-propylamino) -1-piperidinyl, 3-dibutylamino-1-piperazinyl, 3-
(N-ethyl-N-pentylamino) morpholino, 2-
Dihexylaminothiomorpholino, 3-dimethylaminocarbonyl-1-pyrrolidinyl, 3-methylaminocarbonyl-1-piperidinyl, 2-ethylaminocarbonylmorpholino, 4-hydroxy-2,6-dimethyl-1
-Piperidinyl, 2-oxo-1-piperazinyl, 3-
Hydroxyl groups such as oxo-1-piperazinyl and 4,4-methylenedioxy-1-piperazinyl groups, alkoxyalkoxy groups which are linear or branched alkoxy groups having 1 to 6 carbon atoms in the alkoxy moiety, and alkoxy moieties 1 to 1 carbon atoms
An alkoxyalkoxy group which is a linear or branched alkoxy group of 6 or a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as a substituent, and a substituent 1 to 3 substituted with 1 to 3 groups selected from the group consisting of an amino group and an oxo group, which may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms, or 1 to 4 carbon atoms The above-mentioned heterocyclic group substituted with the linear or branched alkylenedioxy group can be exemplified.

Examples of the 5- or 6-membered saturated or unsaturated heterocyclic residue having 1 to 3 nitrogen atoms include pyrrolyl,
2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, 1,2,4-triazolyl, 1,
A 3,4-triazolyl group etc. can be illustrated.

Examples of the above heterocyclic residue substituted with a hydroxyl group, a lower alkoxyalkoxy group, a lower alkoxycarbonyl group as a substituent, a lower alkoxy lower alkoxy group as a substituent, or a lower alkyl group which may have a hydroxyl group include, for example, 4 -Hydroxy-1-piperidinyl, 3-hydroxy-1-piperidinyl, 2-hydroxy-1-piperidinyl, 2-methoxycarbonyl-1-
Pyrrolidinyl, 2-methoxymethoxymethyl-1-pyrrolidinyl, 2- (2-methoxymethoxyethyl) -1-
Imidazolyl, 3-methoxymethoxymethyl-pyrazolyl, 4- (3-ethoxymethoxypropyl) -2-pyrimidyl, 4-methoxymethoxymethyl-2-imidazolin-2-yl, 4-ethoxymethoxymethyl-1-pyrazolidinyl, 2- Hydroxymethyl-1-pyrrolidinyl, 2- (2-hydroxyethyl) -1-imidazolyl, 3-ethoxycarbonyl-1,2,4-triazol-1-yl, 3-hydroxy-1-pyrrolyl, 3-ethoxycarbonyl- 2H-pyrrolyl, 3-hydroxymethyl-pyrazolyl, 4-hydroxy-2-pyridyl, 4
-Ethoxycarbonyl-3-pyridazyl, 4- (3-hydroxypropyl) -2-pyrimidyl, 2-propoxycarbonyl-3-pyrazyl, 2-hydroxy-2-pyrrolinin-1-yl, 4-hydroxymethyl-2-imidazoline -2-yl, 2-methoxycarbonyl-1-imidazolidinyl, 3-methoxymethoxy-1-pyrrolidinyl, 4- (2-ethoxyethoxy) -1-piperidinyl, 4-methoxymethoxy-1-piperidinyl, 3-hydroxy-2 -Pyrazolin-1-yl, 4-hydroxymethyl-1-pyrazolidinyl, 4-ethoxycarbonyl-1-piperazinyl group and the like as a substituent, a hydroxyl group, a linear or branched alkoxy having 1 to 6 carbon atoms in the alkoxy moiety. Alkoxyalkoxy group, which is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms An oxycarbonyl group or an alkoxyalkoxy group, which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy portion, or 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as a substituent. The above-mentioned heterocyclic group substituted with a chain or branched alkyl group can be exemplified.

A hydroxyl group, a lower alkoxy lower alkoxy group as a substituent, a lower alkoxy lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group, a lower alkoxycarbonyl group, a piperidinylcarbonyl group and a cycloalkyl lower group as a substituent. Examples of the pyrrolidinyl group in which 1 to 2 groups selected from the group consisting of an aminocarbonyl group which may have an alkyl group are substituted include 2-methoxymethoxymethyl-1-pyrrolidinyl,
2-methoxymethoxymethyl-4-methoxymethoxy-
1-pyrrolidinyl, 3,4-dihydroxy-1-pyrrolidinyl, 3,4-dimethoxymethoxy-1-pyrrolidinyl, 2-hydroxymethyl-1-pyrrolidinyl, 2-methoxycarbonyl-1-pyrrolidinyl, 2- (1-piperidin Nylcarbonyl) -1-pyrrolidinyl, 2-cyclohexylmethylaminocarbonyl-1-pyrrolidinyl,
4-hydroxy-1-pyrrolidinyl, 2-hydroxymethyl-4-hydroxy-1-pyrrolidinyl, 2-methoxycarbonyl-4-hydroxy-1-pyrrolidinyl,
2- (1-piperidinylcarbonyl) -4-hydroxy-1-pyrrolidinyl, 2-cyclohexylmethylaminocarbonyl-4-hydroxy-1-pyrrolidinyl, 3-
Ethoxycarbonyl-1-pyrrolidinyl, 2-propoxycarbonyl-1-pyrrolidinyl, 3-butoxycarbonyl-1-pyrrolidinyl, 2-pentyloxycarbonyl-1-pyrrolidinyl, 3-hexyloxycarbonyl-1-pyrrolidinyl, 2-hydroxy-1 -Pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, 2-cycloheptylmethylaminocarbonyl-1-pyrrolidinyl, 3
-Cyclooctylmethylaminocarbonyl-1-pyrrolidinyl, 2-cyclopentylmethylaminocarbonyl-
1-pyrrolidinyl, 3-cyclopropylmethylaminocarbonyl-1-pyrrolidinyl, 2-cyclobutylmethylaminocarbonyl-1-pyrrolidinyl, 2- (1-piperidinylcarbonyl) -4-methoxycarbonyl-1-
Pyrrolidinyl, 2-cyclohexylaminocarbonyl-
4-Methyl-1-pyrrolidinyl, 2-ethyl-4-hydroxy-1-pyrrolidinyl, 4-propyl-1-pyrrolidinyl, 2-hydroxymethyl-4-methoxymethoxy-1-pyrrolidinyl, 2-methoxycarbonyl-4-
(2-Ethoxyethoxy) -1-pyrrolidinyl, 2-
(1-Piperidinylcarbonyl) -4-propoxymethoxy-1-pyrrolidinyl, 2-cyclohexylmethylaminocarbonyl-4-butoxymethoxy-1-pyrrolidinyl group and the like have a hydroxyl group and an alkoxy moiety having 1 to 6 carbon atoms as a substituent. A straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety.
1. A straight-chain or branched-chain alkoxy group, which is an alkoxyalkoxy group or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, which may have 1 to 3 hydroxyl groups, as a substituent. 6 straight-chain or branched alkoxycarbonyl group, piperidinyl carbonyl group and cycloalkyl having 3 to 8 carbon atoms, which is a straight-chain or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety as a substituent. An example is a pyrrolidinyl group in which 1 to 2 groups selected from the group consisting of an aminocarbonyl group which may have 1 to 2 alkylalkyl groups are substituted.

Examples of lower alkoxy lower alkoxy groups include methoxymethoxy, 3-methoxypropoxy, 4-ethoxybutoxy, 6-propoxyhexyloxy, 5-isopropoxypentyloxy, 1,1-dimethyl-2-butoxyethoxy, 2 -Methyl-tert-butoxypropoxy, 2-pentyloxyethoxy, hexyloxymethoxy and other alkoxy moieties have 1 to 1 carbon atoms.
There may be mentioned an alkoxyalkoxy group which is a linear or branched alkoxy group of 6.

As the halogen atom, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and element atom.

The carbostyril derivative represented by the above general formula (1) can be produced by various methods. If one example is shown, it can be easily produced by the method shown by the following reaction formula.

[Reaction Formula-1]

[0047]

[Chemical 5]

[In the formula, A, W and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^a is a group —NR ¹ R
² (R ¹ and R ² are the same as above). X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. The reaction of the compound of general formula (2) with the compound of general formula (3) is carried out without solvent or in a suitable solvent in the presence or absence of a basic compound. The reaction is usually at room temperature to 200
C., preferably room temperature to 150.degree. C., generally 1 to
It ends in about 30 hours. Examples of the solvent used here include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated carbonization such as dichloromethane, chloroform and carbon tetrachloride. Hydrogen, lower alcohols such as methanol, ethanol and isopropanol, dimethylformamide (DMF), dimethylsulfoxide (DM
SO), hexamethylphosphoric triamide, pyridine, acetone, acetonitrile, and other polar solvents can be exemplified. Examples of the basic compound used include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium amide, sodium hydride, potassium hydride, triethylamine, and the like. Examples thereof include organic bases such as tripropylamine, pyridine and quinoline. If an alkali metal iodide such as potassium iodide or sodium iodide is added to the reaction system of the reaction, the above reaction can proceed advantageously. The compound of the general formula (3) is usually used in an amount of at least equimolar, preferably equimolar to 8 times the molar amount of the compound of the general formula (2).

In the above reaction formula-1, the lower alkanesulfonyloxy group represented by X is specifically methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butane. Examples thereof include sulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy groups. Specific examples of the arylsulfonyloxy group include phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-
Examples of the substituted or unsubstituted arylsulfonyloxy group such as chlorophenylsulfonyloxy, α-naphthylphenylsulfonyloxy group and the like, and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-
Substitution of phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group, etc. Alternatively, an unsubstituted aralkylsulfonyloxy group can be exemplified.

[Reaction Formula-2]

[0051]

[Chemical 6]

[In the formula, the bonds at the 3 and 4 positions of W, X, A, R and the carbostyril skeleton are the same as described above. The reaction between the compound of the general formula (4) and the compound of the general formula (5) is carried out in a suitable solvent, preferably using a basic compound as a dehydrohalogenating agent, usually at room temperature to 200 ° C., preferably at 50 ° C.
It is carried out under a temperature condition of ~ 150 ° C for about 1 to 30 hours. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane and diethylene glycol dimethyl ether, and aromatic hydrocarbons such as toluene and xylene. , DMF, DMSO, hexamethylphosphoric triamide, and the like. Examples of the basic compound that can be used as a dehydrohalogenating agent include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, potassium metal, and sodium. Examples thereof include inorganic bases such as amides, organic bases such as pyridine, quinoline, triethylamine and tripropylamine. In the reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can be added to the reaction system as a reaction accelerator.
The amount of the compound of the general formula (5) used is not particularly limited,
It is usually an equimolar to 5-fold molar amount, and preferably an equimolar to 2-fold molar amount with respect to the compound of the general formula (4).

[Reaction Formula-3]

[0054]

[Chemical 7]

[Wherein A, W, R ³ , R ⁴ and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. X ¹ represents a halogen atom. ] The reaction of the compound (6) and the compound (7) is the same as the reaction formula-1
Can be carried out under the same conditions as the reaction of the compound (2) with the compound (3).

[Reaction Formula-4]

[0057]

[Chemical 8]

[Wherein A, W, R ⁵ , R ⁶ and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. ] The reaction of the compound (8) and the compound (9) is the same as the reaction formula-1
In a solvent similar to the solvent used in the reaction of the compound (2) of the general formula (2) with the compound of the general formula (3) in, usually room temperature to 100 ° C, preferably room temperature to about 70 ° C, Generally, the reaction is completed in about 0.5 to 5 hours.
The amount of the amine (9) used is usually an equimolar to 2-fold molar amount, and preferably an equimolar to 1.5-fold molar amount with respect to the compound of the general formula (8).

[Reaction Formula-5]

[0060]

[Chemical 9]

[In the formula, A, W, R ² , X ¹ and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^1a is a group -B
- (. B, m, R 7 and R ⁸ are as defined ^{above) (CO) m-NR 7} R 8, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, having a lower alkyl substituent A group consisting of an aminocarbonyl group-substituted lower alkyl group, a hydroxyl group-containing lower alkyl group, an imidazolyl-substituted lower alkyl group, a pyridyl-substituted lower alkyl group, a lower alkyl group, a lower alkoxy lower alkoxy group and a hydroxyl group as a substituent on the pyrrolidine ring Represents a pyrrolidinyl lower alkyl group or a group —SO ₂ D—R ⁹ (D and R ⁹ are the same as above) which may have 1 to 3 groups selected from R ^2a represents R ² other than forming a pyrrolidinyl group together with the nitrogen atom to which R ¹ is bonded. The reaction between the compound (10) and the compound (11) can be carried out under the same conditions as in the reaction between the compound (2) and the compound (3) in the reaction formula-1.

