JP2001172275A - 4-oxybenzopyrane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antiarrhythmic medicine. SOLUTION: This antiarrhythmic medicine containing a 4-oxybenzopyrane derivative represented by formula (D [R1 and R2 are each independently H, a 1 to 6C alkyl or phenyl; R3 is hydroxy or a 1 to 6C alkylcarbonyloxy; R4 is a 3 to 6C cycloalkyl, a 1 to 6C alkyl, a 1 to 6C alkylcarbonyl, a 1 to 6C alkylaminocarbonyl, di 1 to 6C alkylaminocarbonyl, an aryl or a heteroaryl; R5 is H or a 1 to 6C alkyl; X does not exist or means C=0 or SO2; R6 is H, a 1 to 6C alkyl or a 3 to 6C cycloalkyl; R7 is H, a halogen atom, nitro or cyano] or its pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 4-oxybenzopyran derivative having a prolonged refractory period, and is used for treating arrhythmias in mammals including humans.

[0002]

BACKGROUND OF THE INVENTION Benzopyran derivatives include cromakalim (JP-A-58-6758).
683) are known. These 4-acylaminobenzopyran derivatives represented by cromakalim are ATP-sensitive K ⁺
It is known to open channels and be effective in treating hypertension and asthma, but no mention is made of treatment of arrhythmia based on the action of prolonging the refractory period. By the way, conventional antiarrhythmic drugs (e.g.,
Class 1 antiarrhythmic drugs by Vaughan Williams, 3
Group, such as d-sotalol), torsades dep based on prolonged ventricular muscle action potentials associated with prolonged refractory periods
Extremely dangerous arrhythmogenicity, such as ointes, which can induce sudden death has become a therapeutic challenge, and drugs with fewer side effects are desired. In order to solve this problem, the present inventors conducted a search for a compound having a prolonged refractory period in atrial muscles rather than ventricular muscles. We found that the atrial muscle had a selective prolongation of the refractory period without affecting the muscle refractory period and action potential.

[0003]

Means for Solving the Problems As a result of intensive search for 4-oxybenzopyran derivatives, the present inventors have surprisingly found that the compound represented by the formula (I) has a prolonged refractory period, and The present invention was found to be useful as an agent and completed the present invention.

[0004] The present invention relates to a compound of the formula (I)

[0005]

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[Wherein R ¹ and R ² are each independently a hydrogen atom, a C _1-6 alkyl group (the alkyl group is optionally substituted with a halogen atom, a C _1-6 alkoxy group or a hydroxyl group) Or a phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group or a C _1-6 alkoxy group). R ³ represents a hydroxyl group or a C _1-6 alkylcarbonyloxy group, and R ⁴ represents a C _3-6 cycloalkyl group, a C _1-6 alkyl group, a C _1-6 alkylcarbonyl group, a C _{1 -6}
Alkylaminocarbonyl group, di C _1-6 alkylaminocarbonyl group {wherein the C _1-6 alkyl group, C _1-6 alkylcarbonyl group, C _1-6 alkylaminocarbonyl Moto及busy C _1-6 alkylaminocarbonyl group In any case, a halogen atom, a C _1-6 alkoxy group (the alkoxy group may be substituted with a halogen atom), a carboxyl group, a C _1-6 alkoxycarbonyl group, a hydroxyl group, an aryl group or a heteroaryl group (the aryl Group and heteroaryl group each have m R
⁸ (R ⁸ is a halogen atom, a hydroxyl group, C _{1 -6} alkyl group (the alkyl group may be substituted with a halogen atom or a C _1-6 alkoxy group), a C _1-6 alkoxy group (said alkoxy group Optionally substituted with a halogen atom), a nitro group,
Cyano group, formyl group, formamide group, amino group, C
_1-6 alkylamino group, di C _1-6 alkylamino group, C _1-6
Alkylcarbonylamino group, C _1-6 alkylsulfonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyl group, di C _1-6 alkylaminocarbonyl group, C _1-6
Alkylcarbonyl group, C _1-6 alkoxycarbonyl group,
It means an aminosulfonyl group, a C _1-6 alkylsulfonyl group, a carboxyl group or an arylcarbonyl group. ) May optionally be substituted. m represents an integer of 1 to 3, and when m is 2 or 3, R ⁸ may be the same or different. ) May optionally be substituted. ｝,
Aryl group or heteroaryl group: Both the aryl group and the heteroaryl group may be optionally substituted by n R ⁹ (R ⁹ has the same meaning as R ⁸ ). n is 1 to
Represents an integer of 3, and when n is 2 or 3, R ⁹ may be the same or different. ｝ Means R ⁵ is a hydrogen atom or C
X represents a _1-6 alkyl group, X is absent or C = O
Or SO ₂ , and R ⁶ represents a hydrogen atom, a C _1-6 alkyl group (the alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C _1-6 alkoxy group) or C _3-6 cycloalkyl. R ⁷ represents a hydrogen atom, a halogen atom, a nitro group or a cyano group. And a pharmaceutically acceptable salt thereof.

