JPH07196635A - Benzoxazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new benzoxazine derivative having excellent K<+> channel function activities and useful as a medicine. CONSTITUTION:This benzoxazine derivative is expressed by formula I [R1 and R2 each is H or an alkyl or R1 and R2 together denote polymethylene; R3 and R4 each is H, an alkyl, a haloalkyl, a halogen, an alkoxy, amino, an acylamino, nitro, cyano, an alkoxycarbonyl, etc.; R3 and R4 together denote N-O-N=; X is O, S or N-Z (Z is H, an alkyl, an aryl, OH, an alkoxy, cyano, etc.); Y is NR5R6; OR7 or SR8 (R5 and R6 each is H, OH, an alkoxy, an alkyl, etc.; R7 and R8 each is H, an alkyl or an aryl)], e.g. 6-bromo-7-chloro-N,2,2- trimethyl-2H-1,3-benzoxazine-4-carbonamide expressed by formula II. The compound expressed by formula I is obtained by directly reacting, e.g. a compound expressed by formula III (R9 is a lower alkyl) with an amine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzoxazine derivative which is a compound useful as a medicine.

[0002]

2. Description of the Related Art Benzopyran derivatives having various pharmacological actions have been conventionally known. For example, JP-A-60-
No. 97974, No. 61-47416, No. 63-165.
317, 63-196581, 63-2011.
No. 82, No. 63-303977, No. 64-26578.
No. 64-38087, Japanese Patent Laid-Open No. 2-129184, and Journal of Medicinal
Chemistry vol. 33, No. 6, pp1
529-1541, 1990 and the like disclose various benzopyran derivatives in which the 4-carbon atom of the benzopyran ring is directly bonded to a nitrogen atom, and these compounds have antihypertensive action, and are effective in treating heart diseases and the like. It is stated that it can be used for therapy.

Among the benzopyran derivatives disclosed in the above-mentioned documents, cromakalim represented by the following formula has recently attracted attention as a new kind of antihypertensive drug acting on K ⁺ channel together with nicorandil, pinacidil and the like.

[0004]

[Chemical 2] Further, benzopyran derivatives in which the 4-position carbon atom of the benzopyran ring is not directly bonded to the nitrogen atom are also disclosed in JP-A-63-303977, JP-A-64-38087 and WO9.
0/14346, Journal of Het
erocyclic Chemistry Vol. 1
1 (5), pp. 797-802, 1974 and Jou
rnal of Medicinal Chemist
ry vol. 33, No. 6, pp. 1529-15
41, 1990 and the like. Further, benzoxazine derivatives in which the 3-position carbon atom of the benzopyran ring is substituted with a nitrogen atom are disclosed in JP-A-57-130979, JP-A-2-193995, JP-A-5-97824 and the like. However, a compound having a carboxyl group or its derivative as a substituent at the 4-position carbon atom has not yet been known.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have synthesized a benzoxazine derivative having K ⁺ channel activity and having a carboxyl group or its derivative as a substituent at the 4-position carbon atom of the benzoxazine ring. As a result of intensive studies on K ⁺ channel action activity, it was discovered that a novel benzoxazine derivative not described in the literature has such pharmacological activity, and the present invention was completed based on this finding.

[0006]

The compound of the present invention is a novel compound represented by the following general formula (I) and has excellent K
^{It has +} channel action activity.