[Reaction Formula-6]

[0063]

[Chemical 10]

[In the formula, A, W, R ^2a and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^1b is a group -CO-B
^{- (CO) m-NR 7} R 8 (B, m, R 7 and R ⁸ are as defined above.) Shows a. The reaction between the compound of general formula (10) and the compound of general formula (12) is carried out according to a usual amide bond forming reaction.
As the amide bond formation reaction, known amide bond formation reaction conditions can be easily applied. For example (a)
A mixed acid anhydride method, that is, a method in which an alkylhalocarboxylic acid is reacted with a carboxylic acid (12) to give a mixed acid anhydride, and this is reacted with an amine (10), (b) an active ester method, that is, a carboxylic acid (12 ) Is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester and the like, and the amine (10) is reacted therewith, (C)
The carbodiimide method, that is, the method in which the amine (10) is condensed with the carboxylic acid (12) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole. A carboxylic acid anhydride with the dehydrating agent described above, and reacting this with an amine (10), carboxylic acid (12)
Examples thereof include a method of reacting an amine (10) with an ester of a lower alcohol with a high pressure and a high temperature, and a method of reacting an amine (10) with an acid halide of a carboxylic acid (12), that is, a carboxylic acid halide.

The mixed acid anhydride used in the mixed acid anhydride method is obtained by a conventional Schotten-Baumann reaction, and is usually reacted with an amine (10) without isolation to give a compound of the general formula (1f). The compound is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used, and examples thereof include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5. (DBN), 1,8
-Diazabicyclo [5.4.0] undecene-7 (DB
U), organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is usually -20 to 100.
C., preferably at 0 to 50.degree. C.,
The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (10) is usually about -20 to 150 ° C, preferably 10 to 50.
The reaction time is 5 minutes to 10 hours,
It is preferably 5 minutes to 5 hours. The mixed acid anhydride method is generally performed in a solvent. As the solvent to be used, any solvent commonly used in the mixed acid anhydride method can be used, and specifically, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include hydrogens, ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as DMF, DMSO and hexamethylphosphoric triamide. Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. In the method, the carboxylic acid (12), the alkylhalocarboxylic acid and the amine (10) are usually used in equimolar proportions. The alkylhalocarboxylic acid and the carboxylic acid (12) are added to the amine (10). It is preferable to use 1 to 1.5 times the molar amount of each.

Further, the carboxylic acid halide and the amine (10)
When the method of reacting with is adopted, the reaction is carried out in the presence of a basic compound in a suitable solvent. As the basic compound to be used, known compounds can be widely used. For example, in addition to the basic compound used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate. , Sodium methylate, sodium ethylate, and other alcoholates. Examples of the solvent include methanol, ethanol, propanol, butanol and 3-methoxy-1 in addition to the solvent used in the mixed acid anhydride method.
-Alcohols such as butanol, ethyl cellosolve and methyl cellosolve, pyridine, acetone, acetonitrile and the like, and mixed solvents thereof and the like can be mentioned. The usage ratio of the amine (10) and the carboxylic acid halide is
It is not particularly limited and may be appropriately selected within a wide range, but it is usually preferable to use the latter in at least an equimolar amount, preferably in an equimolar to 5-fold molar amount with respect to the former. The reaction is usually about −30 to 180 ° C., preferably 0 to 150.
The reaction is carried out at about C, and the reaction is generally completed in about 5 minutes to 30 hours.

[Reaction Formula-7]

[0068]

[Chemical 11]

[In the formula, the bonds at the 3rd and 4th positions of A, W, X ¹ and the carbostyril skeleton are the same as described above. R ^2b is a cycloalkyl lower alkyl group, a cycloalkyl group, a phenyl group, or a group selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group as a substituent on the phenyl ring. A phenyl lower alkyl group which may have three, a pyrrolidyl substituted lower alkyl group, a thienyl substituted lower alkyl group, a tetrahydropyranyl substituted lower alkyl group, a phenyl lower alkylsulfonyl group,
A phenylsulfonyl group or a cycloalkyl lower alkylsulfonyl group is shown. R ^1c represents the above R ^1a and R ^1b . The reaction between the compound (13) and the compound (14) can be carried out under the same conditions as the reaction between the compound (2) and the compound (3) in the reaction formula-1.

[Reaction Formula-8]

[0071]

[Chemical 12]

[In the formula, A, W, R ^1c and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^2c represents a cycloalkylcarbonyl group or a benzoyl group. The reaction of the compound (13) with the compound (15) can be performed under the same conditions as the reaction of the compound (10) with the compound (12) of the above-mentioned Reaction formula-6.

[Reaction Formula-9]

[0074]

[Chemical 13]

[In the formula, A, W, X ¹ , R ³ , R ⁴ and the bond at the 3,4 position of the carbostyryl skeleton are the same as described above. R ^3a
Represents R ³ other than a hydrogen atom. R ^4a represents R ⁴ other than a hydrogen atom. ] Reaction of compound (16) with compound (17) and compound (1
The reaction of 8) with the compound (19) can be carried out under the same conditions as the reaction of the compound (2) with the compound (3) in the above-mentioned reaction formula-1.

[Reaction Formula-10]

[0077]

[Chemical 14]

[In the formula, A, W, Y, R ⁵ , R ⁶ and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^5a and R ^6a each represent R ⁵ or R ⁶ other than a hydrogen atom. ] Reaction of compound (20) with compound (21) and compound (2
The reaction between 2) and the compound (23) can be carried out under the same conditions as the reaction between the compound (2) and the compound (3) in the above-mentioned reaction formula-2.

[Reaction Formula-11]

[0080]

[Chemical 15]

[In the formula, A, W, R ² , D and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. R ^9a represents a halogen atom. R ^9b is 1 to 3 nitrogen atoms which may have a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group as a substituent or a lower alkoxy lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group. It shows a 5- or 6-membered saturated or unsaturated heterocyclic residue. The reaction between the compound (24) and the compound (25) can be carried out under the same conditions as the reaction between the compound (2) and the compound (3) in the reaction formula-1.

[Reaction Formula-12]

[0083]

[Chemical 16]

[In the formula, the bonds at the 3,4 positions of A, R and the carbostyril skeleton are the same as described above. ] Compound (1n) and phosphorus pentasulfide or

[0085]

[Chemical 17]

The reaction with the Lawesson's reagent represented by the formula (1) is carried out by a conventional inert solvent such as aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride and chloroform. Etc. in a solvent such as halogenated hydrocarbons, dimethylsulfoxide, hexamethylphosphoric triamide and the like. The amount of phosphorus pentasulfide or Lawesson's reagent used is usually 0.2 times to a large excess amount, preferably 0.4 to 2 times the molar amount of the compound (1n). The reaction temperature is usually room temperature to 200 ° C., preferably 5
The reaction time is 0 to 150 ° C and the reaction time is 0.5 to 50 hours.

[0087]

[Reaction formula-13]

[0088]

[Chemical 18]

[Wherein A, W and R are the same as defined above]. The usual catalytic reduction conditions are applied to the reduction of the compound of the general formula (1q). The catalyst used is palladium,
Examples of the metal include palladium-carbon, platinum, Raney nickel, and the like, and such a metal is preferably used in a usual catalytic amount. Examples of the solvent used include alcohols such as methanol, ethanol, and isopropanol,
Examples thereof include ethers such as dioxane and tetrahydrofuran, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate, and fatty acids such as acetic acid. The reduction reaction can be carried out either under normal pressure or under pressure, but it is usually carried out under normal pressure to about ²⁰ kg / cm ² , preferably under normal pressure to 10 kg / cm ² . The reaction temperature is usually about 0 to 150 ° C, preferably room temperature to 100 ° C.
It is good to set the degree.

The dehydrogenation reaction of the compound of the general formula (1p) is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include 2,3-dichloro-5,
6-dicyanobenzoquinone, chloranil (2, 3, 5,
Benzoquinones such as 6-tetrachlorobenzoquinone),
Examples thereof include halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide, and bromine, selenium dioxide, palladium-carbon, palladium-black, palladium oxide, hydrogenation catalysts such as Raney nickel, and the like. The amount of the halogenating agent used is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 5 times, and preferably 1 to 2 times the molar amount of the compound of the general formula (1p). It is good to use it to some extent. When a hydrogenation catalyst is used, it is preferable to use a normal amount of catalyst. As the solvent, for example, dioxane, tetrahydrofuran, methoxyethanol, ethers such as dimethoxyethane, benzene, toluene, xylene, aromatic hydrocarbons such as cumene, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, Examples thereof include alcohols such as butanol, amyl alcohol, and hexanol, polar protic solvents such as acetic acid, and polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction is usually at room temperature to 300 ° C.
The temperature is preferably about room temperature to 200 ° C., and is generally completed in 1 to 40 hours.

The compound of the general formula (3), (7) or (9) as a starting material is easily produced, for example, according to the method shown by the following reaction formula.

[Reaction Formula-14]

[0093]

[Chemical 19]

[Wherein R ^2a , R ^1c , R ^4a , R ^3a , R ^6a , R
^5a , R ³ , R ⁴ , R ⁵ , R ⁶ and X ¹ are the same as above. ] The reaction of compound (26) with compound (27), compound (2
8) and the reaction of the compound (29), the reaction of the compound (30) and the compound (17), the compound (31) and the compound (1
The reaction of 9), the reaction of the compound (32) and the compound (21), and the reaction of the compound (33) and the compound (23) are the same as the reaction of the compound (2) and the compound (3) of the reaction formula-1. It can be done under conditions.

[Reaction Formula-15]

[0096]

[Chemical 20]

[Wherein R ^2a , B, m, X ¹ , R ⁷ , R ⁸ and
R ⁴ , R ¹⁰ , R ¹¹ and R ⁵ are the same as above. X ² represents a halogen atom. E ¹ represents a lower alkylene group which may have a hydroxyl group. A ¹ represents a lower alkylene group.
R ^6b represents a piperidinyl group which may have a lower alkoxy lower alkoxy group or a hydroxyl group as a substituent on the piperidylenyl ring. ] The reaction of compound (26) and compound (34), compound (3
The reaction between 1) and the compound (38) and the reaction between the compound (32) and the compound (42) can be carried out under the same conditions as the reaction between the compound (2) and the compound (3) in the aforementioned Reaction formula-1. Reaction of compound (35) with compound (37), reaction of compound (39) with compound (40) and compound (43) with compound (4)
The reaction of 4) can also be performed under the same conditions as the reaction of the compound (2) and the compound (3) of the above-mentioned reaction formula-1.

The reduction reaction of compound (37), (41) or (45) is carried out in a suitable solvent in the presence of a hydrogenating / reducing agent. Examples of the reducing agent used include sodium borohydride, lithium aluminum hydride, diborane and the like. The amount of the reducing agent used is at least about equimolar amount, preferably equimolar to the starting material.
It is preferable to set the molar amount to about 3 times. When lithium aluminum hydride is used as a reducing agent, it is preferably used in an amount of about equal weight to the starting material. Examples of the solvent used include water, methanol, ethanol,
Examples thereof include lower alcohols such as isopropanol, ethers such as tetrahydrofuran, diethyl ether, diglyme and the like. The reaction is usually -60 to 15
It is carried out at about 0 ° C., preferably in the vicinity of −30 to 100 ° C., and is generally completed in about 10 minutes to 15 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

[Reaction Formula-16]

[0100]

[Chemical 21]

[Wherein R ^1d represents a group — (CO) m—NR ⁷ R
⁸ (m, R ⁷ and R ⁸ are the same as above), a lower alkoxycarbonyl group, a carboxy group, an aminocarbonyl group which may have a lower alkyl group as a substituent, a hydroxyl group, an imidazolyl group, a pyridyl group or a pyrrolidine ring. The above shows a pyrrolidinyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy lower alkoxy group and a hydroxyl group as a substituent. p is 0 or 1
Indicates. R ^2d is a cycloalkyl lower alkyl group, a cycloalkyl group, a phenyl group, or a group selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group as a substituent on the phenyl ring.
A phenyl lower alkyl group, a pyridyl-substituted lower alkyl group, a thienyl-substituted lower alkyl group, a cycloalkylcarbonyl group, a benzoyl group, a tetrahydropyranyl-substituted lower alkyl group, a phenyl lower alkylsulfonyl group, a phenylsulfonyl group, Alternatively, it represents a cycloalkyl lower alkylsulfonyl group. A ¹ is the same as above. The reaction between the compound of general formula (46) and the compound of general formula (47) is carried out in the absence or presence of a dehydrating agent in a solvent-free or suitable solvent. Examples of the solvent used here include alcohols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, aprotic polar solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone. Etc. Examples of the dehydrating agent include desiccants used for dehydrating ordinary solvents such as molecular sieves, mineral acids such as hydrochloric acid, sulfuric acid and boron trifluoride, and organic acids such as p-toluenesulfonic acid. The reaction is usually room temperature to about 200 ° C., preferably room temperature to 150 ° C.
It is carried out at about C and is generally completed in about 1 to 48 hours. The amount of the compound of general formula (47) to be used is not particularly limited, but it is usually at least an equimolar amount, preferably an equimolar to 15-fold molar amount with respect to the compound of general formula (46). The amount of the dehydrating agent used is usually a large excess amount in the case of the desiccant, and the catalytic amount in the case of using the acid. The compound of the general formula (48) thus obtained is
It is subjected to the next reduction reaction without being isolated.