The compound of the present invention has a strong refractory period extending action and can be used as a therapeutic agent for arrhythmia.

Next, each substituent of the compound (I) of the present invention will be described specifically. In this specification, "n" is normal, "i" is iso, "s" is secondary, "t" is tertiary, "c" is cyclo, "o" is ortho,
“M” means meta and “p” means para.

The C _1-6 alkyl group includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-
Butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n
-Pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, cyanomethyl And hydroxymethyl. Preferably, methyl, ethyl, n-propyl, i-propyl and n-butyl are mentioned.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, a fluorine atom, a chlorine atom and a bromine atom are mentioned.

The C _1-6 alkoxy group includes methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-pentyloxy, 2 -Pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy, 2,
2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n -Propoxy and 3,3-dimethyl-n-butoxy. Preferably, methoxy, ethoxy, n-propoxy and i-propoxy are mentioned.

The C _1-6 alkylcarbonyloxy group includes methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy, s-butylcarbonyl Oxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-
Pentylcarbonyloxy, neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 1,1,2-trimethyl -n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxy and 3,3-dimethyl-n-butylcarbonyloxy. Preferably, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy and
t-butylcarbonyloxy.

Examples of the C _3-6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferably, cyclopropyl, cyclobutyl and cyclohexyl are mentioned.

Examples of the C _1-6 alkylcarbonyl group include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, -Pentylcarbonyl, 2-pentylcarbonyl,
Examples include 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl and 3-hexylcarbonyl. Preferably, methyl carbonyl,
Examples include ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl and n-butylcarbonyl.

Examples of the C _1-6 alkylaminocarbonyl group include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylaminocarbonyl and s-butylaminocarbonyl. Carbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-
Examples include pentylaminocarbonyl, neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl, and 3-hexylaminocarbonyl. Preferably, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl and n-butylaminocarbonyl are mentioned.

The di C _1-6 alkylaminocarbonyl group includes dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl,
Di-n-butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-c-butylaminocarbonyl, di-1-
Pentylaminocarbonyl, di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl, di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl , Di-1-hexylaminocarbonyl, di-
2-hexylaminocarbonyl, di-3-hexylaminocarbonyl and the like. Preferably, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl and di-n-butylaminocarbonyl are exemplified.

C _1-6 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, -Pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl and 3-hexyloxy Carbonyl and the like. Preferably, methoxycarbonyl, ethoxycarbonyl, n-
Propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl.

The aryl group includes phenyl, biphenylyl, naphthyl, anthryl, phenanthryl and the like. Preferably, phenyl, biphenylyl and naphthyl are mentioned.

Examples of the heteroaryl group include a 2-thienyl group, a 3-thienyl group, a 2-furyl group, a 3-furyl group,
-Pyranyl group, 3-pyranyl group, 4-pyranyl group, 2-
Benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl Group, 2-benzothienyl group, 3-benzothienyl group,
4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4
-Oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4 −
Pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 1-indolizinyl group, 2
-Indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1
-Indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl group, 2-
Indazolyl group, 3-indazolyl group, 4-indazolyl group, 5-indazolyl group, 6-indazolyl group, 7-
Indazolyl group, 1-purinyl group, 2-purinyl group, 3
-A purinyl group, a 6-purinyl group, a 7-purinyl group, 8-
Purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl Isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group, 3-
Naphthyridinyl group, 4-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl group, 6-quinoxalinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-
Quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-
Cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-
Examples include a ptenidinyl group, a 4-ptenidinyl group, a 6-ptenidinyl group, a 7-ptenidinyl group, and a 3-flazanyl group. Preferably, a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group are exemplified.

The C _1-6 alkylamino group includes methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino -Butylamino, c-butylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino, t-pentylamino, c-pentylamino, 1-hexylamino,
2-hexylamino, 3-hexylamino, c-hexylamino, 1-methyl-n-pentylamino, 1,1,2-trimethyl-n-
Propylamino, 1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamino and the like. Preferably, methylamino, ethylamino, n-propylamino, i-propylamino and n-butylamino are mentioned.

