JPH1077226A - Agent for protecting cytotoxicity induced by beta-amyloid protein - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an agent for protecting cytotoxicity induced by β-amyloid protein having low toxicity, safe and effective for Parkinson's disease, etc., by using a specific substituted 1,4-benzoquinone derivative and its corresponding stubstituted 1,4-hydroquinone derivative as an active ingredient. SOLUTION: This agent for protecting cytotoxicity induced by β-amyloid protein includes a compound of formula I or II (R<1> is an alkyl; R<2> is H, an alkyl or an alkenyl; R<3> and R<4> are each an alkyl or an alkoxy, or form a butadienylene group by connecting each other; X<1> and X<2> are each OH) or its salt. For example, the agent for protecting cytotoxicity induced by β-amyloid protein is effective for familial dysautonomia, tumor of nerve fiber, neuroblastoma, pheochromocytoma, various kinds of dementia, Parkinson's disease, Huntington's chorea, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, scrapie, etc. Espcially, the agent is effective for human Alzheimer's disease, Creutzfeldt-Jakob disease, Parkinson's disease, etc. Further, the agent is also effective for amyloid neuropathy, amyloid diabetes, protection of pancreatic cell, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a cytoprotective agent,
In particular, the present invention relates to an agent for protecting β-amyloid protein-induced cytotoxicity.

[0002]

2. Description of the Related Art The cells constituting living organisms are exposed to the action of various undesirable endogenous or extrinsic factors, and their functions are inhibited, or cell damage and cell degeneration or cell death are induced. It has been known. In addition, various diseases caused by these have become major social problems. The most important neuropathological feature in the brain of a patient with one such disease, Alzheimer's disease, is senile plaque. The senile plaque contains various substances, the main component of which is a β-amyloid protein consisting of 40 to 43 amino acids [Cell, 52, 307-308, 1988
Years and Neurons, 6, 487-498, 199
1 year]. β-amyloid has been shown to show direct neurotoxicity in studies using cultured neurons [Brain Research, 533, 315].
~ 320 pages, 1990 and Science, 25, 2
79-282, 1990], and is considered one of the causes of Alzheimer's disease. Furthermore, recent studies have shown that aggregation of β-amyloid protein is essential for the development of its toxicity [Neurobiology of Aging, 13, 587-590, 1992.
Year and Journal of Molecular Biology, 218, 149-163
1991].

On the other hand, Japanese Patent Application Laid-Open No. 3-81218 and US Pat. No. 5,059,627 disclose a substituted 1,4-benzoquinone derivative and a corresponding substituted 1,4-hydroquinone derivative as an excellent nerve growth factor. ) Is described as being effective in treating Alzheimer's disease. JP-A-7-61923
And EP-A-629400 describe that administration of idebenone at a high dose (270 mg to 360 mg per adult per day) as a therapeutic agent for Alzheimer's senile dementia is clinically effective. I have. Arch. Gerontol. Geriatr., Volume 15, 1992, 249
On page 260, it is described that the efficacy of idebenone in Alzheimer's type senile dementia patients was confirmed by administering 90 mg of idebenone per adult per day. The Journal of Pharmacology and Experimental Therapeutics
armacology and Experimental Therapeutics), 250 volumes,
Pp. 1132-1140, 1989, in N18-RE-105 cells, which are hybrids of rat retinal neurons and neuroblastoma,
Idebenone inhibits glutamate-induced neuronal death, its action is due to reactive oxygen species
Has been reported to be a neuroprotective action based on the elimination action of A.

[0004]

[Problems to be Solved by the Invention] Protect neurons from cytotoxicity of β-amyloid protein which is an endogenous factor of dysfunction or damage of brain neurons or death of the cells, and cerebral nervous system diseases such as Alzheimer's disease and Parkinson's disease Preventing and treating neurodegenerative diseases is an urgent issue. However, no effective means has been found so far for the treatment and prevention of these diseases.

