JPH0725872A - Pyridine compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having a platelet agglutination inhibitory effect and a serotonin receptor antagonism and useful as a preventive and therapeutic agent for cerebral thrombosis, cardiac infarction, peripheral circulatory disorders, etc., an antiemetic and a psychotropic agent. CONSTITUTION:A compound of formula I (R<1> is H or a 1 to 4C alkyl; R<2> is H, a halogen or a 1 to 4C alkyl; A is a direct bond or methylene; Y is a substituted amino or a substituted carbamoyl; n is 0 or 1; The dotted line represents a single bond or a double bond), e.g. 3-(4-methyl-1-piperazinyl) methyl-6-(2-pyridyl)-3,4-dihydro-2H-1-benzopyran-4-one. The compound of formula I can be synthesized by conducting a Mannich reaction between a compound of formula II and a compound of formula NHR<3>R<4> (R<3> and R<4> are each H, a 1 to 4C alkyl or a cycloalkyl. A heterocycle may be formed by bonding R<3> to R<4> together with N) in the presence of formalin or paraformaldehye in a solvent (e.g. acetic anhydride) at 0 to 100 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel and pharmaceutically useful pyridine compound and an intermediate thereof.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 4-82887 discloses a thiochromone derivative having a serotonin antagonistic effect, and Japanese Unexamined Patent Publication No. 4-59725 discloses an anti-allergic agent containing a thiochromanone derivative as an active ingredient. 29128
No. 0 discloses a thiochromone derivative having an action as a serotonin antagonist, and Japanese Patent Publication No. 3-74216 discloses a tetrahydronaphthalene derivative having a thromboxane A ₂ synthase inhibitory action, and JP-A-4-178.
No. 381 discloses a fused 7-membered ring compound having an imidazolyl group having a hypoglycemic action and a platelet aggregation inhibiting action, and further, in Japanese Patent Publication No. 3-72226, spiro-3- having an aldose reductase inhibiting action. Hetero azolidine compounds are disclosed respectively.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel compound which has few side effects and has a remarkable platelet aggregation inhibitory action and serotonin receptor antagonistic action.

[0004]

As a result of intensive studies, the present inventors have found that a certain kind of pyridine compound has a platelet aggregation inhibitory action and a serotonin receptor antagonistic action, and completed the present invention. That is, the present invention is as follows. (1) General formula

[0005]

[Chemical 4]

[In the formula, R ¹ is hydrogen or alkyl having 1 to 4 carbons, and R ² is hydrogen, halogen or 1 to 4 carbons.
4 alkyls, A is a direct bond or methylene, Y
Is an expression

[0007]

[Chemical 5]

(Wherein R ³ and R ⁴ are the same or different and represent hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, cycloalkylalkyl or aralkyl, or R ³ and R ⁴ are bonded to each other. Represents a group forming a heterocycle with an adjacent nitrogen atom), n is 0 or 1, and the bonding site with a dotted line represents a single bond or a double bond. ] The pyridine compound represented by these, or its pharmaceutically acceptable salt. (2) General formula

[0009]

[Chemical 6]

(In the formula, R ¹ is hydrogen or alkyl having 1 to 4 carbons, and R ² is hydrogen, halogen or 1 to 4 carbons.
Four alkyls, Ra is hydrogen, halogen, cyanomethyl, halomethyl, hydroxymethyl or carboxymethyl, n is 0 or 1, and a binding site with a dotted line represents a single bond or a double bond. ) The pyridine compound or its salt represented by these.

In the present specification, halogen means fluorine,
Chlorine, bromine, iodine, and alkyl having 1 to 4 carbons are linear or branched alkyls, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. .

Cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Cycloalkylalkyl is alkyl having 1 to 4 carbon atoms and 3 to 3 carbon atoms. Six cycloalkyls are substituted, and examples thereof include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, and aralkyl is benzyl, 2-phenylethyl, 3-phenylpropyiene. It indicates such as. The group in which R ³ and R ⁴ are bonded to each other to form a heterocycle with the adjacent nitrogen atom is represented by the formula:

[0013]

[Chemical 7]

(In the formula, R ⁵ represents hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl, phenyl which may have a substituent, heteroaromatic ring, aralkyl or heteroarylalkyl, and B represents-. CONH-, -NHCO-
Or alkylene, R ⁶ is a phenyl or heteroaromatic ring which may have a substituent, R ⁷ is hydrogen, and has 1 to 1 carbon atoms.
4 alkyl, phenyl which may have a substituent, R ⁸ represents hydrogen or alkyl having 1 to 4 carbon atoms. ) Shows the group represented by.

Here, hydroxyalkyl means alkyl having 1 to 4 carbon atoms which is substituted with hydroxy, such as hydroxymethyl, 2-hydroxyethyl and 3-.
Hydroxypropyl, 4-hydroxybutyl and the like are shown.

Substituents in phenyl which may have a substituent include halogen, hydroxy, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons (methoxy,
Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.), trifluoromethyl, nitro, amino, cyano and the like.

The heteroaromatic ring is, for example, imidazole,
Pyridine, pyrimidine, etc. are shown. Aralkyl is alkyl having 1 to 4 carbon atoms, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like, and heteroarylalkyl is The alkyl part is an alkyl having 1 to 4 carbon atoms, for example, pyridylmethyl, pyrimidylmethyl, thienylmethyl, furylmethyl, pyrrolylmethyl, 2-pyridylethyl, 2-pyrimidylethyl, 2-thienylethyl, 2-furylethyl,
2-pyrrolylethyl etc. are shown.

The alkylene is an alkylene having 1 to 4 carbon atoms, for example, methylene, ethylene, trimethylene, propylene, tetramethylene and the like, and the halomethyl is, for example, chloromethyl, bromomethyl, fluoromethyl and the like.

The pharmaceutically acceptable salt of the compound represented by formula (I) is hydrochloride, sulfate, hydrobromide, phosphate,
Nitrate, methanesulfonate, fumarate, maleate, benzoate, citrate, malate, mandelate, paratoluenesulfonate, acetate, succinate,
Examples thereof include acid addition salts such as ascorbate, trifluoroacetate and tartrate. Further, the compound of the present invention is a hydrate (monohydrate, hemihydrate, 3/2 hydrate, etc.),
It may be a solvate. Examples of the salt of the general formula (II) include sodium salt, potassium salt, magnesium salt, calcium salt and the like.