Examples of the di C _1-6 alkylamino group include dimethylamino, diethylamino, di-n-propylamino, di-
i-propylamino, di-c-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t
-Butylamino, di-c-butylamino, di-1-pentylamino, di-2-pentylamino, di-3-pentylamino, di
-i-pentylamino, di-neopentylamino, di-t-pentylamino, di-c-pentylamino, di-1-hexylamino, di-2-hexylamino, di-3-hexylamino, di
-c-hexylamino, di- (1-methyl-n-pentyl) amino, di- (1,1,2-trimethyl-n-propyl) amino, di- (1,
2,2-trimethyl-n-propyl) amino, di- (3,3-dimethyl
-n-butyl) amino, methyl (ethyl) amino, methyl (n-
(Propyl) amino, methyl (i-propyl) amino, methyl
(c-propyl) amino, methyl (n-butyl) amino, methyl
(i-butyl) amino, methyl (s-butyl) amino, methyl (t
-Butyl) amino, methyl (c-butyl) amino, ethyl (n-
Propyl) amino, ethyl (i-propyl) amino, ethyl
(c-propyl) amino, ethyl (n-butyl) amino, ethyl
(i-butyl) amino, ethyl (s-butyl) amino, ethyl (t
-Butyl) amino, ethyl (c-butyl) amino, n-propyl
(i-propyl) amino, n-propyl (c-propyl) amino,
n-propyl (n-butyl) amino, n-propyl (i-butyl) amino, n-propyl (s-butyl) amino, n-propyl (t-butyl) amino, n-propyl (c-butyl) amino, i-propyl (c-propyl) amino, i-propyl (n-butyl) amino,
i-propyl (i-butyl) amino, i-propyl (s-butyl) amino, i-propyl (t-butyl) amino, i-propyl (c-butyl) amino, c-propyl (n-butyl) amino, c-propyl (i-butyl) amino, c-propyl (s-butyl) amino, c-
Propyl (t-butyl) amino, c-propyl (c-butyl) amino, n-butyl (i-butyl) amino, n-butyl (s-butyl) amino, n-butyl (t-butyl) amino, n- Butyl (c-butyl)
Amino, i-butyl (s-butyl) amino, i-butyl (t-butyl) amino, i-butyl (c-butyl) amino, s-butyl (t-butyl) amino, s-butyl (c-butyl) Amino and t-butyl
(c-butyl) amino and the like. Preferably, dimethylamino, diethylamino, di-n-propylamino, di-
i-propylamino and di-n-butylamino.

The C _1-6 alkylcarbonylamino group includes methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonyl Amino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-
Examples include pentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino, and 3-hexylcarbonylamino. Preferably, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino and n-butylcarbonylamino are mentioned.

Examples of the C _1-6 alkylsulfonylamino group include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, n-butylsulfonylamino, i-butylsulfonylamino and s-butylsulfonylamino Amino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, i-
Examples include pentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino, 1-hexylsulfonylamino, 2-hexylsulfonylamino, and 3-hexylsulfonylamino. Preferably, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino and n-butylsulfonylamino are exemplified.

The C _1-6 alkylsulfonyl group includes methanesulfonyl and ethanesulfonyl.

The arylcarbonyl group includes benzoyl, p-methylbenzoyl, pt-butylbenzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and p-cyanobenzoyl. Preferably, benzoyl, p-nitrobenzoyl and p-cyanobenzoyl are mentioned.

Preferred compounds used in the present invention include the following compounds.

(1) R ¹ and R ² are both methyl groups;
A 4-oxybenzopyran derivative represented by the formula (I) wherein R ³ is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

(2) The 4-oxybenzopyran derivative or a pharmaceutically acceptable salt thereof according to the above (1), wherein X is C = O and R ⁵ is a hydrogen atom.

(3) The 4-oxybenzopyran derivative or a pharmaceutically acceptable salt thereof according to the above (2), wherein R ⁴ is an alkyl group and R ⁷ is a nitro group.

Hereinafter, specific examples of the compound that can be used in the present invention are shown, but the present invention is not limited to these. “Me” is a methyl group, “Et” is an ethyl group, “Pr” is a propyl group, “Bu” is a butyl group, “Ac” is an acetyl group (COCH ₃ ), and “−” is Each means a bond.

[0031]

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[0032]

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[0033]

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[0034]

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[0035]

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[0036]

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The compound of the present invention has an asymmetric carbon at the 3-position and the 4-position, and there are optical isomers based on the asymmetric carbon. Can be used. In addition, cis or trans isomers based on the configuration at the 3-position and 4-position are included, but the trans-isomer is preferable.

When the compound is capable of forming a salt, its pharmaceutically acceptable salt can also be used as an active ingredient. Pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, acetate, benzoate, tartrate, phosphate, lactate, maleate, fumarate , Malate, gluconate and salicylate. Preferably, hydrochloride and methanesulfonate are used.

[0039]

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the production method of the compound of the present invention will be described.

Among the compounds represented by the general formula (I), the compound represented by the formula (Ia) wherein R ³ is a hydroxyl group is represented by the general formula (2) as shown by the following reaction formula. The compound (3) can be obtained by reacting the compound represented by the compound (3) in an inert solvent. The compound represented by the general formula (2) can be synthesized by a known method (JM Ev
ans et al., J. Med.Chem. 1984, 27, 1127, J. Med.Chem.
1986, 29, 2194; JT North et al. J. Org. Chem. 1995, 6
0, 3397, JP-A-56-57785 and JP-A-5-57785.
6-57786, JP-A-58-188880, JP-A-2-141, JP-A-10-87650
And the method described in JP-A-11-209366).

