JP3219281B2 - Cardioplegic agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cardioprotective agent which is effective as a drug for preventing reperfusion injury in the myocardium.

[0002]

2. Description of the Related Art At the time of reperfusion after a myocardial infarction attack, disorders such as heart failure or arrhythmia due to a decrease in the contractility of the myocardium have often been a problem. Conventionally, Ca antagonists or β-blockers have been clinically used as drugs having a cardioprotective effect. However, although these drugs are drugs that have a protective effect on myocardium by reducing myocardial oxygen consumption, their usefulness against reperfusion injury has not been established.

[0003]

It is an object of the present invention to provide an imide derivative which prevents heart failure or arrhythmia occurring during reperfusion after myocardial infarction treatment.

[0004]

The compound represented by the following general formula (1) is useful as an agent for preventing reperfusion injury in the myocardium, for example, an agent for preventing an injury or the like occurring at the time of reperfusion after a myocardial infarction attack. The inventors have found that the present invention has been completed.

The agent for preventing reperfusion injury in the myocardium of the present invention is represented by the general formula (1)

Embedded image [Wherein M is a general formula

Embedded image (Wherein R ₁ and R ₂ both represent a hydrogen atom, one of them is a hydrogen atom, the other is a hydroxy group, an alkyl group or an alkanoyloxy group, or R 1
₁ and R ₂ together represent an oxo group. E represents a methylene group, an ethylene group or an oxygen atom, and {L} represents a single bond or a double bond. ), A general formula

Embedded image (Wherein F represents a methylene group or an ethylene group,
R ₁ , R ₂ and {L} have the same meaning as described above. )
A group represented by or a general formula

Embedded image (Wherein, R ₁ , R ₂ and {L} represent the same meaning as described above, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent a hydrogen atom or an alkyl group). Group represented, general formula

Embedded image (In the formula, R ₉ and R ₁₀ represent an alkyl group.)

Embedded image (Wherein, R ₁₁ and R ₁₂ are an alkyl group or together represent a lower alkylene group.
Or an integer of 2. W represents a substituted or unsubstituted lower alkylene group, lower alkenylene group or lower alkynylene group; Q ₁ represents a hydrogen atom;
Q ₂ represents a cyano group, a hydroxy group, an alkanoyloxy group, an acyl group, an alkoxy group, a carboxyl group, an esterified carboxyl group or an aminated carboxy group, and Q ₂ represents a substituted or unsubstituted phenyl group or a cyclic amino group Represents the general formula or

Embedded image (Wherein, Y is an oxygen atom, a carbonyl group, a methylene group, a group represented by the general formula -S- (O) _m (where m represents an integer of 0, 1 or 2), a general formula;

Embedded image (Wherein, R ₁₃ represents a hydrogen atom, an alkyl group or an alkanoyl group) or a group represented by the formula:

Embedded image Z represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxy group, a carboxyl group, an esterified carboxyl group or an amino group . )
Represents a group represented by Or an acid addition salt thereof.

The compound represented by the general formula (1) or an acid addition salt thereof, wherein Q ₂ is a substituted or unsubstituted phenyl group or a cyclic amino group, that is, a compound represented by the general formula (1 ′)

Embedded image (Wherein Q ₂ ′ represents a substituted or unsubstituted phenyl group or a cyclic amino group, and M, W and Q ₁ are the same as described above). It is. The compounds represented by the general formula (1) including these novel compounds can be prepared by known methods (for example,
63-183576).

The following is a detailed description of each symbol in the formula.

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R
_The alkyl group in ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ may be linear or branched;
Examples thereof include a lower alkyl group having 1 to 4 carbon atoms, and more specifically, a methyl, ethyl, propyl, 2-propyl or butyl group.

The alkanoyloxy group for R ₁ and R ₂ includes, for example, a lower alkanoyloxy group having 1 to 4 carbon atoms, and more specifically, an acetoxy, propanoyloxy or butanoyloxy group. Can be

The lower alkylene group for R ₁₁ and R ₁₂ may be linear or branched and includes, for example, an alkylene group having 3 to 5 carbon atoms, more specifically, a trimethylene group, a tetramethylene group. And the like.

The lower alkylene group for W may be linear or branched, and includes, for example, an alkylene group having 2 to 6 carbon atoms, and more specifically, ethylene, trimethylene, tetramethylene, pentamethylene. , Hexamethylene and the like. The lower alkylene group may have a substituent, for example, a hydroxy group, an alkyl group, an oxo group, a hydroxyimino group,
Examples include an alkanoyloxy group and an alkoxy group.
Here, examples of the alkyl group and the alkanoyloxy group as the substituent include the same examples as described above. The alkoxy group may be linear or branched and includes, for example, a lower alkoxy group having 1 to 4 carbon atoms. More specifically, a methoxy group, an ethoxy group, a propoxy group, a 2-propoxy group, a butoxy group And the like.