[0005]

Means for Solving the Problems The present inventors have enthusiastically searched for a compound having an action of protecting cells (particularly nerve cells) from the cytotoxicity of β-amyloid protein (protective action of β-amyloid protein-induced cytotoxicity). In addition, a substituted 1,4-benzoquinone derivative having a specific chemical structure and its corresponding substituted 1,4-hydroquinone derivative have an excellent protective effect, and furthermore have extremely low toxicity and excellent properties as a safe drug. Have been found for the first time, and based on this, the present invention has been completed. That is, the present invention provides:

Embedded image Or

Embedded image [Wherein, R ¹ is a lower alkyl group, R ² is hydrogen, an optionally substituted alkyl group or an optionally substituted alkenyl group, and R ³ and R ⁴ are each an optionally substituted lower alkyl group. Or a lower alkoxy group, or R
³ and R ⁴ may form one butadienylene group,
X ¹ and X ² each represent a hydroxyl group which may be esterified or etherified.] (Hereinafter abbreviated as compound (I) and compound (II), respectively)
Or a β-amyloid protein-induced cytotoxicity protective agent comprising a salt thereof, (2) the agent according to the above (1), which is a preventive / therapeutic agent for Parkinson's disease, Huntington's disease or Creutzfeld-Jakob disease; ) R ¹ is a C _1-4 alkyl group; R ² is (a) hydrogen, (b) (i) C _1-4 alkyl, (ii) hydroxyl, (iii) oxo, (iv) amino, (v) mono —C _1-6 alkylamino,
(Vi) di-C _1-6 alkylamino, (vii) carboxy,
(Viii) C _1-4 alkoxy-carbonyl, (ix) C _1-4 alkyl, hydroxyl, carboxy and C _1-6 alkoxy-
C _1-14 aryl optionally having one or two substituents selected from carbonyl, (x) C _1-4 alkyl, hydroxyl group, carboxy and C _1-6 alkoxy-carbonyl, A 5- to 6-membered heterocyclic group optionally having 2 and (xi) a C _1-22 alkyl group optionally having 1 to 10 substituents selected from halogen, or (c) (i ) C _1-4 alkyl, (ii) hydroxyl, (iii) oxo, (iv) amino, (v) mono-C _1-6 alkylamino,
(Vi) di-C _1-6 alkylamino, (vii) carboxy,
(Viii) C _1-4 alkoxy-carbonyl, (ix) C _1-4 alkyl, hydroxyl, carboxy and C _1-6 alkoxy-
C _1-14 aryl optionally having one or two substituents selected from carbonyl, (x) C _1-4 alkyl, hydroxyl group, carboxy and C _1-6 alkoxy-carbonyl, R ³ and R ⁴ are a 5- to 6-membered heterocyclic group optionally having 2 and a C _2-15 alkenyl group _optionally having 1 to 10 substituents selected from (xi) halogen; (A) hydroxyl group, halogen, nitro, optionally halogenated C _1-3 alkyl, carboxy, C _1-6 alkoxy-carbonyl, 3-
C _{1-6 optionally} having 1 to 3 substituents selected from pyridyl, 1-imidazolyl and 5-thiazolyl
An alkyl group or (b) a C _1-3 alkoxy group;
³ and R ⁴ together with the carbon atoms to which they are attached, C _1-3
Forming a benzene ring which may have 1 to 3 substituents selected from alkyl, C _1-3 alkoxy, hydroxyl, nitro and halogen; X ¹ and X ² are each a hydroxyl group, C _2-10 alkanoyl, benzoyl (4) the agent according to the above (1), which is nicotinoyl which may be quaternized, hemi-acyl succinate, C _1-8 alkoxy, C _7-13 aralkyloxy, tetrahydropyranyloxy or tetrahydrofuryloxy; R ¹ is a C _1-3 alkyl group, R ² is a C _6-14 alkyl group substituted with a hydroxyl group, R ³ and R ⁴ are each a C _1-3 alkoxy group, and X ¹ and X ² are each a hydroxyl group. The agent according to (1), the formula (5)

Embedded image Wherein each symbol has the same meaning as described above, or the agent according to the above (1), which comprises a compound thereof or a salt thereof, and (6) the agent according to the above (1), which comprises idebenone. And the like.