When the compound of the present invention has an asymmetric carbon, it exists as a racemate or an optical isomer, and the present invention includes all of them. The pyridine compound of the present invention is
It can be produced by the following method. Method 1: In the general formula (I), A is methylene and Y is N.
A compound in which R ³ R ⁴ (R ³ and R ⁴ have the same meanings as described above) and a binding site with a dotted line is a single bond can be produced by the following steps.

[0021]

[Chemical 8]

(In the formula, R ⁹ represents halogen such as chlorine and bromine, paratoluenesulfonyloxy or methanesulfonyloxy, and the other symbols have the same meanings as described above.) Step a is the same as compound (1) in general. Formula HNR ³ R ⁴ (wherein
R ³ and R ⁴ are as defined above. The compound (2) is obtained by subjecting the compound represented by the formula (1) to a Mannich reaction in the presence of formalin or paraformaldehyde in a suitable solvent. Examples of the solvent used include acetic anhydride, acetic acid, formic acid, methanol, ethanol, isopropyl alcohol and the like, 0 to 100 ° C,
It can be performed in 10 minutes to 10 hours.

In step b, compound (3) is obtained by reacting compound (1) with formalin or paraformaldehyde in the presence of a base in a suitable solvent.
Examples of the solvent used include methanol, ethanol, isopropyl alcohol, water and the like, and examples of the base include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. This reaction can usually be performed at 0 to 100 ° C for 1 to 24 hours.

Further, in the step c, the compound (4) is obtained by reacting the compound (3) with a halogenating agent, paratoluenesulfonyl chloride or methanesulfonyl chloride in the presence of a catalyst, if necessary. Examples of the catalyst used as necessary include hexamethylphosphoric triamide, dimethylformamide and the like. Examples of the halogenating agent include triphenylphosphine and carbon tetrahalide, N-chlorosuccinimide or N-bromosuccinimide, thionyl chloride, phosphorus tribromide or phosphorus bromide. This reaction is in a solvent,
Or it is carried out without solvent, and examples of the solvent used include chloroform, dichloromethane, dichloroethane,
Examples include benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
It can be carried out at -80 ° C for 1-10 hours.

Then, in the step d, the compound of formula (4) is prepared by reacting the compound of formula (4) in the presence of a base with the general formula HNR ³ R ⁴ (wherein R ³ ,
R ⁴ has the same meaning as above. Compound (2) is obtained by reacting with a compound represented by Examples of the solvent used include diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, and the like, and examples of the base include triethylamine, pyridine, picoline, N-methylmorpholine, sodium hydrogen carbonate, and the like. Potassium bicarbonate, sodium carbonate,
Examples include potassium carbonate. Reaction temperature is usually 0 to 1
At 50 ° C, the reaction time is usually 30 minutes to 10 hours.

The method for producing the compound (2) through steps b to c and d is appropriately selected and applied from the well-known methods usually used for the conversion reaction of an alcohol derivative to an amine derivative. . Method 2: In the general formula (I), A is methylene and Y is N.
The compound in which R ³ R ⁴ (R ³ and R ⁴ have the same meanings as described above) and the bonding site with the dotted line is a double bond can be produced by the following steps.

[0027]

[Chemical 9]

(In the formula, X represents halogen such as chlorine and bromine, and other symbols have the same meanings as described above.) In step e, compound (1) is added in a suitable solvent, if necessary in the presence of a catalyst. Compound (5) is obtained by reacting with a halogenating agent. Examples of the solvent include chloroform, dichloromethane, dichloroethane, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, acetic acid and the like. Further, examples of the catalyst used as needed include Lewis acids such as aluminum chloride and stannic chloride. As a halogenating agent, bromine, chlorine, N-
Bromosuccinimide, N-chlorosuccinimide, etc. are used in an amount of 1 to 1.2 mol. Reaction temperature is usually 0
At ~ 110 ° C, the reaction time is usually 1-10 hours.

In step f, compound (5) is added in a suitable solvent,
Compound (6) is obtained by treating with a deoxidizing agent.
Examples of the solvent include chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, and the like.As the deoxidizing agent, triethylamine, pyridine, picoline, N-methylmorpholine, Examples thereof include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. The reaction temperature is usually 0 to 100 ° C., and the reaction time is usually 1 to 10 hours. In the step g, the compound (7) is obtained in the same manner as in the step c. Method 2 ′: Compound (7) can also be produced by the following steps.

[0030]

[Chemical 10]

(In the formula, each symbol has the same meaning as above.) In the above reaction, step h is the step b and step i is the step f.
Then, the step j is performed in the same manner as the step c, and the step k is performed in the same manner as the step d, to obtain the compound (7). Method 3: In the general formula (I), A is a direct bond and Y is N
The compound in which R ³ R ⁴ (R ³ and R ⁴ have the same meanings as described above) and the bonding site with the dotted line is a double bond can be produced by the following steps.

[0032]

[Chemical 11]

(In the formula, each symbol has the same meaning as described above.) During the above reaction, step l is carried out in the same manner as in step e except that the number of moles of the halogenating agent used is changed to give compound (11). Obtainable. 2 halogenating agents used
~ 2.4 mol.

The step m is carried out in the same manner as the step f to obtain the compound (12). In step n, the compound (12) is reacted with the general formula HNR ³ R ⁴ (in the formula, R ³ and R ⁴ have the same meanings as described above) in the presence of a deoxidizing agent in a suitable solvent. 13) is obtained. Examples of the solvent include chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, and the like, and deoxidizing agents include triethylamine, pyridine, picoline, N-methylmorpholine, and N-methylmorpholine. -Methylpiperazine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. The reaction temperature is usually 0 to 100 ° C., and the reaction time is 1 to 10 hours. This reaction is appropriately selected and applied from well-known methods that are usually used for a conversion reaction from a halogenated compound to an amine derivative.

Method 4: In the general formula (I), a compound in which A is methylene and Y is CONR ³ R ⁴ (R ³ and R ⁴ are as defined above) can be produced by the following method.

[0036]

[Chemical 12]

(In the formula, each symbol has the same meaning as described above.) In step o or step p, compound (14) or compound (15) is reacted with a cyanating agent in a suitable solvent to give compound (16). ) Is obtained. Examples of the solvent include methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and the like, and examples of the cyanating agent include sodium cyanide, potassium cyanide, and the like.
The reaction temperature is usually from room temperature to the boiling point of the solvent used, and the reaction time is usually 1 to 10 hours.