General formula

[Chemical 3] (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group which may have a substituent or a polymethylene group together; R ₃ and R ₄ are the same or different. Hydrogen atom, lower alkyl group, lower haloalkyl group, halogen atom, lower alkoxy group, lower haloalkoxy group, amino group, acylamino group, nitro group,
Represents a cyano group, lower alkoxycarbonyl, lower alkylsulfonyl group, arylsulfonyl group, or R
₃ and R ₄ together represent = N-O-N; X is O,
S or N-Z is shown, wherein Z is a hydrogen atom, lower alkyl group, aryl group, hydroxyl group, lower alkoxy group, cyano group, carbamoyl group or sulfamoyl group; Y is -NR ₅ R ₆ , -OR ₇ or indicates -SR _8, wherein R
₅ and R ₆ are the same or different and each is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group which may have a substituent, a saturated or unsaturated lower alkyl group which may have a substituent, a substituent Represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, a heteroaryl group which may have a substituent, or R ₅ and R ₆
Together represent, together with the nitrogen atom, a nitrogen-containing heterocycle which may have a substituent, R ₇ and R ₈ are hydrogen atoms,
A lower alkyl group or an aryl group is shown). In the definition of the compound represented by the general formula (I), the lower alkyl group or the alkyl group portion of lower haloalkyl means an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. Examples of such lower alkyl groups include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group,
Examples thereof include i-butyl group, s-butyl group and t-butyl group. In addition, the halogen atom of lower haloalkyl is
It means chlorine, fluorine, bromine or iodine, preferably chlorine or fluorine. Examples of the lower haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group and a pentafluoroethyl group.

Halogen atom means chlorine, fluorine, bromine,
It means iodine, preferably chlorine or fluorine.

The lower alkoxy group is an alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, n-
Propoxy group, i-propoxy group, n-butoxy group, i
Examples thereof include -butoxy group, s-butoxy group, t-butoxy group.

Examples of the acylamino group include lower alkylcarboxylic acid amino groups such as acetylamino group, propionic acid amino group, butyric acid amino group and valeric acid amino group.

Examples of the lower alkylsulfonyl group include lower alkylsulfonyl groups such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and butylsulfonyl group.

Examples of the arylsulfonyl group include a phenylsulfonyl group, a naphthylsulfonyl group, a tolylsulfonyl group, a xylylsulfonyl group, a biphenylsulfonyl group and the like.

The aryl group means a monovalent substituent obtained by removing one hydrogen atom from an aromatic hydrocarbon, and specifically,
Examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Particularly preferred is the phenyl group. The carbon atom on the ring of the aryl group is a halogen atom, a lower alkyl group,
It may be substituted with one or more groups such as an amino group, a nitro group and a trifluoromethyl group. The lower haloalkoxy group means a haloalkyloxy group having 1 to 6 carbon atoms, and the halogen atom means chlorine, fluorine, bromine or iodine, preferably chlorine or fluorine.
Examples of the lower haloalkoxy group include fluoromethyloxy group, difluoromethyloxy group, trifluoromethyloxy group, fluoroethyloxy group, difluoroethyloxy group, trifluoroethyloxy group, pentafluoroethyloxy group and the like. . The saturated or unsaturated lower alkyl group means an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group. , I-propyl group, n-butyl group, s-butyl group,
Examples thereof include t-butyl group, pentyl group, hexyl group, vinyl group, allyl group, butenyl group, pentenyl group, ethynyl group, propynyl group and butynyl group.

The cycloalkyl group is preferably one having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

The heteroaryl group means an aryl group containing a hetero atom, specifically, a pyridyl group, a pyrimidinyl group, a quinolinyl group, a pyrazinyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a thiadiazole group, a tetrazolyl group. And so on.

Examples of the nitrogen-containing heterocycle include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazyl group and morpholino group. Examples of the substituent include an optionally protected hydroxyl group, halogen atom, lower alkyl group, lower alkoxy group, lower alkylcarbonyl group, amino group, nitro group, lower haloalkyl group, lower haloalkoxy group, cyano group and the like. . The compound represented by the general formula (I) is, for example, the compound represented by the general formula (II)

[Chemical 4] (Wherein R ₁ , R ₂ , R ₃ , and R ₄ have the same meanings as described above, and R ₉ represents a lower alkyl group), and may be produced by directly reacting the compound with an amine. I can. This reaction is preferably carried out in water, an alcohol such as methanol, ethanol, propanol, a solvent such as tetrahydrofuran, dioxane, dichloromethane or a mixture thereof. This reaction is preferably carried out under cooling under a slightly mild condition such as room temperature or under heating. In addition, the compound of the general formula (I) is represented by the general formula (III)

