JPH09235227A - Cardiac insufficiency treating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cardiac insufficiency treating agent, containing a compound expressed by a specific chemical structural formula and having strong heart rate reducing activity as an active component and effective for improving cardiac function. SOLUTION: This agent is composed of a benzopyran derivative of formula I (R<1> and R<2> are each H, a halogen, an alkylamine, an alkylcarbonyl, etc.; R<3> and R<4> are each H, an alkyl, etc., or R<3> and R<4> form a cycloalkyl group together with the carbon to which R<3> and R<4> are bonded; R<5> is OH, etc.; R<6> is H, or forms a ring together with R<5> ; R<7> and R<8> are each H or an alkyl, or form a pyrrolidinyl ring, an imidazolidinyl ring, etc., together with the nitrogen atom) or a pharmaceutically permissible salt of the compound. As a compound of formula I, 3,4-dihydro-2,2-dimethyl6-nitro-trans-4-(1pyrrolidinyl)-2H-1 benzopyran-3-ol of formula II, etc., is cited. A compound of formula III as a compound of formula I is obtained by reacting a compound of formula IV with a compound of the formula NHR<7> R<8> .

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a use of a benzopyran derivative having a pharmacological activity for treating heart failure in mammals including humans.

[0002]

2. Description of the Related Art JP-A-51-1477 (British Patent No. 1495526, US Pat. No. 4,048,317), JP-A-56-5
7785 (European Patent 28064, US Patent 43
63811), JP-A-56-57786 (European patent 28449, US Pat. No. 4,366,163), and WO.
Japanese Patent No. 8501290 (European Patent Publication No. 157843) discloses the possibility that benzopyran derivatives can be used for the treatment of hypertension, but does not mention the possibility of treating heart failure pathology. . Heart failure, which is a dysfunctional state of the heart, is a disease based on a decrease in cardiac contractility, and a drug that increases myocardial contractility is used clinically for the treatment thereof. However, these drugs are said to have a problem of myocardial energy excessive consumption due to the action of increasing the heart rate, and it is said that there is a problem in the life prognosis improving effect at the time of long-term administration. Therefore, there is a need for a drug that reduces the myocardial energy expenditure by reducing the heart rate.

[0003]

Means for Solving the Problems Among the benzopyran derivatives, the present inventors have extensively searched for a compound having a low antihypertensive effect and decreasing heart rate, and as a result, have found that the compound represented by the formula (I) has a strong inhibitory effect. The present invention has been completed by discovering that it has a pulsating action and is useful as a therapeutic agent for heart failure.

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

[0005]

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[In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkyl group. Amino 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 Group or C _1-6 alkoxycarbonyl group, R ³ and R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group or a phenyl group, or R ³ and R ⁴ are taken together. Means a C _3-6 cycloalkyl group, R ⁵ is a hydroxyl group, a C _1-6 alkoxy group or C
_1-6 means a bond together with or R ⁶ means an alkylcarbonyl group, R ⁶ means a bond or together with R ⁵ means a hydrogen atom, R ⁷ and R ⁸ independently represents a hydrogen atom or a C _1-6 alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl. , Perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl,
1,3-perhydrooxaazepinyl, 1,4-perhydrooxaazepinyl, 1,3-thiazolidinyl, 1,
4-perhydrothiazolinyl, 1,3-perhydrothiazolidinyl, 1,4-perhydrothiazolidinyl group, or R ⁷ and R ⁸ together form a bond be optionally substituted by R ⁹ together with the nitrogen atom to which they are good pyrrole ring (R ⁹ represent. the same meanings as R ¹⁾ means. ] A therapeutic agent for heart failure comprising a benzopyran derivative represented by the following formula or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound used in the present invention has a strong heart rate reducing action, is effective in improving heart function, and can be used as a therapeutic agent for heart failure.

Next, each substituent of the compound (I) used in the present invention will be explained more specifically. In the present specification, "n" means normal, "i" means iso, "s" means secondary, "t" means tertiary, and "c" means cyclo.

Examples of the halogen atom include 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.

C _1-6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and s-
Butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, t-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl,
Examples include 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl and 3,3-dimethyl-n-butyl. Preferred examples include methyl, ethyl, n-propyl, i-propyl, n-butyl and the like.

C _1-6 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-
Butoxy, s-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy, t-pentyloxy, 1-hexyloxy, 2-hexyloxy, 3 -Hexyloxy,
1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, 3,3-dimethyl-n-butoxy and the like can be mentioned. Preferably, methoxy, ethoxy, n-propoxy and i-propoxy are mentioned.