In step q, the compound (17) is obtained by hydrolyzing the compound (16). This reaction is performed using an acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or an alkali (for example, sodium hydroxide, etc.) usually used for hydrolysis.
Potassium hydroxide, barium hydroxide, etc.). The solvent used is usually water, and may be a mixture with acetic acid, formic acid, methanol, ethanol or the like. The reaction temperature is usually 0 to 100 ° C., and the reaction time is usually 1 to 24 hours.

In step r, the compound (17) is reacted with a halogenating agent, an acid halide or the like in a suitable solvent to give a reactive derivative of carboxylic acid, and then the compound of the general formula HNR
^The compound (18) is obtained by reacting with ³ R ⁴ (wherein R ³ and R ⁴ have the same meanings as described above). Examples of the solvent include chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dioxane and the like, and the halogenating agent is the same as that used in step c. Examples of the acid halide used include pivaloyl chloride and isobutyl chloroformate. The reaction temperature is usually -50 to 50 ° C, and the reaction time is usually 1 to 24 hours. In addition, this reaction is appropriately selected and applied from the methods usually used for amidation reaction of carboxylic acid.

Method 5: In the general formula (I), A is a direct bond, Y is CONR ³ R ⁴ (in the formula, R ³ and R ⁴ have the same meanings as described above), and a bonding site accompanied by a dotted line is double. The compound that is a bond can be produced by the following method.

[0041]

[Chemical 13]

(In the formula, each symbol has the same meaning as above.) In the above reaction, step s is the same as step o or step p, step t is the same as step q, and step u is the same as step r. Can be done individually. Method 6: In the general formula (I), A is a direct bond and Y is C
ONR ³ R ⁴ (in the formula, R ³ and R ⁴ have the same meanings as described above) and a compound having a single bond at the binding site accompanied by a dotted line can be produced by the following method.

[0043]

[Chemical 14]

(In the formula, R ¹⁰ is alkyl such as methyl and ethyl, and other symbols have the same meanings as described above.) Step v is compound (1) in a suitable solvent in the presence of a base to form a carbonate ester. Compound (2
2) is obtained. As the solvent, diethyl ether, tetrahydrofuran, dioxane, dimethylformamide,
Examples thereof include dimethyl sulfoxide, and examples of the base include sodium hydride, sodium methoxide, sodium ethoxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. Examples of the carbonic acid esters include dimethyl carbonate and diethyl carbonate, and the carbonic acid esters can be usually used at -10 to 100 ° C for 1 to 10 hours.

The step w can be performed in the same manner as the step q, and the step x can be performed in the same manner as the step r. Method 7: Compound (1) as a starting material can be produced by the following steps.

[0046]

[Chemical 15]

(In the formula, Z is halogen such as chlorine and bromine, R ¹¹ is halogen such as chlorine and bromine or hydroxyl group, m is 2 or 3, and other symbols are as defined above.) y is obtained by treating Compound (25) with magnesium in an anhydrous solvent, if necessary, in the presence of a catalyst to give a Grignard reagent, and then performing a coupling reaction with Compound (26),
Then, the compound (1) is obtained by treating with an acid to deprotect the ketal. As the anhydrous solvent used in the coupling reaction, an ether solvent such as diethyl ether, tetrahydrofuran, dioxane or a mixture thereof is used, and if necessary, in the presence of a catalyst, usually 0 to 80 ° C.,
It can be performed in 1 to 24 hours. Examples of the catalyst used if necessary include bis (1,3-diphenylphosphinopropane) nickel (II) chloride and the like, and examples of the acid used for deprotecting the ketal include:
For example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like can be mentioned, which can be usually carried out by treating at 0 to 100 ° C. for 1 to 24 hours. A catalyst such as methyl iodide or ethyl bromide may be used when preparing the Grignard reagent of the compound (25).

In step z, when R ¹¹ of compound (27) is a hydroxyl group, the compound (1) is cyclized with a dehydrating agent such as polyphosphoric acid or phosphorus pentoxide in the absence of solvent or a suitable solvent. ) Is obtained. Examples of the solvent used include benzene, toluene, xylene, chloroform, dichloromethane, dichloroethane and the like, which can be usually carried out by treating at 20 to 180 ° C. for 1 to 24 hours.

R ^{11 of the} compound (27) is halogen (chlorine,
Bromine, etc.) in the presence of a catalyst in a suitable solvent,
The compound (1) can also be obtained by carrying out the Friedel-Crafts reaction and ring closure. Examples of the solvent include chloroform, dichloromethane, dichloroethane, carbon disulfide, nitrobenzene and the like, and examples of the catalyst include:
For example, aluminum chloride, ferric chloride, and other catalysts usually used in Friedel-Crafts reaction can be mentioned. The reaction temperature is usually 0 to 100 ° C., and the reaction time is usually 1 to 24 hours. The compound (25) can be produced from the compound (28) according to the following step aa.

[0050]

[Chemical 16]

(In the formula, each symbol has the same meaning as above.) During the above reaction, compound (28) is reacted with ethylene glycol in the presence of an acid catalyst in a suitable solvent to give compound (25). To be Examples of the solvent used include benzene, toluene, xylene, chloroform,
Examples of the acid catalyst used include dichloromethane, dichloroethane, and the like. Sulfuric acid, paratoluenesulfonic acid, camphorsulfonic acid, phosphorus oxychloride, boron trifluoride ether complex, oxalic acid, and the like can be given. The reaction temperature is usually 20 to 120 ° C., and the reaction time is usually 1 to 24
It's time. During the reaction, the water produced can be removed continuously with a water separator or with a dehydrating agent. As the dehydrating agent, orthoester, molecular sieve and the like are used.

When an asymmetric carbon is present in the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof, it is usually produced as a racemate, but these are usually prepared by fractional recrystallization or chromatography. Can be optically resolved into optical isomers by the method. Further, an optical isomer can be produced using an optically active raw material compound.