The reduction reaction of the compound of the general formula (48) includes
Although various methods can be applied, for example, a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane and the like. The amount of the reducing agent used is at least an equimolar amount, preferably an equimolar to 10-fold molar amount with respect to the compound of the general formula (48). This reduction reaction is usually carried out using a suitable solvent, for example, lower alcohols such as water, methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether and diglyme, and the like, usually about -60 to 50 ° C, preferably -30. It is carried out at 10 ° C. to room temperature for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

The reduction of the compound of the general formula (48) can also be carried out by catalytic hydrogenation in the presence of a catalyst in a suitable solvent. As the solvent used, for example, water, acetic acid, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether, ethyl acetate and acetic acid. Examples thereof include esters such as methyl and aprotic polar solvents such as dimethylformamide. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like. The amount of the catalyst used is generally about 0.02 to 1 times the amount of the compound of the general formula (48). The reaction temperature of the reaction is usually about -20 to 150 ° C, preferably about 0 to 100 ° C, the hydrogen pressure is usually about 1 to 10 atm, and the reaction is generally completed in about 0.5 to 10 hours. To do.

[Reaction Formula-17]

[0105]

[Chemical formula 22]

[Wherein R ^2e represents a cycloalkyl group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group,
A phenyl group which may have 1 to 3 groups selected from the group consisting of a cyano group, a carboxy group and a lower alkoxy group,
A pyridyl group, a thienyl group or a tetrahydropyranyl group is shown. R ^1c is the same as above. The reaction between the compound (49) and the compound (50) can be carried out under the same reaction conditions as those for the reaction between the compound (46) and the compound (47) in the above reaction formula-16.

The reaction for converting the compound (51) to the compound (3d) can be carried out under the same reaction conditions as the reaction for converting the compound (48) to the compound (3c).

[Reaction Formula-18]

[0109]

[Chemical formula 23]

[In the formula, R ^3a , A ¹ , p, R ^4a , R ^5a and R ^6a are the same as defined above. R ^4b is a cycloalkyl group, a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group on the phenyl ring as a substituent, a phenyl group, a pyridyl group,
An imidazolyl group or a tetrahydropyranyl group is shown. R
^5b and R ^6b each represent a hydrogen atom, a cycloalkyl group or a piperidinyl group which may have a lower alkoxy lower alkoxy group or a hydroxyl group as a substituent on the piperidinyl ring. ] Reaction of compound (52) and compound (53), compound (5
The reaction of 5) and the compound (56), the reaction of the compound (58) and the compound (59), and the reaction of the compound (61) and the compound (62) are performed by the reaction of the compound (46) of the reaction formula-16.
Can be carried out under the same conditions as in the reaction of the compound (47).

The reaction for converting the compound (54) into the compound (7d), the reaction for converting the compound (57) into the compound (7e), the reaction for converting the compound (60) into the compound (9d) and the compound (6).
The reaction for converting 3) to the compound (9e) can be carried out by the reaction formula-16
Can be carried out under the same conditions as the reaction for converting the compound (48) to the compound (3c).

[Reaction Formula-19]

[0113]

[Chemical formula 24]

[Wherein

[0115]

[Chemical 25]

Represents a cycloalkyl group. R ^1c ,
R ^3a and R ^5a are the same as above. ] The reaction of compound (64) and compound (50), compound (6
The reaction of 4) with the compound (56) and the reaction of the compound (64) with the compound (62) are carried out by the reaction of the compound (4) of the reaction formula-16.
It can be carried out under the same conditions as in the reaction of 6) with compound (47).

The reaction for leading the compound (65) to the compound (3e), the reaction for leading the compound (66) to the compound (7f) and the reaction for leading the compound (67) to the compound (9f) are the same as those of the above-mentioned reaction formula-16. It can be carried out under the same conditions as in the reaction which leads compound (48) to compound (3c).

Compound (5) used as a starting material
Is manufactured, for example, by the following method.

[Reaction Formula-20]

[0120]

[Chemical formula 26]

[In the formula, R ³ , R ⁴ , X, A and X ¹ are the same as defined above. The reaction of the compound (7) and the compound (68) can be carried out under the same conditions as the reaction of the compound (2) and the compound (3) of the reaction formula-1.

[Reaction Formula-21]

[0123]

[Chemical 27]

[In the formula, X, A, R ⁵ and R ⁶ are the same as defined above. The reaction between the compound (74) and the compound (9) can be carried out under the same conditions as in the reaction between the compound (8) and the compound (9) in the reaction formula-4.

[Reaction Formula-22]

[0126]

[Chemical 28]

[Wherein R ¹² is a hydroxyl group, a lower alkoxy lower alkoxy group as a substituent, a lower alkoxy lower alkoxy group as a substituent, or a lower alkyl group which may have a hydroxyl group, a lower alkoxycarbonyl group, a piperidinylcarbonyl group or A pyrrolidinyl group which may have one aminocarbonyl group which may have a cycloalkyl lower alkyl group as a substituent is shown. R ¹³ represents a cycloalkyl lower alkyl group or a hydrogen atom as a substituent. The reaction of the compound (69) with the compound (70) can be carried out under the same conditions as the reaction of the compound (10) with the compound (12) of the reaction formula-6. In the reaction, the 1-position of the pyrrolidine ring is protected with a protecting group such as a phenyl lower alkoxycarbonyl group such as a benzyloxycarbonyl group, reacted with the compound (70), and then catalytic hydrogenation of the compound (48) of the reaction formula-16. The compound may be deprotected by reduction under the same conditions as in the reduction reaction of.

[Scheme-23]

[0129]

[Chemical 29]

[In the formula, X ¹ , X ² , A, R ³ and R ⁴ are the same as defined above. ] The reaction of the compound (72) and the compound (7) is the above-mentioned reaction formula-
Can be carried out under the same conditions as the reaction of the compound (2) with the compound (3).

The reaction for converting the compound (73) to the compound (1r) can be carried out by heating the compound (73) in the presence of an acid or a basic compound. Examples of the acid used here include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid. As the basic compound,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate can be exemplified. The reaction is usually 50 to 15
The reaction is carried out at 0 ° C., preferably around 70 to 120 ° C., and the reaction is generally completed in about 0.5 to 24 hours.

[Reaction Formula-24]

[0133]

[Chemical 30]

[In the formula, A, R ⁵ , R ⁶ , W and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. ] The reaction between the compound (75) and the compound (9) is carried out by the reaction formula-
It can be carried out under the same conditions as the reaction of the compound (10) with the compound (12) of No. 6.

The reaction of the compound (76) with phosphorus pentasulfide or Lawesson's reagent can be carried out under the same conditions as the reaction of the compound (1n) of the above reaction formula-12 with phosphorus pentasulfide or Lawesson's reagent. In the reaction, a compound in which only the side chain amide carbonyl group or the side chain amide carbonyl group and the 2-position carbonyl group of the carbostyryl skeleton are simultaneously thiocarbonylated is obtained.

R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom, an oxygen atom or a sulfur atom, In the case of the compound (1) in which a lower alkoxy lower alkoxy group is substituted above, R ⁹ is a 5- or 6-membered saturated or unsaturated heterocyclic residue having 1 to 3 nitrogen atoms having a lower alkoxy lower alkoxy group. In the case of the compound (1) which is a group, in the case of the compound (1) in which a pyrrolidinyl group is formed together with the nitrogen atom to which R ¹ and R ² are bonded, and a lower alkoxy lower alkoxy group is substituted on the pyrrolidinyl group, When R ¹ or R ³ is a pyrrolidinyl lower alkyl group having at least one lower alkoxy lower alkoxy group as a substituent on the pyrrolidine ring, or R ⁵ or R ^{5 When 6} is a piperidinyl lower alkyl group having at least one lower alkoxy lower alkoxy group as a substituent on the piperidinyl ring,
By hydrolyzing these, the corresponding R
^A compound (1) in which ⁷ and R ⁸ or R ¹⁰ and R ¹¹ are the above-mentioned heterocyclic groups substituted with a hydroxyl group, a compound (1) in which R ⁹ is the above-mentioned heterocyclic group, and R ¹ or R ³ is a pyrrolidine ring Compound (1), which is a pyrrolidinyl lower alkyl group having at least one hydroxyl group as a substituent on the above, R ⁵ or R ⁶
Is a piperidinyl lower alkyl group having at least a hydroxyl group as a substituent on the piperidinyl ring.

Any ordinary hydrolysis reaction conditions can be applied to the hydrolysis reaction. The hydrolysis reaction is usually carried out in the presence of a basic compound, a mineral acid, an organic acid or the like in a suitable solvent. Examples of the basic compound include sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate and the like, mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, and organic acids such as acetic acid and p-toluene. Examples thereof include aromatic sulfonic acids such as sulfonic acid and Lewis acids such as boron trichloride. Examples of the solvent include water, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, solvents such as acetic acid and mixed solvents thereof. You can The reaction is usually room temperature to about 200 ° C., preferably room temperature to 150 ° C.
It progresses in the vicinity of ° C, and generally ends in about 0.5 to 30 hours.

The compound (1) in which R ¹ or R ³ is a lower alkyl group substituted with a lower alkoxycarbonyl group is a compound (1) in which the corresponding R ¹ or R ³ is a lower alkyl group substituted with a carboxy group. You can lead to 1).

The hydrolysis reaction can be carried out in a suitable solvent or without solvent in the presence of an acid or a basic compound. Examples of the solvent used include lower alcohols such as water, methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, and fatty acids such as acetic acid and formic acid. Examples thereof include mixed solvents. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and formic acid,
Examples thereof include acetic acid and organic acids such as aromatic sulfonic acid, and examples of the basic compound include metal carbonates such as sodium carbonate and potassium carbonate and sodium hydroxide,
Examples thereof include metal hydroxides such as potassium hydroxide and calcium hydroxide. The reaction is usually at room temperature to 200 ° C.
Approximately, preferably room temperature to around 150 ° C., the reaction proceeds appropriately, and is generally completed in about 0.5 to 25 hours.

R ¹ is a group —CO—B— (CO) m—NR ⁷
When the compound (1) represents R ⁸ and R 3 is a group -E-.
In the case of the compound (1) showing CO—NR ¹⁰ R ¹¹ , they are reduced to the corresponding R by reducing them under the same conditions as in the reduction reaction of the compound (37) of the reaction formula-15.
It can lead to ¹ group -CH ₂ -B- (CO) compound that exhibits ^{m-NR 7 R 8 (1} ), compounds wherein R ³ represents a group _{^{-E-CH 2 -NR 10 R 11}} (1) ..

R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom, an oxygen atom or a sulfur atom. In the case of the compound (1) in which the lower alkyl group having at least one lower alkoxy lower alkoxy group is substituted, R ⁹ has 1 to 1 nitrogen atom having a lower alkyl group having at least one lower alkoxy lower alkoxy group. In the case of the compound (1) which is a 5- or 6-membered saturated or unsaturated heterocyclic residue having 3 or a pyrrolidinyl group is formed with the nitrogen atom to which R ¹ and R ² are bonded, a lower group on the pyrrolidinyl group In the case of the compound (1) in which a lower alkyl group having at least one alkoxy lower alkoxy group is substituted, these are each substituted with the above lower alkoxy lower alkoxy group. By hydrolyzing under the same conditions as the hydrolysis of the compound (1) having a heterocyclic group in which a group is substituted, a nitrogen atom, an oxygen atom together with a nitrogen atom to which the corresponding R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ are bonded, heterocyclic saturated 5- or 6-membered formed without or via an atom or a sulfur atom, compounds in which a lower alkyl group having at least one hydroxyl group is substituted on the heterocyclic ring (1), R ⁹ is Compound (1) which is a 5- or 6-membered saturated or unsaturated heterocyclic residue having 1 to 3 nitrogen atoms having a lower alkyl group having at least one hydroxyl group, and a nitrogen atom to which R ¹ and R ² are bonded A pyrrolidinyl group can be formed together therewith, leading to a compound (1) in which a lower alkyl group having at least one hydroxyl group is substituted on the pyrrolidinyl group.

In the case of the compound (1) in which R ³ , R ⁷ or R ⁸ is a lower alkyl group having a hydroxyl group, the hydroxyl group is once converted into a tetrahydropyranyloxy group or a 1,1-dimethylmethylenedioxy group. The compound is protected with a lower alkylenedioxy group or the like, and the protected compound is represented by the reaction formula-1
~ By subjecting to various reactions shown in Reaction Formula-22 and finally deprotecting the protected group, R ³ , R ⁷ or R
It is also possible to lead to a desired compound (1) in which ⁸ is a lower alkyl group having a hydroxyl group. The deprotection reaction is performed by hydrolyzing under the same conditions as the hydrolysis of the compound (1) having a heterocycle substituted with the lower alkoxy lower alkoxy group.

