JP2006347942A - beta-AMYLOID FORMATION INHIBITOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a β-amyloid formation inhibitor containing a compound having a skeleton quite different from that of a compound previously reported to have β-amyloid formation inhibiting action as an active ingredient. <P>SOLUTION: This β-amyloid formation inhibitor contains the compound expressed by formula (I) (R is H, a 1-6C alkyl, an acyl or a saccharide residue; X is O or S; and Y is O or S) or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a β-amyloid production inhibitor useful as an agent for preventing or treating Alzheimer's disease.

  In recent years, with the increase in the elderly population, there is a strong demand for the development of pharmaceuticals effective for the treatment of senile dementia. Alzheimer's disease, a typical disease of senile dementia, is a neurodegenerative disease characterized by brain atrophy, senile plaque deposition, and neurofibrillary tangles. Deletion of neurons causes dementia. In Alzheimer's disease patients, histopathological studies result in the deposition of senile plaques, which causes neuronal loss and brain atrophy.

  Β amyloid, which is the main component of senile plaques, has a cytotoxic effect and is one cause of neuronal cell death in Alzheimer's disease (Non-Patent Documents 1 to 4).

  β-amyloid is an easily aggregated peptide consisting of 39 to 43 amino acids, and is produced by processing the precursor amyloid precursor protein (Non-patent Documents 5 and 6).

  The amyloid precursor protein is a protein having a transmembrane site (Non-patent Document 7), which is cleaved at the α site near the 17th residue of β amyloid, and a fragment having a molecular weight of about 120 kDa including the N-terminus is secreted extracellularly. (Non-patent document 8). On the other hand, β-amyloid is present in the C-terminal region of the amyloid precursor protein, and β-amyloid produced by cleavage at both ends of β-amyloid is secreted extracellularly.

  A drug that suppresses the production of β-amyloid is expected as a therapeutic agent for Alzheimer's disease or a drug that suppresses progression.

  Accordingly, research on drugs that suppress the production of β-amyloid is also underway. For example, rhodanine derivatives (Patent Document 1), benzimidazole derivatives (Patent Document 2), vinpocetine derivatives (Patent Document 3), aromatic amide derivatives ( Patent document 4) is known.

で示されるアルクチゲニン(arctigenin)又はその誘導体等のリグナン骨格を有する化合物は、免疫抑制作用及び抗糖尿病作用を有することが知られているが（特許文献５及び６）、これらの化合物とβアミロイド生成抑制作用との関係については何ら報告されていない。 On the other hand, the following formula (I-1):

It is known that compounds having a lignan skeleton such as arctigenin or derivatives thereof represented by the above formula have immunosuppressive and antidiabetic effects (Patent Documents 5 and 6), and β-amyloid formation with these compounds There is no report on the relationship with the inhibitory action.

Japanese Unexamined Patent Publication No. 6-192091 US Pat. No. 5,552,426 International Publication No. 96/25161 Pamphlet International Publication No. 2004/014843 Pamphlet JP-A-5-32580 JP-A-5-32659 Yankner, B. et al., Science, 245, 417-420 (1989) Cai, X., Gold, T. & Younkin, S., Science, 259, 514-516 (1993) Rose, A., Nature Med. 2, 267-269 (1996) Scheuner, D. et al., Nature Med., 2, 864-869 (1996) Haass, C. & Selkoe, D., Cell, 75, 1039-1042 (1993) Roher, A.E. et al., Proc. Natl. Acad. Sci. USA, 90, 10836-10840 (1993) Kang, J. et al., Nature, 325, 733-736 (1987) Seubert, P. et al., Nature, 361, 260-262 (1993)

  An object of the present invention is to provide a β amyloid production inhibitor containing as an active ingredient a compound having a skeleton completely different from the compounds that have been reported to have a β amyloid production inhibitory action.