[Chemical 5] (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above), if necessary, can also be obtained by subjecting the compound to a usual esterification reaction or amidation reaction. it can. For example, in a compound of the general formula (III) and an inert solvent, HNR ₅ R ₆ , HOR ₇ and HSR ₈ (wherein R ₅ ,
R ₆ , R ₇ , and R ₈ have the same meanings as described above) can be obtained by reacting them with a suitable condensing agent. Examples of the condensing agent used here include amidating reagents such as carbonyldiimidazole, triphenylphosphine and 2,2′-dipyridyldisulfide. The compounds represented by the general formula (II) and the general formula (III) can be represented by, for example, the general formula (IV)

[Chemical 6] (R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above, Z
Represents a leaving group such as a halogen atom, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group) and is substituted with a carboxyl group or an alkoxycarbonyl group. This substitution reaction is carried out, for example, in an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide or the like, using a 0-valent or 2-valent palladium catalyst such as bistriphenylphosphine palladium acetate, in the presence or absence of a lower alcohol, and monooxidation. It can be obtained by reacting carbon at 0 to 130 ° C. Here, the compound represented by the general formula (IV), which is a raw material compound, is disclosed in, for example, JP-A-5-9
It can be synthesized by the method described in Japanese Patent No. 7824. The compound of the present invention can also be obtained by applying the specific production method described in the examples. Hereinafter, the present invention will be described in more detail based on examples. The invention is in no way limited by these examples.

[0017]

【Example】

Example 1 6-Bromo-7-chloro-N, 2,2-trimethyl-2
H-1,3-benzoxazine-4-carboxamide (1) 6-bromo-7-chloro-3,4-dihydro-
2,2-Dimethyl-2H-1,3-benzoxazine-
3.5 ml of trifluoromethanesulfonic anhydride in 100 ml of a dichloromethane solution of 4.0 g of 4-one, 2,6-
3.5 ml of lutidine was added under ice cooling and stirred for 1 hour. The residue obtained by distilling off the solvent is purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ : hexane = 1: 1) to give 6-bromo-7-chloro-4 represented by the following formula.
-5.8 g of trifluoromethanesulfonyloxy-2,2-dimethyl-2H-1,3-benzoxazine were obtained. NMR (CDCl ₃ ) δ: 1.65 (6H, s), 7.
03 (1H, s), 7.59 (1H, s) MS m / z: 421 (M ⁺ ).

[Chemical 7] (2) 6-Bromo-7-chloro-4-trifluoromethanesulfonyloxy-2,2-dimethyl-2H-1,3
A mixture of 1.0 g of benzoxazine, 89 mg of bistriphenylphosphine palladium acetate, 0.66 ml of triethylamine, 4 ml of anhydrous methanol, and 15 ml of anhydrous tetrahydrofuran under a carbon monoxide atmosphere.
The mixture was stirred with ice cooling for 15.5 hours. Water was added and the mixture was extracted with ethyl acetate. After drying the organic matter, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (developing solution:
CH ₂ Cl ₂ : hexane = 2: 1) and 6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazine-4-carboxylic acid methyl ester represented by the following formula: 150 mg Got NMR (CDCl ₃ ) δ: 1.65 (6H, s), 3.
97 (3H, s), 6.95 (1H, s), 8.09
(1H, s). MS m / z: 331 (M ⁺ )

[Chemical 8] (3) 6-Bromo-7-chloro-2,2-dimethyl-2
A mixture of 90 mg of H-1,3-benzoxazine-4-carboxylic acid methyl ester, 3 ml of 40% methylamine methanol solution, and 3 ml of tetrahydrofuran at room temperature was added.
Stir for 5 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solution: CH ₂ Cl ₂ : h
After refining with hexane = 1: 1) and recrystallizing with hexane, the melting point of 100-102 ° C represented by the following formula 6-
Bromo-7-chloro-N, 2,2-trimethyl-2H-
50 mg of 1,3-benzoxazine-4-carbamide
Obtained. _{NMR (CDCl 3) δ: 1.56} (6H, s). 2.
94 (3H, d), 6.94 (1H, S), 7.04-
7.58 (1H, brs), 8.81 (1H, s). MS m / z: 330 (M ⁺ )