[0042]

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(Wherein, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X have the same meanings as described above.) The compound represented by the general formula (2) and the compound (3) The following may be mentioned as the solvent used in the reaction of)). Sulfoxide solvents represented by dimethyl sulfoxide, amide solvents represented by dimethylformamide or dimethylacetamide, ethyl ether, ether solvents represented by dimethoxyethane or tetrahydrofuran, dichloromethane, chloroform,
Halogen solvents represented by dichloroethane, acetonitrile, nitrile solvents represented by propionitrile, benzene, aromatic hydrocarbon solvents represented by toluene, hexane, hydrocarbon solvents represented by heptane, ethyl acetate And ester-based solvents represented by Further, the reaction can be carried out under the condition without solvent. Preferably, an ether-based solvent and a nitrile-based solvent are used.

The reaction temperature is usually from -80 ° C to the reflux temperature of the reaction solvent used, preferably from -10 ° C.
１００100 ° C.

The molar ratio of the starting materials for the compound (3) / the compound (2) is in the range of 0.5 to 4.0, preferably 1.0 to 2.0.

In the reaction, an acid catalyst may be used.

Examples of the acid catalyst used include inorganic acids such as hydrochloric acid and sulfuric acid, aluminum chloride, titanium tetrachloride, boron trifluoride diethyl ether complex, perchloric acid, lithium perchlorate, and ytterbium trifluoromethanesulfonate. And Lewis acids.

Preferably, sulfuric acid and perchloric acid are used.

Among the compounds represented by the general formula (I), those not included in the compound represented by the formula (Ia) (R
³ is a C _1-6 alkylcarbonyloxy group)
Are disclosed in JP-A-52-91866 and JP-A-10-8.
It can be produced by a method similar to the production method described in JP-A-7650.

Among the compounds represented by the general formula (I), an optically active compound is synthesized by a method of optically resolving a racemate (JP-A-3-141286, US Pat. No. 5,097,037).
And EP 409165). The optically active form of the compound represented by the general formula (2) can be synthesized by an asymmetric synthesis method (Japanese Unexamined Patent Application Publication No.
507645, JP-A-5-301878, JP-A-7-285983, European Patent 5353
No. 77, U.S. Pat. No. 5,420,314).

As described above, the present inventors have found that the compound represented by the general formula (I) has a strong refractory period extending action. Refractory period prolongation is one of the mechanisms by which antiarrhythmic effects are effective, and is an important indicator that can extrapolate the efficacy of clinical arrhythmias. Conventional antiarrhythmic drugs whose main mechanism is refractory period prolongation (eg, Vaughan Wi
illiams, which belong to the third group of antiarrhythmic drugs by lliams, are extremely dangerous arrhythmias that can induce sudden death such as torsades de pointes based on prolonged ventricular muscle action potential associated with prolonged refractory period Evoked action is a serious issue, and arrhythmias mainly composed of atrial muscles (supraventricular tachycardia,
Atrial flutter, atrial fibrillation, etc.). In order to solve this problem, the present inventors conducted a search for a compound having a prolonged refractory period in atrial muscles rather than ventricular muscles. We found that the atrial muscle had a selective prolongation of the refractory period without affecting the muscle refractory period and action potential. The difference of the present inventors from the existing technology is that these compounds were able to impart a selective prolongation of refractory period to atrial muscles, which indicates that the activity of the isolated ventricular muscles was increased. It has also been shown that it has no effect on the duration of the potential and has no effect on the electrocardiogram QT of the anesthetized animal. From the above, the present compound does not have an arrhythmia-inducing action in ventricular muscle, and can provide a possibility that atrial muscle can contribute to safer use in arrhythmias mainly composed of atrial muscles as compared with existing techniques. This technique involves the treatment or prophylaxis of atrial arrhythmias, such as anti-atrial fibrillation, anti-atrial flutter, and anti-atrial tachycardia, including paroxysmal, chronic, pre-, intra-, or post-operative Use, prevention of progression to embolism based on atrial arrhythmia, prevention of ventricular arrhythmia or transition to tachycardia due to atrial arrhythmia or tachycardia, atrial arrhythmia that can transition to ventricular arrhythmia or tachycardia or It is useful for the purpose of preventing deterioration of life prognosis based on tachycardia preventive action.

The present invention provides a pharmaceutical or veterinary composition comprising an effective amount of a compound of general formula (I) for these treatments.

The administration form of the compound according to the present invention includes:
Parenteral administration or tablet by injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc.
Capsules, granules, pills, syrups, solutions, emulsions,
Oral administration by a suspension or the like can be mentioned.

The above-mentioned pharmaceutical or veterinary composition containing the compound of the present invention contains the compound of the present invention in an amount of about 0.01 to 99.5%, preferably about 0.
Contains 1-30%.

In addition to the compounds according to the invention or to the compositions containing said compounds, other pharmaceutically or veterinarily active compounds can be included. These compositions can also include more than one of the compounds according to the present invention.

The clinical dose of the compound of the present invention varies depending on the age, body weight, patient sensitivity, degree of symptoms, etc., but the effective dose is usually 0.003 to 1.5 g, preferably 0.01 to 1.5 g per day for an adult. It is about 0.6 g. However, if necessary, an amount outside the above range can be used.

