JP2007056003A - New prophylactic or therapeutic agent of cardiac failure - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic or therapeutic agent of cardiac failure. <P>SOLUTION: The prophylactic or therapeutic agent of the cardiac failure contains a phenoxyaniline derivative or phenoxypyridine derivative having an NCX-inhibiting activities, or pharmaceutically acceptable salts of the derivatives as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel preventive or therapeutic agent for heart failure comprising a phenoxyaniline derivative or phenoxypyridine derivative having NCX inhibitory activity as an active ingredient.

Intracellular free Ca ²⁺ is an important ion that regulates the contraction of the myocardium and various smooth muscles, the release of neurotransmitters, and gene expression. The regulation of the Ca ²⁺ concentration is controlled by the Ca and sarcoplasmic reticulum membranes. It is regulated by ^{2 +} -pump, Ca ²⁺ channel and Na ⁺ / Ca ²⁺ exchange transporter (NCX). Among these, NCX plays an important role in contraction / relaxation of the myocardium and vascular smooth muscle (see Non-Patent Document 1).

  Examples of NCX inhibitors include isothiourea derivatives such as (2- [2- [4 [nitrobenzyloxy] phenyl] ethyl] isothio-ureamethanesulfate] (KB-R7943) and 2- [4-[(2,5-difluorophenoxy) methoxy] phenyl. ] There have been reports of phenoxyaniline derivatives such as -5-ethyoxyline (SEA0400), and KB-R7943 has been confirmed to be effective against ischemia-reperfusion models of heart and kidney (see Non-Patent Document 2).

  On the other hand, Patent Documents 1 to 3 disclose phenoxyaniline derivatives as compounds that inhibit NCX, and Patent Documents 4 and 5 disclose phenoxypyridine derivatives.

  It has also been revealed that these phenoxyaniline derivatives and phenoxypyridine derivatives have high selectivity for NCX (see Non-Patent Document 3).

  Furthermore, Patent Document 6 discloses that the above phenoxyaniline derivative and phenoxypyridine derivative having NCX inhibitory activity have a blood pressure lowering effect on hypertension, and Patent Document 7 discloses that the above phenoxyaniline derivative having NCX inhibitory activity and It has been disclosed that phenoxypyridine derivatives have an excellent renal protective action against chronic kidney disease.

  In addition to the above, Patent Document 8 discloses a phenoxypyridine derivative having an NCX inhibitory action, and the urinary albumin leakage inhibitory effect in diabetic early nephropathy model rats has been confirmed.

  However, there has been no report on the application of phenoxyaniline derivatives and phenoxypyridine derivatives having NCX inhibitory activity to the treatment of heart failure.

Ann. Rev. Physiol. Volume 52, page 467 (1990) J. et al. Pharmacol. Exp. Ther. 296, 412 (2001) J. et al. Pharmacol. Exp. Ther. 298, 249 (2001) WO99 / 20598 gazette WO98 / 43943 Japanese Patent Laid-Open No. 10-218844 Japanese Patent Laid-Open No. 10-265460 Japanese Patent Laid-Open No. 11-049752 WO2003 / 068263 WO2003 / 061700 WO2004 / 000813 Publication

  An object of the present invention is to provide a preventive or therapeutic agent for heart failure.

  The present inventors have found that the phenoxyaniline derivative and phenoxypyridine derivative having an NCX inhibitory action of the present invention suppress the decrease in cardiac function in an animal model that develops heart failure, and have completed the present invention. It was.

  That is, the present invention provides the formula (1)

[Wherein, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom or a nitro group;

Indicates. R ⁴ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or a substituted or unsubstituted C ₁ -C ₆ alkoxy group, Z represents a nitro group, an amino group, or NHC (O) CH ₂ R ⁵ R ⁵ represents a hydrogen atom, a substituted or unsubstituted C _{1 to} C ₆ alkyl group, a substituted or unsubstituted C _{1 to} C ₆ alkoxy group, a halogen atom, a hydroxy group, a C _{2 to} C ₇ acyloxy group, NR ⁶ R ⁷ or

R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or an N-methyl-4-piperidinyl group, and R ⁸ represents a hydrogen atom, a hydroxy group, or C _{2 to} C _{7 represents an} alkoxycarbonyl group, Y represents a methylene group, an epoxy group, a thio group or an NR ⁹ group, and n represents an integer of 1 to 4. R ⁹ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or a substituted or unsubstituted phenyl group. ] Or a pharmaceutically acceptable salt thereof as an active ingredient.
Furthermore, Formula (2)

[Wherein, R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group, R ¹¹ represents a halogen atom or a nitro group, and R ¹² represents a hydrogen atom or a halogen atom. ] The phenoxyaniline derivative | guide_body or its pharmacologically acceptable salt represented by these is an active ingredient for the prevention or treatment of heart failure.