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

C _1-6 alkylamino groups include methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t -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 and 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, t-butyl (c-
Butyl) amino and the like. Preferably, dimethylamino, diethylamino, di-n-propylamino, di-i-
Examples include propylamino and di-n-butylamino.

C _1-6 alkylcarbonylamino groups include 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, 3-hexylcarbonylamino and the like. Preferably, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-
Butylcarbonylamino may be mentioned.

The C _1-6 alkylsulfonylamino group includes methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, n-butylsulfonylamino, i-butylsulfonylamino and s-butylsulfonyl. Amino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, i-
Examples thereof include pentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino, 1-hexylsulfonylamino, 2-hexylsulfonylamino, 3-hexylsulfonylamino and the like. Preferably, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, n-
Butyl sulfonylamino is mentioned.

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

Examples of the di C _1-6 alkylaminocarbonyl group include 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-
Examples thereof include 2-hexylaminocarbonyl and di-3-hexylaminocarbonyl. Preferred are dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl.

C _1-6 alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, 1 -Pentylcarbonyl, 2-pentylcarbonyl,
Examples include 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl and 3-hexylcarbonyl. Preferred are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl and n-butylcarbonyl.

Examples of the C _1-6 alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, 1 -Pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxy Carbonyl and the like can be mentioned. Preferably, methoxycarbonyl, ethoxycarbonyl, n-
Examples include propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl.

The preferred compounds used in the present invention include the following compounds.

(1) R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group. groups, C _{1 -6} alkylcarbonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyl group or gripping C
_1-6 means an alkylaminocarbonyl group, R ³ and R
⁴ independently represent a C _1-6 alkyl group or a C _3-6 cycloalkyl group together with the carbon atom to which R ³ and R ⁴ are taken together and R ⁵ is a hydroxyl group or C _1-6 means an alkylcarbonyloxy group or together with R ⁶ means a bond, R ⁶ means a hydrogen atom or R ⁵
Together with means a bond, R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-6 alkyl group,
R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, 1,3
A thiazolidinyl group, or a pyrrole ring in which R ⁷ and R ⁸ together are optionally substituted with R ⁹ together with the nitrogen atom to which they are attached (R ⁹ has the same meaning as R ¹ A benzopyran derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

(2) R ⁷ and R ⁸ together mean a pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl group together with the nitrogen atom to which they are bonded, or R ⁷ and R ⁸ together since an optionally pyrrole ring optionally substituted by R ⁹ together with the nitrogen atom to which they are attached (R ⁹ has the same meaning as R ^1.) meaning the compound of formula (1) described.

(3) The compound described in (2) above, wherein R ³ and R ⁴ are the same C _1-6 alkyl group.

(4) R ² is a hydrogen atom, a halogen atom, a cyano group, an amino group, a C _1-6 alkylcarbonylamino group, an aminocarbonyl group, a C _1-6 alkylaminocarbonyl group or a di-C _1-6 alkylamino group. The above (3) which is a carbonyl group
A compound as described.

(5) The compound described in (4) above, wherein R ² is a hydrogen atom, a halogen atom, an amino group or a C _1-6 alkylcarbonylamino group.

(6) R ¹ is hydrogen atom, halogen atom, nitro group, cyano group, formyl group, amino group, C _1-6 alkylamino group, di C _1-6 alkylamino group, C _1-6 alkylcarbonyl group The compound according to (5) above, which is an amino group, an aminocarbonyl group, a C _1-6 alkylcarbonylamino group or a di-C _1-6 alkylaminocarbonyl group.

(7) R ¹ is a hydrogen atom, nitro group, cyano group, C _1-6 alkylcarbonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyl group or di C _1-6 alkylaminocarbonyl group. A certain compound according to the above (6).

(8) The compound described in (7) above, wherein R ² is a hydrogen atom.

(9) R ¹ is a hydrogen atom, R ² is a methylcarbonylamino group, R ³ and R ⁴ are methyl groups, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ are together. A benzopyran derivative represented by the formula (I) which is a pyrrolidinyl group together with the nitrogen atom to which they are bound, or a pharmaceutically acceptable salt thereof.

(10) R ¹ is a nitro group, R ² is a methylcarbonylamino group, R ³ and R ⁴ are methyl groups, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ are taken together. Of the formula (I) in which they are pyrrolidinyl groups together with the nitrogen atom to which they are attached.
A benzopyran derivative represented by: or a pharmaceutically acceptable salt thereof.

(11) R ¹ is a nitro group, R ² is an amino group, R ³
And R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom,
A benzopyran derivative of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together are a pyrrolidinyl group together with the nitrogen atom to which they are attached.