The compounds of the present invention are formulated for administration by conventional pharmaceutical means. That is, tablets, capsules, granules, and pills for oral administration are excipients such as sucrose, lactose,
Glucose, starch, mannitol; binders such as hydroxypropylcellulose, syrup, acacia,
Gelatin, sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants such as starch,
It is prepared using carboxymethylcellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; a lubricant such as talc, magnesium or calcium stearate, silica; a lubricant such as sodium laurate, glycerol and the like.

Injections, solutions, emulsions, suspensions, syrups and aerosols can be used as a solvent for the active ingredient, for example, water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; Agents such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents such as carboxymethyl sodium salt, cellulose derivatives such as methylcellulose, tragacanth, Natural rubbers such as gum arabic; prepared using preservatives, for example, esters of parahydroxybenzoic acid, benzalkonium chloride, sorbate and the like.

As the ointment which is a transdermal absorption preparation, for example, white petrolatum, liquid paraffin, higher alcohol, macrogol ointment, hydrophilic ointment, aqueous gel base and the like are used.
Suppositories are prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides, coconut oil, polysorbate and the like.

[0060]

(Synthesis example)

Synthesis Example 1 trans-6-acetylamino-3,4-dihydro-2,2
-Dimethyl-4- (2-phenylethoxy) -2H-1-benzopyran-3-ol

[0062]

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6-acetylamino-3,4-epoxy-3,
4-dihydro-2,2-dimethyl-2H-1-benzopyran
(0.50 g, 2.1 mmol) and 2-phenethyl alcohol (0.50 g
A catalytic amount of concentrated sulfuric acid was added to a solution of acetonitrile (2.5 mL) in 2.5 mL, 4.2 mL) at room temperature, and the mixture was stirred at room temperature for 5 hours.
Ethyl acetate was added, and the organic phase was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (chloroform: ethyl acetate = 1: 1).
Then, the obtained pink amorphous was recrystallized from hexane-ethyl acetate to obtain the desired product as pink crystals (yield 4).
0%).

Mp .: 141.2-143.2 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.18 (s, 3H), 1.39 (s, 3H), 2.15
(s, 3H), 2.92-2.96 (m, 2H), 3.68 (d, J = 8.2 Hz,
1H), 3.85-3.98 (m, 2H), 4.32 (d, J = 8.2 Hz, 1H),
6.70 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H),
7.27-7.38 (m, 6H) MS (EI) m / z; 355 [M] ⁺ , 105 (bp).

The following compounds were obtained in the same manner.
(Synthesis Example 2 to Synthesis Example 16, where Synthesis Example 14 is the (-) form of Synthesis Example 1, Synthesis Example 15 is the (+) form of Synthesis Example 1, and Synthesis Example 16 is the (+) form of Synthesis Example 13. ) Body.)

Synthesis Example 2 trans-6-acetylamino-3,4-dihydro-2,2
-Dimethyl-7-nitro-4- (2-phenylethoxy)
-2H-1-benzopyran-3-ol

[0067]

Embedded image

Yield 30% mp .: 123.5-127.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.20 (s, 3H), 1.39 (s, 3H), 1.92
(d, J = 3.5 Hz, 1H), 2.27 (s, 3H), 2.98-3.02 (m, 2
H), 3.63 (dd, J = 3.5, 8.2 Hz, 1H), 3.91-3.97 (m,
1H), 4.15-4.20 (m, 1H), 4.33 (d, J = 8.2 Hz, 1H),
7.23-7.35 (m, 5H), 7.60 (s, 1H), 8.69 (s, 1H), 9.9
0 (bs, 1H). MS (EI) m / z; 400 [M] ⁺ , 105 (bp).

Synthesis Examples 3 to 16

[0070]

Embedded image

[0071]

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Synthesis Example 3 21% yield Yellow solid ¹ H-NMR (CDCl ₃ ) δ: 1.24 (s, 3H), 1.39 (s, 3H), 2.10
(d, J = 4.4 Hz, 1H), 2.26 (s, 3H), 3.06 (t, J = 6.
6 Hz, 2H), 3.70 (dd, A part of AB, J = 7.4and 4.4
Hz, 1H), 3.95-4.02 (m, 1H), 4.05-4.15 (m, 1H), 4.3
7 (d, B part of AB, J = 7.4 Hz, 1H), 7.38-7.55 (m,
4H), 7.61 (s, 1H), 8.66 (s, 1H), 9.90 (s, 1H). MS (EI) m / z; 468 [M] ⁺ , 354 (bp).

[0073] Synthesis Example 4 13% yield a yellow oil _{^{1 H-NMR (CDCl 3)}} δ: 1.23 (s, 3H), 1.41 (s, 3H), 2.01
(d, J = 4.2 Hz, 1H), 2.27 (s, 3H), 2.97 (t, J = 6.
5 Hz, 2H), 3.70 (dd, A part of AB, J = 8.1and 4.2
Hz, 1H), 3.90-3.98 (m, 1H), 4.00-4.15 (m, 1H), 4.3
6 (d, B part of AB, J = 8.1 Hz, 1H), 7.21 (d, J =
8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.60 (s, 1
H), 8.63 (s, 1H), 9.89 (s, 1H). MS (FAB) m / z; 435 [M + H] ⁺ .