  Since the compounds of formulas (1) and (2) having NCX inhibitory activity of the present invention have an excellent preventive or therapeutic action for heart failure, it is possible to provide a preventive or ameliorating agent for heart failure.

  In the present invention, the compound that inhibits NCX preferably inhibits the NCX activity derived from the heart by 50% or more at a concentration of 3 μM. The method for measuring heart-derived NCX activity is described in J. Org. Biol. Chem. 257, p. 5111 (1982) and the references cited therein.

Furthermore, compounds that specifically inhibit NCX are preferred for the purpose of preventing side effects. A compound that specifically inhibits NCX refers to a compound that hardly inhibits other ion channels, transporters, enzymes, and receptors at concentrations that inhibit NCX. Specifically, for example, Ca ^{2+ at} a concentration of 3 μM. channel, Na ⁺ channel, K ⁺ channel, Na ⁺ / H ⁺ transporter, norepinephrine transporter, Na ⁺ , K ⁺ -ATPase, Ca ²⁺ -ATPase, phospholipase A ₂ , phospholipase C, phospholipase C constitutive native-oxide synthetase, adenosine receptor, adrenergi receptor, glutamate receptor, bradykinin receptor, LTB4 receptor, it is preferable not to PAF receptor inhibited more than 50%.

The measuring method using each ion channel, transporter, enzyme, and receptor is described in J. Org. Pharmacol. Exp. Ther. 298 pages 249 (2001) and the literature cited therein.
Examples of compounds that specifically inhibit NCX include phenoxyaniline derivatives and phenoxypyridine derivatives.

  Preferably, formula (1)

[Wherein, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom or a nitro group;

Indicates. R ⁴ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or a substituted or unsubstituted C ₁ -C ₆ alkoxy group, Z represents a nitro group, an amino group, or NHC (O) CH ₂ R ⁵ R ⁵ represents a hydrogen atom, a substituted or unsubstituted C _{1 to} C ₆ alkyl group, a substituted or unsubstituted C _{1 to} C ₆ alkoxy group, a halogen atom, a hydroxy group, a C _{2 to} C ₇ acyloxy group, NR ⁶ R ⁷ or

R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or an N-methyl-4-piperidinyl group, and R ⁸ represents a hydrogen atom, a hydroxy group, or C _{2 to} C _{7 represents an} alkoxycarbonyl group, Y represents a methylene group, an epoxy group, a thio group or an NR ⁹ group, and n represents an integer of 1 to 4. R ⁹ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or a substituted or unsubstituted phenyl group. Or a pharmaceutically acceptable salt thereof.

  More preferably, from the viewpoint of NCX inhibitory activity, the formula (2)

[Wherein, R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group, R ¹¹ represents a halogen atom or a nitro group, and R ¹² represents a hydrogen atom or a halogen atom. ] The 2-phenoxy aniline derivative represented by this, or its pharmaceutically acceptable salt.

In the formulas (1) and (2), the C ₁ -C ₆ alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an iso group. Propoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1 , 2-dimethylpropoxy group, hexyloxy group, isohexyloxy group and the like.

The substituent of the substituted C ₁ -C ₆ alkoxy group, chloro group, fluoro group, a nitro group, an amino group, dimethylamino group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a phenyl group, a hydroxy group, a cyano group, And a carbamoyl group.

  A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The C ₁ -C ₆ alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, etc. .

Examples of the substituent of the substituted C ₁ -C ₆ alkyl group include chloro group, fluoro group, nitro group, amino group, dimethylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, phenyl group, methoxy group, ethoxy group, Examples thereof include a hydroxy group, a cyano group, and a carbamoyl group.