(12) R ¹ is a nitro group, R ² is a hydrogen atom, R ³
And R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom,
A benzopyran derivative of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together are a pyrrolidinyl group together with the nitrogen atom to which they are attached.

(13) R ¹ is a nitro group, R ² is a hydrogen atom, R ³
And R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom,
A formula (R ⁹ represents the same meaning as R ¹ ) which together represents a pyrrole ring in which R ⁷ and R ⁸ together are optionally substituted by R ⁹ together with the nitrogen atom to which they are attached. A benzopyran derivative represented by I) or a pharmaceutically acceptable salt thereof.

Specific examples of the compounds that can be used in the present invention are shown below, but the present invention is not limited to these. In addition, Me means a methyl group, Et means an ethyl group, Pr means a propyl group, Bu means a butyl group, and Ac means an acetyl group (COCH ₃ ).

[0036]

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[0037]

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[0038]

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[0039]

[Chemical 6]

The compound used in the present invention has a pyran ring of 3
It has asymmetric carbons at the 4th and 4th positions, and there is an optically active substance based on the asymmetric carbons, but it can be used for the purpose of the present invention like the racemic form. The relative arrangement of the 3-position and 4-position of the pyran ring is trans. When the compound is a compound capable of forming a salt, a pharmaceutically acceptable salt thereof can also be used as an active ingredient.

[0041]

BEST MODE FOR CARRYING OUT THE INVENTION

Next, a method for producing the compound used in the present invention will be described.

Of the compounds represented by the general formula (I),
R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-6 alkyl group, or together with the nitrogen atom to which R ⁷ and R ⁸ are bonded, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl , Piperazinyl,
Perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-perhydrooxazepinyl,
1,4-perhydrooxaazepinyl, 1,3-thiazolidinyl, 1,4-perhydrothiazolinyl, 1,3-
A compound (represented by the general formula (IV)) meaning a perhydrothiazolidinyl or 1,4-perhydrothiazolidinyl group is represented by the general formula (II) as shown by the following reaction formula. It is obtained by reacting the compound represented by the formula (III) with a compound represented by the general formula (III) in an inert solvent.
In the formula (IV), R ⁵ is a hydroxyl group and R ⁶ is a hydrogen atom.

[0044]

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Examples of the solvent used for the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) include the following. Sulfoxide solvent represented by dimethyl sulfoxide, amide solvent represented by dimethylformamide or dimethylacetamide, ethyl ether, dimethoxyethane or ether solvent represented by tetrahydrofuran, halogen system represented by dichloromethane, chloroform, dichloroethane Examples thereof include solvents, alcoholic solvents represented by methanol, ethanol, or propanol. The reaction can also be carried out under the condition of no solvent. Preferably, an alcohol solvent is used.

The reaction temperature is usually from -20 ° C to the reflux temperature of the reaction solvent used, preferably from 60 ° C to 10 ° C.
0 ° C.

The molar ratio of the reaction raw materials is such that the compound (III) / compound (II) is in the range of 0.5 to 4.0, preferably 1.0 to 2.0.

The compound represented by the general formula (II) can be obtained by a known method (for example, J. Med. Chem. 1983, 2).
6,1582 and J. Med. Chem. 1984, 2
7, 1127).

Of the compounds represented by the general formula (I),
R ⁷ and R ⁸ are bonded together to form a pyrrole ring together with the nitrogen atom to which they are bonded (general formula (V
As represented by the following reaction formula, the compound represented by the general formula (II) is reacted with the compound represented by the general formula (V) in the presence of a base in an inert solvent. You can get it. In the formula (VI), R ⁵ is a hydroxyl group and R ⁶ is a hydrogen atom.

[0050]

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Examples of the solvent used for the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (V) include the following. Sulfoxide solvent represented by dimethyl sulfoxide, amide solvent represented by dimethylformamide or dimethylacetamide, ethyl ether, dimethoxyethane or ether solvent represented by tetrahydrofuran, halogen system represented by dichloromethane, chloroform, dichloroethane Examples thereof include solvents, alcoholic solvents represented by methanol, ethanol, or propanol. The reaction can also be carried out under the condition of no solvent. Preferred are sulfoxide solvents and amide solvents.

Examples of the base include sodium hydride, potassium hydride and potassium t-butoxide, and preferably sodium hydride.

The reaction temperature is usually from -20 ° C to the reflux temperature of the reaction solvent used, preferably from 0 ° C to 60 ° C.
It is.