Synthesis Example 5 60% yield Yellow amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.22 (s, 3H), 1.41 (s, 3H), 1.98
(d, J = 4.0 Hz, 1H), 2.27 (s, 3H), 2.97 (t, J = 6.
5 Hz, 2H), 3.69 (d, A part of AB, J = 8.2 and 4.0
Hz, 1H), 3.90-4.00 (m, 1H), 4.05-4.15 (m, 1H), 4.3
5 (d, B part ofAB, J = 8.2 Hz, 1H), 6.98-7.05 (m,
2H), 7.20-7.25 (m, 2H), 7.60 (s, 1H), 8.62 (s, 1
H), 9.88 (s, 1H). MS (FAB) m / z; 419 [M + H] ⁺ .

Synthesis Example 6 17% Yield Yellow Oil ¹ H-NMR (CDCl ₃ ) δ: 1.23 (s, 3H), 1.40 (s, 3H), 2.09
(d, J = 4.2 Hz, 1H), 2.27 (s, 3H), 3.00 (t, J = 6.6
Hz, 2H), 3.69 (d, A part of AB, J = 7.6 and 4,2 H
z, 1H), 3.93-3.99 (m, 1H), 4.09-4.15 (m, 1H), 4.36
(d, B part ofAB, J = 7.6 Hz, 1H), 6.93-7.05 (m, 3
H), 7.25-7.40 (m, 1H), 7.60 (s, 1H), 8.66 (s, 1H),
9.89 (s, 1H). MS (FAB) m / z; 419 [M + H] ⁺ .

Synthesis Example 7 10% Yield Yellow Oil ¹ H-NMR (CDCl ₃ ) δ: 1.21 (s, 3H), 1.41 (s, 3H), 2.00
(s, 1H), 2.25 (s, 3H), 2.90-3.20 (m, 2H), 3.50-4.
40 (m, 4H), 7.20-7.30 (m, 4H), 7.64 (s, 1H), 8.68
(s, 1H), 9.90 (s, 1H). MS (FAB) m / z; 435 [M + H] ⁺ .

[0077] Synthesis Example 8 20% yield a yellow oil _{^{1 H-NMR (CDCl 3)}} δ: 1.21 (s, 3H), 1.40 (s, 3H), 1.96
(d, J = 4.0 Hz, 1H), 2.27 (s, 3H), 2.94 (t, J = 6.
6 Hz, 2 H), 3.80 (s, 3H), 3.65 (dd, A partof AB, J
= 8.2 and 4.0 Hz, 1H), 3.85-3.95 (m, 1H), 4.05-4.
15 (m, 1H), 4.34 (d, B part of AB, J = 8.2 Hz, 1
H), 6.86 (d, J = 8.6 Hz and 2H), 7.19 (d, J = 8.6 H
z, 2 H), 7.60 (s, 1H), 8.68 (s, 1H), 9.90 (s, 1H). MS (FAB) m / z; 431 [M + H] ⁺ .

Synthesis Example 9 25% Yield Yellow solid ¹ H-NMR (CDCl ₃ ) δ: 1.25 (s, 3H), 1.42 (s, 3H), 2.13
(d, J = 4.3 Hz, 1H), 2.26 (s, 3H), 3.20-3.25 (m, 2
H), 3.74 (dd, A part of AB, J = 7.8 and 4.3Hz, 1
H), 3.85-3.95 (m, 1H), 4.00-4.10 (m, 1H), 4.41 (d,
B part of AB, J = 7.8 Hz, 1H), 6.95-7.00 (m, 1H),
7.10-7.20 (m, 2H), 7.61 (s, 1H), 8.69 (s, 1H), 9.89
(s, 1H). MS (FAB) m / z; 453 [M + H] ⁺ .

Synthesis Example 10 29% Yield Yellow Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.19 (s, 3H), 1.37 (s, 3H), 1.94
(d, J = 3.8 Hz, 1H), 2.24 (s, 3H), 3.05-3.15 (m, 2
H), 3.66 (dd, A part of AB, J = 8.1 and 3.8Hz, 1
H), 3.90-4.00 (m, 1H), 4.05-4.12 (m, 1H), 4.35 (d,
B part of AB, J = 8.1 Hz, 1H), 7.05-7.15 (m, 2H),
7.28-7.35 (m, 2H), 7.58 (s, 1H), 8.67 (s, 1H), 9.88
(s, 1H). MS (FAB) m / z; 434 [M] ⁺ .

Synthesis Example 11 26% yield Yellow amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.22 (s, 3H), 1.41 (s, 3H), 2.00
(br s, 1H), 2.27 (s, 3H), 3.00-3.10 (m, 2H), 3.68
(br d, A part of AB, J = 8.1 Hz, 1H), 3.92-4.00
(m, 1H), 4.10-4.18 (m, 1H), 4.37 (d, B part of AB,
J = 8.1 Hz, 1H), 7.00-7.10 (m, 2H), 7.20-7.32 (m,
2H), 7.61 (s, 1H), 8.69 (s, 1H), 9.91 (s, 1H). MS (FAB) m / z; 419 [M + H] ⁺ .