[0053]

The compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is, surprisingly, adenosine-5'-
It shows inhibitory activity against platelet aggregation caused by diphosphate (ADP), and also serotonin (5-
HT) receptors (eg 5-HT ₃ , 5-HT ₂ , 5
-HT _1A, etc.) as a prophylactic / therapeutic agent, antiemetic agent or psychotropic drug for cerebral blood vessel disorders such as cerebral thrombosis and cerebral embolism, ischemic heart disease such as myocardial infarction and circulatory disorders such as peripheral circulatory disorder. It is useful. In addition, the general formula (I
The compounds of I) are useful as synthetic intermediates for the compounds of general formula (I).

Pharmacological Experiment 1: Inhibitory Effect on Platelet Aggregation Male rabbits (Blood weight about 3 kg, citrated blood (9 volumes per 3.8% sodium citrate solution) were collected with a siliconized syringe. Blood immediately 2
Centrifuge at 00 × g for 10 minutes and use the supernatant as platelet rich plasma (PRP). The remaining blood is centrifuged at 1400 xg for 10 minutes, and the supernatant is made platelet poor plasma (PPP). Platelet aggregation is performed by the method of Bourne et al. [Journal of Physiology (J. Physiol.), Vol. 168, 178-
195 (1963)], using a platelet aggregometer. That is, 3 μl of the test liquid was added to 300 μl of PRP stirred at 37 ° C. and 1200 rpm, and 2
After a minute, the change in light transmittance when an aggregation-inducing substance is added is continuously recorded. In addition, calibration is P
Perform with RP (0%) and PPP (100%). ADP of 15 μM is used as the platelet aggregation-inducing substance, and the effect of the test drug is obtained by using the maximum aggregation value as an index to determine the inhibition rate relative to the control group.

Pharmacological Experiment 2: Affinity to Serotonin 1A Receptor A specific serotonin 1A (5-HT _1A ) receptor binding test was conducted in the Journal of Neurochemistry (J.Neur).
ochem.), Vol. 44, p. 1685 (1985). A crude synaptosome fraction was isolated from 9-10 week old Wistar rat hippocampus, and 50 mM Tris-hydrochloric acid buffer solution (pH 7.
It is suspended in 4) and used for the experiment. Next, the synaptosome suspension was tritiated with several concentrations of the test compound 8-
Add OH-DPAT (final concentration 0.2 nM) and react at 37 ° C for 12 minutes. After the reaction, the reaction mixture
tman) GF / B glass filter is suction filtered, the filter is washed with 50 nM Tris-hydrochloric acid buffer (pH 7.7), and the radioactivity remaining on the filter is measured with a liquid scintillation counter. Non-specific binding is determined in the presence of 10 ^-5 M serotonin (5-HT). The 50% control concentration (IC ₅₀ ) was determined graphically and the inhibition constant (Ki value)
Ask for.

Pharmacological Experiment 3: Affinity to Serotonin 2 Receptor A specific serotonin 2 (5-HT ₂ ) receptor binding test was conducted.
It is carried out according to the method described in Mol. Pharmacol., Vol. 21, p. 301 (1981). Crude synaptosome fraction was isolated from 9-10 week old Wistar rat hippocampus and contained 1 mM manganese chloride.
It is suspended in 0 mM Tris-HCl buffer (pH 7.7) and used for the experiment. Next, several concentrations of the test compound and tritiated ketanserin (final concentration 0.2 nM) are added to the synaptosome suspension and reacted at 37 ° C. for 20 minutes. After the reaction, the reaction solution was suction filtered with a Whatman GF / B glass filter to obtain 50 nM Tris-HCl buffer (pH
After washing the filter in 7.7), the radioactivity remaining on the filter is measured with a liquid scintillation counter. Non-specific binding is determined in the presence of 10 ^-5 M mianserin. Graphically determine 50% control concentration (IC ₅₀ ),
The inhibition constant (Ki value) is determined.

Pharmacological Experiment 4: Affinity for Serotonin 3 Receptor A specific serotonin 3 (5-HT ₃ ) receptor binding test was conducted.
Biochem.Pharmaco
l.), Vol. 38, page 1693 (1989). (1) Preparation of synaptic membrane The cerebral cortex separated from a male Wistar rat brain having a body weight of 180 to 250 g, which was extracted immediately after decapitation and sacrifice, was stored at −80 ° C. until measurement. The cryopreserved cerebral cortex was homogenized with 20 volumes of ice-cold 0.32M sucrose solution (Polytron PT-10, 15000 rpm, 1 minute), centrifuged at 1000 × g for 10 minutes, and the supernatant was further 40,000 ×. Centrifuge at g for 15 minutes. The obtained precipitate was homogenized (15000 rpm, 1: 1) with 20 volumes of ice-cold 50 mM HEPES buffer (pH 7.4).
0 seconds) and left at 37 ° C for 10 minutes, then 40,000 × g
Centrifuge for 15 minutes at. 2 for the purpose of washing the obtained sediment
Homogenize with 1 volume of the above buffer (15000 rp
m, 10 seconds) and centrifuge at 40,000 × g for 15 minutes. The finally obtained precipitate is homogenized (15000 rpm, 20 seconds) with 30 times the amount of the above buffer solution to prepare a synaptic membrane sample. In the above operation, all operations that do not indicate temperature are performed under ice cooling.

(2) Examination of properties of ³ H-granisetron binding ³ H-granisetron (final concentration 0.1-2.0 nM; specific activity 2257.0 GBq / m) was added to 0.9 ml of synaptic membrane sample.
mol, New England Nuclear Co., Ltd.) solution 0.0
5 ml and solvent (50 mM HEPES buffer, pH
7.4) or tropisetron solution (final concentration 1 μM)
Add 0.05 ml and react at 25 ° C. for 30 minutes. After the reaction, the reaction solution was suction-filtered with a Whatman GF / B glass filter treated with 0.1% polyethyleneimine, and immediately the filter was washed 3 times with 3 ml of ice-cooled 50 mM Tris-hydrochloric acid buffer solution (pH 7.4). To do. The radioactivity on the filter is measured with a liquid scintillation counter (Beckman, model LS3801) after adding ACS-scintillator (Amersham). tropis
The amount of binding in the presence of etron was defined as the amount of non-specific binding, and the total amount of binding (using solvent instead of 1 μM of tropisetron)
The value obtained by subtracting the amount of non-specific binding is defined as the amount of specific binding. (3) ³ H-granisetron binding inhibitory effect (examination by substitution method) To 0.9 ml of a synapse membrane sample, 0.05 ml of ³ H-granisetron prepared so as to have a final concentration of 1 nM and 0.05 ml of a test solution or a solvent were added, Incubate at 25 ° C for 30 minutes. The operation after the reaction is performed in the same manner as in (2). (4) Study of ³ H-granisetron binding inhibition mode (study by saturation method) The test of (2) is performed in the presence and absence of the general formula (I).