In the above formulas (I) and (II), the "lower alkyl group" represented by R ¹ includes, for example, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl and butyl groups. Examples of the “alkyl group” of the “optionally substituted alkyl group” for R ² include methyl,
And C _1-22 alkyl groups such as ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, heptadecyl, eicosyl, docosyl and the like.
Preferably, it is a linear C _6-14 alkyl group. Examples of the “alkenyl group” of the “optionally substituted alkenyl group” for R ² include, for example, ethenyl, 1-propenyl, 3-methyl-2-butenyl, 2,6-dimethyl-
A straight-chain or branched alkenyl group having 2 to 15 carbon atoms such as 2,6-octadienyl is mentioned. The number of double bonds is usually 1 to 3, and these double bonds may be conjugated. Examples of the substituent of the “optionally substituted alkyl group” and the “optionally substituted alkenyl group” include a C _1-4 alkyl group (eg, methyl, ethyl,
Propyl, butyl), hydroxyl group, oxo group, amino group, mono-C _1-6 alkylamino group (eg, methylamino, ethylamino), di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino), Carboxyl group, alkoxycarbonyl group (eg, C _1-4 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propionyloxycarbonyl, butoxycarbonyl), aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, indanyl, etc.) C _6-14 aryl group), heterocyclic group (eg, 2-pyridyl, 3-pyridyl, 2-thienyl, 3
A 5- to 6-membered heterocyclic group such as -thienyl), halogen (fluorine, chlorine, bromine, iodine) and the like. Of these, a hydroxyl group is preferred. When the substituent is an aryl or heterocyclic group, these may further have one or more substituents at any position on the ring, and examples of the substituent include C _1-4 Alkyl (eg, methyl,
Ethyl, propyl, butyl), hydroxyl, carboxyl,
C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) and the like. The number of substituents that the “alkyl group” or “alkenyl group” may have is not particularly limited as long as the object is achieved,
The number is 10, preferably 1 to 6. Further, the same carbon atom may be substituted with the same or different substituent. For example, there are two methyl groups and one hydroxyl group. The substituent may be substituted at any position as long as it can be substituted, for example, the 1-position or the ω-position is preferable.

The “lower alkyl group” of the “optionally substituted lower alkyl group” for R ³ or R ⁴ includes, for example, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec- Butyl, t-butyl,
C _1-6 alkyl such as amyl and hexyl.
Particularly, C _1-3 alkyl is preferable. Examples of the substituent of the “optionally substituted lower alkyl group” include a hydroxyl group, a halogen (eg, fluorine, chlorine, bromine, iodine), nitro, a C _1-3 alkyl which may be halogenated (eg, , Trifluoromethyl), carboxyl, C
Examples thereof include _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl and the like), 3-pyridyl, 1-imidazolyl, 5-thiazolyl and the like. The “lower alkoxy” represented by R ³ or R ⁴ includes, for example, C _1-3 alkoxy such as methoxy, ethoxy, propoxy and i-propoxy. When R ³ and R ⁴ represent a butadienyl group, a benzene ring is formed together with the carbon to which R ³ and R ⁴ are bonded, and the formed benzene ring is substituted with 1 to 3 substituents at any position on the ring. And the substituent may be, for example, lower (C
_1-3 ) alkyl (eg, methyl, ethyl, propyl, etc.), lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.), hydroxyl, nitro, halogen and the like.

In the above formula (II), examples of the “esterified hydroxyl group” represented by X ¹ or X ² include acyloxy carboxylate, acyloxy phosphate and the like. The acyl carboxylate of the acyloxy carboxylate includes, for example, formyl or a chain or cyclic alkanoyl having 2 to 10 carbon atoms such as acetyl, propionyl, isobutyryl, decanoyl, cyclopentyl or cyclohexylcabonyl, for example, arylcarbonyl such as benzoyl, And nicotinoyl which may be graded, and half-acyl succinate. X
Examples of the “etherified hydroxyl group” represented by ¹ or X ² include, for example, alkoxy, aralkyloxy and the like. Examples of the alkoxy include methoxymethoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, t-butoxy, sec-butoxy, amyloxy (pentyloxy), hexyloxy, tetrahydropyranyloxy and tetrahydrofuryloxy. C _1-8 alkoxy is exemplified. Especially, C _1-3 alkoxy is preferable. Examples of the aralkyloxy include C _7-13 aralkyloxy such as benzyloxy.