The molar ratio of the starting materials is as follows: base / compound (V)
Is in the range of 0.5 to 2.0, preferably 1.0 to
The range is 1.5.

The molar ratio of the reaction raw materials is such that the compound (V) / compound (II) is in the range of 0.5 to 2.0, preferably 1.0 to 2.0.

Of the compounds represented by the general formula (I), compounds in which R ⁷ and R ⁸ together represent a pyrrole ring together with the nitrogen atom to which they are bonded (represented by the general formula (VI) Is a compound represented by the general formula (VII), which is easily obtained by treating the general formula (II) with ammonia, as shown by the following reaction formula (from the compound of the general formula (II) to Conversion to the compound of formula (VII) is known, and is disclosed, for example, in JP-A-58-67683, JP-A-58-188880 and JP-A-58.
It can be achieved according to the method described in Japanese Patent Publication No. 20177776. ) And a compound represented by the general formula (VIII) in the presence of an acid catalyst in an inert solvent. In the formula (VI), R ⁵ is a hydroxyl group and R ⁶ is a hydrogen atom.

[0057]

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Examples of the solvent used for the reaction of compound (VII) and compound (VIII) include the following. Sulfoxide solvents represented by dimethyl sulfoxide, amide solvents represented by dimethylformamide or dimethylacetamide, ethyl ether, dimethoxyethane or ether solvents represented by tetrahydrofuran, dichloromethane, chloroform,
Halogen-based solvent represented by dichloroethane,
The reaction can also be carried out under the condition of no solvent. Further, an acid catalyst may be used as it is as a solvent.

The reaction temperature is usually from under ice cooling to the reflux temperature of the reaction solvent used.

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

Examples of the acid catalyst used include hydrochloric acid, sulfuric acid, formic acid, acetic acid and propionic acid.

Of the compounds represented by the general formula (VII), an optically active substance is synthesized by a method of optically resolving a racemate (JP-A-3-141286, US Pat. No. 50970).
37 publication, European Patent 409165 publication). Further, the optically active compound of the compound represented by the general formula (II) is synthesized by an asymmetric synthesis method (JP-A-5-301878, European Patent 53).
5377, US 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 heart rate reducing action. It has no heart-suppressing effect and has a heart rate-reducing effect, and a decrease in myocardial oxygen consumption based on this effect reduces the exercise load of the myocardium and exhibits antianginal effects, and has an antiarrhythmic effect by prolonging the effective refractory period it is conceivable that. Therefore, it is expected that the compound according to the present invention is also useful for the treatment of cardiovascular diseases in consideration of oxygen consumption or energy consumption or metabolism related to heart movement and the treatment mainly considering a heart rate decreasing effect. Is done. For example, as an anti-heart failure agent for mammals including humans, or a therapeutic agent for cardiovascular disease that induces heart failure, for example, a therapeutic agent for ischemic heart disease, an antibody solution reservoir, a therapeutic agent for pulmonary hypertension, a therapeutic agent for valvular disease, congenital It is useful as a therapeutic agent for congenital heart disease, a therapeutic agent for myocardial disease, a therapeutic agent for pulmonary edema, a therapeutic agent for exertional angina, a therapeutic agent for myocardial infarction, an antiarrhythmic agent, and an anti-atrial fibrillation agent.

The present invention provides pharmaceutical compositions containing an effective amount of a compound of general formula (I) for these treatments.

The dosage form of the compound according to the present invention is:
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 a compound according to the invention comprises about 0.01-99.5%, preferably about 0.1-9%, by weight of the total composition of a compound according to the invention.
Contains ~ 30%.

In addition to the compounds of the present invention or compositions containing such compounds, other pharmaceutically or veterinary active compounds can be included. In addition, these compositions may contain a plurality of the compounds according to the present invention.

The clinical dose of the compound used in the present invention may be increased or decreased according to the age, body weight, patient sensitivity, degree of symptoms or administration method. The usual effective dose is 0.001 mg / kg to 50 mg / kg / day for adults, preferably 0.01 m
It is about g / kg to 20 mg / kg. However, if necessary, an amount outside the above range can be used.

The compounds provided herein 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 hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbit, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, Prepared using polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol and the like.

Injectables, solutions, emulsions, suspensions, syrups and aerosols include active ingredient solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surface active agents. Agents such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl sodium salt, cellulose derivatives such as methylcellulose, tragacanth, Natural gums such as gum arabic; prepared by using preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like.

As the ointment which is a transdermal 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.