The lower alkenylene group for W may be linear or branched and includes, for example, alkenylene groups having 2 to 6 carbon atoms. More specifically, ethenylene, propenylene, butenylene, pentenylene, hexenylene , Methylbutenylene and the like.

The lower alkynylene group in W may be linear or branched, and includes, for example, an alkynylene group having 2 to 6 carbon atoms. More specifically, ethynylene, propynylene, butynylene, pentynylene, methylbutynylene And the like.

The alkanoyloxy group, acyl group, alkoxy group and esterified carboxyl group in Q ₁ have the same meanings as described above. Examples of the acyl group include an alkanoyl group having 2 to 5 carbon atoms and a benzoyl group. Examples of the alkanoyl group having 2 to 5 carbon atoms include an acetyl group, a propionyl group, a 2-propionyl group, and a butanoyl group. The alkoxy group may be linear or branched, and examples thereof include a lower alkoxy group having 1 to 4 carbon atoms. More specifically, a methoxy group, an ethoxy group, a propoxy group, a 2-propoxy group,
Butoxy group and the like. Examples of the esterified carboxyl group include a carboxyl group esterified with an alkyl group. Here, examples of the alkyl group include the same examples as above. The aminated carboxyl group includes an amide with an unsubstituted or alkyl-substituted primary or secondary amine, such as carbamoyl group, N-methylcarbamoyl group, N, N
-Dimethylcarbamoyl group and the like.

Examples of the substituent of the phenyl group of Q ₂ and Q ₂ ′ include the same examples as the group represented by Z. Examples of the cyclic amino group include a cyclic amine having 4 to 7 carbon atoms, and more specifically, 1-pyrrolidinyl, 1-piperidinyl, hexamethyleneimino and the like.

Examples of the acid that forms an acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like, or acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, and the like.
Organic acids such as fumaric acid and maleic acid are included.

The compound of the present invention may contain an asymmetric carbon atom depending on the type of the substituent, and such a compound includes an optical isomer and a geometric isomer. The compounds of the present invention include mixtures of these isomers and isolated ones.

The compound represented by the general formula (1) or an acid addition salt thereof can be administered orally or parenterally when the compound is used as a drug for preventing reperfusion injury in cardiac muscle. That is, it can be orally administered in the form of commonly used dosage forms, for example, tablets, capsules, syrups, suspensions, etc., or injected in the form of solutions, such as solutions, emulsions, suspensions, etc. It can be administered as an agent. It can also be administered rectally in the form of suppositories. Such a dosage form can be produced according to a general method by mixing an active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added.

The dosage and number of administrations vary depending on symptoms, age, body weight, dosage form and the like. However, in the case of oral administration, it is usually 1 to 1000 mg per day for an adult, and in the case of parenteral administration, 0.1 to 1000 mg. -100 mg may be administered once or in several divided doses.

The compound of the present invention represented by the general formula (1) is produced by the method described in JP-A-63-183576, that is, by the following production methods a) to e) as described above. be able to.

Production method a)

Embedded image [Wherein, M, W, Q ₁ and Q ₂ represent the same meaning as described above, and X represents a leaving group (for example, a halogen atom such as chlorine, bromine or iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group) And the like, such as an alkyl or arylsulfonyloxy group. That is, the imide derivative (1) can be produced by reacting the compound of the general formula (3) with the amine derivative of the general formula (4) in an inert organic solvent. The imide derivative (1) can be produced by reacting the compound represented by the general formula (5) with the compound represented by the general formula (6) in a suitable organic solvent in the presence of an acid binder. The imide derivative (1) can be produced by reacting the compound of the general formula (7) with the amine derivative of the general formula (8) in a suitable organic solvent in the presence of an acid binder. .

Production method b)

Embedded image (Wherein, M, Q ₁ and Q ₂ represent the same meaning as described above.
W ₁ represents a lower alkenylene group or a lower alkynylene group, and W ₂ represents a lower alkylene group. ) The alkylene compound represented by the general formula (1-2) included in the imide derivative (1) is a olefin derivative and an acetylene derivative corresponding to the alkylene compound, that is, the compound represented by the general formula (1-1) is hydrogen. It can be produced by performing an addition reaction.

