JP2008088166A - New prophylactic or therapeutic agent for parkinson's disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic or therapeutic agent for Parkinson's disease. <P>SOLUTION: The prophylactic or therapeutic agent for Parkinson's disease comprises a phenoxyaniline derivative, a phenoxypyridine derivative, or a salt thereof, having NCX inhibiting action. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel preventive or therapeutic agent for Parkinson's disease containing a phenoxyaniline derivative or a phenoxypyridine derivative having NCX (sodium / calcium exchange system) inhibitory activity.

Intracellular free Ca ²⁺ is an important ion that controls the contraction of the myocardium and various smooth muscles, the release of neurotransmitters, and gene expression, but NCX present in the cell membrane is a major factor in regulating this Ca ²⁺ concentration. It plays a role (see Non-Patent Document 1).

  NCX inhibitors include isothiourea derivatives such as (2- [2- [4 [nitrobenzyloxy] phenyl] ethyl] isothio-ureamethanesulfonate] (KB-R7943), 2- [4-[(2,5-difluorophenyl) There are reports of phenoxyaniline derivatives such as methoxy] phenoxy] -5-ethoxyaniline (SEA0400), and KB-R7943 has been confirmed to be effective against ischemia-reperfusion models of heart and kidney (Non-patent Document 2 and 3).

  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 4).

  Furthermore, the phenoxyaniline derivative (SEA0400) having NCX inhibitory activity has been confirmed to be effective against ischemia-reperfusion models of the brain and heart (see Non-Patent Documents 4 and 5).

  However, there has been no report on application of phenoxyaniline derivatives and phenoxypyridine derivatives having NCX inhibitory activity to the treatment of Parkinson's disease.

Ann. Rev. Physiol. 52: 467 (1990) Nippon Yakurigaku Zasshi. 111, 105 (1998) J. Pharmacol. Exp. Ther. 296-412 (2001) J. Pharmacol. Exp. Ther. 298-249 (2001) Eur J Pharmacol. 458, 155 (2003) WO99 / 20598 gazette WO98 / 43943 Japanese Patent Laid-Open No. 10-218844 Japanese Patent Laid-Open No. 10-265460 JP 11-49752 A

  An object of this invention is to provide the preventive or therapeutic agent of Parkinson's disease.

  The present inventors have found that phenoxyaniline derivatives and phenoxypyridine derivatives having an NCX inhibitory action of the present invention suppress neuronal degeneration in an animal model that develops Parkinson's disease, and have completed the present invention.

  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 or a halogen atom;

Indicates. R ⁴ represents a hydrogen atom, a substituted or unsubstituted C _{1 to} C ₆ alkyl group, or a substituted or unsubstituted C _{1 to} 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 to} 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, is a preventive or therapeutic agent for Parkinson's disease.
Furthermore, Formula (2)

[Wherein R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₆ alkoxy group, and R ¹¹ and R ¹² represent a halogen atom. ] The Parkinson's disease preventive or therapeutic agent containing the 2-phenoxy aniline derivative represented by this, or its pharmaceutically acceptable salt.

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

  In the present invention, the compound that inhibits NCX preferably inhibits brain-derived NCX activity at a concentration of 3 μM by 50% or more. In addition, the measuring method of brain-derived NCX activity is described in J. Pharmacol. Exp. Ther. Pp. 298-249 (2001) and references cited therein.

Furthermore, compounds that specifically inhibit NCX are preferred for the purpose of preventing side effects. The compound that specifically inhibits NCX refers to a compound that hardly inhibits other ion channels, transporters, enzymes, and receptors at a concentration that inhibits 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, 5-lipoxygenase, inducible nitric-oxidesynthetase, It is preferable not to inhibit constitutive nitric-oxide synthetase, adenosine receptor, adrenergic receptor, glutamate receptor, bradykinin receptor, LTB4 receptor, and PAF receptor by 50% or more.

The measurement method using each ion channel, transporter, enzyme, and receptor is described in J. Pharmacol. Exp. Ther., Pages 298-249 (2001) and the references cited therein.
Examples of compounds that specifically inhibit NCX include phenoxyaniline derivatives and phenoxypyridine derivatives. For example, the compound shown by Formula (1) and Formula (2) is mentioned.

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. .

The substituent of the substituted C ₁ -C ₆ alkyl 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 methoxy group, an 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. Examples thereof include an acetoxy group, a propionyloxy group, an isopropionyloxy group, a cyclohexylenyloxy group, and a benzoyloxy group.