[0072]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Synthesis Example 1

[0074]

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Optically active 3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran 2,2-dimethyl-7-nitro-2H-1-benzopyran (1. 026 g, 5.0 mmol), 4-phenylpyridine-N-oxide (17.1 mg, 0.10 mmo)
l), manganese-salen complex (IX) (see formula below) 5
1.8 mg, 0.05 mmol (this compound is known and can be synthesized according to US Pat. No. 5,420,314) is dissolved in methylene chloride (7.5 ml), and at 0 ° C., 3.4 ml of sodium hypochlorite (1. (77 mol / l) was added dropwise over 10 minutes. After 1 hour sodium hypochlorite 0.
6 ml, after 2 hours 0.3 ml of sodium hypochlorite
After adding, the mixture was further stirred at 0 ° C. for 1 hour. After separating the methylene chloride layer, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with water, dried over sodium sulfate, and then the solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 9: 1 (V /
V)) The title compound (1.026 g, 93%) was obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (s, 3H), 1.59 (s,
3H), 3.48 (d, J = 4.5Hz, 1H), 3.89 (d, J = 4.5Hz, 1H),
7.32 (d, J = 8Hz, 1H), 7.48-7.81 (m, 2H) Optical purity> 99% [Column: Chiralcel OJ (manufactured by Daicel Chemical Industries, Ltd.), Mobile phase: Hexane / isopropanol = 4/1, detection Wavelength: 254 nm, flow velocity: 0.
5 ml / min, column temperature: 40 ° C., retention time: 17.0
Min (35.9 min for optical isomers)]

[0077]

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Synthesis Example 2

[0079]

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3,4-dihydro-2,2-dimethyl-6
-Nitro-trans-4- (1-pyrrolidinyl) -2H
-1-Benzopyran-3-ol 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran (790 m
g, 3.6 mmol) was dissolved in ethanol (9 ml), pyrrolidine (450 μl, 5.4 mmol) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature,
The solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 5: 1 (V / V)) to obtain the title compound (624 mg, 59%) as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (s, 3H), 2.03
(s, 3H), 1.75-2.05 (m, 4H), 2.71-3.19 (m, 5H), 3.55
(d, J = 10Hz, 1H), 3.99 (d, J = 10Hz, 1H), 6.75 (d, J = 9H
z, 1H), 7.78-7.83 (m, 2H) MS: 292 (M ⁺ ), 221 (100%), 203 (53%), 163 (43%)

Synthesis Example 3

[0083]

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6-Acetylamino-3,4-dihydro-
2,2-Dimethyl-trans-4- (1-pyrrolidinyl) -2H-1-benzopyran-3-ol 6-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H- 1-benzopyran (9
60 mg, 4.1 mmol) in ethanol (20 ml)
Pyrrolidine (410 μl, 4.9 mm)
ol) was added and the mixture was heated under reflux for 1.5 hours. After cooling to room temperature, the solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, methanol: ethyl acetate = 20:
1 (V / V)) The title compound (1.229 g, 98%) was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (s, 3H), 1.48 (s,
3H), 1.71-2.21 (m, 4H), 2.11 (s, 3H), 2.68-3.23 (m, 5
H), 3.51 (d, J = 10Hz, 1H), 3.92 (d, J = 10Hz, 1H), 6.64
(d, J = 9Hz, 1H), 6.84-7.09 (m, 1H), 7.12-7.42 (m, 1H),
7.51-7.67 (m, 1H) MS: 304 (M ⁺ ), 232 (100%), 173 (45%)

Synthesis Example 4

[0087]

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6-Acetylamino-3,4-dihydro-
2,2-Dimethyl-trans-4- (1-pyrrolidinyl) -2H-1-benzopyran-3-ol 7-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6- Nitro-2H-1-benzopyran (606 mg, 2.2 mmol) was dissolved in ethanol (23 ml) and then pyrrolidine (275 μm).
1, 3.3 mmol) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 3: 1 (V / V)) to give the title compound (582 mg, 76).
%) As yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (s, 3H), 1.52 (s,
3H), 1.70-2.12 (m, 4H), 2.22 (s, 3H), 2.83-3.16 (m, 5
H), 3.50 (d, J = 10Hz, 1H), 3.93 (d, J = 10Hz, 1H), 8.10
(s, 2H), 10.33-10.56 (brs, 1H) MS: 350 (M + 1), 277 (100%), 232 (68%), 162 (56%)

Synthesis Example 5

[0091]