In the above compound (I), R ¹ is C _1-3 alkyl, R ² is C _6-14 alkyl substituted with a hydroxyl group, and R ³ is C _3-14 alkyl.
_1-3 alkoxy, and compounds in which R ⁴ is C _1-3 alkoxy is preferable. In the compound (II), R ¹ is C _1-3 alkyl, R ² is C _6-14 alkyl substituted with a hydroxyl group, R ³ is C _1-3 alkoxy, and R ⁴ is C _1-3 alkoxy, X Compounds in which ¹ is a hydroxyl group and X ² is a hydroxyl group are preferred.
Among the compounds (I) and (II), a compound excellent in central migration is preferable. Specific examples include idebenone. Idebenone is published in Tokubo 62-31
No. 34, whose chemical name is 6
-(10-hydroxydecyl) -2,3-dimethoxy-
5-methyl-1,4-benzoquinone. Compound (I)
And (II) may form a salt depending on the type of the substituent, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, Or salts with acidic amino acids. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be
Of these, pharmaceutically acceptable salts are preferred.

Compounds (I) and (II) or salts thereof can be prepared by a method known per se, for example, Chemical and Pharmaceutical Burtin.
rmaceutical Bulletin), 30, 2797, 19
1982, pp. 33, 4422, 1985, JP-A-5
1-128932, JP-A-63-45257, JP-A-Showa 5
It can be produced by the method described in JP-A-7-109739, JP-A-61-044840 or a method analogous thereto.

In using the compounds (I), (II) or salts thereof as the agent for protecting β-amyloid protein-induced neurotoxicity of the present invention, a method known per se, for example, Japanese Patent Publication No. 1-2727, Kosho 63-511
No. 23, Japanese Patent Publication No. 1-39405,
Various pharmaceutical forms (eg, tablets, capsules, fine granules, granules, powders, etc.) as pharmaceutical compositions according to the method described in JP-A-81212 or a method analogous thereto.
And can be administered orally or parenterally to mammals, including humans. The preparation used in the preparation of the present invention includes pharmacologically acceptable carriers generally used in preparations, and various organic or inorganic carrier substances commonly used as preparation materials are used. For example, an appropriate amount may be appropriately selected from an excipient, a binder, a disintegrant, and a lubricant. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, glucose, sorbite, talc, cyclodextrin and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, arabic gum, polyethylene glycol, and the like. . Disintegrators include starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Further, the preparation of the present invention may be a sustained-release preparation that can be produced using known means. Such sustained-release preparations can be prepared by a method known per se, for example, fats and oils (eg, triglycerides),
It can be obtained by coating tablets, granules, fine granules and capsules with appropriate amounts of polyglycerin fatty acid esters, hydroxypropyl cellulose and the like.

The dose varies depending on the type and symptoms of the target disease. For example, when the nerve cells are orally administered to protect the neurons from the cytotoxicity of β-amyloid protein, for example, the dose is administered per adult (60 kg) per day, Compounds (I), (I
I) or 10 mg to 5000 mg, preferably 180 mg to 1500 mg, more preferably 270 mg to
The dose is 1440 mg, but may be reduced as necessary according to the type and symptom of the disease. The β-amyloid protein-induced neurocytotoxic protective agent of the present invention is useful for treating and preventing cerebral dysfunction in mammals including humans. Examples of the target disease include familial autonomic dysfunction, nerve fiber tumor, and neurological dysfunction. Blastoma, pheochromocytoma,
Various dementias (eg, senile dementia, Alzheimer's disease, etc.), Parkinson's disease, Huntington's disease, Creutzfeld-Jakob disease, mad cow disease, scrapie and the like. In particular, the agent of the present invention is effective against Alzheimer's disease, Creutzfeld-Jakob disease and Parkinson's disease in humans, and is effective against mad cow disease and sheep scrapie in animals. Further, the agent of the present invention is also effective for amyloid neuropathy, amyloid diabetes (protection of Langerhans cells), protection of pancreatic cells, and the like.