（式中、Ｒは水素原子、Ｃ_１−６−アルキル基、アシル基又は糖残基を表し；Ｘは酸素原子又は硫黄原子を表し；Ｙは酸素原子又は硫黄原子を表す。）
で示される化合物又はその薬学的に許容される塩を含有するβアミロイド生成抑制剤。 The gist of the present invention is as follows.
(1) The following formula (I):

(In the formula, R represents a hydrogen atom, a C _1-6 -alkyl group, an acyl group or a sugar residue; X represents an oxygen atom or a sulfur atom; Y represents an oxygen atom or a sulfur atom.)
(Beta) amyloid production inhibitor containing the compound shown by these, or its pharmacologically acceptable salt.

(2) The β amyloid production inhibitor according to (1), wherein in formula (I), R is a substituted or unsubstituted C _1-6 -saturated aliphatic acyl group or a substituted or unsubstituted benzoyl group.
(3) The β amyloid production inhibitor according to (1) or (2), which is a preventive / therapeutic agent for Alzheimer's disease.

（式中、Ｒ^１はベンゾイル基、３，４−ジメチルベンゾイル基、２−カルボキシベンゾイル基又はグリシル基を表す。）
で示される化合物又はその薬学的に許容される塩。 (4) The following formula (Ia):

(In the formula, R ¹ represents a benzoyl group, a 3,4-dimethylbenzoyl group, a 2-carboxybenzoyl group, or a glycyl group.)
Or a pharmaceutically acceptable salt thereof.

で示される化合物又はその薬学的に許容される塩。 (5) The following formula (Ib):

Or a pharmaceutically acceptable salt thereof.

  According to the present invention, it is possible to provide a new type of β-amyloid production inhibitor containing a compound having a lignan skeleton as an active ingredient.

Hereinafter, the present invention will be described in detail.
In the present specification, the C _1-6 -alkyl group and “C _1-6 -alkyl” in each substituent may be any of linear, branched and cyclic (C _3-6 -cycloalkyl). For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl Groups.

Examples of the acyl group represented by R in the formula (I) include formyl group, acetyl group, propionyl group (propanoyl group), butyryl group (butanoyl group), pivaloyl group, valeryl group (pentanoyl group), and hexanoyl group. C _1-6 etc. _- saturated aliphatic acyl groups; _-; acyl group derived from amino acids such as glycyl group; a benzoyl group, an aromatic acyl group such as a naphthoyl group unsaturated aliphatic acyl group C _3-6 such as acryloyl groups (Aroyl group). These acyl groups include a C _1-6 -alkyl group, a C _2-6 -alkenyl group, a C _2-6 -alkynyl group, an aromatic group, an acyl group, an acyloxy group (for example, an acetoxy group), a hydroxyl group, a carboxyl group, It may be substituted with one or more substituents selected from a halogen atom, a C _1-6 -alkoxy group (for example, methoxy group, ethoxy group, propoxy group), 4-methylpiperazinomethyl group and the like. Examples of the substituted aromatic acyl group include a 3,4-dimethylbenzoyl group, a 2-carboxybenzoyl group, and a 4- (4-methylpiperazinomethyl) benzoyl group.

  The sugar residue represented by R in the formula (I) is preferably a monosaccharide or oligosaccharide having a saccharide unit of 1 to 10, particularly 1 to 5, such as glucose, mannose, galactose, glucosamine, mannosamine, galactosamine and the like. Hexasaccharides, pentoses such as arabinose, xylose, ribose, maltose, lactose, trehalose, cellobiose, isomaltose, gentiobiose, melibiose, laminaribiose, chitobiose, xylobiose, mannobiose, sophorose Isomaltotriose, maltotetraose, maltopentaose, mannotriose, manninotriose, etc., and hydrolysates such as starch, cellulose, chitin, chitosan (for example, pharmacopec dextrin, acrodextrin, Ritesshugamu, such as Cerro dextrin), and the like.

  When the compound represented by the formula (I) has a basic functional group such as an amino group or a nitrogen-containing heterocyclic group (for example, a piperazino group), pharmaceutically acceptable salts thereof include, for example, hydrochloride, sulfuric acid Inorganic acid salts such as salt, hydrobromide, nitrate, phosphate, trifluoroacetate, tartrate, citrate, malate, maleate, fumarate, methanesulfonate, benzenesulfone Examples thereof include organic acid salts such as acid salts and toluene sulfonates, and when having an acidic functional group such as a carboxyl group, pharmaceutically acceptable salts thereof include alkali metal salts such as sodium salts. Some compounds may form hydrates, but it goes without saying that their use falls within the scope of the present invention.