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6-Acetylamino-3,4-dihydro-
2,2-Dimethyl-7-nitro-trans-4- (1-
Pyrrolidinyl) -2H-1-benzopyran-3-ol 6-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (1.11 g, 4 0.0 mmol) was dissolved in ethanol (20 ml), and then pyrrolidine (0.57) was added.
g, 8.0 mmol) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 2: 1 (V / V)) to give the title compound (197 mg, 14
%) As yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (s, 3H), 1.49 (s,
3H), 1.75-2.08 (m, 4H), 2.21 (s, 3H), 2.62-3.29 (m, 5
H), 3.50 (d, J = 10Hz, 1H), 3.95 (d, J = 10Hz, 1H), 7.47
(s, 1H), 8.54 (s, 1H), 9.62-10.02 (brs, 1H) MS: 349 (M ⁺ ), 277 (100%), 218 (41%), 162 (28%)

Synthesis Example 6

[0095]

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6-amino-3,4-dihydro-2,2-
Dimethyl-7-nitro-trans-4- (1-pyrrolidinyl) -2H-1-benzopyran-3-ol 6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-trans-4- (1-Pyrrolidinyl) -2H-1-benzopyran-3-ol (2.54
g, 7.3 mmol) was dissolved in ethanol (20 ml), followed by 35% hydrochloric acid (1.50 g) and water (1.5 g).
Was added and the mixture was heated under reflux for 2 hours. After cooling to room temperature, water was added to neutralize with saturated aqueous sodium hydrogen carbonate solution,
It was extracted four times with chloroform. The chloroform layers were combined and dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 1: 2 (V /
V)) The title compound (2.22 g, 99%) was obtained as brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (s, 3H), 1.46 (s, 3H), 1.65-2.
20 (m, 4H), 2.71-3.26 (m, 5H), 3.63 (d, J = 10Hz, 1H),
4.43 (d, J = 10Hz, 1H), 5.54-6.05 (brs, 2H), 6.83 (s, 1
H), 7.46 (s, 1H)

Synthesis Example 7

[0098]

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3,4-dihydro-2,2-dimethyl-7
-Nitro-trans-4- (1-pyrrolidinyl) -2H
-1-Benzopyran-3-ol 3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (812 m
g, 3.7 mmol) was dissolved in ethanol (8 ml), pyrrolidine (620 μl, 7.4 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature,
The solvent was distilled off to obtain a brown oily substance. This oily substance was subjected to silica gel column column chromatography (elution solvent, hexane: ethyl acetate = 3: 1 (V / V)) to obtain the title compound (816 mg, 76%) as an orange oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (s, 3H), 1.51 (s,
3H), 1.68-2.09 (m, 4H), 2.58-3.31 (m, 5H), 3.61 (d, J
= 10Hz, 1H), 3.99 (d, J = 10Hz, 1H), 7.20-7.75 (m, 3H) MS: 292 (M +), 220 (100%), 203 (14%), 163 (13%)

Synthesis Example 8

[0102]

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Optical activity 3,4-dihydro-2,2-dimethyl-7-nitro-trans-4- (1-pyrrolidinyl) -2H-1-benzopyran-3-ol Optical activity 3 obtained in Synthesis Example 1 , 4-epoxy-3,4
-Dihydro-2,2-dimethyl-7-nitro-2H-1
-Benzopyran (664 mg, 3.0 mmol) was added to ethanol (6 ml) and dissolved by heating at 50 ° C,
Pyrrolidine (500 μl, 6.0 mmol) was added, and the mixture was heated under reflux for 1 hr. After returning to room temperature, the solvent was distilled off and the resulting oily residue was subjected to silica gel column column chromatography (eluting solvent, hexane: ethyl acetate = 3: 1).
(V / V)) The title compound (757 mg, 86%) was obtained as an orange oil. Spectral data were consistent with Synthesis Example 7.

Synthesis Example 9

[0105]

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3,4-dihydro-2,2-dimethyl-7
-Nitro-trans-4- (1-pyrrolyl) -2H-1
-Benzopyran-3-ol 4-amino-3,4-dihydro-2,2-dimethyl-7
-Nitro-trans-2H-1-benzopyran-3-ol (311 mg, 1.3 mmol) in acetic acid (6 ml)
2,5-dimethoxytetrahydrofuran (0.19 ml, 1.44 mmol) was added, and the mixture was stirred at 60 ° C. for 1.5 hours. After returning to room temperature, saturated sodium hydrogen carbonate was added, and the mixture was extracted 3 times with chloroform and dried over sodium sulfate. The residue obtained after distilling off the solvent was subjected to silica gel column column chromatography (eluting solvent,
Hexane: ethyl acetate = 3: 1 (V / V)) The title compound (299 mg, 80%) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (s, 3H), 1.53 (s,
3H), 2.49-2.94 (brs, 1H), 3.86 (d, J = 10Hz, 1H), 4.8
7 (d, J = 10Hz, 1H), 5.94-6.23 (m, 2H), 6.39-6.84 (m, 3
H), 7.30-7.65 (m, 2H) MS: 289 (M + 1), 288 (M ⁺ ), 217 (22%), 180 (38%), 68 (35
%)