Production method c)

Embedded image (Wherein M, Q ₁ and Q ₂ represent the same meaning as described above.) The general formula (1) included in the imide derivative (1)
The compound represented by -3) is a compound represented by the general formula (9):
It can be produced by subjecting a propargyl derivative to a piperidine derivative represented by the general formula (8) and formaldehyde in a Mannich-type reaction in an inert solvent.

Production method d)

Embedded image (Wherein M, Q ₁ and Q ₂ represent the same meaning as described above.) The general formula (1) included in the imide derivative (1)
The compound represented by -4) is obtained by bringing the compound represented by the general formula (1-3) into contact with hydrogen in an appropriate solvent in the presence of a catalytic reduction catalyst and performing equimolar hydrogenation. Can be manufactured.

Production method e)

Embedded image (Wherein M, Q ₁ and Q ₂ represent the same meaning as described above.) The general formula (1) included in the imide derivative (1)
The compound represented by -5) can be produced by reacting the compound represented by the general formula (10) with the compound represented by the general formula (8) in an inert organic solvent.

Embedded image (Wherein M, Q ₁ and Q ₂ represent the same meaning as described above.) The general formula (1) included in the imide derivative (1)
The compound represented by -6) is a compound represented by the general formula (5) and the compound represented by the general formula (11) in an inert solvent,
It can be produced by reacting in the presence of a base.

[0026]

EXAMPLES Example 1 N- (4-bromobutyl) cyclohexane-1,2-dicarboximide (1.5 g, 5.2 mmol), 4- (p-chlorophenyl) -4-hydroxypiperidine (1 g, 4.7 m)
mol), anhydrous potassium carbonate (719 mg, 5.2 mmol) and dry dimethylformamide (15 ml) were added for 5 hours.
Heated to 0-110 ° C. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, further washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude oily substance, which was purified by column chromatography using 150 g of silica gel and chloroform as an eluent. Further treatment with 12% hydrogen chloride / diethyl ether gave 1.5 g (69.3%) of N- [4- [4
-(4-Chlorophenyl) -4-hydroxypyridino] butyl] cyclohexane-1,2-dicarboximide hydrochloride was obtained. Melting point 224-225 ° C

The following compounds were obtained according to the method of Example 1. Example 2 A reaction was carried out in the same manner as in Example 1 except that 4-cyano-4-phenylpiperidine hydrochloride (1.05 g, 4.73 mmol) was used in place of 4- (p-chlorophenyl) -4-hydroxypiperidine, to give N- [4-[(4-Cyano)-(4-phenyl) piperidino] butyl] cyclohexane-1,2-dicarboximide hydrochloride (1.14 g, 56.2% was obtained. Melting point: 215-216 ° C.)

Example 3 A reaction was carried out in the same manner as in Example 1 except that 4-carbamoyl-4-piperidinopiperidine (1 g, 4.73 mmol) was used instead of 4- (p-chlorophenyl) -4-hydroxypiperidine. There was obtained N- [4- (4-carbamoyl-4-piperidinopiperidine) butyl] cyclohexane-1,2-dicarboximide hydrochloride (1.3 g, 53.9%). 278-279 ° C

Example 4 In the same manner as in Example 1 except that N- (3-bromopropylcyclohexane-1,2-dicarboximide was used instead of N- (4-bromobutyl) cyclohexane-1,2-dicarboximide. The reaction was performed and N- [3- [4- (4-
Chlorophenyl) -4-hydroxypiperidino] propyl] cyclohexane-1,2-dicarboximide hydrochloride was obtained. 233-234 ° C

Example 5 N- (2-bromoethyl) is used instead of N- (4-bromobutyl) cyclohexane-1,2-dicarboximide
The reaction was carried out in the same manner as in Example 1 using cyclohexane-1,2-dicarboximide, and N- [2- [4- (4-
Chlorophenyl) -4-hydroxypiperidino] ethyl] cyclohexane-1,2-dicarboximide hydrochloride was obtained. 223-224 ° C

Example 6 Instead of 4- (p-chlorophenyl) -4-hydroxypiperidine, 4-phenylpiperidine (2.2 g, 13.9 mmol) was used.
l) was reacted in the same manner as in Example 1 to give N- [4-
(4-phenylpiperidino) butyl] cyclohexane-
There was obtained 1,2-dicarboximide hydrochloride (1.6 g, 55.9%). 184-186 ° C

Example 7 Instead of 4- (p-chlorophenyl) -4-hydroxypiperidine, 4-piperidinopiperidine (0.8 g, 4.7 mmol) was used.
l), the reaction was carried out in the same manner as in Example 1, and N- [4-
(4-Piperidinopiperidine) butyl] cyclohexane-1,2-dicarboximide hydrochloride (1.3 g, 62.7%)
I got Melting point 296-297 ° C

Example 8 Myocardial ischemia of the active ingredient of the present invention was evaluated using the rate of recovery of cardiac contractility when the isolated perfused heart of a rat was placed in a hypoxia state (hypoxia) and then reoxygenated. / The protective effect of reperfusion injury was determined.