In the case of a compound in which R ⁷ or R ⁸ is a hydrogen atom, the site to which the hydrogen atom is bonded is once protected with a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group and then protected. The compound represented by the reaction formula-1
It is also possible to lead to the desired compound (1) in which R ⁷ or R ⁸ is a hydrogen atom by subjecting to various reactions shown in Reaction Formula-22 and finally deprotecting the protected group. ..
The deprotection reaction is carried out by hydrolysis under the same conditions as the reaction for hydrolyzing the compound in which R ¹ or R ³ is a lower alkoxycarbonyl group-substituted lower alkyl group.

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid and benzoic acid can be mentioned.

Of the carbostyril derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting a pharmaceutically acceptable basic compound. . Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The target compound thus obtained in each step can be easily isolated and purified by a conventional separation means. Examples of the separating means include solvent extraction method, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography and the like.

The present invention naturally includes optical isomers.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients which are usually used such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.) and the like can be mentioned. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipient, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate,
Calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrators such as lactose, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium salt base, lauryl Absorption promoters such as sodium sulfate, glycerin, humectants such as starch, starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder,
Lubricants such as polyethylene glycol can be exemplified. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthanthene and the like. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When formed into the form of these solutions, pills and suspensions, they are used as diluents. All those customary in the art can be used, such as water, ethyl alcohol,
Examples thereof include propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be included in the preparation.

The amount of the compound of the general formula (1) to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1
~ 30% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replenisher such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected according to the usage, age of the patient, sex and other conditions, degree of disease, etc. It is recommended that the daily dose be about 0.1-10 mg / kg body weight. In addition, 1 to 200 active ingredients in the dosage unit form
It is good to contain mg.

[0152]

[Examples] Reference examples, examples, pharmacological test results and formulation examples are listed below.

Reference Example 1 27 g of 1- (2-aminoethyl) -4-methoxymethoxypiperidine was added dropwise at room temperature to a solution of 15 g of benzaldehyde in 300 ml of ethanol, and the mixture was stirred at the same temperature for 1 day. After that, 5 g of 10% Pd-C is added to the reaction solution to absorb hydrogen at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off,
The filtrate is diluted with ethyl acetate. After extraction with 10% hydrochloric acid, the aqueous layer is made alkaline with aqueous potassium hydroxide solution and extracted with ethyl acetate. After washing with water and drying over magnesium sulfate, the solvent is distilled off. The obtained residue is purified by silica gel column chromatography (eluent: 10% methanol-chloroform) to obtain 25.50 g of 1- (2-benzylaminoethyl) -4-methoxymethoxypiperidine.

Light yellow oily ¹ H-NMR (CDCl ₃ ) δ; 1.35-1.75
(4H, m), 1.75-2.0 (2H, m), 2.0
-2.2 (2H, m), 2.47 (2H, t, J = 6.
1Hz), 2.69 (2H, t, J = 6.1Hz),
3.37 (3H, s), 3.5-3.7 (1H, m),
3.80 (2H, s), 4.68 (2H, s), 7.2
-7.4 (5H, m).

Reference Example 2 3.0 g of aniline / hydrochloride and 7 ml of triethylamine
1.7 ml of chloroacetyl chloride is added dropwise to a solution of 30 ml of dichloromethane in. After stirring at room temperature for 3 hours, water,
Wash with saturated aqueous sodium hydrogen carbonate solution and dry over magnesium sulfate. The residue obtained by distilling off the solvent was crystallized from ethyl acetate-n-hexane and 2.45 g of N-
(2-Chloroacetyl) aniline is obtained as a light brown solid. Obtained N- (2-chloroacetyl) aniline 2.
45 g, 4-methoxymethoxypiperidine 2.8 g, sodium iodide 2.45 g and triethylamine 2.3.
A suspension of 30 ml of acetonitrile in 30 ml is heated to reflux for 1.5 hours. The reaction solution is diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate; n-hexane = 1: 1) to obtain 3.
64 g of 1- (anilinocarbonylmethyl) -4-methoxymethoxypiperidine are obtained as a pale yellow oil.

1- (anilinocarbonylmethyl) -4-
A solution of 3.64 g of methoxymethoxypiperidine in 10 ml of tetrahydrofuran was added to lithium aluminum hydride 63
0 mg of tetrahydrofuran in 50 ml suspension,
Heat to reflux for 3 hours. Then, 1.5 ml of 10% aqueous potassium hydroxide solution and 1.5 ml of water are added to the reaction solution, diluted with ethyl acetate, and then filtered. The solvent of the filtrate is distilled off, and 3.
41 g of 1- (2-anilinoethyl) -4-methoxymethoxypiperidine are obtained.

Brown oily ¹ H-NMR (CDCl ₃ ) δ; 1.6-1.7 (2
H, m), 1.9 (2H, m), 2.2 (2H, m),
2.60 (2H, t, J = 6Hz), 2.9 (2H,
m), 3.14 (2H, t, J = 6Hz), 3.37
(3H, s), 3.6 (1H, m), 4.69 (2H,
s), 6.7 (2H, m), 7.18 (2H, dd, J
= 7.3 Hz, 8.5 Hz).

Reference Example 3 1-Benzyloxycarbonyl-4-methoxymethoxy-L-proline 19.3 g, cyclohexylmethylamine 8.5 ml and N-hydroxysuccinimide 7.5
13.4 g of dicyclohexylcarbodiimide was added to a solution of 200 g of dioxane in 200 ml at room temperature.
After stirring for an hour, heat at 60 ° C. for 1 hour. Allow to cool and filter,
The solvent of the filtrate is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: 5% methanol / chloroform) to give 21.2 g of N- (1-benzyloxycarbonyl-4-methoxymethoxy-L-prolyl) -N-. Cyclohexylmethylamine is obtained as a pale yellow oil.

21.2 g of the obtained N- (1-benzyloxycarbonyl-4-methoxymethoxy-L-prolyl) -N-cyclohexylmethylamine in ethanol 20
2 g of 10% Pd-C is added to the 0 ml solution and hydrogenated for 3 hours. After the catalyst is filtered off, the filtrate is distilled off to obtain 14.9 g of N- (4-methoxymethoxy-L-prolyl) -N-cyclohexylmethylamine.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 0.9-1.8 (11
H, m), 2.0 (1H, m), 2.5 (1H, m),
2.96 (1H, dd, J = 3.8Hz, 12.5H
z), 3.08 (2H, dd, J = 6.5Hz, 12.
5Hz), 3.24 (1H, d, J = 12.5Hz),
3.37 (3H, s), 4.15 (1H, t, J = 8.
3 Hz), 4.3 (1H, m), 4.62 (1H, d,
J = 7 Hz), 4.66 (1H, d, J = 7 Hz),
7.94 (1H, br).

Reference Example 4 1- (2-Cyclooctylaminoethyl) -4 was prepared in the same manner as in Reference Example 1 using 3 g of 1- (2-aminoethyl) -4-methoxymethoxypiperidine and 2 g of cyclooctanone. -4.3 g of methoxymethoxypiperidine are obtained.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 1.3-2.0 (18
H, m), 2.05-2.2 (2H, m), 2.44
(2H, t, J = 6.1Hz), 2.55-2.85
(5H, m), 3.37 (3H, s), 3.5-3.6.
5 (1H, m), 4.68 (2H, s).

Reference Example 5 To a solution of 1.19 g of 1- (2-cyclooctylaminoethyl) -4-methoxymethoxypiperidine and 0.67 ml of triethylamine in 10 ml of dichloromethane was added dropwise 0.49 ml of 3-chloropropanesulfonyl chloride at 0 ° C. .. Then, after stirring at room temperature for 1 day, the reaction solution is washed with water. After drying over magnesium sulfate, the solvent is distilled off. The obtained residue is subjected to silica gel chromatography (eluent;
2% methanol / dichloromethane) and 1.
2 g of 1- {2- [N- (3-chloropropylsulfonyl) -N-cyclooctylamino] ethyl} -4-methoxymethoxypiperidine are obtained.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 1.35-2.05
(18H, m), 2.15-2.35 (4H, m),
2.57 (2H, t), 2.7-2.9 (2H, m),
3.16 (2H, t, J = 7.6Hz), 3.27 (2
H, t, J = 7.0 Hz), 3.37 (3H, s),
3.55-3.7 (1H, m), 3.69 (2H, t,
J = 6 Hz), 3.75-3.9 (1H, m), 4.6
8 (2H, s).

Reference Example 6 6- (4-chlorobutoxy) carbostyril 53.3 g
A solution of 32 g of sodium sulfite in 500 ml of water and 200 ml of ethanol is heated under reflux for 1 day. 3 days after cooling
The filtrate is acidified with dilute hydrochloric acid and the solvent is distilled off. Water was added to the obtained residue and the precipitate was collected by filtration to obtain 47.5 g of 6- (4-
Hydroxysulfonylbutoxy) carbostyril is obtained.

White powder.

Reference Example 7 300 g of phosphorus oxychloride was added to 47.5 g of 6- (4-hydroxysulfonylbutoxy) carbostyril, and the mixture was heated under reflux for 5 hours. Phosphorus oxychloride is distilled off under reduced pressure, and the obtained residue is diluted with chloroform. Next, ice is added, the organic layer is separated, dried over magnesium sulfate, and then the solvent is distilled off. Crystallized from n-hexane to give 48.17 g of 4-
(2-Chloro-6-quinolyloxy) butylsulfonyl chloride is obtained.

White powder.

Reference Example 8 1- [2- (2-chlorobenzylamino) ethyl] -4
-To a solution of 1.6 g of methoxymethoxypiperidine and 1 ml of triethylamine in 25 ml of dichloromethane was added 4-
(2-Chloro-6-quinolyloxy) butylsulfonyl chloride (1.75 g) is added at 0 ° C, and the mixture is stirred at room temperature for 1 day. The reaction solution is washed with water and dried over magnesium sulfate.
The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: 3% methanol / dichloromethane) to obtain 2.63 g of 2-chloro-6-.
[4- {N- (2-chlorobenzyl) -N- [2- (4
-Methoxymethoxy-1-piperidinyl) ethyl] aminosulfonyl} butoxy] quinoline is obtained.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 7.80-8.05
(2H, m), 7.58 (1H, d, J = 7.4H
z), 7.15-7.45 (5H, m), 7.07 (1
H, d, J = 2.6 Hz), 4.65 (2H, s),
4.60 (2H, s), 4.12 (2H, t, J = 5.
8 Hz), 3.45-3.60 (1 H, m), 3.10
-3.45 (7H, m), 2.60-2.80 (2H,
m), 2.44 (2H, t, J = 6.2Hz), 1.9
2-2.22 (6H, m), 1.75-1.92 (2
H, m), 1.45 to 1.75 (2H, m).

Reference Example 9 A suspension of 30 g of 6- (4-chlorobutoxy) carbostyril, 103 ml of benzylamine and 33 g of sodium iodide in 300 ml of dimethylformamide at 80 ° C.
Heat and stir for hours. After allowing to cool, the reaction solution is poured into water and the precipitated crystals are collected by filtration. Wash with water and diethyl ether to give 29.1 g of 6- (4-benzylaminobutoxy).
Get Carbostyril.

Light yellow powder.

Reference Example 10 To 10 ml of an aqueous solution of 0.38 g of carbon disulfide and 0.4 g of sodium hydroxide, 1.28 g of 6- (3-aminopropoxy) carbostyryl hydrochloride was added at 0 ° C. Then, after stirring at 80 ° C. for about 2 hours, 0.55 g of ethyl chlorocarbonate is added at 35 ° C., and the mixture is further stirred for 30 minutes. The reaction solution is poured into water and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off, and diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration, and then subjected to silica gel column chromatography (eluent; 3.3% methanol / dichloromethane). Purification gives 0.22 g of 6- (3-isothiocyanatopropoxy) carbostyril.

Reference Example 11 1- [2- (Cyclooctylmethylamino) ethyl]-
A solution of 3.13 g of 4-methoxymethoxypiperidine and 1.0 ml of 3-chloropropane isocyanate in 20 ml of dichloromethane is stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure, and 4.2 g of N-cyclooctylmethyl-N-
[2- (4-Methoxymethoxy-1-piperidinyl) ethyl] -N '-(3-chloropropyl) urea is obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.15
-1.8 (15H, m), 1.85-2.2 (6H,
m), 2.25-2.4 (2H, m), 2.51 (2
H, t, J = 5 Hz), 2.75-2.85 (2H,
m), 3.10 (2H, d, J = 7.5 Hz), 3.2
5-3.3 (4H, m), 3.37 (3H, s), 3.
55-3.7 (3H, m), 4.68 (2H, s).

The compounds shown in Tables 1 to 14 below are obtained in the same manner as in Reference Examples 1, 2 and 5 using appropriate starting materials.

[0177]

[Table 1]

[0178]

[Table 2]

[0179]

[Table 3]

[0180]

[Table 4]

[0181]

[Table 5]

[0182]

[Table 6]

[0183]

[Table 7]

[0184]

[Table 8]

[0185]

[Table 9]

[0186]

[Table 10]

[0187]

[Table 11]

[0188]

[Table 12]

[0189]

[Table 13]

[0190]

[Table 14]

The compounds shown in Table 15 below are obtained in the same manner as in Reference Example 3 using appropriate starting materials.