  Among the compounds represented by the formula (I), the compound represented by the formula (Ia) or (Ib) is a novel compound and can be produced, for example, as follows.

That is, (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) described in Example 4 of JP-A-5-32580 (Patent Document 5). By reacting tetrahydrothiophen-2-one with benzoyl chloride or 3,4-dimethylbenzoyl chloride in the presence of a base such as triethylamine, in formula (Ia), R ¹ is a benzoyl group or 3,4 -A compound which is a dimethylbenzoyl group can be produced. In addition, the (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one is converted into phthalic acid monot in the presence of dicyclohexylcarbodiimide. -By reacting with butyl ester to obtain a precursor, and then treating with trifluoroacetic acid in dichloromethane, a compound in which R ¹ is a 2-carboxybenzoyl group in the above formula (Ia) is produced. Can do. Further, the (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one is reacted with N- (t in the presence of dicyclohexylcarbodiimide. -By reacting with -butoxycarbonyl) glycine and then deprotecting by treatment with hydrogen chloride gas, the hydrochloride of the compound in which R ¹ is a glycyl group in the formula (Ia) can be produced. .

  Further, the compound represented by the above formula (Ib) is produced by reacting arctigenin with 4- (4-methylpiperazinomethyl) benzoyl chloride dihydrochloride in the presence of a base such as triethylamine. be able to.

  Of the compounds represented by the formula (I), compounds other than the compounds represented by the formula (Ia) or (Ib) are disclosed in, for example, JP-A-5-32580 (Patent Document 5), It can be produced according to the method described in JP-A-5-32659 (Patent Document 6).

For example, in the formula (I), a compound in which R is a C _1-6 -alkyl group is obtained by reacting a compound in which R is a hydrogen atom with a corresponding alkyl halide in the presence of a base such as potassium carbonate. Can be manufactured.

  In the above formula (I), a compound in which R is a sugar residue can be produced by reacting a compound in which R is a hydrogen atom with a corresponding halogenated sugar such as a glycosyl halide. Here, as the halogenated sugar, it is preferable to use a sugar group whose hydroxyl group is protected with a protecting group. In this case, the deprotection reaction may be carried out by a conventional method after the reaction, if necessary.

  To purify the product, a commonly used technique such as column chromatography using silica gel or the like as a carrier or recrystallization using ethyl acetate, acetone, hexane, methanol, ethanol, chloroform, dimethyl sulfoxide, water or the like is used. You can do it. Examples of column chromatography elution solvents include chloroform, methanol, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.

  The β-amyloid production inhibitor of the present invention contains a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “arctigenins”) as an active ingredient, and is effective for Alzheimer's disease. It is useful as a therapeutic agent, a preventive agent, a progression inhibitor, a senile plaque production inhibitor, and an inhibitor of nerve cell loss due to senile plaque deposition.

  Hereinafter, the dosage and formulation of the β-amyloid production inhibitor of the present invention containing archigenin will be described.

  Arctigenins can be administered to animals and humans as they are or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and is appropriately selected and used as necessary, and includes oral preparations such as tablets, capsules, granules, fine granules, powders, and parenteral preparations such as injections and suppositories. It is done.

  In order to exert the desired effect as an oral preparation, it varies depending on the age, body weight, and degree of disease of the patient, but usually 0.1 mg to 2 g as the weight of archigenin in adults divided into several times a day. It is appropriate to take.

  The oral preparation is produced according to a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like.

  In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients. Specific examples of each are as follows.

[Binder]
Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant]
Starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low substituted hydroxypropylcellulose.

[Surfactant]
Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80.

[lubricant]
Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Flowability promoter]
Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

  Arctigenins can also be administered as suspensions, emulsions, syrups, and elixirs, and these various dosage forms may contain flavoring agents and colorants.