(1) Test compound The specimen number and compound name are as follows. S-4: N- [4- [4- (4-fluorobenzoyl)
Piperidinyl] -3-hydroxybutyl] cyclohexane-1,2-dicarboximide S-5: N- [4- [4- (4-fluorobenzoyl)
Piperidinyl] butyl] -4-cyclohexene-1,2
-Dicarboximide S-6: N- [4- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] butyl]] cyclohexane-
1,2-dicarboximide hydrochloride S-7: N- [4- [4- (4-fluorobenzyl) piperidinyl] butyl] cyclohexane-1,2-dicarboximide hydrochloride S-8: N- [4 -[4-[(4-fluorophenyl)
Sulfonyl] piperidinyl] butyl] cyclohexane-
1,2-dicarboximide hydrochloride S-9: N- [4- [4-[(4-fluorophenyl)
Thio] piperidinyl] butyl] cyclohexane-1,2
-Dicarboximide hydrochloride S-10: N- [4- [4- (4-fluorophenoxy) piperidinyl] butyl] cyclohexane-1,2-
Dicarboximide hydrochloride S-11: N- [4- [4-[(4-fluorophenyl) sulfinyl] piperidinylbutyl] cyclohexane-1,2-dicarboximide hydrochloride S-21: N- [4 -[4- (2-furoyl) 1-piperazinyl] butyl] cyclohexane-1,2-dicarboximide hydrochloride S-22: N- [4- (4-phenylpiperidino) butyl] cyclohexane-1,2 -Dicarboximide hydrochloride S-32: N- [3- [4- (4-chlorophenyl)-
4-Hydroxypiperidino] propyl] cyclohexane-1,2-dicarboximide hydrochloride

(2) Test method and results 1) Recovery rate of cardiac contractility The method of Takeo et al. (J. Pharmacol. Exp. Ther, 248: 306-31)
4, 1988). That is, weight 200-
An isolated heart of a male Wistar rat of 250 g was attached to a Langendorff apparatus, and Krebs-Henseleit nutrient solution (Krebs-Henseleit) aerated with 95% N ₂ -5% CO ₂ was used.
buffer) for 20 minutes (hypoxia period). After that, 4% with the same nutrient solution saturated with 95% O ₂ -5% CO _2.
Reoxygenated for 5 minutes. Specimens are dissolved in physiological saline or distilled water and injected at a flow rate of 0.1 ml / min or less from the upper inlet of the cannula attached to the aortic root during the period of hypoxia (from 3 minutes to 20 minutes after initiation). did. The systolic force was estimated as isometric tension generated by an initial tension of 1.5 g. Cardiac contractility recovery rate when a sample is injected at a rate of 30 μg / min to 330 μg / min (recovery rate from initial value)
Are as shown in Tables 1 and 2.

[Table 1]

[Table 2] As for the specimen S-6, a perfusate during cardiac perfusion was collected and measured as follows. 2) Creatine kinase (CK) free enzyme method (J. Mol. Cell. Cardiol., 7: 463-483, 1975; 1)
1: 387-406, 1979). The results were as shown in FIG. 3) UV change The UV change of the perfusate was measured by the absorbance method (J. Pharmacol. Ex.
r., 243: 1131-1138, 1987). The results were as shown in FIG. 4) Release of ATP metabolite HPLC method (Circ. Res., 45: 218-225, 1979; J. Mol.
Cell. Cardiol., 15: 577-594, 1983). The results were as shown in FIG.

(3) Discussion 1) Recovery rate of systolic force The drug-treated group during the hypoxic load period with the active ingredient of the present invention has a remarkable recovery of the systolic force after reoxygenation as compared with the untreated group (control). It is. This result suggests that the active ingredient of the present invention has a protective effect on ischemia-reperfusion myocardial injury. 2) Release of CK Release of CK from drug-untreated hypoxic / reoxygenated myocardium is remarkable. This is thought to be due to cardiomyocyte necrosis or increased cell membrane permeability. On the other hand, CK release during reoxygenation was significantly suppressed in the S-6 treated group, suggesting prevention of cell necrosis. 3) UV change Due to hypoxia loading / reoxygenation, UV (254 n
m) It is reported that the absorbance increases. Since this phenomenon is hardly observed in a normal perfused heart, it is considered to be a phenomenon caused by deterioration of myocardial metabolism. As shown in FIG. 2, the treatment of S-6 markedly suppresses the increase in UV absorbance of the perfusate, suggesting that S-6 has an effect of preventing deterioration of myocardial metabolism. 4) Release of ATP metabolite If the heart is treated with hypoxia / reoxygenation, a large amount of ATP metabolite is released during hypoxia and reoxygenation. The resulting loss of ATP metabolites leads to a decrease in ATP salvage synthesis during reoxygenation, which is thought to impair the recovery of cardiac contractility. Release inhibition was observed.