[0192]

[Table 15]

The compounds shown in Tables 16 to 22 below are obtained in the same manner as in Reference Example 5 using appropriate starting materials.

[0194]

[Table 16]

[0195]

[Table 17]

[0196]

[Table 18]

[0197]

[Table 19]

[0198]

[Table 20]

[0199]

[Table 21]

[0200]

[Table 22]

Example 1 6- (4-Bromobutoxy) carbostyril 800 m
1 g of 1- (2-benzylaminoethyl) -4-methoxymethoxypiperidine (700 mg) and sodium hydrogencarbonate (330 mg) in dimethylformamide (20 ml).
Heat and stir at 00 ° C. for 6 hours. After cooling, water is added to the reaction solution and an oily substance is obtained by decanting. This was dissolved in chloroform, washed with water, dried over magnesium sulfate, and the solvent was distilled off to give 1.07 g of 6- [4- {N- [2-
(4-Methoxymethoxy-1-piperidinyl) ethyl]
-N-benzylamino} butoxy] carbostyril is obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.5-
1.9 (8H, m), 2.12 (2H, m), 2.5
(4H, m) 2.6 (2H, m) 2.7 (2H,
m), 3.36 (3H, s), 3.6 (1H, m),
3.60 (2H, s), 3.95 (2H, t, J = 6H
z), 4.67 (2H, s), 6.71 (1H, d, J
= 9.5 Hz), 6.93 (1H, d, J = 2.5H)
z), 7.12 (1H, dd, J = 2.5Hz, 9H
z), 7.2-7.3 (6H, m).

Example 2 1.07 g of 6- [4- {N- [2- (4-methoxymethoxy-1-piperidinyl) ethyl] -N-benzylamino} butoxy] carbostyril methanol 10 ml
10% hydrochloric acid (10 ml) is added to the solution and the mixture is stirred at room temperature for 1 day. The reaction solution is washed with chloroform, made alkaline with 10% aqueous potassium hydroxide solution, and extracted with chloroform. After washing with water and drying over magnesium sulfate, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; 5% methanol / chloroform), and recrystallized from ethyl acetate-diethyl ether to give 3
30 mg of 6- [4- {N- [2- (4-hydroxy-
1-Piperidinyl) ethyl] -N-benzylamino} butoxy] carbostyril is obtained.

White powder, mp 126-131 ° C.

Example 3 6- [4- (N-ethoxycarbonylmethyl-N-cyclooctylmethyl) butoxy] carbostyril 795m
5 g of 1N sodium hydroxide aqueous solution and 5 ml of methanol are added to g, and the mixture is stirred at 50 ° C. for 2 hours. 1 reaction mixture
Neutralize with 0% aqueous hydrochloric acid, collect the precipitated solid by filtration, and
91 mg of 6- [4- (N-carboxymethyl-N-cyclooctylmethyl) butoxy] carbostyril are obtained.

White powder, mp 154-155 ° C.

Example 4 0.44 g of 6-hydroxycarbostyril, 0.45 g of potassium carbonate and 1- {2- [N- (3-chloropropylsulfonyl) -N-cyclooctylamino] ethyl}
A suspension of 1.2 g of -4-methoxymethoxypiperidine in 30 ml of dimethylformamide is heated and stirred at 90 ° C for 1 day. The reaction solution is poured into water and extracted with ethyl acetate. After washing with water and drying over magnesium sulfate, the obtained residue is subjected to silica gel column chromatography (eluent: 5%
0.76 after purification with methanol / dichloromethane
g of 6- [3- {N- [2- (4-methoxymethoxy-
1-Piperidinyl) ethyl-N-cyclooctylaminosulfonyl} propoxy] carbostyril is obtained.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 7.75 (1 H, d,
J = 9.5 Hz), 7.35 (1H, d, J = 9H)
z), 7.15 (1H, dd, J = 9Hz, 2.6H
z), 7.01 (1H, d, J = 2.6 Hz), 6.7
3 (1H, d, J = 9.5Hz), 4.68 (2H,
s), 4.15 (2H, t, J = 5.8Hz), 3.7
5-3.95 (1H, m), 3.58-3.69 (1
H, m), 3.37 (3H, s), 3.22-3.35.
(4H, m), 2.75-2.90 (2H, m), 2.
55-2.68 (2H, m), 2.18-2.40 (4
H, m), 1.40-2.05 (18H, m).

Example 5 2-Chloro-6- [4- {N- (2-chlorobenzyl)
A solution of 2.63 g of -N- [2- (4-methoxymethoxy-1-piperidinyl) ethyl] aminosulfonyl} butoxy] quinoline in 50 ml of acetic acid is heated under reflux for 3.5 hours. The solvent was distilled off under reduced pressure to obtain crude 6- [4- {N-
To (2-chlorobenzyl) -N- [2- (4-methoxymethoxy-1-piperidinyl) ethyl] aminosulfonyl} butoxy] carbostyril, 10 ml of methanol and 10 ml of 5% hydrochloric acid aqueous solution were added, and the mixture was stirred at room temperature for 1 day.
It is made alkaline with aqueous potassium hydroxide solution and extracted with ethyl acetate. After washing with water and drying with magnesium sulfate, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; 10% methanol / dichloromethane) to give 1.4 g of 6- [4- {N- (2-chlorobenzyl) -N- [2- (. 4-Hydroxy-1-piperidinyl) ethyl] aminosulfonyl} butoxy] carbostyril is obtained.

White powder, mp 147-152 ° C.

Example 6 6- (4-benzylaminobutoxy) carbostyril 8
To a dichloromethane solution of g and 7.6 ml of triethylamine at 0 ° C., 6.6 ml of 3-chloropropanesulfonyl chloride is added dropwise, and the mixture is stirred at room temperature for 1 day. The reaction solution is washed with 10% hydrochloric acid and water and then dried over magnesium sulfate. The residue obtained by distilling off the solvent is dioxane 30 m
It is dissolved in 1 l, 10 ml of 10% aqueous potassium hydroxide solution is added, and the mixture is stirred at room temperature for 30 minutes. After neutralizing with 10% hydrochloric acid,
Extract with chloroform and dry with magnesium sulfate. The solvent was distilled off and the obtained residue was crystallized with diethyl ether to obtain 7.3 g of 6- {4- [N- (3-chloropropylsulfonyl) -N-benzylamino] butoxy} carbostyril.

White powder ¹ H-NMR (CDCl ₃ ) δ; 1.6-1.7 (4
H, m), 2.25-2.35 (2H, m), 3.11
(2H, t, J = 7.5Hz), 3.25-3.35.
(2H, m), 3.67 (2H, t, J = 6.0H
z). 3.9-4.0 (2H, m), 4.44 (2H,
s), 6.71 (2H, d, J = 9.5Hz), 6.9.
2 (1H, d, J = 2.5 Hz), 7.09 (2H, d
d, J = 2.5 Hz, 9.0 Hz), 7.3-7.4.
(6H, m), 7.73 (1H, d, J = 9.5H
z).

Example 7 6- {4- [N- (3-chloropropylsulfonyl)-
N-benzylamino] butoxy} carbostyril 1.0
g and 1,2,4-triazole 600 mg at 140 ° C
Heat and stir for 3 hours. The reaction solution is diluted with dioxane and the precipitated crystals are collected by filtration. After purification by color chromatography (eluent; 3% methanol / chloroform), recrystallization from ethyl acetate was performed and 327 mg of 6- [4- {N was obtained.
-[3- (1,2,4-Triazol-1-yl) propylsulfonyl] -N-benzylamino} butoxy] carbostyril is obtained.

Light yellow powder, mp 137-139 ° C.

Example 8 6.7 g of 6- (4-chlorobutyl) carbostyril, 1
A solution of 5 g of-(2-aminoethyl) -4-methoxymethoxypiperidine, 4.0 g of sodium iodide and 2.3 g of sodium hydrogen carbonate in 30 ml of dimethylformamide was stirred at 80 ° C for 4 hours. The reaction solution is diluted with chloroform, washed with water and extracted with 5% hydrochloric acid. It is made alkaline with 10% potassium hydroxide and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off to give 9.01 g.
To give 6- {4- [2- (4-methoxymethoxy-1-piperidinyl) ethyl] aminobutoxy} carbostyril.

Pale yellow oily ¹ H-NMR (CDCl ₃ ) δ; 1.5-1.7 (2
H, m), 1.75-1.9 (4H, m), 2.15.
2.3 (2H, m), 2.6-2.7 (2H, m),
2.7-2.8 (2H, m), 2.85-2.95 (4
H, m), 3.45 (3H, s), 3.5-3.65.
(1H, m), 3.95-4.05 (2H, m), 4.
65 (2H, s), 6.64 (1H, d, J = 9.5H
z), 6.91 (1H, d, J = 2.5 Hz), 7.0
5 (1H, dd, J = 2.5Hz, 9.0Hz), 7.
39 (1H, d, J = 9.0 Hz), 7.70 (1H,
d, J = 9.5 Hz), 8.00 (1H, br).

Example 9 6- {4- [2- (4-methoxymethoxy-1-piperidinyl) ethyl] aminobutoxy} carbostyril 2.
5 g, cyclohexyl methanesulfonyl chloride 1.5
g and 1.35 ml of triethylamine in 30 ml of dichloromethane are stirred at room temperature for 16 hours. After washing with water and drying with magnesium sulfate, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; 3% methanol / chloroform) to give 620 mg of 6- {4- {N- [2- (4-methoxymethoxy-1-
Piperidinyl) ethyl] -N-cyclohexylmethylsulfonylamino} butoxy] carbostyril is obtained.

Light yellow oily ¹ H-NMR (CDCl ₃ ) δ; 1.0-2.0 (19
H, m), 2.1-2.3 (2H, m), 2.4-2.
6 (2H, m), 2.7-2.9 (2H, m), 3.2
-3.4 (4H, m), 3.36 (3H, s), 3.5
-3.65 (1H, m), 3.95-4.05 (2H,
m), 4.67 (2H, s), 6.71 (1H, d, J
= 9.5 Hz), 7.13 (1H, dd, J = 2.5H)
z, 9.0 Hz), 7.34 (1H, d, J = 9.0H)
z), 7.75 (1H, d, J = 9.5Hz).

Example 10 0.22 g of 6- (3-isothiocyanatopropoxy) carbostyril and 1- [2- (cyclooctylmethylamino) ethyl] -4-methoxymethoxypiperidine.
A solution of 3 g of chloroform in 30 ml is stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: 3% methanol / dichloromethane) to give 0.36 g of 6- [3-
Obtain {N- (2- (4-methoxymethoxy-1-piperidinyl) ethyl-N-cyclooctylmethylamino} thiocarbonylaminopropoxy] carbostyril.

Colorless oil.

Example 11 6-Hydroxycarbostyril 1.6 g, potassium carbonate 1.4 g and N-cyclooctylmethyl-N- [2-
(4-Methoxymethoxy-1-piperidinyl) ethyl]
A solution of 4.2 g of -N '-(3-chloropropyl) urea in 20 ml of dimethylformamide is heated and stirred at 80 ° C for 1 day. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing with water and drying over magnesium sulfate, the solvent is distilled off. The obtained residue is purified by silica gel chromatography (eluent; 5% methanol / dichloromethane) to give 0.76 g of 6- [3- {N- [2- (4-methoxymethoxy-1-piperidinyl) ethyl]. -N-cyclooctylmethylamino} carbonylaminopropoxy]
Get Carbostyril.

Brown oily ¹ H-NMR (CDCl ₃ ) δ; 7.73 (1 H, d,
J = 9.5 Hz), 7.40 (1H, br), 7.29
(1H, d, J = 11.4Hz), 7.15 (1H, d
d, J = 11.4 Hz, 2.5 Hz), 7.01 (1
H, d, 2.5 Hz), 6.70 (1 H, d, J = 9.
5 Hz), 4.65 (2H, s), 4.06 (2H, s)
t, J = 6.2 Hz), 3.15-3.65 (8H,
m), 3.10 (2H, d, J = 7.5 Hz), 2.6
5-2.90 (2H, m), 2.35-2.60 (2
H, m), 2.10-2.35 (2H, m), 1.97.
-2.10 (2H, t, J = 6.5Hz), 1.10-
1.97 (19H, m).

Example 12 A solution of 6- [3- (N-cyclohexyl-N-methylaminocarbonyl) propoxy] carbostyril 0.68 g and Lawesson's reagent 0.81 g in toluene 10 ml was added to 1.
Heat to reflux for 5 hours. After cooling, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (eluent: 2
% Methanol / dichloromethane) to give 0.69
g of 6- [3- (N-cyclohexyl-N-methylaminothiocarbonyl) propoxy] thiocarbostyril is obtained.

Yellow powder mp 170-172 ° C.