  In order to exert the desired effect as a parenteral agent, it varies depending on the age, body weight, and degree of disease of the patient, but is usually intravenous, intravenous drip up to 0.01 to 600 mg as the weight of archigenin in adults. Intravenous injection, subcutaneous injection, and intramuscular injection are appropriate.

  This parenteral preparation is produced according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like as diluents. be able to. Furthermore, you may add a bactericidal agent, antiseptic | preservative, and a stabilizer as needed. In addition, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, the water can be removed by a normal freeze-drying technique, and the liquid preparation can be re-prepared from the freeze-dried product immediately before use. Furthermore, an isotonic agent, stabilizer, preservative, soothing agent and the like may be added as necessary.

  Examples of other parenteral preparations include coating solutions for external use, ointments and the like, suppositories for rectal administration, and the like, and are produced according to a conventional method.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.

[Example 1] (2R, 3R) -3- (3,4-dimethoxybenzyl) -2- {4- [4- (4-methylpiperazinomethyl) benzoyloxy] -3-methoxybenzyl} butyrolactone ( Synthesis of compound number 1)

A 300 ml eggplant flask is charged with 1.99 g (5.3 mmol) of archtigenin and 86 ml of dichloromethane, and then in the presence of 3.8 ml (27.3 mmol) of triethylamine, 4- (4-methylpiperazinomethyl) benzoyl chloride · dihydrochloric acid. 2.93 g (8.5 mmol) of salt was added little by little and allowed to react at room temperature for 24 hours. The solvent of the reaction solution was distilled off under reduced pressure, dissolved in 80 ml of ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution (100 ml × 3) and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (elution solvent, chloroform: ethyl acetate = 5: 1, chloroform: methanol = 10: 1) to give the title compound 2 .49 g (80.0%) was obtained.
Melting point: 58-60 ° C
¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s), 2.59 (12H, m), 3.00 (2H, m), 3.59 (2H, s), 3.75 ( 3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.87 (1H, m), 4.20 (1H, m), 6.52 (1H, d, J = 2.0 Hz), 6.56 (1H, dd, J = 8.1, 2.0 Hz), 6.72 (1H, dd, J = 7.8, 2.2 Hz), 6.79 (1H, d, J = 7.8 Hz), 6.80 (1H, d, J = 2.2 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.47 (2H, d, J = 8) .3 Hz), 8.14 (2H, d, J = 8.3 Hz)

Example 2 Synthesis of (3R, 4R) -3- (4-benzoyloxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (Compound No. 2)

In a 25 ml eggplant flask, (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (JP-A-5-32580 (patented) Compound 519 mg (1.3 mmol) in Example 4 of literature 5) and 5 ml of dichloromethane were added, and then 0.18 ml (1.4 mmol) of benzoyl chloride was added in the presence of 0.25 ml (1.8 mmol) of triethylamine. And allowed to react at room temperature for 1 hour. The reaction solution was washed twice with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 709.7 mg of crude crystals. This was purified by flash column chromatography (elution solvent, hexane: chloroform: acetone = 10: 10: 1) to obtain 569 mg (89.0%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.30-2.60 (3H, m), 2.94-3.24 (5H, m), 3.75 (3H, s), 3.82 (3H , S), 3.85 (3H, s), 6.53 (1H, d, J = 2.2 Hz), 6.58 (1H, dd, J = 8.5, 2.2 Hz), 6.80 (3H, m), 7.07 (1H, d, J = 8.5 Hz), 7.47-7.64 (3H, m), 8.19 (2H, m)

Example 3 (3R, 4R) -4- (3,4-Dimethoxybenzyl) -3- [4- (3,4-dimethylbenzoyloxy) -3-methoxybenzyl] tetrahydrothiophen-2-one (compound Synthesis of number 3)