[0037]

[Brief description of the drawings]

FIG. 1 shows a case where a sample S-6 is injected into a heart.
FIG. 4 is a graph showing the results of measurement of creatine kinase released into the heart perfusate.

FIG. 2 shows a case where a sample S-6 is injected into a heart.
It is the figure which showed the result of having measured the UV absorbance of the heart perfusate with time as a graph.

FIG. 3 shows a case where a sample S-6 is injected into a heart.
It is the figure which showed the result of having measured the ATP metabolite liberated in the heart perfusate by the graph.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-183576 (JP, A) JP-A-51-131871 (JP, A) JP-A-49-132069 (JP, A) JP-A 64-64 83065 (JP, A) JP-A-57-197265 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 401/06 A61K 31/454 A61P 9/00 C07D 405/14 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) Wherein M is a general formula (Wherein R ₁ and R ₂ both represent a hydrogen atom, one of them is a hydrogen atom, the other is a hydroxy group, an alkyl group or an alkanoyloxy group, or R 1
₁ and R ₂ together represent an oxo group. E represents a methylene group, an ethylene group or an oxygen atom, and {L} represents a single bond or a double bond. A group represented by the general formula: (Wherein F represents a methylene group or an ethylene group,
R ₁ , R ₂ and {L} have the same meaning as described above. )
Or a group represented by the general formula: (Wherein, R ₁ , R ₂ and {L} represent the same meaning as described above, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent a hydrogen atom or an alkyl group). A group represented by the general formula: (Wherein, R ₉ and R ₁₀ represent an alkyl group) or a general formula: (Wherein, R ₁₁ and R ₁₂ are an alkyl group or together represent a lower alkylene group.
Or an integer of 2. W represents a substituted or unsubstituted lower alkylene group, lower alkenylene group or lower alkynylene group; Q ₁ represents a hydrogen atom;
Q ₂ represents a cyano group, a hydroxy group, an alkanoyloxy group, an acyl group, an alkoxy group, a carboxyl group, an esterified carboxyl group or an aminated carboxy group, and Q ₂ represents a substituted or unsubstituted phenyl group or a cyclic amino group Or a compound of the general formula (Wherein, Y is an oxygen atom, a carbonyl group, a methylene group, a group represented by the general formula -S- (O) _m (where m represents an integer of 0, 1 or 2), a general formula: Formula 8 (Wherein, R ₁₃ represents a hydrogen atom, an alkyl group or an alkanoyl group) or a group represented by the formula: Z represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxy group, a carboxyl group, an esterified carboxyl group or an amino group . )
Represents a group represented by And the like. Or an acid addition salt thereof as an active ingredient. 2. A compound represented by the general formula (1 ′): [Wherein M is a general formula: (Wherein R ₁ and R ₂ both represent a hydrogen atom, one of them is a hydrogen atom, the other is a hydroxy group, an alkyl group or an alkanoyloxy group, or R 1
₁ and R ₂ together represent an oxo group. E represents a methylene group, an ethylene group or an oxygen atom, and {L} represents a single bond or a double bond. A group represented by the general formula: (Wherein F represents a methylene group or an ethylene group,
R ₁ , R ₂ and {L} have the same meaning as described above. )
A group represented by the general formula: (Wherein, R ₁ , R ₂ and {L} represent the same meaning as described above, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent a hydrogen atom or an alkyl group). A group represented by the general formula: (Wherein, R ₉ and R ₁₀ represent an alkyl group) or a group represented by the general formula: (Wherein, R ₁₁ and R ₁₂ are an alkyl group or together represent a lower alkylene group.
Or an integer of 2. W represents a substituted or unsubstituted lower alkylene group, lower alkenylene group or lower alkynylene group; Q ₁ represents a hydrogen atom;
A cyano group, a hydroxy group, an alkanoyloxy group, an acyl group, an alkoxy group, a carboxyl group, an esterified carboxyl group or an aminated carboxy group, and Q ₂ ′ represents a substituted or unsubstituted phenyl group, or a cyclic amino group; Represents a group. Or an acid addition salt thereof.