When the compound of the present invention is used as a medicine,
Generally, it can be safely administered to a patient in the form of tablets, powders, granules, capsules, injections, infusions, etc. by mixing with excipients, diluents, solubilizing agents and the like. The dose may vary depending on the patient's symptoms, body weight, age, etc., but is usually in the range of 1 to 500 mg per adult and is administered once or several times a day.

[0060]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1: 6-Bromo-4-ethylenedioxy-3,4-dihydro-2H-1-benzopyran-4
Synthesis of 4-one 20 g of 6-bromo-3,4-dihydro-2H-1-benzopyran-4-one was dissolved in 260 ml of benzene, 1.68 g of paratoluenesulfonic acid and 19.2 g of ethylene glycol were added, and the mixture was stirred and refluxed. Meanwhile, water was removed with a water separator over 25 hours. After cooling, water was added and the mixture was made alkaline with sodium hydrogen carbonate and then extracted with benzene. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. When the residue is distilled under reduced pressure,
Boiling point 155-167 ° C / 1mmHg 18.6g of target product
Got

Reference Example 2: 6- (2-pyridyl) -3,4
-Synthesis of dihydro-2H-1-benzopyran-4-one After adding a catalytic amount of methyl iodide to 4.48 g of magnesium and 50 ml of a dry tetrahydrofuran-diethyl ether mixed solution (10: 1), 6-bromo-4-ethylene was added. 220 ml of a solution of 50 g of dioxy-3,4-dihydro-2H-1-benzopyran-4-one in tetrahydrofuran-diethyl ether (10: 1) at 40 ° C. at 40 ° C.
It was dripped for 1 minute and stirred at 45 ° C. for 2.5 hours. Further, 30.6 g of 2-bromopyridine and bis (1,
3-diphenylphosphinopropane) nickel (II)
280 ml of a tetrahydrofuran-diethyl ether (10: 1) solution of chloride 0.59 g was added dropwise at 45 to 49 ° C for 22 minutes, and the mixture was stirred at 46 ° C for 4 hours. After standing overnight, ammonium chloride (20.7g) aqueous solution 500ml
Was added dropwise while cooling, and the temperature was returned to room temperature. The mixture was acidified with hydrochloric acid, washed with ethyl acetate, the aqueous layer was stirred at 50 ° C. for 40 minutes, made alkaline with an aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography to give 19.9 g of the desired product.
Got Hydrochloride melting point 228-231 ° C (decomposition).

Reference Example 3: 3-Bromo-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
Synthesis of 1-one 6- (2-pyridyl) -3,4-dihydro-2H-1-
Benzopyran-4-one (10.0 g) was dissolved in acetic acid (150 ml), and 1 ml of acetic acid solution (80 ml) containing bromine (6.5 g) was dissolved at 20 ° C.
It was dripped for 5 minutes. Stir at 42 ° C for 50 minutes and then cool,
A catalytic amount of aluminum chloride was added at 17 ° C, and the mixture was stirred at room temperature for 2 hours, and further stirred at 50 ° C for 3 hours. After cooling, acetic acid was distilled off under reduced pressure, water was added, the mixture was made alkaline with sodium hydrogen carbonate, and then extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Recrystallization from diisopropyl ether gave 7.18 g of the desired product having a melting point of 97-99 ° C.

Reference Example 4: 6- (2-pyridyl) -4H-
Synthesis of 1-benzopyran-4-one 3-bromo-6- (2-pyridin) -3,4-dihydro-2H-1-benzopyran-4-one 12.0 g was dissolved in dichloroethane 70 ml and triethylamine 20.
5 g was added, and the mixture was heated with stirring at 60 ° C. for 2.5 hours. After cooling, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 60:
Then, 5.22 g of the desired product was obtained. Melting point of hydrochloride 2
48-251 ° C.

Reference Example 5: 3-Cyanomethyl-6- (2-
Synthesis of pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one 5.65 g of potassium cyanide was dissolved in 60 ml of water to give 3
-(N, N-Dimethylamino) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-
4-one dihydrochloride monohydrate [3-bromo-6- (2
-Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one with N, N-dimethylamine and 37%
8.8 g and 100 ml of methanol were added, and the mixture was heated at 40 ° C. for 2.5 hours while stirring. After cooling at room temperature, methanol was distilled off under reduced pressure, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.12 g of the desired product. Melting point 109-111
° C.

Reference Example 6: 4-oxo-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-3
-Synthesis of acetic acid 4-oxo-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-3-acetonitrile 3.4
Dissolve 3 g in 15 ml of acetic acid, add 20 ml of concentrated hydrochloric acid, and add 2.
Reflux for hours. After cooling, the mixture was made alkaline with sodium hydrogen carbonate, adjusted to pH 5 with acetic acid, and extracted with ethyl acetate. After washing the organic layer with water, it was dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was recrystallized from an acetone-diisopropyl ether mixed solution and had a melting point of 143-145 ° C.
2.39 g of the desired product of

Reference Example 7: 3,3-dibromo-6- (2-
Synthesis of pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one 6- (2-pyridyl) -3,4-dihydro-2H-1-
Benzopyran-4-one hydrochloride 10 g, acetic acid 150 ml
80 ml of acetic acid solution containing 13 g of bromine at 20 ° C.
The mixture was added dropwise for 8 minutes and heated at 54 ° C. for 1 hour. Then, a catalytic amount of aluminum chloride was added, and the mixture was further heated at 53 ° C. for 3 hours. The reaction solution was cooled, and acetic acid was distilled off under reduced pressure, then made alkaline with an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.3 g of the desired product as a brown oily substance. This was used as it was in the next reaction (Reference Example 8).