(3R, 4R) -3- (4-Hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (Japanese Patent Laid-Open No. 5-32580) under a stream of argon in a 50 ml eggplant flask. No. 4 (Patent Document 5), compound described in Example 4) (1.02 g, 2.7 mmol) was dissolved in dichloromethane, triethylamine (0.91 ml, 6.5 mmol), followed by 3,4-dimethylbenzoyl chloride (556 mg). A solution of (3.3 mmol) in dichloromethane was added. Gas was immediately generated, and the reaction solution changed from pale yellow to reddish brown. The mixture was further stirred for 1 hour, and the reaction solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.38 g of crude crystals. This was purified by flash column chromatography (elution solvent, hexane: chloroform: acetone = 10: 10: 1) to obtain 1.14 g (82.7%) of the title compound as a white amorphous substance.
¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 2.35 (3H, s), 2.50-2.60 (3H, m), 2.90-3.21 (5H M), 3.74 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 6.52 (1H, d, J = 2.0 Hz), 6.58 ( 1H, dd, J = 7.8, 2.0 Hz), 6.76 (2H, m), 6.77 (1H, d, J = 7.8 Hz), 7.06 (1H, d, J = 8) .3 Hz), 7.26 (1 H, d, J = 8.1 Hz), 7.91 (1 H, d, J = 8.1 Hz), 7.96 (1 H, s)

[Example 4] (3R, 4R) -3- [4- (2-carboxybenzoyloxy) -3-methoxybenzyl] -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (Compound No. 4) ) Synthesis

(1) A chloroform solution of 1.75 g (7.9 mmol) of phthalic acid mono-t-butyl ester was placed in a 50 ml eggplant flask under an argon stream, stirred in an ice bath, and 1.76 g (8.5 mmol) of dicyclohexylcarbodiimide. Was added. Next, (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (JP-A-5-32580 (Patent Document 5)) ) Compound of Example 4) 2.00 g (5.2 mmol) was added and stirred at room temperature for 4 hours, 363 mg (3 mmol) of 4-dimethylaminopyridine was added, and the mixture was further stirred at room temperature for 1 hour. Thereafter, 500 mg of phthalic acid mono-t-butyl ester in dichloromethane and 500.5 mg of dicyclohexylcarbodiimide were added and reacted at room temperature for 16 hours. An excess amount of ethyl acetate was added to the reaction solution to remove insoluble matters, and the solvent was distilled off under reduced pressure to obtain 4.00 g of a crude product. This was purified by flash column chromatography (elution solvent, hexane: chloroform: acetone = 10: 10: 1) to obtain 1.87 g (61.9%) of the t-butyl ester (precursor) of the title compound. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 2.90-3.22 (6H, m), 3.78 (3H, s), 3.81 (3H, s), 3.85 (3H, s), 6.53 (1H, m), 6.58 (1H, m), 6.77-6.81 (3H, m), 7.18 (1H, d, J = 8.3 Hz), 7.54-7.59 (2H, m), 7.72-7.75 (1H, m), 7.90-7.92 (1H, m)

(2) Into a 100 ml eggplant flask, a solution of 1.87 g (3.2 mmol) of the t-butyl ester (precursor) of the title compound obtained in (1) above in dichloromethane was placed in an ice bath, and trifluoromethane was added in an ice bath. Acetic acid 5 ml (64 mmol) was added little by little and stirred for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 1.77 g (100%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.96 (3H, m), 3.00 (4H, m), 3.25 (1H, dd, J = 5.4, 5.8 Hz), 3.76 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 6.47 (1H, d, J = 2.0 Hz), 6.57 (1H, dd, J = 8) .3, 2.0 Hz), 6.63 (1H, dd, J = 7.8, 1.7 Hz), 6.73 (1H, s), 6.77 (1H, d, J = 8.3 Hz) 7.10 (1H, d, J = 7.8 Hz), 7.63-7.69 (2H, m), 7.91-7.98 (2H, m)

Example 5 Synthesis of (3R, 4R) -4- (3,4-dimethoxybenzyl) -3- (4-glycyloxy-3-methoxybenzyl) tetrahydrothiophen-2-one hydrochloride (Compound No. 5)