The dosage form of the preparation of the present invention may be any dosage form that can be orally administered to the above-mentioned diseases. Among them, tablets, fine granules, capsules and the like are preferable. The amount of compound (I) or (II) or a salt thereof used is, for example, about 30 mg or more, preferably about 30 mg to 100 mg per tablet or capsule, and per granule or fine granule. It is about 30 mg or more, preferably about 30 mg to 100 mg. For the treatment of the above-mentioned diseases of animals, particularly livestock such as cattle and sheep, in addition to the above-mentioned dosage forms, the agent of the present invention may be administered in the form of livestock feed. The agent of the present invention comprises a compound (I) or (II)
Or, in addition to its salts, other drugs such as central drugs (eg, anxiolytics, sleep-inducing drugs, schizophrenia drugs, Parkinson drugs, etc.), antihypertensive drugs, antidiabetic drugs, antilipidemic drugs, etc. It may be used in combination with an adult disease treating agent. Further, it may be used in combination with various brain function improving agents (cerebral circulation improving agents and brain metabolic activators), acetylcholinesterase inhibitors and the like. In addition, nutrients such as vitamins, digestion and absorption promoters,
It may be used in combination with a gastrointestinal drug or the like.

The compounds (I) and (II) or their salts have extremely low toxicity, and have almost no side effects or toxicity even after long-term administration. For example, if the acute toxicity LD ₅₀ value of idebenone mouse, male, both female 10,
000mg / kg or more, in rats, males LD ₅₀ value 10,000mg / kg or more, about female 10,000mg /
kg. Also, Human Psychopharmacology, 11, 53-65, 199
In six years, idebenone was given to Alzheimer's disease patients for 60 months at a dose of 90 mg three times a day (270 m / day).
g) or the liver laboratory test values GPT and GOT values when administered at a dose of 120 mg three times a day (360 mg per day). As a result, the change was small, and there was little change from the control group (placebo group). It is not found and its toxicity is described as extremely small. When the agent of the present invention is a sustained-release preparation, it is preferably administered so that the amount of compound (I), (II) or a salt thereof released per day is 90 mg or more, preferably 150 mg or more. In addition, when the biological availability (bioavailability) of the compound (I), (II) or a salt thereof is improved, the release amount may be appropriately reduced. The compound (I) or (II) or a salt thereof in the preparation of the present invention is one of the compounds used in the method of treatment.
If necessary, the daily dose may be divided into a plurality of times a day. In such a case, the dose may be divided into 2 to 6 times a day. It is preferably administered three times a day. 1
The dose per administration is the daily dose divided by the number of administrations. The administration timing is not particularly limited, but administration after each meal is preferred.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in more detail with reference to experimental examples and examples.

【Example】

Experimental Example 1 The protective effect of idebenone on neuronal toxicity in rat hippocampal neurons by β-amyloid protein 1-40 (hereinafter abbreviated as Aβ1-40) was examined. (Experimental method) The hippocampus was taken out from the brain of a rat fetus, cultured for 6 days, and the effect of idebenone on neuronal cell death induced by adding Aβ1-40 was examined. Cultured rat hippocampal neurons used in the experiment were prepared by the following method. The hippocampus was removed from the SD rat brain of the 18th day of the embryo under ice cooling and 0.25% trypsin and 0.1 in Hank's solution.
The cells were treated with mg / ml of deoxyribonuclease I at 37 ° C. for 10 minutes. After filtering the enzyme-treated cells through a filter, 50 units / ml penicillin, 50 μg / ml streptomycin, 10% fetal bovine serum and 1% B2
Suspension in Eagle-MEM medium containing 7 supplements (GIBCO) and 100,000 cells / 300 μl / we in a 48-well plate (COSTAR) coated with poly-L-lysine
The cells were diluted with a medium so as to be ll. The culture was performed at 37 ° C. in the presence of 5% carbon dioxide. On day 4 of culture, 50 uni
t / ml penicillin, 50 μg / ml streptomycin,
10 mM HEPES-Na (pH 7.3) and N2supp
The medium was replaced with Eagle-MEM medium (MEM-N2) containing lement. Further, on day 7 of the culture, Aβ1-40
The medium was changed to MEM-N2 containing (Bachem) and the drug, and the effect of the drug on Aβ1-40 toxicity was examined. Toxicity is measured by measuring the activity of lactate dehydrogenase (LDH) released from the damaged cells into the medium over 3-5 days after the treatment, and using that as an index,
Four days after the addition, the cells were fixed with 4% paraformaldehyde, stained with an anti-MAP2 antibody (Amersham), photographed at random under a microscope, and the number of nerve cells contained in the visual field was measured. (Experimental results) LD in medium 3-5 days after drug addition
As a result of examining the leakage of H activity as an index, Aβ1-40 showed toxicity in a dose-dependent manner (FIG. 1). On the other hand, 100 nM of idebenone suppressed the leakage of LDH over 3 to 5 days after the addition (FIG. 2). This is because idebenone is Aβ1-
It is considered that the toxicity to 40 hippocampal neurons was suppressed. Furthermore, when the neurons were stained with an anti-MAP2 antibody, the number of surviving neurons was almost the same as that of the control at 100 nM of idebenone, and Aβ1-
40 inhibited the decrease in the number of nerve cells and significantly suppressed (protective action) the death of nerve cells (FIG. 3). From these results,
It can be seen that idebenone has a protective effect on β-amyloid hippocampal neurotoxicity.