The C ₂ -C ₇ acyloxy group means a linear or branched acyloxy group having 2 to 7 carbon atoms, and the acyl moiety may be cyclic or contain an aromatic group. For example, an acetoxy group, a propionyloxy group, an isopropionyloxy group, a cyclohexylenyloxy group, a benzoyloxy group, and the like can be given.

The C ₂ -C ₇ alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, and the alkoxyl moiety may be cyclic or contain an aromatic group. Good. Specifically, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, iso Pentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, 1-methylbutoxycarbonyl group, 2-methylbutoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, hexyloxycarbonyl group, isohexyloxycarbonyl Groups and the like.

  As the substituent of the substituted phenyl group, chloro group, fluoro group, nitro group, amino group, dimethylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, methyl group, ethyl group, methoxy group, ethoxy group, hydroxy group , A cyano group, a carbamoyl group, and the like.

  Examples of compounds that exhibit particularly good cardiac function improving action

The compound (SEA0400) represented by these can be mentioned. The compounds represented by the formulas (1) and (2) are described in WO98 / 43943, WO99 / 20598, JP-A-10-265460, JP-A-10-21884, JP-A-11-49752, and JP-A-11-92454. It can be synthesized by the method.

  In the present invention, the therapeutic agent for heart failure means a therapeutic agent for acute and chronic heart failure based on ischemic heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, valvular disease, and hypertension, and restores myocardial contractility. It has an excellent cardiac function improving action.

  The therapeutic agent of the present invention is appropriately prepared orally or in a suitable pharmaceutical composition form (tablets, pills, capsules, granules, dry syrups, injections, patches, etc.) using known carriers, diluents and the like. Can be used parenterally.

  In order to produce solid agents, various additives such as excipients, disintegrants, binders, lubricants, and coating bases are used, and they are produced by stirring granulation method, fluidized bed granulation method, and crushing granulation method. it can. In addition, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers and the like can be added as necessary. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.

  The dose of the active ingredient of the medicament of the present invention varies depending on age, body weight, administration form, etc., but is usually 0.1 to 1000 mg / day for an adult, and this is administered once or several times a day.

  Hereinafter, although this invention is demonstrated using a formulation example, a test example, etc., this invention is not limited to these test examples.

Formulation Example 1 Tablet SEA0400 50mg
Lactose 40mg
Corn starch 49.75mg
Crystalline cellulose 17mg
Carmellose calcium 17mg
Hydroxypropylcellulose 5.25mg
Magnesium stearate 1mg
180mg total

  SEA0400, lactose, corn starch, crystalline cellulose, carmellose calcium are mixed uniformly, 10% hydroxypropylcellulose aqueous solution is added thereto, kneaded and dried, and the granules are passed through a 30M sieve to obtain uniform granules. Then, magnesium stearate was added and compressed into tablets.

Formulation Example 2 Injection SEA0400 15 mg
Egg yolk lecithin 50mg
Soybean oil 300mg
Concentrated glycerin 69mg
Sodium hydroxide Appropriate amount of water for injection Total 3mL

  After dissolving 15 mg of drug, 50 mg of egg yolk lecithin and 300 mg of soybean oil in a small amount of chloroform, the chloroform is evaporated. Add 2.7 g of water for injection to which concentrated glycerin and sodium hydroxide (pH adjuster) have been added in advance to a predetermined concentration, and then emulsify with a homogenizer rough emulsifier and a French press (Aminco) to obtain a fat emulsion. It was.

Test Example 1 Effect of NCX inhibitor on myocardial contractility reduction in rats with ischemic heart failure In the rat coronary artery ligation model, myocardial infarction is formed in the left ventricle by ligating the left coronary artery, eventually becoming heart failure and reducing myocardial contractility (Br. J. Pharmacol. 112, 837 (1994)). This test was performed by partially changing the method described in American Journal Physiology Vol. 278, H300 (2000). Specifically, it was performed as follows.

<Method>
A model in which the myocardial contractility was reduced by ligation (ischemia) and reperfusion of the left coronary artery of 9-week-old SD rats was prepared. In the experiment, an ischemia / reperfusion model (MI) and a sham-operated rat (Sham) as a control animal were used, and the test was divided into four groups as follows (each group consists of 6 cases).