Example 13 A solution of 13.7 g of 6- [3- (N-cyclohexyl-N-methylaminocarbonyl) propoxy] carbostyril and 4.45 g of phosphorus pentasulfide in 200 ml of benzene is heated under reflux for 5 hours. After allowing to cool, the insoluble matter is distilled off, and then the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: 5% methanol / dichloromethane) to give 7.2 g of 6- [3- (N-cyclohexyl-N-methylaminothiocarbonyl) propoxy] carbostyril. To get

Yellow powder, mp 167-170 ° C.

Compounds shown in Tables 23 to 56 below are obtained in the same manner as in Example 4 using appropriate starting materials.

[0228]

[Table 23]

[0229]

[Table 24]

[0230]

[Table 25]

[0231]

[Table 26]

[0232]

[Table 27]

[0233]

[Table 28]

[0234]

[Table 29]

[0235]

[Table 30]

[0236]

[Table 31]

[0237]

[Table 32]

[0238]

[Table 33]

[0239]

[Table 34]

[0240]

[Table 35]

[0241]

[Table 36]

[0242]

[Table 37]

[0243]

[Table 38]

[0244]

[Table 39]

[0245]

[Table 40]

[0246]

[Table 41]

[0247]

[Table 42]

[0248]

[Table 43]

[0249]

[Table 44]

[0250]

[Table 45]

[0251]

[Table 46]

[0252]

[Table 47]

[0253]

[Table 48]

[0254]

[Table 49]

[0255]

[Table 50]

[0256]

[Table 51]

[0257]

[Table 52]

[0258]

[Table 53]

[0259]

[Table 54]

[0260]

[Table 55]

[0261]

[Table 56]

(1) ¹ H-NMR (CDCl ₃ ) δ;
1.2-2.0 (21H, m), 2.15-2.25
(2H, m) 2.7-2.9 (2H, m) 3.1-
3.3 (4H, m), 3.3-3.5 (2H, m),
3.6-3.7 (1H, m), 3.9-4.1 (2H,
m), 6.71 (1H, d, J = 9.5 Hz), 6.9
-7.4 (3H, m), 7.74 (1H, d, J = 9.
5 Hz).

(2) ¹ H-NMR (CDCl ₃ ) δ;
1.4-1.9 (10H, m), 2.1-2.3 (2
H, m), 2.45-2.55 (4H, m), 2.6-
2.7 (2H, m), 2.7-2.8 (2H, m),
3.54 (2H, s), 3.65-3.75 (2H,
m), 3.86 (6H, s), 3.97 (2H, t, J
= 6.5 Hz), 6.70 (1H, d, J = 9.5H)
z), 6.75-6.85 (2H, m), 6.91 (1
H, m), 6.97 (1H, d, J = 2.5 Hz),
7.13 (1H, dd, J = 2.5Hz, 9.0H
z), 7.29 (1H, d, J = 9.0 Hz), 7.7
3 (1H, d, J = 9.5 Hz).

(3) ¹ H-NMR (CDCl ₃ ) δ;
1.35-1.7 (6H, m), 1.7-2.0 (4
H, m), 2.05-2.25 (2H, m), 2.4-
2.65 (4H, m), 2.65-2.85 (4H,
m), 3.6-3.8 (3H, m), 3.97 (2H,
t, J = 6 Hz), 6.72 (1H, d, J = 9.5H)
z), 6.97 (1H, d, J = 2.5Hz), 7.0
5-7.2 (2H, m), 7.37 (1H, d, J = 9
Hz), 7.38-7.58 (1H, m), 7.63
(1H, dt, J = 7.5Hz, 1.5Hz), 7.7
5 (1H, d, J = 9.5 Hz), 8.41-8.61
(1H, m).

(4) ¹ H-NMR (CD ₃ OD) δ;
1.40-1.95 (10H, m), 2.25 (2H,
brt, J = 8.5 Hz), 2.40-2.90 (8
H, m), 3.50-3.70 (1H, m), 3.85.
(2H, s), 4.03 (2H, t, J = 6.5H
z), 6.60 (1H, d, J = 9.5 Hz), 6.9
4 (2H, brs), 7.15-7.35 (4H,
m), 7.92 (1H, d, J = 9.5Hz).

(5) ¹ H-NMR (CDCl ₃ ) δ;
1.15-2.00 (25H, m), 2.20 (2H,
brd, J = 6.5 Hz), 2.45-2.60 (2
H, m), 2.85 (2H, brs), 3.05-3.
50 (4H, m), 4.01 (2H, t, J = 6.5H
z), 6.71 (1H, d, J = 9.5 Hz), 7.0
0 (1H, brs), 7.10-7.40 (3H,
m), 7.76 (1H, d, J = 9.5 Hz).

(6) ¹ H-NMR (CD ₃ OD) δ;
1.15-1.90 (23H, m), 2.01 (2H, m
brt, J = 12 Hz), 2.10-2.35 (2H,
m), 2.29 (6H, s), 2.35-2.60 (6)
H, m), 3.01 (2H, brd, J = 12Hz),
4.06 (2H, t, J = 6Hz), 6.61 (1H,
d, J = 9.5 Hz), 7.15-7.35 (3H,
m), 7.92 (1H, d, J = 9.5Hz).

(7) ¹ H-NMR (CD ₃ OD) δ;
0.90-1.10 (2H, m), 1.15-2.15
(19H, m), 2.60-3.75 (13H, m),
4.07 (2H, t, J = 6Hz), 6.62 (1H,
d, J = 9.5 Hz), 7.15-7.35 (3H,
m), 7.94 (1H, d, J = 9.5 Hz).

(8) ¹ H-NMR (CD ₃ OD) δ;
1.45-2.10 (10H, m), 2.25-2.5
0 (2H, m), 2.61 (1H, brs), 2.75
-3.30 (5H, m), 2.98 (3H, s), 3.
03 (3H, s), 3.77 (1H, brs), 4.0
6 (2H, brs), 4.38 (1H, brd, J = 1
2Hz), 6.51 (1H, d, J = 9.5Hz),
7.16 (2H, brs), 7.29 (1H, br)
s), 7.40-7.60 (5H, m), 7.91 (1
H, d, J = 9.5 Hz).

(9) ¹ H-NMR (CDCl ₃ ) δ;
1.40-2.05 (8H, m), 2.15-2.70
(5H, m), 2.90-3.20 (2H, m), 3.
35-3.80 (6H, m), 3.97 (2H, t, J
= 6.5 Hz), 6.70 (1H, d, J = 9.5H)
z), 6.98 (1H, d, J = 2.5 Hz), 7.1
0-7.60 (6H, m), 7.74 (2H, d, J =
9.5 Hz).

(10) ¹ H-NMR (CD ₃ OD) δ;
1.4-1.9 (6H, m), 2.3-2.7 (16
H, m), 3.55-3.75 (4H, m), 4.01.
(2H, t, J = 6.5 Hz), 6.01 (1H, d,
J = 9.5 Hz), 7.15-7.45 (8H, m),
7.91 (1H, d, J = 9.5 Hz).

(11) ¹ H-NMR (CD ₃ OD) δ;
1.10-1.95 (19H, m), 2.24 (2H,
d, J = 7 Hz), 2.57 (2H, t, J = 7H
z), 2.70 (2H, t, J = 6Hz), 2.90-
3.10 (4H, m), 3.74 (2H, t, J = 5.
5 Hz), 4.07 (2H, t, J = 6 Hz), 6.6
2 (1H, d, J = 9.5 Hz), 7.15-7.35
(3H, m), 7.92 (1H, d, J = 9.5H
z).

(12) ¹ H-NMR (CD ₃ OD) δ;
1.30-1.75 (6H, m), 2.46 (2H,
t, J = 6 Hz), 2.77 (2H, t, J = 6H)
z), 3.60 (2H, s), 3.96 (2H, t, J
= 6 Hz), 4.05 (2H, t, J = 6 Hz), 6.
61 (1H, d, J = 9.5 Hz), 6.91 (1H,
s), 7.05 (1H, s), 7.10-7.35 (8)
H, m), 7.60 (1H, s), 7.91 (1H,
d, J = 9.5 Hz).

(13) ¹ H-NMR (CDCl ₃ ) δ;
1.2-1.9 (19H, m), 1.95-2.1 (2
H, m), 2.15-2.25 (2H, m), 2.49
(2H, t), 2.7-2.85 (2H, m), 3.1
(2H, d, J = 7.5Hz), 3.27 (2H,
t) 3.3-3.45 (2H, m), 3.65-3.
8 (1H, m), 4.07 (2H, t, J = 6Hz),
6.7 (1H, d, J = 9.5Hz), 7.00 (1
H, d, J = 2.5Hz), 7.15 (1H, dd, J
= 2.5Hz, 9Hz), 7.3 (1H, d, J = 9H
z), 7.73 (1 H, d, J = 9.5 Hz).

(14) ¹ H-NMR (CDCl ₃ ) δ;
1.5-1.9 (8H, m), 2.12 (2H, m),
2.5 (4H, m), 2.6 (2H, m), 2.7 (2
H, m), 3.36 (3H, s), 3.6 (1H,
m), 3.60 (2H, s), 3.95 (2H, t, J
= 6 Hz), 4.67 (2H, s), 6.71 (1H,
d, J = 9.5 Hz), 6.93 (1H, d, J = 2.
5Hz), 7.12 (1H, dd, 2.5Hz, 9H
z), 7.2-7.3 (6H, m).

(15) ¹ H-NMR (CDCl ₃ ) δ;
1.7-2.0 (8H, m), 2.3 (2H, m),
2.5 (2H, m), 2.8 (2H, m), 3.37
(3H, s), 3.4 (2H, m), 3.5 (2H,
m), 3.6 (1H, m), 4.02 (2H, t, J =
6 Hz), 4.68 (2H, s), 6.63-6.73
(4H, m), 6.97 (1H, d, J = 2.5H
z), 7.12-7.23 (3H, m), 7.33 (1
H, d, J = 9 Hz), 7.74 (1H, d, J = 9.
5 Hz).

(16) ¹ H-NMR (CDCl ₃ ) δ;
7.75 (1H, d, J = 9.5Hz), 7.35 (1
H, d, J = 9 Hz), 7.15 (1H, dd, J = 9)
Hz, 2.6 Hz), 7.01 (1H, d, J = 2.6)
Hz), 6.73 (1H, d, J = 9.5 Hz), 4.
68 (2H, s), 4.15 (2H, t, J = 5.8H
z), 3.75-3.95 (1H, m), 3.58-
3.69 (1H, m), 3.37 (3H, s), 3.2
2-3.35 (4H, m), 2.75-2.90 (2
H, m), 2.55-2.68 (2H, m), 2.18
-2.40 (4H, m), 1.40-2.05 (18
H, m).

(17) ¹ H-NMR (CDCl ₃ ) δ;
7.73 (1H, d, J = 9.5 Hz), 7.40 (1
H, br), 7.29 (1H, d, J = 11.4H
z), 7.15 (1H, dd, J = 11.4 Hz, 2.
5 Hz), 7.01 (1H, d, J = 2.5 Hz),
6.70 (1H, d, J = 9.5Hz), 4.65 (2
H, s), 4.06 (2H, t, J = 6.2Hz),
3.15-3.65 (8H, m), 3.10 (2H,
d, J = 7.5 Hz), 2.65-2.90 (2H,
m), 2.35-2.60 (2H, m), 2.10-
2.35 (2H, m), 1.97-2.10 (2H,
t, J = 6.5 Hz), 1.10-1.97 (19H,
m).

(18) ¹ H-NMR (CDCl ₃ ) δ;
1.15-1.85 (15H, m), 2.2-2.4
(2H, m), 2.45-2.8 (4H, m), 2.8
5-3.1 (4H, m), 3.15-3.4 (10H,
m), 4.05-4.2 (4H, m), 4.55-4.
7 (4H, m), 6.72 (1H, d, J = 9.5H
z), 7.0 (1H, d, J = 2.5 Hz), 7.15
(1H, dd, J = 2.5Hz, 9.0Hz), 7.3
2 (1H, d, J = 9Hz), 7.74 (1H, d, J
= 9.5 Hz).

(19) ¹ H-NMR (CDCl ₃ ) δ;
1.10-2.00 (23H, m), 2.10-2.6
5 (8H, m), 2.80-3.25 (2H, m),
3.36 (3H, s), 3.45-3.65 (2H,
m), 3.95-4.10 (2H, m), 4.63 (2
H, s), 6.70 (1H, d, J = 9.5 Hz),
6.99 (1H, brs), 7.15 (1H, brd,
J = 9 Hz), 7.31 (1H, d, J = 9 Hz),
7.74 (1H, d, J = 9.5 Hz).

(20) ¹ H-NMR (CDCl ₃ ) δ;
1.5-1.7 (2H, m), 1.75-1.9 (4
H, m), 2.15-2.3 (2H, m), 2.6-
2.7 (2H, m), 2.7-2.8 (2H, m),
2.85-2.95 (4H, m), 3.45 (3H,
s), 3.5-3.65 (1H, m), 3.95-4.
05 (2H, m), 4.65 (2H, s), 6.64
(1H, d, J = 9.5 Hz), 6.91 (1H, d,
J = 2.5 Hz), 7.05 (1H, dd, J = 2.5
Hz, 9.0 Hz), 7.39 (1H, d, J = 9.0)
Hz), 7.70 (1H, d, J = 9.5 Hz), 8.
00 (1H, br).