Example 1 Preparation of 90 mg idebenone tablets Idebenone 90.0 g Lactose (EP) 233.2 g Alpha-modified starch 11.2 g Calcium salt of carboxymethyl cellulose (ECG 505) 67.3 g Magnesium stearate (EP) 1.1 g Hydroxypropyl methyl cellulose USP (Pharmacoat 606) 5.6 g Polyethylene glycol (NF 6000) 1.4 g Propylene glycol (EP) 0.5 g Talc (EP) 1.8 g Titanium oxide (EP E171) 2.7 g Red pigment 30 (E172) 0.2 g Total amount 415.0 g Idebenone and water were added to the excipient, kneaded, and dried. To the obtained dry kneaded product, after adding the above-mentioned disintegrant and lubricant and homogenizing, compress with a compression tablet machine,
11m diameter containing 90mg idebenone per tablet
1,000 tablets having a thickness of 4.3 mm and a weight of 415 mg were produced.

Example 2 Preparation of 120 mg idebenone tablets Idebenone 120.0 g Lactose (EP) 203.2 g Alpha starch starch 11.2 g Carboxymethyl cellulose calcium salt (ECG 505) 67.3 g Magnesium stearate (EP) 1.1 g Hydroxypropyl methyl cellulose USP (Pharmacoat 606) 5.6 g Polyethylene glycol (NF 6000) 1.4 g Propylene glycol (EP) 0.5 g Talc (EP) 1.8 g Titanium oxide (EP E171) 2.7 g Red pigment 30 (E172) 0.2 g Total amount 415.0 g Idebenone and water were added to the excipient and kneaded, and the obtained kneaded product was dried. After adding the above-mentioned disintegrant and lubricant to this and homogenizing, it is compressed with a compression tablet machine,
1 tablet containing 120 mg of idebenone per tablet
1,000 tablets of 1 mm, 4.3 mm thickness and 415 mg weight were produced.

[0018]

Industrial Applicability The β-amyloid protein-induced cytotoxicity protective agent of the present invention has low toxicity and is safe. Useful target diseases include, for example, familial autonomic dysfunction, nerve fiber tumor, neuroblastoma, pheochromocytoma, various dementias, Parkinson's disease, Huntington's disease, Creutzfeld-Jakob disease, mad cow disease, scrapie, etc. Is mentioned. Particularly, it is effective against Alzheimer's disease, Creutzfeld-Jakob disease and Parkinson's disease in humans, and is effective against mad cow disease and scrapie of sheep in animals. Further, the agent of the present invention is also effective for amyloid neuropathy, amyloid diabetes (protection of Langerhans cells), protection of pancreatic cells, and the like.

[Brief description of the drawings]

FIG. 1 is a graph showing the correlation between the amount of Aβ1-40 on rat hippocampal neurons and cytotoxicity.