Reference Example 8: Synthesis of 3-bromo-6- (2-pyridyl) -4H-1-benzopyran-4-one 3,3-dibromo-6- (2-pyridyl) -3,4-dihydro- 2.0 g of 2H-1-benzopyran-4-one was dissolved in 70 ml of dichloroethane, and triethylamine 1 was added.
0 g was added, and the mixture was heated at 60 ° C. for 2.5 hours. After cooling, triethylamine was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.89 g of the desired product.
Melting point 155-157 [deg.] C.

Reference Example 9: 3-Bromo-3-hydroxymethyl-6- (2-pyridyl) -3,4-dihydro-2H
Synthesis of -1-benzopyran-4-one 3-bromo-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one (500 mg) in methanol (8 ml), sodium hydrogencarbonate (400 mg) and 3
4% of 7% formalin was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into 20 ml of ice water, and the precipitated crystals were collected by filtration to obtain 270 mg of the desired product. This product was used in the next reaction (Reference Example 10) without purification.

Reference Example 10: 3-Hydroxymethyl-6-
Synthesis of (2-pyridyl) -4H-1-benzopyran-4-one 3-bromo-3-hydroxymethyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
To 270 mg of -one, 10 ml of dichloroethane and 1.5 ml of triethylamine were added, and the mixture was stirred at room temperature for 2 hours and further at 50 ° C for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 130 mg of the desired product. Melting point 170-171 [deg.] C.

Reference Example 11: 3-chloromethyl-6- (2
-Pyridyl) -4H-1-benzopyran-4-one Synthesis 3-hydroxymethyl-6- (2-pyridyl) -4H-
Thionyl chloride 2 was added to 3.6 g of 1-benzopyran-4-one.
0 ml, hexamethylphosphoric triamide (HMP
A) Add 20 ml and tetrahydrofuran 100 ml,
Stir at room temperature for 3 hours. Furthermore, it heated at 40 degreeC and stirred for 2 hours. After completion of the reaction, the solvent was evaporated, the mixture was poured into ice water, neutralized with potassium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain 3.0 g of the desired product. Melting point 155-157
° C.

Reference Example 12: 7- (2-pyridyl) -2,
3,4,5-Tetrahydro-1-benzoxepin-5
Synthesis of 1-one After adding a catalytic amount of methyl iodide to 728 mg of magnesium and 10 ml of a mixed solution of dry tetrahydrofuran-diethyl ether (10: 1), 7-bromo-5-ethylenedioxy-2,3,4,5-tetrahydro was added. 25 ml of a tetrahydrofuran-diethyl ether (10: 1) solution of 8.55 g of -1-benzoxepin-5-one was added to 38-
The mixture was added dropwise at 49 ° C for 40 minutes and stirred at 45 ° C for 2.5 hours. Further, to the reaction solution, 45 ml of a solution of 4.8 g of 2-bromopyridine and 50 mg of bis (1,3-diphenylphosphinopropane) nickel (II) chloride in 60 ml of tetrahydrofuran-diethyl ether (10: 1) was added.
The mixture was added dropwise at 49 ° C for 22 minutes and stirred at 46 ° C for 4 hours. After standing overnight, 100 ml of saturated aqueous ammonium chloride was added dropwise while cooling, and the temperature was returned to room temperature. After acidifying with hydrochloric acid, it was washed with ethyl acetate, and the aqueous layer was stirred at 50 ° C. for 40 minutes. The mixture was made alkaline with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.5 g of the desired product. The melting point of the hydrochloride salt is 200 to 201 ° C.

Example 1: Synthesis of 3- (4-methyl-1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one N-methyl A mixture of 1.98 g of piperazine dihydrochloride and 0.81 g of 37% formalin was mixed with 6.39 g of acetic anhydride.
After dropping at 0 to 75 ° C for 5 minutes, the mixture was heated and stirred at 80 ° C for 23 minutes. Furthermore, 6- (2-pyridyl) -3,4 was added to the reaction solution.
-Dihydro-2H-1-benzopyran-4-one hydrochloride (2.0 g) was added, the mixture was heated with stirring at 83 to 85 ° C for 30 minutes and then cooled, and the solvent was evaporated under reduced pressure. After crystallization with acetone,
Recrystallization from methanol gave 1.33 g of the desired product of trihydrochloride monohydrate. Melting point 197-1200C.

Example 2: Synthesis of 3- (4-methyl-1-piperazinyl) methyl-6- (2-pyridyl) -4H-1-benzopyran-4-one 6- (2-pyridyl) -4H-1 -Benzopyran-4-
1.67 g of on was treated in the same manner as in Example 1 to obtain 2.25 g of a composition. Recrystallization from methanol gave 1.06 g of the desired product of trihydrochloride / hemihydrate. Melting point 2
82-284 ° C (decomposition).

Example 3: Synthesis of 3- (4-methyl-1-piperazinyl) -6- (2-pyridyl) -4H-1-benzopyran-4- 3-bromo-6- (2-pyridyl) -4H 0.8 g of -1-benzopyran-4-one was dissolved in 20 ml of chloroform, 2.66 g of N-methylpiperazine was added, and the mixture was stirred and refluxed for 7 hours. After cooling, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The hydrochloride was recrystallized from ethanol to obtain 0.32 g of the desired dihydrochloride. Melting point 285-288 [deg.] C. (decomposition).

Example 4: 3- (2- (N-cyclohexyl-N-methylamino) -2-oxoethyl) -6-
Synthesis of (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one 4-oxo-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-3-acetic acid 0.5 g was dissolved in 10 ml of chloroform, 0.19 g of triethylamine was added with stirring under ice cooling, 0.22 g of pivaloyl chloride was added dropwise, and the mixture was stirred for 1 hour. Further, 0.2 g of cyclohexylmethylamine was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution to make it alkaline, and then extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The hydrochloride was recrystallized from a mixed solution of ethanol-diisopropyl ether to obtain 0.24 g of the desired hydrochloride. Melting point 178-1
81 ° C.

Example 5: Synthesis of 3- (4- (2-methoxyphenyl) -1-piperazinyl) methyl-6- (2-pyridyl) -4H-1-benzopyran-4-one 3-chloromethyl-6 -(2-Pyridyl) -4H-1-
To 813 mg of benzopyran-4-one, 30 ml of tetrahydrofuran, 400 mg of triethylamine, 1- (2-
Methoxyphenyl) piperazine (800 mg) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was poured into ice water and the precipitated crystals were collected by filtration. The obtained crystals were converted into hydrochloride and recrystallized from ethanol to obtain 500 mg of the desired product of trihydrochloride monohydrate. Melting point 228-234 [deg.] C (decomposition).