[Formulation Example]

Formulation Example 1 Tablet Synthetic Example Compound 4 10 g Lactose 260 g Microcrystalline Cellulose 600 g Corn Starch 350 g Hydroxypropyl Cellulose 100 g CMC-Ca 150 g Magnesium Stearate 30 g Total 1,500 g The above ingredients were mixed by a conventional method and then in one tablet. 10,000 sugar-coated tablets containing 1 mg of the active ingredient are prepared.

Formulation Example 2 Capsule Synthetic Example Compound 4 10 g Lactose 440 g Microcrystalline cellulose 1,000 g Magnesium stearate 50 g Total amount 1,500 g The above ingredients were mixed by a conventional method and then filled into a gelatin capsule to prepare one capsule. 10,000 capsules containing 1 mg of active ingredient are prepared.

Formulation Example 3 Soft Capsule Synthesis Example Compound 4 10 g PEG400 479 g Saturated fatty acid triglyceride 1,500 g Mint oil 1 g Polysorbate 80 10 g Total amount 2,000 g Soft gelatin capsule No. 3 was mixed by the conventional method after mixing the above components. To prepare 10,000 soft capsules containing 1 mg of active ingredient per capsule.

Formulation Example 4 Ointment Synthetic Example Compound 4 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 prepared by a conventional method. Mix to make 1% ointment.

Formulation Example 5 Suppository Synthetic Example Compound 1 1 g Wittepsol H15 ^* 478 g Wittepsol W35 ^* 520 g Polysorbate 80 1 g Total amount 1,000 g “ ^* Trade name of triglyceride compound Witepsol = Witepsol” The above components are melt-mixed by a conventional method, poured into a suppository container, and cooled and solidified to prepare 1,000 1 g suppositories containing 1 mg of the active ingredient.

Formulation Example 6 Injectable Compound 4 1 mg Distilled water for injection 5 mL When used, dissolve and use.

[Pharmacological Test Example]

Effect on Heart Rate Test Method Heart was removed from Hartley male guinea pig and 95% O ₂ /
The right atrium was separated in Krebs Henseleit solution which was aerated with 5% CO ₂ . The sample was suspended in an organ bath filled with a nutrient solution maintained at 31 ° C. with a tension of 1 g.

Following equilibration with nutrient exchange, the specimens were cumulatively applied with isoproterenol to determine the maximum response. After washing with the drug, equilibration was performed for 60 minutes while exchanging the nutrient solution, and the effect was observed by applying each compound.
As a result, the action when each compound was applied at 100 μM and 300 μM was expressed as a percentage change with the maximum reaction of isoproterenol obtained in advance as 100%.

Results The compound according to the present invention showed a concentration-dependent heart rate reducing action.

[0119]

[Table 1]

[0120]

EFFECT OF THE INVENTION The compound used in the present invention enhances myocardial contractility and is useful for improving cardiac function. Therefore, the present invention can provide a useful agent for treating heart failure.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/445 A61K 31/445 31/495 31/495 31/535 31/535 31/55 31 / 55 // C07D 311/68 C07D 311/68 405/04 207 405/04 207 493/04 106 493/04 106A (72) Inventor Toru Yamashita 1470 Shiraoka, Shirooka-cho, Minamisaitama-gun, Saitama Nissan Chemical Industry Co., Ltd. Biological Science In the laboratory

Claims (14)