Synthesis Example 12 17% Yield Yellow Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.24 (s, 3H), 1.42 (s, 3H), 2.05
(s, 1H), 2.27 (s, 3H), 3.21 (t, J = 6.5 Hz, 2H),
3.73 (dd, A part of AB, J = 8.0 and 4.0 Hz, 1H), 3.
90-4.00 (m, 1H), 4.05-4.15 (m, 1H), 4.39 (dd, B pa
rt of AB, J = 8.0 and 1.0 Hz, 1H), 7.30-7.37 (m, 1
H), 7.45-7.53 (m, 2H), 7.62 (s, 1H), 7.65-7.66 (m,
1H), 8.71 (s, 1H), 9.92 (s, 1H). MS (FAB) m / z; 469 [M + H] ⁺ .

Synthesis Example 13 30% Yield Yellow amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.21 (s, 3H), 1.41 (s, 3H), 2.04
(d, J = 4.0 Hz, 1H), 2.28 (s, 3H), 2.91 (t, J = 6.
5 Hz, 2H), 3.66 (dd, A part of AB, J = 8.2and 4.0
Hz, 1H), 3.80-3.94 (m, 1H), 4.05-4.15 (m, 1H), 4.3
3 (dd, B partof AB, J = 8.2 and 0.7 Hz, 1H), 5.19
(br s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.12 (d, J =
8.4 Hz, 2H), 7.60 (s, 1H), 8.64 (s, 1H), 9.90 (s,
1H). MS (FAB) m / z; 417 [M + H] ⁺ .

Synthesis Example 14 ((-)-form of Synthesis Example 1) (+)-(3R *, 4R *)-6-acetamide-3,4-epoxy-3,4-
Dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran
(99% ee or more) [α] ²⁶ _D = -14.9 (c 0.4, EtOH)

Synthesis Example 15 ((+) form of Synthesis Example 1) (-)-(3R *, 4R *)-6-acetamide-3,4-epoxy-3,4-
Dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran
(99% ee or more) [α] ²⁶ _D = +13.9 (c 0.76, EtOH)

Synthesis Example 16 ((+)-form of Synthesis Example 13) (+)-(3R *, 4R *)-6-acetamide-3,4-epoxy-3,4-
Dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran
(99% ee or more) [α] ²⁶ _D = +5.30 (c 0.44, EtOH)

[Formulation Examples]

Formulation Example 1 Tablet Compound of the present invention 10 g Lactose 260 g Microcrystalline cellulose 600 g Corn starch 350 g Hydroxypropylcellulose 100 g CMC-Ca 150 g Magnesium stearate 30 g Total amount 1,500 g Manufacture 10,000 sugar-coated tablets containing 1 mg of active ingredient.

Formulation Example 2 Capsule Compound of the present invention 10 g Lactose 440 g Microcrystalline cellulose 1,000 g Magnesium stearate 50 g Total amount 1,500 g After mixing the above components by a conventional method, the mixture is filled into a gelatin capsule, and 1 mg is contained in one capsule. To produce 10,000 capsules containing the active ingredient.

Formulation Example 3 Soft Capsule Compound of the present invention 10 g PEG400 479 g Saturated fatty acid triglyceride 1,500 g Mentha oil 1 g Polysorbate (Polysorbate) 80 10 g Total amount 2,000 g Fill to make 10,000 capsules of soft capsules containing 1 mg of active ingredient in one capsule.

Formulation Example 4 Ointment Compound of the present invention 1.0 g Liquid paraffin 10.0 g Cetanol 20.0 g White petrolatum 68.4 g Ethyl paraben 0.1 g l-menthol 0.5 g Total amount 100.0 g The above components were mixed by a conventional method. And 1% ointment.

Formulation Example 5 Suppository Compound of the present invention 1 g Witepsol H15 * 478 g Witepsol W35 * 520 g Polysorbate 80 1 g Total amount 1,000 g "* Trade name of triglyceride compound Witepsol = Witepsol" The components are melt-mixed in a conventional manner, poured into a suppository container, cooled and solidified to produce 1,000 gram suppositories containing 1 mg of the active ingredient.

Formulation Example 6 Injection 1 mg of the compound of the present invention is dissolved in 5 mL of distilled water for injection.

[Pharmacological Test Example] Effect on Refractory Period in Left Atrial Muscle and Right Ventricular Papillary Muscle Test Method Heart was excised from guinea pig and insufflated with 95% O ₂ + 5% CO ₂
The left atrium or right ventricular papillary muscle was separated in a rebs-Henseleit solution. Specimens are 1 Hz,
Stimulate with a voltage 1.5 times the threshold value that responds to the stimulus (basic stimulus; S1).
Recording was made on a hot pen recorder via a strain pressure amplifier. The refractory period was defined as the smallest interval between S1 and a special stimulus (S2) that resulted in a measurable contraction. The interval between S1 and S2 starts at 150 ms for the left atrial muscle sample, shortens by 10 ms until 100 ms, and then by 5 ms until the refractory period, and starts at 300 ms for the right ventricular papillary muscle sample, It was shortened by 10 ms until the refractory period. S2 was set to twice the threshold value for responding to the stimulus. The experimental temperature was 36 ± 1 ° C. The solvent did not affect the refractory period of either the left atrial muscle or the right ventricular papillary muscle. After measuring the basal values before adding the compound, the compound was added cumulatively and the refractory period was measured after 15 minutes incubation at each concentration.