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.

  “Pharmaceutically acceptable salts thereof” include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, succinic acid, Mention may be made of salts with organic acids such as fluoroacetic acid, dichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, gluconic acid, benzenesulfonic acid and citric acid. In addition, the compound of this invention can exist also as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.

  Examples of compounds that selectively inhibit NCX represented by formulas (1) and (2) include:

2- [4-[(2,5-difluorophenyl) methoxy] phenoxy] -5-ethoxyaniline (SEA0400), or

で表される化合物2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]aniline（ＳＥＡ０４７９)を挙げることができる。なお、式（１）及び（２）であらわされる化合物は ＷＯ９８／４３９４３，ＷＯ９９／２０５９８，特開平１０−２６５４６０，特開平１０−２１８８４４，特開平１１−４９７５２，特開平１１−９２４５４に記載の製造方法により合成することができる。

And 2- [4-[(2,5-difluorophenyl) methoxy] phenoxy] aniline (SEA0479) represented by the formula: The compounds represented by the formulas (1) and (2) are described in WO98 / 43943, WO99 / 20598, JP-A-10-265460, JP-A-10-218844, JP-A-11-49754, and JP-A-11-92454. It can be synthesized by the method.

  In the present invention, Parkinson's disease is a neurodegenerative disease whose main symptoms are resting tremor, rigidity, ataxia, and posture reflex disorder, and is a disease that occurs frequently in middle-aged and elderly people. Pathologically, it is characterized by degeneration of nigrostriatal dopaminergic neurons and appearance of Lewy bodies.

  In the present invention, the therapeutic agent for Parkinson's disease refers to a drug that improves symptoms such as resting tremor, rigidity, immobility, and posture reflex disorder at the onset of Parkinson's disease, or a drug that suppresses the progression of the above symptoms. Preferably, an agent that suppresses the progression of Parkinson's disease by suppressing cell death of nigrostriatal dopamine nervous system is shown.

  The Parkinson's disease preventive agent in the present invention refers to a drug that is administered before the onset of the above-mentioned Parkinson's disease and suppresses the onset or reduces the symptoms after the onset. Preferably, the agent which suppresses the onset of Parkinson's disease or reduces the symptoms after the onset by suppressing cell death of nigrostriatal dopamine nervous system is shown.

  The therapeutic or preventive agent for Parkinson's disease in the present invention can be used alone, but L-dopa, dopamine agonist, MAO-B (monoamine oxidase B) inhibitor, COMT (catechol-O-methyltransferase) inhibition. It can also be used in combination with existing Parkinson's disease drugs such as drugs.

  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 the age, body weight, dosage form, etc., but is usually 0.1 to 1000 mg / day for an adult, and this is administered once or several times a day.

Formulation examples of the present invention are as follows.
(Formulation example 1)
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 to this, kneaded and dried, and the granules are passed through a 30M sieve to obtain uniform granules. Add magnesium stearate and compress into tablets.

(Formulation example 2 injection)
SEA0400 15mg
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 so as to obtain a predetermined concentration, and then emulsify with a homogenizer rough emulsifier and French press (Aminco) to obtain a fat emulsion. And

(Test Example 1)
Effects of NCX inhibitor (SEA0400) on MPTP-induced Parkinson's disease model mice Mice that received subcutaneous administration of MPTP (methylphenyltetrahydropyridine), a dopamine neurotoxin, had decreased dopamine neuron damage and striatal and substantia nigra dopamine content. It is an upcoming animal model of Parkinson's disease. Specifically, it was performed as follows.

<Method>
A model for developing Parkinson's disease was prepared by subcutaneously administering MPTP (10 mg / kg) to 7-7 week-old C57BL / 6J male mice four times a day at intervals of 2 hours. In the experiment, MPTP-administered mice and control saline-administered mice were used and divided into 5 groups as follows (monoamine measurement, 6 to 12 cases per group in the rotarod test, and immunostaining experiments). And 5 to 6 cases each in a group).