(21) ¹ H-NMR (CDCl ₃ ) δ;
1.0-2.0 (19H, m), 2.1-2.3 (2
H, m), 2.4-2.6 (2H, m), 2.7-2.
9 (2H, m), 3.2-3.4 (4H, m), 3.3
6 (3H, s), 3.5-3.65 (1H, m), 3.
95-4.05 (2H, m), 4.67 (2H, s),
6.71 (1H, d, J = 9.5 Hz), 7.13 (1
H, dd, J = 2.5 Hz, 9.0 Hz), 7.34
(1H, d, J = 9.0 Hz), 7.75 (1H, d,
J = 9.5 Hz).

(22) ¹ H-NMR (CDCl ₃ ) δ;
1.6-1.7 (4H, m), 2.25-2.35 (2
H, m), 3.11 (2H, t, J = 7.5 Hz),
3.25-3.35 (2H, m), 3.67 (2H, m
t, J = 6.0 Hz). 3.9-4.0 (2H, m),
4.44 (2H, s), 6.71 (2H, d, J = 9.
5Hz), 6.92 (1H, d, J = 2.5Hz),
7.09 (1H, d, J = 2.5Hz, 9.0Hz),
7.3-7.4 (6H, m), 7.73 (1H, d, J
= 9.5 Hz).

Example 146 Using the appropriate starting materials and in the same manner as in Examples 1 and 8 above, Examples 4, 14-75, 115-130, 1
The compounds 37, 140, 141, 142 and 145 are obtained.

Example 147 Using the appropriate starting materials, in the same manner as in Example 2, the above Examples 14-18, 20-26, 28-42, 48-52,
54, 55, 57, 71-75, 78-96, 99, 1
02-104, 106, 115, 117, 119, 12
4, 126-132 and 134 compounds are obtained.

Example 148 The compound of the above Example 113 was obtained in the same manner as in Example 3 using appropriate starting materials.

Example 149 The compounds of Examples 76 to 92, 94 to 114 and 144 were obtained in the same manner as in Example 5 using appropriate starting materials.

Example 150 Examples 14-71, 76-141 and 143-145 were prepared in the same manner as Examples 6 and 9 using appropriate starting materials.
To obtain the compound of

Example 151 The compounds of Examples 115 to 122 and 124 to 126 were obtained in the same manner as in Example 7 using appropriate starting materials.

Example 152 The compound of the above Example 132 was obtained in the same manner as in Example 10 using appropriate starting materials.

Example 153 The above Examples 131 and 133 are obtained in the same manner as in Example 11 using appropriate starting materials.

Pharmacological Test Example I The inhibitory effect on platelet aggregation of the test compound was determined by the method of Born et al. [J. Physiol., London, 162, 67 (196).
2)], the platelet aggregometer [Platelet Aggregation T
racer, manufactured by Nikko Bioscience Co., Ltd.].

[0293] Blood collected from human was mixed with 3.8% sodium citrate at a ratio of 1 volume to 9 volumes of the blood, and this sample was centrifuged at 1100 rpm for 10 minutes to obtain platelet-rich plasma [platelet]. rich plasma (PRP)] was obtained. The remaining sample was further centrifuged at 3000 rpm for 15 minutes to perform platelet poor plasma (PP
P)] was obtained.

[0294] The number of platelets in the PRP obtained above was determined by using the Coulter Counter (Coulter elect).
ronics inc.), and the PRP solution was prepared by diluting the PRP with PPP so that the platelet count was 300,000 / μl.

2 μl of a solution containing the test compound at a predetermined concentration and 200 μl of the PRP solution prepared above were placed in a cell for agglutination measurement, heated at 37 ° C. for 1 minute, and then adenosine dichloride was added to this cell. Phosphate (ADP, Sigma) or collagen suspension (Collagen Reagent Hor
20 μl of either m, Hormon-Chemie) was added to induce platelet aggregation, and the change in the permeability was measured to prepare a platelet aggregation curve. The final concentrations of ADP and collagen were 7.5 μM and 20 μM, respectively.
It was prepared to be g / ml.

[0296] Maximum Aggregatio of Platelets
n Rate (MAR)] was calculated from the platelet aggregation curve by the following formula.

MAR = (b−a) / (c−a) × 100 where a is the transmittance of PRP obtained by the same test,
b indicates the permeability of the PRP solution containing the test compound and the aggregation inducer in the above test at the maximum change, and c indicates the permeability of PPP determined by the same test.

Also, the MAR was similarly calculated for the control to which the test compound was not added, and the rate of inhibition (%) of the platelet aggregation of each test compound at various concentrations in the above test was calculated based on this value. , Calculated by the following formula.

[0299]

[Equation 1]

The platelet aggregation inhibitory rate (%) at various concentrations of the test compound was determined, and from the above values, 5 of each test compound was obtained.
The 0% platelet aggregation inhibitory concentration (IC ₅₀ ) was determined.

The above IC ₅₀ values obtained by using the compounds obtained in the above Examples as test compounds are shown in Table 57 and Table 5.
8 shows.

[0302]

[Table 57]

[0303]

[Table 58]

Pharmacological Test Example II The effects of increasing the heart rate and lowering blood pressure were measured by using a miscellaneous dog (body weight: 10
It was measured as follows using 20 kg). That is, the dog was anesthetized by intravenous administration of sodium pentobarbital, fixed in the dorsal position, and tested under artificial respiration. Blood pressure was measured by a blood pressure transducer (P23XL, Gould Statham Instruments I) via a cannula inserted in the femoral artery.
nc.). The heart rate was measured by the pulse wave of the above blood pressure through a tachometer. These signals were recorded on a hot pen recorder (Recti-Horiz 8K, NEC Sanei).

The compound obtained in each of the above Examples was used as a test compound, and the compounds were dissolved in N, N'-dimethylformamide to obtain 300 μg / kg from the cannula inserted into the femoral vein of the test dog. The test compound was administered in an amount and the heart rate after administration of the test compound was measured as described above, and the maximum change value thereof was determined.

The results obtained are shown in Table 59.

[0307]

[Table 59]

Pharmacological Test Example III 0.1% Ethylenediaminetetraacetic acid disodium salt (EDTA.4N from healthy humans with normal platelet function)
a) Blood is collected by adding blood and platelet-rich plasma (PR)
P) was separated. Then, Tyrode buffer (50 mM Tris, 0.1% EDTA, Ca (-), Mg (-),
The cells were washed twice with 0.14% BSA added (pH = 7.4), adjusted to a platelet count of 300,000 / μl and suspended in the same buffer (EDTA-WP). As for collagen, 4 mg of Sigma type I (from bovine skin) was dissolved in 0.25 ml of 83.5 mM acetic acid, and 8 ml of distilled water was added.
After ultrasonically suspending at 2 ° C. for 2 minutes, 5 ml of the supernatant was taken as a collagen solution. The compound is 2 _x 10 ^-2 as much as possible
Dimethylformamide (D
It was dissolved in MF). The platelet adhesion tracer (Nikko Bioscience), which is usually used for the platelet aggregation test method, is used to measure the change in turbidity of the platelet suspension and the change in transmitted light through the glass cuvette to measure the platelet adhesion. did. Note that the sensitivity of the recorder is five times higher than normal (20
The change was traced as mV). Add 200 μl of EDTA-WP to the attached glass qubit and further add 1 μl of the compound solution and incubate at room temperature for 5 minutes, then set the cuvette on the platelet tracer and wait for 1 minute until 37 ° C. Collagen solution 20 μl (50 μg
/ Ml) before and after addition to measure platelet adhesion.

The collagen adhesion inhibition rate (%) of each test compound at various concentrations in the above test was calculated by the following formula.

[0310]

[Equation 2]

The results are shown in Table 60.

[0312]

[Table 60]

Pharmacological Test IV The cyclic AMP phosphodiesterase inhibitory action of the compound of the present invention was examined by Biochimica et Biophysica Acta Vol. 429,
485-497 (1976) and Biochemical Medicine Vol. 10, 3
The measurement was performed according to the method described on pages 01 to 311 (1974).

That is, a solution of MgCl ₂ (1 mmol) in Tris-HCl buffer (50 mmol) was added to platelets obtained by further centrifuging the human PRP sample used in the pharmacological test example 1 at 3000 rpm for 10 minutes. (PH
7.4, 10 ml) was added, and the platelets were ground with a homogenizer, then freeze-thawed twice, further subjected to ultrasonic treatment and ultracentrifugation, and the supernatant was used as a crude enzyme solution.

10 ml of this crude enzyme solution was added to Tris-HCl.
DE buffered with buffer (pH 6.0, 50 mmol)
It was passed through an AE-cellulose column and washed and eluted with 30 ml of the same buffer. Using sodium acetate-Tris-HCl buffer solution, 0.5 ml /
Elution was carried out in 5 ml fractions at a flow rate of minutes (total eluate volume, about 300 ml). This gives 100
It has a weak activity of 2 nanomol / ml / min or less at a high cyclic AMP substrate concentration of micromolar, and 0.4
10 at low micromolar cyclic AMP substrate concentration
A fraction having a strong activity of 0 pmol / ml / min or more was obtained and used as a cyclic AMP phosphodiesterase.

0.1 ml of test compound aqueous solutions with various concentrations and cyclic AMP (tritium cyclic AMP)
Tris-HCl buffer containing 0.4 μmol (pH
8.0, 40 mmol, containing 50 μg of bovine serum albumin and 4 mmol of MgCl ₂ ) and mixed with the substrate solution.
2 ml was prepared.

0.2 ml of the cyclic AMP phosphodiesterase solution was added to the above substrate solution, and the mixture was kept at 30 ° C. for 2 hours.
After reacting for 0 minutes, tritium cyclic AMP was changed to tritium 5′-AMP. The reaction solution was immersed in boiling water to stop the reaction, and then cooled in ice water. Add 0.05ml of snake venom (1mg / ml) to this,
By reacting for 10 minutes with tritium 5'-AMP to tritium adenosine, the reaction solution was passed through a cation exchange resin to adsorb tritium adenosine, washed with distilled water, and eluted with 1.5 ml of 3N ammonia water. .. The phosphodiesterase activity of this eluate was measured by measuring the amount of tritium adenosine produced using a liquid scintillation counter according to a conventional method.

From this result, the phosphodiesterase activity value (Vs) of the test compound at each concentration was determined, and from the activity value (Vc) of the control (water containing no test compound), the phosphodiesterase inhibition rate (%) was calculated by the following formula. Was calculated.

Phosphodiesterase inhibition rate (%) =
[(Vc-Vs) / Vc] × 100 The phosphodiesterase inhibition rate (%) at various concentrations of the test compound was determined, and from these values, 5 of each test compound was obtained.
The 0% phosphodiesterase inhibitory concentration (IC ₅₀ ) was determined.

Table 61 shows the IC ₅₀ values obtained by using the compounds obtained in the above Examples as test compounds.

[0321]

[Table 61]

Formulation Example 1 Preparation of tablets 5 mg each of 6- [4- {N-cyclooctylmethyl-N- [2- (4-hydroxy-1-piperidinyl)
1000 tablets for oral administration containing ethyl] amino} butoxy] carbostyril are prepared according to the following formulation.

Arrangement Amount (g) 6- [4- {N-cyclooctylmethyl-N- [2- (4-hydroxy-1-piperidinyl) ethyl] 5 amino} butoxy] carbostyryl lactose (Japanese Pharmacopoeia) 50 Corn starch ( Japanese Pharmacopoeia 25) Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium stearate (Japanese Pharmacopoeia) 1 That is, 6- [4- {N-cyclooctylmethyl-N] −
[2- (4-hydroxy-1-piperidinyl) ethyl]
Amino} butoxy] carbostyril, lactose, corn starch and crystalline cellulose are mixed thoroughly, the mixture is granulated with a 5% aqueous solution of methylcellulose and carefully dried through a 200 mesh screen. The dried granules are passed through a 200 mesh screen and mixed with magnesium stearate and pressed into tablets.

Formulation Example 2 Preparation of capsules 10 mg each of 6- [3- {N-benzyl-N-
[2- (4-hydroxy-1-piperidinyl) ethyl]
1000 2-piece hard gelatin capsules for oral use containing Aminosulfonyl} propoxy] carbostyril are prepared by the following formulation.

Arrangement Amount (g) 6- [3- {N-benzyl-N- [2- (4-hydroxy-1-piperidinyl) ethyl] 10 aminosulfonyl} propoxy] carbostyril lactose (Japanese Pharmacopoeia) 80 starch (Japanese Pharmacopoeia product) 30 Talc (Japanese Pharmacopoeia product) 5 Magnesium stearate (Japanese Pharmacopoeia product) 1 That is, each of the above components is finely powdered and sufficiently stirred to form a uniform mixture, and then the desired mixture is obtained. Fill into gelatin capsules for oral administration with dimensions.

Formulation Example 2 Preparation of Injection A sterilized aqueous solution suitable for parenteral administration is prepared according to the following formulation.