Results The compounds according to the present invention showed a strong prolonged refractory period on the atria.

[0095]

[Table 1]

[0096]

Industrial Applicability The compounds of the present invention exhibit a refractory period extending action and are useful for ameliorating arrhythmias. Therefore, the present invention can provide a useful therapeutic agent for arrhythmia.

Continuing from the front page (72) Inventor Yukihiro Shigeta 722-1, Tsuboi-cho, Funabashi-shi, Chiba Nissan Chemical Industry Co., Ltd. (72) Inventor Toru Tsukagoshi 722-1, Tsuboi-cho, Funabashi-shi, Chiba Nissan Chemical Industry Co., Ltd. In the laboratory (72) Inventor Toru Yamashita 1470 Shirooka, Shirooka-cho, Shiraoka-cho, Minami-Saitama-gun, Saitama F-term (reference) in Nissan Chemical Industry Co., Ltd.

Claims (6)

[Claims] 1. A compound of the formula (I) Wherein R ¹ and R ² are each independently a hydrogen atom, C _1-6
An alkyl group (the alkyl group may be optionally substituted with a halogen atom, a C _1-6 alkoxy group or a hydroxyl group) or a phenyl group (the phenyl group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, C _1-6 alkyl group or
It may be optionally substituted by a C _1-6 alkoxy group. R ³ represents a hydroxyl group or a C _1-6 alkylcarbonyloxy group, R ⁴ represents a C _3-6 cycloalkyl group, a C _1-6 alkyl group, a C _1-6 alkylcarbonyl group, C _1-6 alkylaminocarbonyl group, di C _1-6 alkylaminocarbonyl group ｛The C _1-6 alkyl group, C _1-6 alkylcarbonyl group, C _1-6 alkylaminocarbonyl group and di C _1-6 alkyl Each aminocarbonyl group is a halogen atom, a C _1-6 alkoxy group (the alkoxy group may be substituted with a halogen atom), a carboxyl group, a C _1-6 alkoxycarbonyl group, a hydroxyl group, an aryl group or a heteroaryl. group (the aryl group, m-number of R ⁸ are both heteroaryl group (R ⁸ is a halogen atom, a hydroxyl group, C _{1 -6} alkyl group (the alkyl group is a halogen atom or a
A C _1-6 alkoxy group (optionally substituted with a C _1-6 alkoxy group), a C _1-6 alkoxy group (the alkoxy group may be substituted with a halogen atom), a nitro group, a cyano group, a formyl group, a formamide group, an amino Group, C _1-6 alkylamino group, di C _1-6
Alkylamino group, C _1-6 alkylcarbonylamino group,
C _1-6 alkylsulfonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyl group, di C _1-6 alkylaminocarbonyl group, C _1-6 alkylcarbonyl group, C _1-6
It means an alkoxycarbonyl group, an aminosulfonyl group, a C _1-6 alkylsulfonyl group, a carboxyl group or an arylcarbonyl group. ) May optionally be substituted. m represents an integer of 1 to 3, and when m is 2 or 3, R ⁸ may be the same or different. ) May optionally be substituted. ｝, An aryl group or a heteroaryl group ｛
R ⁹ (R ⁹ has the same meaning as R ⁸ ). n represents an integer of 1 to 3, and when n is 2 or 3, R ⁹ may be the same or different. ⁵ , R ⁵ represents a hydrogen atom or a C _1-6 alkyl group, X represents absent or represents C = O or SO ₂ , and R ⁶ represents a hydrogen atom, C _{1- 6 represents} an alkyl group (the alkyl group may be substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group) or a C _3-6 cycloalkyl group, and R ⁷ represents a hydrogen atom, a halogen atom, Group or cyano group. Or a pharmaceutically acceptable salt thereof. 2. The 4-oxybenzopyran derivative or a pharmaceutically acceptable salt thereof according to claim ^1, wherein R ¹ and R ² are both a methyl group and R ³ is a hydroxyl group. 3. The 4-oxybenzopyran derivative or the pharmaceutically acceptable salt thereof according to claim 2, wherein X is C = O and R ⁵ is a hydrogen atom. ^4. The 4-oxybenzopyran derivative or the pharmaceutically acceptable salt thereof according to claim 3, wherein R ⁴ is an alkyl group and R ⁷ is a nitro group. 5. A medicament comprising the 4-oxybenzopyran derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A therapeutic agent for arrhythmia, comprising the 4-oxybenzopyran derivative or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.