[Claims] 1. Formula (I): [In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, an amino group, a C _1-6 alkylamino group, a 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 or C _1-6 alkoxycarbonyl group, R ³ and R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group or a phenyl group, or R ³ and R ⁴ together mean C _{3 -6} cycloalkyl group together with the carbon atoms to which they are attached, R ⁵ is a hydroxyl group, a C _1-6 alkoxy group or C _1-6 alkylcarbonyloxy group means Or R ⁶ together means a bond, R ⁶ means a hydrogen atom or together with R ⁵ means a bond, and R ⁷ and R ⁸ each independently represent hydrogen. An atom or a C _1-6 alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
Perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-perhydrooxazepinyl,
1,4-perhydrooxaazepinyl, 1,3-thiazolidinyl, 1,4-perhydrothiazolinyl, 1,3-
Perhydrothiazolidinyl, 1,4-perhydrothiazolidinyl group, or R ⁷ and R ^{8 taken} together are optionally substituted by R ⁹ together with the nitrogen atom to which they are attached. Means a pyrrole ring (R ⁹ has the same meaning as R ¹ ). ] A therapeutic agent for heart failure comprising a benzopyran derivative represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient. 2. R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group,
Amino group, C _1-6 alkylamino group, di C _1-6 alkylamino group, C _1-6 alkylcarbonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyl group or di C _1-6 alkylaminocarbonyl group Means a group, R ³ and R ⁴ are each independently a C _1-6 alkyl group or R ³
R ⁴ together with the carbon atom to which they are attached
C _3-6 cycloalkyl group, R ⁵ represents a hydroxyl group or a C _1-6 alkylcarbonyloxy group, or together with R ^{6 represents} a bond, R ⁶ represents a hydrogen atom Or R ⁵ together means a bond, R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-6 alkyl group, or R ⁷ and R ⁸ together represent Together with the nitrogen atom to which is bonded pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
Morpholinyl, 1,3-thiazolidinyl or means a group, or R ⁷ and R ⁸ are optionally optionally substituted pyrrole ring by R ⁹ together with the nitrogen atom to which they are attached together (R ⁹ is The same meaning as R ¹ is shown), The therapeutic agent for heart failure according to claim 1. 3. R ⁷ and R ⁸ together mean a pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl group together with the nitrogen atom to which they are attached, or R ⁷ and R ⁸ together 3. The therapeutic agent for heart failure according to claim 2, which means a pyrrole ring (R ⁹ has the same meaning as R ¹ ), which may be optionally substituted with R ⁹ together with the nitrogen atom to which they are attached. 4. The therapeutic agent for heart failure according to claim ^3, wherein R ³ and R ⁴ are the same C _1-6 alkyl group. 5. R ² is a hydrogen atom, a halogen atom, a cyano group, an amino group, a C _1-6 alkylcarbonylamino group, an aminocarbonyl group, a C _1-6 alkylaminocarbonyl group or a di-C _1-6 alkylaminocarbonyl group. The therapeutic agent for heart failure according to claim 4, which is a base. 6. The therapeutic agent for heart failure according to claim 5, wherein R ² is a hydrogen atom, a halogen atom, an amino group or a C _1-6 alkylcarbonylamino group. 7. R ¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a C _1-6 alkylcarbonylamino. 7. The therapeutic agent for heart failure according to claim 6, which is a group, an aminocarbonyl group, a C _1-6 alkylcarbonylamino group or a di-C _1-6 alkylaminocarbonyl group. 8. R ¹ is hydrogen atom, nitro group, cyano group, C
_The therapeutic agent for heart failure according to claim 7, which is a _1-6 alkylcarbonylamino group, an aminocarbonyl group, a C _1-6 alkylaminocarbonyl group or a di-C _1-6 alkylaminocarbonyl group. 9. The therapeutic agent for heart failure according to claim 8, wherein R ² is a hydrogen atom. 10. R ¹ is a hydrogen atom, R ² is a methylcarbonylamino group, R ³ and R ⁴ are methyl groups, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ are together. 2. The therapeutic agent for heart failure according to claim 1, which is a pyrrolidinyl group together with the nitrogen atom to which they are bonded. 11. R ¹ is a nitro group, R ² is a methylcarbonylamino group, R ³ and R ⁴ are methyl groups, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ are taken together. 2. The therapeutic agent for heart failure according to claim 1, which is a pyrrolidinyl group together with the nitrogen atom to which they are bonded. 12. R ¹ is a nitro group, R ² is an amino group, R ³ and
The therapeutic agent for heart failure according to claim 1, wherein R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ together are a pyrrolidinyl group together with the nitrogen atom to which they are bonded. . 13. R ¹ is a nitro group, R ² is a hydrogen atom, R ³ and
The therapeutic agent for heart failure according to claim 1, wherein R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ together are a pyrrolidinyl group together with the nitrogen atom to which they are bonded. . 14. R ¹ is a nitro group, R ² is a hydrogen atom, R ³ and
R ⁴ is a methyl group, R ⁵ is a hydroxyl group, R ⁶ is a hydrogen atom, and R ⁷ and R ⁸ together are a pyrrole optionally substituted by R ⁹ together with the nitrogen atom to which they are bonded. Ring (R ⁹
Represents the same meaning as R ¹ . ) Means a therapeutic agent for heart failure according to claim 1.