Arrangement Amount (g) 6- [4- {N-cyclohexylmethyl-N- (2,3-dihydroxypropyl) amino} butoxy 1 cis] carbostyryl polyethylene glycol (Japanese Pharmacopoeia) (molecular weight: 4000) 0.3 Chloride Sodium (Japanese Pharmacopoeia) 0.9 Polyoxyethylenesorbitan monooleate (Japanese Pharmacopoeia) 0.4 Sodium metabisulfite 0.1 Methyl-paraben (Japanese Pharmacopoeia) 0.18 Propyl-paraben (Japan Pharmacopoeia) 0.02 100 ml of distilled water for injection, that is, the above-mentioned parabens, sodium metabisulfite and sodium chloride are dissolved in about half amount of distilled water at 80 ° C with stirring, and the resulting solution is 40 ° C. To 6- [4- {N-cyclohexylmethyl-N-
(2,3-Dihydroxypropyl) amino} butoxy]
Carbostyril, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved, and then distilled water for injection is added to the resulting solution to make the final volume, and sterile filtered using an appropriate filter paper. To prepare an injection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/47 AED 31/495 ACD 7252-4C 31/535 ABX 7252-4C C07D 215/36 401 / 12 8829-4C 401/14 8829-4C 405/12 215 8829-4C 409/12 215 8829-4C 413/12 8829-4C 417/12 215 9051-4C 491/113 7019-4C (72) Inventor Nobuyuki Koga 1-16-7 Minamikurahonmachi, Tokushima City, Tokushima Prefecture (72) Inventor Mikiyasu Saito 10 463 Kagasuno, Kawauchi Town, Tokushima City, Tokushima Prefecture (72) Inventor Takao Nishi Taro Yasu, Kitajima Town, Itano County, Tokushima Prefecture 2 House number 28

Claims (2)

[Claims] 1. A general formula:[In formula, A shows a lower alkylene group. R is a group -NR¹
R², Group-SO₂NR³R^FourOr group -Y-NR^FiveR⁶To
Show. R¹Is a group-(CO) l-B- (CO) m-NR⁷
R⁸(Here, 1 and m are 0 or 1. B is a lower alcohol.
Indicates a xylene group. R⁷And R⁸Are the same or different,
Hydrogen atom, lower alkyl group which may have a hydroxyl group,
Alternatively, it represents a lower alkanoyl group. Also R⁷And R⁸Is
Along with the nitrogen atom to which these bind,
Preferably bound to each other via a sulfur atom
May form a saturated 5- or 6-membered heterocycle. The complex
The ring has a hydroxyl group, a lower alkoxy or a lower alkoxy group or
As a lower alkyl group that may have a hydroxyl group, a substituent
Amino group, which may have a lower alkyl group,
Lucoxy lower alkoxy group, oxo group and substituent
Aminocarbonyl group which may have a lower alkyl group
1 to 3 groups selected from the group consisting of may be substituted.
In addition, a lower alkylenedioxy group is substituted on the heterocycle
You may stay. ); Lower alkoxycarbonyl group substituted lower
Alkyl group; carboxy group substituted lower alkyl group; Substituent
Which may have a lower alkyl group as
Nyl group substituted lower alkyl group; lower alkyl group having hydroxyl group
Group; imidazolyl substituted lower alkyl group; pyridyl substituted
Lower alkyl group; lower alkyl group as a substituent on the pyrrolidine ring
Alkyl group, lower alkoxy, lower alkoxy group and hydroxyl group
Pyro that may have 1 to 3 groups selected from the group consisting of
Lysinyl lower alkyl group; or group -SO₂-DR
⁹(D represents a lower alkylene group. R⁹Is a halogen source
A 5- or 6-membered saturated or branched-chain compound having 1 to 3 nitrogen atoms
Represents an unsaturated heterocyclic residue. Substituents on the heterocycle
Hydroxyl group, lower alkoxy, lower alkoxy group, lower
Lucoxycarbonyl group or lower alkoxy lower alkyl
Lower alkyl group which may have a Coxy group or a hydroxyl group
May have. ) Is shown. R²Is a hydrogen atom;
Chloroalkyl lower alkyl group; cycloalkyl group;
Nyl group; halogen atom as a substituent on the phenyl ring, low
-Grade alkyl groups, cyano groups, carboxy groups and lower alcohols
Having 1 to 3 groups selected from the group consisting of xy groups.
Phenyl lower alkyl group; pyridyl-substituted lower alkyl
Group; thienyl-substituted lower alkyl group; cycloalkylcarbyl
Bonyl group; Benzoyl group; Tetrahydropyranyl substitution Low
Primary alkyl group; phenyl lower alkylsulfonyl group;
Phenylsulfonyl group; or cycloalkyl lower alkyl
A sulfonyl group is shown. R¹And R²These combine
A pyrrolidinyl group may be formed with the nitrogen atom. The pi
Hydroxyl, lower alkoxy, lower alcohol on the loridinyl group
Xy group, lower alkoxy lower alkoxy group or hydroxyl group
Lower alkyl groups that may have, lower alkoxycarls
As a carbonyl group, a piperidinyl carbonyl group, and a substituent
May have a cycloalkyl lower alkyl group.
Substitution of 1 to 2 groups selected from the group consisting of minocarbonyl groups
It is assumed that R³Has a hydrogen atom and a hydroxyl group
Sometimes lower alkyl groups; carboxy-substituted lower alkyl
Kill group; Lower alkyl substituted with lower alkoxycarbonyl group
Group; Group -E- (CO) n-NR^TenR¹¹(Where E is hydroxyl
A lower alkylene group which may have a group is shown. n is 0
Or 1 is shown. R^TenAnd R¹¹Are the same or different,
Elementary atom; lower alkyl group which may have a hydroxyl group;
Represents a lower alkanoyl group. Also R^TenAnd R¹¹This
If the nitrogen atom and oxygen atom are
5 or 6 member satiety with or without sulfur atom
You may form the sum heterocycle. On the heterocycle, hydroxyl
Group; oxo group; lower alkoxy lower alkoxy group; lower
Alkoxy having a lower alkoxy group or hydroxyl group
A lower alkyl group; and a lower alkyl group as a substituent
A group selected from the group consisting of amino groups which may have 1
~ 3 may be substituted. Also, on the heterocycle,
The alkylenedioxy group may be substituted. ); Or
A lower alkyl group or a lower alkyl group as a substituent on the pyrrolidine ring
Selected from the group consisting of lucoxy lower alkoxy group and hydroxyl group
Pyrrolidinyl lower alkyl which may have 1 to 3 groups
Indicates a kill group. R^FourIs a hydrogen atom; a cycloalkyl group;
Cycloalkyl lower alkyl group; substituent on the phenyl ring
As a halogen atom, a lower alkyl group and a lower alkoxy group.
May have 1 to 3 groups selected from the group consisting of
Phenyl lower alkyl group; phenyl group; low thienyl substitution
Primary alkyl group; pyridyl-substituted lower alkyl group; imidazo
Ryl-substituted lower alkyl group; or tetrahydropyranyl group
A substituted lower alkyl group is shown. Y is a group —NHCO—, a group —
NHC (= S)-or a group -C (= S)-is shown. R^Five
And R⁶Are the same or different and each is a hydrogen atom;
Group; cycloalkyl group; cycloalkyl lower alkyl
A group; or a lower alkoxy group as a substituent on the piperidinyl ring
Pipette which may have a lower alkoxy group or hydroxyl group
A lysinyl lower alkyl group is shown. W is an oxygen atom or sulfur
Indicates a yellow atom. Between the 3rd and 4th carbons of the carbostyril skeleton
The bond indicates a single bond or a double bond. ] Represented by
At least selected from lumbostyryl derivatives or salts thereof
Platelets containing one kind as an active ingredient
Aggregation inhibitor. 2. A general formula: [In formula, A shows a lower alkylene group. ^RA is a group -NR
¹ R ² , a group —SO ₂ NR ³ R ⁴ or a group —Y—NR ⁵ R ⁶
Indicates. R ¹ is a group-(CO) l-B- (CO) m-NR
⁷ R ⁸ (wherein, 1 and m are 0 or 1; B is a lower alkylene group; R ⁷ and R ⁸ are the same or different and are a lower alkyl group which may have a hydrogen atom or a hydroxyl group; or A lower alkanoyl group, R ⁷ and R ⁸
May be bonded to each other through a nitrogen atom, an oxygen atom, or a sulfur atom together with the nitrogen atom to which they are bonded to form a 5- or 6-membered saturated heterocycle. The heterocycle includes a hydroxyl group, a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group, an amino group which may have a lower alkyl group as a substituent, a lower alkoxy lower alkoxy group, an oxo group and a substituent group. 1 to 3 groups selected from the group consisting of an aminocarbonyl group which may have a lower alkyl group may be substituted. Further, a lower alkylenedioxy group may be substituted on the heterocycle. ); Lower alkoxycarbonyl group-substituted lower alkyl group; Carboxy group-substituted lower alkyl group; Aminocarbonyl group-substituted lower alkyl group which may have a lower alkyl group as a substituent; Lower hydroxyl group-containing lower alkyl group; imidazolyl-substituted lower alkyl group; Pyridyl-substituted lower alkyl group; pyrrolidinyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of lower alkyl group, lower alkoxy lower alkoxy group and hydroxyl group on the pyrrolidine ring; or group -SO ₂ -DR
⁹ (D represents a lower alkylene group. R ⁹ represents a 5- or 6-membered saturated or unsaturated heterocyclic residue having 1 to 3 halogen atoms or nitrogen atoms. Represents a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxy lower alkoxy group, or a lower alkyl group which may have a hydroxyl group. R ² is a hydrogen atom; a cycloalkyl lower alkyl group; a cycloalkyl group; a phenyl group; a group selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a carboxy group and a lower alkoxy group as a substituent on the phenyl ring. 1 to 3 phenyl lower alkyl groups; pyridyl substituted lower alkyl groups; thienyl substituted lower alkyl groups; cycloalkylcarbonyl groups; benzoyl groups; tetrahydropyranyl substituted lower alkyl groups; phenyl lower alkylsulfonyl groups; phenylsulfonyl Or a cycloalkyl lower alkylsulfonyl group. R ¹ and R ² may form a pyrrolidinyl group together with the nitrogen atom to which they are attached. On the pyrrolidinyl group, a hydroxyl group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy group or a lower alkyl group having a hydroxyl group, a lower alkoxycarbonyl group,
One or two groups selected from the group consisting of a piperidinylcarbonyl group and an aminocarbonyl group which may have a cycloalkyl lower alkyl group as a substituent are substituted. R ³ is a lower alkyl group which may have a hydrogen atom or a hydroxyl group; a carboxy-substituted lower alkyl group; a lower alkoxycarbonyl group-substituted lower alkyl group;
^{- (CO) n-NR 10} R 11 (.R 10 and R ¹¹ .n is 0 or 1 indicating a lower alkylene group which may where E having a hydroxyl group are the same or different, a hydrogen atom; A lower alkyl group which may have a hydroxyl group; or a lower alkanoyl group, and R ¹⁰ and R ¹¹ are 5- or 6-membered with or without a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded. On the heterocycle, a hydroxyl group; an oxo group; a lower alkoxy lower alkoxy group; a lower alkoxy lower alkoxy group or a lower alkyl group which may have a hydroxyl group; and a substituent 1 to 3 groups selected from the group consisting of an amino group which may have a lower alkyl group may be substituted, and a lower alkylenedioxy group is substituted on the heterocycle. It may be);. Or pyrrolidine ring on the lower alkyl group as a substituent, a group selected from lower alkoxy-lower alkoxy group and a hydroxyl group consisting 1
A pyrrolidinyl lower alkyl group which may have 3 is shown. R ⁴ may have a hydrogen atom; a cycloalkyl group; a cycloalkyl lower alkyl group; 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group as a substituent on the phenyl ring. Phenyl lower alkyl group; phenyl group; thienyl substituted lower alkyl group; pyridyl substituted lower alkyl group; imidazolyl substituted lower alkyl group; or tetrahydropyranyl substituted lower alkyl group. Y is a group —NHCO—, a group —NHC (=
S)-, or a group -C (= S)-. R ⁵ and R
⁶ is the same or different and is a hydrogen atom; a lower alkyl group;
A cycloalkyl group; a cycloalkyl lower alkyl group; or a piperidinyl lower alkyl group which may have a lower alkoxy lower alkoxy group or a hydroxyl group as a substituent on the piperidinyl ring. W represents an oxygen atom or a sulfur atom. The carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton represents a single bond or a double bond. However, W is an oxygen atom and R ¹
Is a lower alkyl group having a hydroxyl group, R ² is
It should not be a hydrogen atom, a cycloalkyl group or a phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom on the phenyl ring as a substituent. Further, when R ¹ and R ² form a pyrrolidinyl group, the pyrrolidinyl group is not a pyrrolidinyl group in which one hydroxyl group or a lower alkyl group having a hydroxyl group is substituted. ] The carbostyril derivative or its salt represented by these.