[Chemical 9]

Example 2 6-Bromo-7-chloro-N- (2-cyanoethyl)-
2,2-Dimethyl-2H-1,3-benzoxazine-
4-Carboxamide 6-Bromo-7-chloro-2,2-dimethyl-2H-
A mixture of 90 mg of 1,3-benzoxazine-4-carboxylic acid methyl ester, 0.2 ml of 2-cyanoethylamine and 3 ml of tetrahydrofuran was stirred at room temperature for 15 hours, and 0.2 ml of 2-cyanoethylamine was added to the mixture.
The mixture was stirred for an hour, 0.3 ml of 2-cyanoethylamine was further added, and the mixture was stirred for 13 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solution: CH ₂ C).
l ₂ : hexane = 1: 1) and then recrystallized from a mixture of ethyl acetate and hexane to give a melting point of 1
6-Bromo-7-chloro-N- (2-cyanoethyl) -2,2-dimethyl- represented by the following formula at 09-111 ° C.
2H-1,3-benzoxazine-4-carboxamide 3
6 mg was obtained. NMR (CDCl ₃ ) δ: 1.59 (6H, s), 2.
71 (2H, t), 3.68 (2H, dt), 6.98
(1H, s), 7.63-8.00 (1H, brs),
8.78 (1H, s). MS m / z: 369 (M ⁺ )

[Chemical 10]

Example 3 N, 2,2-Trimethyl-6-nitro-2H-1,3-
Benzoxazine-4-carbamide (1) 6-nitrosalicylamide 4.0 g, acetone 7
A mixture of 0 ml, 2,2-dimethoxypropane 3 ml and p-toluenesulfonic acid 840 mg was heated under reflux for 21 hours. Water was added to the residue obtained by distilling off the solvent, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried, and then the solvent was distilled off to recrystallize the resulting crystal, which was recrystallized from ethanol. Dihydro-2,2-
1.24 g of dimethyl-6-nitro-2H-1,3-benzoxazin-4-one was obtained. NMR (CDCl ₃ ) δ: 1.63 (6H, s),
7.15 (1H, d), 8.29 (1H, dd), 8.
48 (1H, d), 9.00 (1H, brs) MS m / z: 222 (M ⁺ ).

[Chemical 11] (2) 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,3-benzoxazin-4-one is represented by the following formula in the same manner as in Example 1 (1). Ru 4-
Trifluoromethanesulfonyloxy-2,2-dimethyl-6-nitro-2H-1,3-benzoxazine was obtained. NMR (CDCl ₃ ) δ: 1.72 (6H, s), 6.
93 (1H, d), 8.22 (1H, d), 8.29
(1H, dd) MS m / z: 354 (M ⁺ ).

[Chemical 12] (3) 4-trifluoromethanesulfonyloxy-2,
Using 2-dimethyl-6-nitro-2H-1,3-benzoxazine in the same manner as in Example 1 (2), 2,2-dimethyl-6-nitro-2H-1 represented by the following formula: ，
3-Benzoxazine-4-carboxylic acid methyl ester was obtained. NMR (CDCl ₃ ) δ: 1.72 (6H, s), 4.
00 (3H, s), 6.93 (1H, d), 8.28
(1H, dd), 8.79 (1H, d). MS m / z: 264 (M ⁺ )

[Chemical 13] (4) 2,2-Dimethyl-6-nitro-2H-1,3-
Using benzoxazine-4-carboxylic acid methyl ester, in the same manner as in Example 1 (3), melting point 132-13
N, 2,2-trimethyl-6- represented by the following formula at 3 ° C
Nitro-2H-1,3-benzoxazine-4-carboxamide was obtained. _{NMR (acetone-d 6) δ} : 1.63 (6H,
s), 2.90 (3H, d), 7.00 (1H, d),
7.70-8.65 (1H, brs), 8.28 (1
H, dd), 9.33 (1H, d). MS m / z: 263 (M ⁺ )

[Chemical 14]