FIG. 2. Effect of Aβ1-40 (1 on rat hippocampal neurons.
0 μM) is a graph showing the results of the protective effect of idebenone against cytotoxicity. In the figure, the open circles represent the control, the filled circles represent the addition of idebenone (0.01 μM), the open triangles represent the addition of idebenone (0.1 μM), and the closed triangles represent Aβ1-40 (10 μM).
M), open squares are Aβ1-40 (10 μM) and idebenone (0.01 μM) added, black squares are Aβ1-40
(10 μM) and idebenone (0.1 μM) addition.

FIG. 3 is a graph showing the results of the protective effect of idebenone on rat hippocampal neuronal cell death (expressed by the number of surviving cells) exerted by Aβ1-40.

Claims (6)

[Claims] (1) Formula (1) Or [Wherein, R ¹ is a lower alkyl group, R ² is hydrogen, an optionally substituted alkyl group or an optionally substituted alkenyl group, and R ³ and R ⁴ are each an optionally substituted lower alkyl group. Or a lower alkoxy group, or R
³ and R ⁴ may form one butadienylene group,
X ¹ and X ² each represent a hydroxyl group which may be esterified or etherified.] Or a salt thereof, the β-amyloid protein-induced cytotoxicity protective agent. 2. The method according to claim 1, which is an agent for preventing or treating Parkinson's disease, Huntington's disease or Creutzfeld-Jakob disease. R ¹ is a C _1-4 alkyl group; R ² is (a) hydrogen, (b) (i) C _1-4 alkyl, (ii) hydroxyl, (iii) oxo, (iv) amino, (V) mono-C _1-6 alkylamino,
(Vi) di-C _1-6 alkylamino, (vii) carboxy,
(Viii) C _1-4 alkoxy-carbonyl, (ix) C _1-4 alkyl, hydroxyl, carboxy and C _1-6 alkoxy-
C _1-14 aryl optionally having one or two substituents selected from carbonyl, (x) C _1-4 alkyl, hydroxyl group, carboxy and C _1-6 alkoxy-carbonyl, A 5- to 6-membered heterocyclic group optionally having 2 and (xi) a C _1-22 alkyl group optionally having 1 to 10 substituents selected from halogen, or (c) (i ) C _1-4 alkyl, (ii) hydroxyl, (iii) oxo, (iv) amino, (v) mono-C _1-6 alkylamino,
(Vi) di-C _1-6 alkylamino, (vii) carboxy,
(Viii) C _1-4 alkoxy-carbonyl, (ix) C _1-4 alkyl, hydroxyl, carboxy and C _1-6 alkoxy-
C _1-14 aryl optionally having one or two substituents selected from carbonyl, (x) C _1-4 alkyl, hydroxyl group, carboxy and C _1-6 alkoxy-carbonyl, R ³ and R ⁴ are a 5- to 6-membered heterocyclic group optionally having 2 and a C _2-15 alkenyl group _optionally having 1 to 10 substituents selected from (xi) halogen; (A) hydroxyl group, halogen, nitro, optionally halogenated C _1-3 alkyl, carboxy, C _1-6 alkoxy-carbonyl, 3-
C _{1-6 optionally} having 1 to 3 substituents selected from pyridyl, 1-imidazolyl and 5-thiazolyl
An alkyl group or (b) a C _1-3 alkoxy group;
³ and R ⁴ together with the carbon atoms to which they are attached, C _1-3
Forming a benzene ring which may have 1 to 3 substituents selected from alkyl, C _1-3 alkoxy, hydroxyl, nitro and halogen; X ¹ and X ² are each a hydroxyl group, C _2-10 alkanoyl, benzoyl , agent according to claim 1, wherein the quaternized optionally nicotinoyl, succinic acid half-acyl, C _1-8 alkoxy, C _7-13 aralkyloxy, tetrahydropyranyloxy or tetrahydrofuryl oxy. 4. R ¹ is a C _1-3 alkyl group, R ² is a C _6-14 alkyl group substituted by a hydroxyl group, R ³ and R ⁴ are
The agent according to claim 1, wherein each of the _1-3 alkoxy group, X ¹ and X ² is a hydroxyl group. 5. A compound of the formula 2. The agent according to claim 1, comprising a compound represented by the formula: wherein each symbol is as defined in claim 1, or a salt thereof. 6. The agent according to claim 1, comprising idebenone.