Group 1: Saline (subcutaneous administration) + vehicle (intraperitoneal administration) (4 times a day)
Group 2: Saline (subcutaneous administration) + SEA0400 10 mg / kg (intraperitoneal administration) (four times a day)
Group 3: MPTP (subcutaneous administration) + vehicle (intraperitoneal administration) (4 times a day)
Group 4: MPTP (subcutaneous administration) + SEA0400 3 mg / kg (intraperitoneal administration) (four times a day)
Group 5: MPTP (subcutaneous administration) + SEA0400 10 mg / kg (intraperitoneal administration) (4 times a day)

  Solvent and SEA0400 were administered 4 times a day immediately before each of the 4 MPTP administrations. Three days after the end of administration of MPTP and SEA0400, the striatal dopamine (DA) and dopamine metabolite (DOPAC) contents were measured by high performance liquid chromatography (HPLC), and the striatal dopaminergic nerve fiber density and substantia nigra cells The number was evaluated by the reactivity of tyrosine hydroxylase (TH) antibody, which is a marker of the dopamine nervous system. Motor dysfunction was evaluated by the rotarod test one day after the end of SEA0400 administration.

<Result>
MPTP administration decreased the content of DA (FIG. 1) and its metabolite DOPAC (FIG. 2) in the striatum, but the decrease was significantly suppressed by SEA0400 pre-administration. MPTP administration decreased the TH responsiveness of the striatum (FIG. 3) and substantia nigra (FIG. 4), but the decrease was significantly suppressed by SEA0400 pre-administration. Furthermore, in the rotarod test, SEA0400 pre-administration significantly suppressed motor dysfunction caused by MPTP administration (FIG. 5).

(Test Example 2)
<Method>
The effect of NCX inhibitor (SEA0479) on MPTP-induced Parkinson's disease model mice was evaluated using the same method as in Test Example 1 above. The animal group was set as follows.

Group 1: Saline (subcutaneous administration) + vehicle (intraperitoneal administration) (4 times a day)
Group 2: MPTP (subcutaneous administration) + vehicle (intraperitoneal administration) (4 times a day)
Group 3: MPTP (subcutaneous administration) + SEA0479 10 mg / kg (intraperitoneal administration) (4 times a day)

  In addition, as an evaluation index, the dopamine (DA) content of the striatum, the striatal dopaminergic nerve fiber density and the number of substantia nigra cells were used.

<Result>
Similar to SEA0400 in Test Example 1, pre-administration of SEA0479 resulted in a decrease in the amount of DA in the striatum caused by MPTP administration (FIG. 6), a decrease in striatal dopaminergic nerve fiber density (FIG. 7), and substantia nigra. A decrease in the number of cells (FIG. 8) was significantly suppressed.

  From the above results, SEA0400 and SEA0479 showed a dopamine neuroprotective action and a motor dysfunction improving action in Parkinson's disease model mice.

It is the result which showed the effect of SEA0400 in Parkinson's disease model mice, using dopamine content in the striatum as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice (Dunnett's test)) . It is the result which showed the effect of SEA0400 in Parkinson's disease model mice, using dopamine metabolite (DOPAC) content in the striatum as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice) (Dunnett's test)). It is the result which showed the effect of SEA0400 in Parkinson's disease model mice, using tyrosine hydroxylase (TH) antibody-responsive nerve fiber density in the striatum as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice (Dunnett's test)). It is the result which showed the effect of SEA0400 in Parkinson's disease model mice, using tyrosine hydroxylase (TH) antibody-reactive cells in the substantia nigra as an index (** p <0.01 versus vehicle-treated mice; #p <0.05, ## p <0.01 versus MPTP-treated mice (Dunnett's test)). Results of SEA0400 in Parkinson's disease model mice with motor dysfunction as an index (rotor rod test) (* p <0.05 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice (Dunnett's test) ). It is the result which showed the effect of SEA0479 in Parkinson's disease model mice, using dopamine content in the striatum as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice (Dunnett's test)) . It is the result which showed the effect of SEA0479 in Parkinson's disease model mice, using tyrosine hydroxylase (TH) antibody-responsive nerve fiber density in the striatum as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP-treated mice (Dunnett's test)). It is the result which showed the effect of SEA0479 in Parkinson's disease model mouse | mouth using the tyrosine hydroxylase (TH) antibody reaction cell number in the substantia nigra as an index (** p <0.01 versus vehicle-treated mice; #p <0.05 versus MPTP- treated mice (Dunnett's test)).

Claims (2)

Formula (1)

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

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, a preventive or therapeutic agent for Parkinson's disease. Formula (2)

[Wherein R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group, and R ¹¹ and R ¹² represent a halogen atom. ] The preventive or therapeutic agent of Parkinson's disease containing the 2-phenoxy aniline derivative represented by this, or its pharmaceutically acceptable salt.

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