Example 4 N- (2-cyanoethyl) -2,2-dimethyl-6-di
Toro-2H-1,3-benzoxazine-4-carbore
Amido 2,2-Dimethyl-6-nitro-2H-1,3-benzoxazine-4-carboxylic acid methyl ester is represented by the following formula having a melting point of 185-187 ° C. in the same manner as in Example 2. N- (2-cyanoethyl) -2,2-dimethyl-6-nitro-2H-1,3-benzoxazine-4
-Carboxamide was obtained. 270 MHz-NMR (CDCl ₃ ) δ: 1.66 (6
H, s), 2.74 (2H, t), 3.68 (2H, d
t), 6.92 (1H, d), 7.78 (1H, br
s), 8.27 (1H, dd), 9.42 (1H,
d). MS m / z: 302 (M ⁺ )

[Chemical 15]

Example 5 2,2-bis (fluoromethyl) -N-methyl-6-ni
Toro-2H-1,3-benzoxazine-4-carbore
Bromide (1) 5-nitro-salicylamide 4.0 g, 1,3-difluoro-acetone 6.2 g, was a mixture of pyrrolidine 1.8ml and benzene 300ml and heated under reflux for 2 hours.
The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solution; CH ₂ Cl ₂ : methanol = 99: 1) to be represented by the following formula: 2,2-bis (fluoromethyl)- 3,4-dihydro-6-nitro-
1.5 g of 2H-1,3-benzoxazin-4-one was obtained. NMR (DMSO-d ₆ ) δ: 4.68 (4H, d),
7.25 (1H, d), 8.36 (1H, dd), 8.
57 (1H, d), 9.75 (1H, brs). MS m / z: 258 (M ⁺ )

[Chemical 16] (2) 2,2-bis (fluoromethyl) -3,4-dihydro-6-nitro-2H-1,3-benzoxazine-
A mixture of 0.26 g of 4-one, 0.25 g of phosphorus pentachloride and 1.6 g of phosphorus oxychloride was heated and stirred at 70 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (developing solution: CH ₂
Cl ₂ ) to give 4-chloro-2,2-bis (fluoromethyl) -6-nitro-2H-1,3-benzoxazine (0.19 g) having a melting point of 75-77 ° C. and represented by the following formula. . NMR (CDCl ₃ ) δ: 4.55 (4H, d), 6.
96 (1H, d), 8.26 (1H, dd), 8.45
(1H, d). MS m / z: 276 (M ⁺ )

[Chemical 17] (3) 4-chloro-2,2-bis (fluoromethyl)-
6-nitro-2H-1,3-benzoxazine 0.18
g, bis (triphenylphosphine) palladium acetate 15 mg, silver carbonate 0.19 g, absolute ethanol 1.
A mixture of 2 ml and 3 ml of anhydrous N, N-dimethylformamide was added, and this was heated and stirred at 60 ° C. for 1 hour under a carbon monoxide atmosphere. Water and acetic acid ethyl ester were added to the reaction mixture, and the insoluble matter was filtered off by Celite filtration, followed by extraction with acetic acid ethyl ester. The organic layer was washed with saturated brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solution; hexane: acetic acid ethyl ester =
After purification by 5: 1), 0.14 g of 2,2-bis (fluoromethyl) -6-nitro-2H-1,3-benzoxazine-4-carboxylic acid ethyl ester represented by the following formula was obtained. NMR (CDCl ₃ ) δ: 1.43 (3H, t), 4.
46 (2H, q), 4.68 (4H, d), 6.90
(1H, d), 8.16 (1H, dd), 8.54 (1
H, d). MS m / z: 314 (M ⁺ )