(1) A dichloromethane solution of 1.09 g (6.2 mmol) of Nt-butoxycarbonylglycine was placed in a 200 ml eggplant flask under an argon stream, and 1.29 g (6.2 mmol) of dicyclohexylcarbodiimide was added in an ice bath. . After stirring for 10 minutes, (3R, 4R) -3- (4-hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one (JP-A-5-32580 ( 2.00 g (5.2 mmol) of the compound described in Example 4 of Patent Document 5) was added. The reaction was allowed to proceed at room temperature for about 16 hours, an excess amount of ethyl acetate was added to the reaction solution to remove insoluble matters, and the solvent was distilled off under reduced pressure. By purifying 3.36 g of the obtained white amorphous substance by flash column chromatography (elution solvent, hexane: ethyl acetate = 1: 1), Nt-butoxycarbonyl body (precursor) of the title compound. 66 g (93.9%) were obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.20-2.60 (3H, m), 2.90-3.20 (5H, m), 3.75 (3H , S), 3.80 (3H, s), 3.85 (3H, s), 4.20 (2H, br d, J = 5.6 Hz), 6.50 (1H, d, J = 2. 2 Hz), 6.55 (1 H, dd, J = 8.1, 2.2 Hz), 6.71 (1 H, d, J = 8.3 Hz), 6.75 (1 H, br s), 6.77. (1H, d, J = 8.1 Hz), 6.97 (1H, d, J = 8.3 Hz)

(2) Add Nt-butoxycarbonyl (precursor) of the title compound obtained in (1) above and anhydrous ether to a 200 ml eggplant flask and inject hydrogen chloride gas under ice cooling to perform deprotection. It was. The hydrochloride insoluble in ether was collected by filtration and dried under reduced pressure to obtain 1.88 g (75.1%) of the title compound.
Melting point: 105.5-106.3 ° C
¹ H-NMR (CD ₃ OD) δ: 2.20-2.70 (2H, m), 2.80-3.29 (5H, m), 3.30 (2H, m), 3.74 ( 3H, s), 3.76 (3H, s), 3.80 (3H, s), 4.13 (2H, s), 6.60 (1H, s), 6.64 (1H, m), 6.79-6.89 (3H, m), 7.04 (1H, d, J = 8.1 Hz)

[Example 6] Examination of β-amyloid production inhibitory action As a cultured human nervous system cell that overexpresses Alzheimer's disease amyloid precursor protein, Swedish mutant precursor protein (APP695NL) which is one of the causative genes of familial Alzheimer's disease The glial cell line mutation H4 into which was introduced was used.
The test compound was dissolved in dimethyl sulfoxide and diluted with the culture medium at the time of addition.

H4-1NL is evenly spread on a 6-well plate in Dulbecco's Modified Eagle Meduim containing 10% fetal bovine serum + 150 μg / ml hygromycin B, and cultured overnight in a CO ₂ incubator. did.

The supernatant of each well was extract | collected after culture | cultivation, (beta) amyloid (A (beta) 1-40) in a supernatant liquid was quantified using Human Amyloid (beta) (1-40) measurement kit (L) -IBL.
The results (inhibition rate) are shown in Table 1.

Claims (5)

Formula (I):

(In the formula, R represents a hydrogen atom, a C _1-6 -alkyl group, an acyl group or a sugar residue; X represents an oxygen atom or a sulfur atom; Y represents an oxygen atom or a sulfur atom.)
(Beta) amyloid production inhibitor containing the compound shown by these, or its pharmacologically acceptable salt. The β amyloid production inhibitor according to claim 1, wherein, in the formula (I), R is a substituted or unsubstituted C _1-6 -saturated aliphatic acyl group or a substituted or unsubstituted benzoyl group.   The β-amyloid production inhibitor according to claim 1 or 2, which is a prophylactic / therapeutic agent for Alzheimer's disease. Formula (Ia):

(In the formula, R ¹ represents a benzoyl group, a 3,4-dimethylbenzoyl group, a 2-carboxybenzoyl group, or a glycyl group.)
Or a pharmaceutically acceptable salt thereof. Formula (Ib):

Or a pharmaceutically acceptable salt thereof.