Example 6: 4- (4-Methyl-1-piperazinyl) methyl-7- (2-pyridyl) -2,3,4
Synthesis of 5-tetrahydro-1-benzoxepin-5-one A mixture of 1.3 g of N-methylpiperazine dihydrochloride and 0.42 g of 37% formalin was added with 60 g of 2.1 g of acetic anhydride.
After dropping at 75 ° C for 5 minutes, the mixture was heated with stirring at 80 ° C for 23 minutes. Furthermore, 7- (2-pyridyl) -2,3,3 was added to the reaction solution.
1.0 g of 4,5-tetrahydro-1-benzoxepin-5-one.hydrochloride was added, and the mixture was stirred at 83 to 85 ° C for 30 minutes, cooled, and the solvent was evaporated under reduced pressure. After crystallizing with acetone and recrystallizing from ethanol, 1.33 g of the desired product of hydrochloride / hemihydrate was obtained. Melting point 165-167 ° C
(Disassembly).

The following compounds are produced in the same manner as in the above Reference Examples and Examples. (7) 3- (N-cyclohexyl-N-methylamino)
Methyl-6- (2-pyridyl) -3,4-dihydro-2
H-1-benzopyran-4-one dihydrochloride monohydrate, melting point 154-155 ° C (decomposition). (8) 3- (N, N-dipropylamino) methyl-6-
(2-Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one dihydrochloride monohydrate, melting point 167
~ 170 ° C (decomposition). (9) 3-piperidinomethyl-6- (2-pyridyl)-
3,4-Dihydro-2H-1-benzopyran-4-one dihydrochloride hemihydrate, melting point 194-196 ° C (decomposition). (10) 3- (N-2-cyclohexylethyl-N-methylamino) methyl-6- (2-pyridyl) -3,4-
Dihydro-2H-1-benzopyran-4-one dihydrochloride hemihydrate, melting point 154-156 ° C. (11) 3-piperidinomethyl-6- (2-pyridyl)
-4H-1-benzopyran-4-one dihydrochloride dihydrate.

(12) 3- (4-isopropyl-1-piperazinyl) methyl-6- (2-pyridyl) -3,4-
Dihydro-2H-1-benzopyran-4-one trihydrochloride monohydrate, melting point 155-160 ° C (decomposition). (13) 3- (2-methyl-1H-imidazole-1-
Iyl) methyl-6- (2-pyridyl) -4H-1-benzopyran-4-one dihydrochloride monohydrate, melting point 255
˜264 ° C. (decomposition). (14) 3- (N-cyclohexylmethyl-N-methylamino) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.dihydrochloride.
Hemihydrate, melting point 131-134 ° C. (15) 3-morpholinomethyl-6- (2-pyridyl)
-3,4-Dihydro-2H-1-benzopyran-4-one dihydrochloride, melting point 199-200 ° C (decomposition). (16) 3- (N, N-diisopropylamino) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1
-Benzopyran-4-one dihydrochloride, melting point 176-1
79 ° C (decomposition).

(17) 3- (4- (2-pyrimidinyl)
-1-Piperazinyl) methyl-6- (2-pyridyl)-
3,4-Dihydro-2H-1-benzopyran-4-one-3-hydrochloride monohydrate, mp 183-186 ° C. (18) 3- (N-cyclohexyl-N-methylamino) methyl-6- (2-pyridyl) -4H-1-benzopyran-4-one dihydrochloride hemihydrate. (19) 3- (4- (3-pyridylaminocarbonyl)
-1-Piperidinyl) methyl-6- (2-pyridyl)-
3,4-Dihydro-2H-1-benzopyran-4-one trihydrochloride hemihydrate, mp 193-197 ° C (decomposition). (20) 3- (2-methyl-1H-imidazole-1-
Il) Methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.hydrochloride dihydrate, mp 181-184 ° C (decomposition). (21) 3- (N, N-dimethylamino) methyl-6-
(2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one dihydrochloride monohydrate, melting point 191
~ 194 ° C.

(22) 3- (4- (2-hydroxyethyl) -1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
-On, trihydrochloride, monohydrate, melting point 167-170 ° C
(Disassembly). (23) 3- (4- (2-methoxyphenyl) -1-piperazinyl) methyl-6- (2-pyridyl) -3,4-
Dihydro-2H-1-benzopyran-4-one trihydrochloride 5/2 hydrate, melting point 167-169 ° C (decomposition). (24) 3- (4- (4-nitrophenyl) -1H-imidazol-1-yl) methyl-6- (2-pyridyl)
-3,4-Dihydro-2H-1-benzopyran-4-one dihydrochloride trihydrate, melting point 198-201 ° C. (25) 3- (4-benzyl-1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-
1-benzopyran-4-one trihydrochloride, melting point 237-
239 ° C (decomposition). (26) 3- (4-Ethyl-1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1
-Benzopyran-4-one trihydrochloride monohydrate, mp 168-171 ° C.

(27) 3- (4-benzyl-1-piperidyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one dihydrochloride.1
/ 2 hydrate, mp 169-172 ° C. (28) 3- (4- (3-pyridylaminocarbonyl)
-1-Piperidyl) methyl-6- (2-pyridyl) -4
H-1-benzopyran-4-one dihydrochloride dihydrate, melting point 248-255 ° C (decomposition). (29) 3- (4- (2-pyrimidinyl) -1-piperazinyl) methyl-6- (2-pyridyl) -4H-1-
Benzopyran-4-one dihydrochloride trihydrate, melting point 2
45-248 ° C (decomposition). (30) 3- (2,2-dimethyl-3,4-dihydro-
2H-1,4-benzoxazin-4-yl) methyl-
6- (2-pyridyl) -3,4-dihydro-2H-1-
Benzopyran-4-one, melting point 130-132 ° C. (31) 3- (4- (3-trifluoromethylphenyl) -1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
On, melting point 136-138 ° C.