[Chemical 18] (4) 2,2-bis (fluoromethyl) -6-nitro-
A mixture of 0.08 g of 2H-1,3-benzoxazine-4-carboxylic acid ethyl ester, 0.12 ml of 40% methylamine methanol solution and 3 ml of ethanol was stirred at room temperature for 20 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution; CH ₂ Cl ₂ : methanol = 100: 1).
2,2-bis (fluoromethyl) -N-methyl-6-nitro-2H-1 represented by the following formula and having a melting point of 156-158 ° C., and recrystallized from a mixed solution of hexane and acetic acid ethyl ester. , 3-benzoxazine-4-
70 mg of carboxamide was obtained. NMR (CDCl ₃ ) δ: 2.92 (3H, d), 4.
62 (4H, d) 6.93 (1H, d), 6.90-
7.55 (1H, brs), 8.23 (1H, dd),
9.39 (1H, d). MS m / z: 299 (M ⁺ )

[Chemical 19]

Example 6 N- (2-cyanoethyl) -2,2-bis (fluorome)
Cyl) -6-nitro-2H-1,3-benzoxazine
-4-Carboxamide 2,2-bis (fluoromethyl) -6-nitro-2H-
Melting point: 152-154 ° C in the same manner as in Example 5 (4) using 1,3-benzoxazine-4-carboxylic acid ethyl ester, 2-cyanoethylamine and ethanol.
N- (2-cyanoethyl) -2,2 represented by the following formula
-Bis (fluoromethyl) -6-nitro-2H-1,3
-Benzoxazine-4-carboxamide was obtained. NMR (acetone-d ₆ ) δ: 2.84 (2H,
t), 3.71 (2H, q), 4.81 (4H, d),
7.17 (1H, d), 8.37 (1H, dd), 8.
45-8.85 (1H, brs), 9.33 (1H,
d). MS m / z: 338 (M ⁺ )

[Chemical 20]

Test Example 1 Test Method Using Isolated Rat Aorta Male Sprague Dawley rat (450 g-
The thoracic aorta was taken out from 600 g) and used as a circular specimen with a width of 2 mm. This sample is Krebs-Henseleit
Solution (NaCl: 119, KCl: 4.8CaCl ₂ ·
2H ₂ O: 2.53, KH ₂ PO ₄ : 1.2, MgSO
_{4 · 7H 2 O: 1.2,} NaHCO 3: 24.8, glucose; 10 (mM), 37 ℃ ) was suspended under tension of 2g in organ bath (Organ bath bath) of 10ml containing 95% oxygen , 5% carbon dioxide gas was aerated. The contraction response of the sample was recorded isometrically with an FD pickup. After equilibration for 1-1.5 hours, 30 mM potassium chloride is added to contract the tissue, and the activity of the test compound that relaxes the sustained contraction by potassium chloride is 50% of the maximum relaxing action of the compound. Inhibitory concentration (E
It was evaluated by determining the C ₅₀ ). The test compound is
The compound of the present invention obtained in the above example was used. The results are shown in Table 1 below.

[Table 1]

[0024]

INDUSTRIAL APPLICABILITY The compound of the present invention has excellent K ⁺ channel action activity and is useful as a medicine.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area // (C07D 498/04 265: 16 271: 08)

Claims (1)

[Claims] 1. A general formula: (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group which may have a substituent or a polymethylene group together; R ₃ and R ₄ are the same or different. Hydrogen atom, lower alkyl group, lower haloalkyl group, halogen atom, lower alkoxy group, lower haloalkoxy group, amino group, acylamino group, nitro group, cyano group, lower alkoxycarbonyl group, lower alkylsulfonyl group, arylsulfonyl group Show or R
₃ and R ₄ together represent = N-O-N =; X represents O, S or N-Z, wherein Z represents a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group, a lower alkoxy group. Represents a cyano group, a carbamoyl group or a sulfamoyl group;
Y is _-NR 5 _R 6, shows the -OR ₇ or -SR _8, wherein _{R 5} and _{R 6} are the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, which may have a substituent Amino group, saturated or unsaturated lower alkyl group which may have a substituent, aryl group which may have a substituent, cycloalkyl group which may have a substituent, which has a substituent Optionally represents a heteroaryl group, or R ₅ and R ₆ together represent, together with a nitrogen atom, a nitrogen-containing heterocycle which may have a substituent, and R ₇ and R ₈
Represents a hydrogen atom, a lower alkyl group or an aryl group).