Group I: Oral administration of Sham + solvent (twice a day)
Group II: Oral administration of MI + solvent (twice a day)
Group III: MI + SEA0400 10 mg / kg orally (twice a day)
Group IV: MI + SEA0400 30 mg / kg orally (twice a day)

  The solvent and SEA0400 were continuously orally administered twice a day from the day after the treatment (first time 8:30 to 9:30, second time 16:30 to 17:30). Seven days after ischemia-reperfusion, a catheter tip transducer was inserted retrogradely from the right carotid artery to the left ventricle under anesthesia, and the left ventricular pressure and the first derivative of the left ventricular pressure (LVdp / dt) were measured. The results are shown in FIG.

  One week after myocardial ischemia / reperfusion, LVdp / dt, which is an index of myocardial contractility, is as follows: Group I: 7780 ± 365 mmHg / s, Group II: 5983 ± 296 mmHg / s, Group III: 6300 ± 319 mmHg / s, IV Group: 7367 ± 247 mmHg / s. The value of the SEA0400 administration group (Group IV) was significantly increased as compared with the solvent administration group (Group II).

  From the above results, SEA0400 significantly suppressed the decrease in myocardial contractile force observed in the rat ischemia-reperfusion model, and showed an effect of improving cardiac function.

Test Example 2 Effect of SEA0400 on Decreased Cardiac Function in Canine Frequent Paging-Induced Heart Failure Model In dog canine frequent paging-induced heart failure model, chronic high-frequency pacing is applied to the myocardium to eventually become heart failure and decrease myocardial contractility (Circulation). 75, 857 (1987)). This test was performed by partially changing the method described in Circulation Research Vol. 87, p.690 (2000). Specifically, it was performed as follows.

<Method>
The beagle dog was opened under anesthesia and the lead of an animal cardiac pacemaker was attached to the right ventricular wall. Furthermore, a telemetry transmitter cannula was placed in the left ventricular apex and internal thoracic artery for measurement of left ventricular pressure. After recovering from the implant surgery, chronic high frequency paging (220 beats / min) was performed to induce heart failure. Three weeks later, after confirming the decrease in myocardial contractility, SEA0400 (0.3, 1.0, and 3.0 mg / kg) intravenously administered to the left ventricular pressure and the first derivative of the left ventricular pressure (LVdp / dt) The effect was examined. The results are shown in FIG.

<Results and discussion>
By applying a high frequency paging load to the dog, a decrease in the left ventricular pressure differential value (± LVdp / dt), which is an index of myocardial contractile force, was observed. SEA0400 significantly increased ± LVdp / dt at doses of 1.0 and 3.0 mg / kg.

  From the above results, SEA0400 showed a significant myocardial contractility increasing effect in a dose-dependent manner in a canine high frequency paging-induced heart failure model.

  According to the present invention, development of an excellent preventive or therapeutic agent for heart failure is expected.

FIG. 1 shows the results of measuring changes in ventricular contraction rate when SEA0400 was administered to a rat ischemic heart failure model. FIG. 2 shows the results of measuring changes in ventricular contraction rate and dilatation rate when SEA0400 was administered to a canine heart failure model.

Claims (2)

The following formula (1)

[Wherein, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom or a nitro group;

Indicates. R ⁴ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or a substituted or unsubstituted C ₁ -C ₆ alkoxy group, Z represents a nitro group, an amino group, or NHC (O) CH ₂ R ⁵ R ⁵ represents a hydrogen atom, a substituted or unsubstituted C _{1 to} C ₆ alkyl group, a substituted or unsubstituted C _{1 to} C ₆ alkoxy group, a halogen atom, a hydroxy group, a C _{2 to} C ₇ acyloxy group, NR ⁶ R ⁷ or

R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, or an N-methyl-4-piperidinyl group, and R ⁸ represents a hydrogen atom, a hydroxy group, or C _{2 to} C _{7 represents an} alkoxycarbonyl group, Y represents a methylene group, an epoxy group, a thio group or an NR ⁹ group, and n represents an integer of 1 to 4. R ⁹ represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group or a substituted or unsubstituted phenyl group. Or a pharmaceutically acceptable salt thereof as an active ingredient. The following formula (2)

[Wherein, R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group, R ¹¹ represents a halogen atom or a nitro group, and R ¹² represents a hydrogen atom or a halogen atom. ] The prophylactic or therapeutic agent of heart failure which uses the 2-phenoxy aniline derivative represented by these, or its pharmacologically acceptable salt as an active ingredient.

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