(32) 3- (3,4-dihydro-2H-
1,4-Benzoxazin-4-yl) methyl-6-
(2-Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one, melting point 165-167 ° C. (33) 3- (4- (2- (4-pyridyl) ethyl)-
1-piperazinyl) methyl-6- (2-pyridyl)-
3,4-dihydro-2H-1-benzopyran-4-one, mp 148-149 ° C. (34) 3- (4-Methyl-1-piperazinyl) methyl-6- (3-pyridyl) -3,4-dihydro-2H-1
-Benzopyran-4-one trihydrochloride 3/2 hydrate,
Melting point 175-178 [deg.] C (decomposition). (35) 3- (2-phenyl-1H-imidazole-1
-Yl) methyl-6- (2-pyridyl) -4H-1-benzopyran-4-one.hydrochloride monohydrate, melting point 222
~ 225 ° C. (36) 3- (N, N-dimethylamino) methyl-6-
(3-Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one dihydrochloride hemihydrate, melting point 1
79-182 ° C (decomposition).

(37) 3- (4- (2-methoxyphenyl) -1-piperazinyl) methyl-6- (3-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
On-trihydrochloride, melting point 180-183 ° C (decomposition). (38) 3- (4- (2-pyrimidinyl) -1-piperazinyl) methyl-6- (3-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.3 hydrochloride.
Hemihydrate, mp 163-166 ° C. (39) 3- (4-Nicotinoylamino) -1-piperidyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one-3-hydrochloride-1
Hydrate, melting point 198-201 ° C (decomposition). (40) 3- (4-Methyl-1-piperazinyl) methyl-6- (4-pyridyl) -3,4-dihydro-2H-1
-Benzopyran-4-one trihydrochloride 3/2 hydrate,
Melting point 180-184 ° C (decomposition). (41) 3- (4- (2-pyrimidinyl) -1-piperazinyl) methyl-6- (4-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one-3-hydrochloride.
Monohydrate, melting point 184-187 ° C (decomposition).

(42) 3- (4- (3-Pyridylaminocarbonyl) -1-piperidyl) methyl-6- (3-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.3 hydrochloric acid Salt monohydrate, melting point 182-185
° C (decomposition). (43) 3- (2- (4-methyl-1-piperazinyl)
-2-oxoethyl) -6- (2-pyridyl) -3,4
-Dihydro-2H-1-benzopyran-4-one dihydrochloride, melting point 151-154 ° C (decomposition). (44) 3- (2- (N, N-dimethylamino) -2-
Oxoethyl) -6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.hydrochloride, mp 198-200 ° C. (45) 3- (N, N-dimethylamino) methyl-6-
(4-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one dihydrochloride hemihydrate, melting point 2
01-203 ° C. (46) 3- (2-Cyclohexylamino-2-oxoethyl) -6- (2-pyridyl) -3,4-dihydro-
2H-1-benzopyran-4-one, melting point 204-20
5 ° C.

(47) 4-Dimethylaminomethyl-7-
(2-pyridyl) -2,3,4,5-tetrahydro-1
-Benzoxepin-5-one dihydrochloride monohydrate,
Melting point 188-190 <0> C (decomposition). (48) 4- (N-cyclohexyl-N-methylamino) methyl-7- (2-pyridyl) -2,3,4,5-
Tetrahydro-1-benzoxepin-5-one dihydrochloride monohydrate, melting point 141-145 ° C (decomposition). (49) 4- (4- (2- (4-pyridyl) ethyl)-
1-piperazinyl) methyl-7- (2-pyridyl)-
2,3,4,5-Tetrahydro-1-benzoxepin-5-one trihydrochloride dihydrate, mp 154-156
° C (decomposition). (50) 3- (4-Methyl-1-piperazinyl) methyl-6- (6-methyl-2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one. (51) 8-Chloro-3- (4-methyl-1-piperazinyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.

(52) 6-Methyl-3- (4-methyl-)
1-piperazinyl) methyl-8- (2-pyridyl)-
3,4-dihydro-2H-1-benzopyran-4-one. (53) 3-Methylaminomethyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
-On. (54) 3-Benzylaminomethyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4
-On. (55) 6- (2-Pyridyl) -3-pyrrolidinylmethyl-3,4-dihydro-2H-1-benzopyran-4-
on. (56) 3- (1-Piperazinyl) methyl-6- (2-
Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.

(57) 3- (4-Phenyl-1-piperazinyl) -6- (2-pyridyl) -3,4-dihydro-
2H-1-benzopyran-4-one. (58) 3- (4- (4-Methoxybenzyl) -1-piperidyl) methyl-6- (2-pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one. (59) 3- (1-Imidazolyl) methyl-6- (2-
Pyridyl) -3,4-dihydro-2H-1-benzopyran-4-one.

[0090]

The compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is surprisingly adenosine-
It shows inhibitory activity against platelet aggregation caused by 5'-diphosphate (ADP), and also serotonin (5-HT) receptors, such as 5-HT ₃ , 5-H.
T ₂ , 5-HT _1A, etc.), and a prophylactic / therapeutic agent, an antiemetic agent for cerebrovascular disorders such as cerebral thrombosis and cerebral embolism, ischemic heart disease such as myocardial infarction, and circulatory disorders such as peripheral circulatory disorders. Useful as a psychotropic drug. Also,
The compound of general formula (II) is useful as a synthetic intermediate for the compound of general formula (I).

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/44 ACP 9454-4C AEN 9454-4C // (C07D 405/04 213: 00 311: 00) (C07D 405/04 213: 00 313: 00) (72) Inventor Hiroshi Ochi Address: 955, Ozai, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ is hydrogen or alkyl having 1 to 4 carbons, R ² is hydrogen, halogen or alkyl having 1 to 4 carbons, A is a direct bond or methylene, and Y is ] (In the formula, R ³ and R ⁴ are the same or different and represent hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, cycloalkylalkyl or aralkyl, or R ³ , R 4
⁴ represents a group which is bonded to form a heterocycle with the adjacent nitrogen atom. ), N is 0 or 1
, The binding site with a dotted line indicates a single bond or a double bond. ] The pyridine compound represented by these, or its pharmaceutically acceptable salt. 2. A general formula: (In the formula, R ¹ is hydrogen or alkyl having 1 to 4 carbons, R ² is hydrogen, halogen or alkyl having 1 to 4 carbons, and Ra is hydrogen, halogen, cyanomethyl, halomethyl, hydroxymethyl or carboxy. Methyl, n
Indicates 0 or 1, and the binding site with a dotted line indicates a single bond or a double bond. ) The pyridine compound or its salt represented by these.