WO2008016002A1

WO2008016002A1 - AMYLOID β PRODUCTION REGULATOR CONTAINING PROTON PUMP INHIBITOR

Info

Publication number: WO2008016002A1
Application number: PCT/JP2007/064872
Authority: WO
Inventors: Masayasu Okochi; Shinji Tagami; Masatoshi Takeda; Naohiro Itoh
Original assignee: Osaka University; Juridical Foundation Osaka Industrial Promotion Organization; Shionogi & Co., Ltd.
Priority date: 2006-07-31
Filing date: 2007-07-30
Publication date: 2008-02-07
Also published as: JPWO2008016002A1; TW200817002A

Abstract

It is intended to provide an Aβ production regulator which contains as the active ingredient a compound having a proton pump (H+/K+ATPase) inhibitory effect. The above regulator is useful as a drug for preventing and/or treating neurodegenerative diseases based on Aβ sedimentation such as Alzheimer's disease and Down's syndrome.

Description

Specification

Amyloid production inhibitor containing proton pump inhibitor

Technical field

[0001] The present invention relates to a medicament for suppressing the deposition of amyloid / 3 protein in the nervous system. More specifically, a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof is used as an active ingredient to suppress or remove the deposit of amyloid β in the nervous system. Thus, for example, it relates to a medicament for preventing and / or treating neurodegenerative diseases based on amyloid I deposition such as Alzheimer's disease and Down's syndrome.

Background art

[0002] Amyloid 0 (hereinafter referred to as は β) is a major constituent of senile plaques frequently found in the brain of Alzheimer's disease patients, one of the neurodegenerative diseases. Α Although / 3 is also present in the brain of normal people, it is thought that it is quickly broken down! / It has been found that this protein is produced secondary by 0-secretase and γ-secretase during the metabolism of amyloid precursor protein (/ 3 APP). β APP is normally degraded by α-secretase, in which case Α / 3 is not produced. Αβ has two isoforms, A / 3 1-40 and A / 3 1-42 (43), but they are produced at the metabolic stage of / 3 によって by 0 secretase and γ-secretase, not at the transcriptional level. It is considered. Most of される / 3 produced in the brain is A / 3 1-40, but less soluble A / 3 1-42 (43) is agglomerated. It has been elucidated whether it is deeply involved! / ,!

[0003] In Alzheimer's disease, Aβ aggregates to form insoluble fibers and deposits in the brain to form senile plaques. Α Since / 3 acts as a cytotoxin for nerve cells, / 3 is currently being investigated as a radical treatment method for Alzheimer's disease by controlling the metabolic system of APP and Aβ and suppressing Aβ production. In other words, β-secretase inhibition is one of the most notable methods for inhibiting β production.

A number of 0 secretase inhibitors have already been proposed S. Haas et al. (C. Haass et al.) Is the action of _bafilomycin (BM), a vacuolar (type V) H ⁺ _{-ATP aSe} inhibitor Consider Weeden mutant [Reported that BM suppressed Aβ production in cultured cells incorporating APP!

The Swedish mutation is one of the familial Alzheimer's disease mutations of β APP, which has a high affinity for β-secretase and is known to easily produce Α / 3. A / 3 production in such a culture system Suppression is thought that BM inhibits β-secretase. However, according to the report, however, ΒΜ increased むしろ / 3 production in wild-type cells, and V-type H ⁺ -ATPase inhibitors generally inhibit 0 APP metabolism. I can't say that.

[0004] Generally, V-type ATPase is an ion-transporting ATPase that exists in intracellular membranes such as lysosomes, endosomes, and Golgi bodies and is important for pH control and substance storage in vacuoles. In particular, V-type H + —ATPase is present in many tissues and cells of the human body and is called “the universal proton pump for eukaryotic cells” (Non-patent Document 2), and is involved in the maintenance of various physiological functions. Inhibitors such as conkanamycin and bafilomycin are expected to have many effects such as cancer cell proliferation and metastasis suppression, and the possibility of treating Alzheimer's disease is also mentioned (Patent Document 1).

[0005] Research has also been conducted on the mechanism by which Aβ exhibits toxicity to nerve cells. For example, the treatment of Alzheimer's disease with a depolarization inhibitor has been proposed based on the hypothesis that Α / 3 induces cell membrane depolarization and exhibits cytotoxicity! (Patent Document 2). Omebrazole, which is known as a proton pump inhibitor of gastric parietal cells, is also listed as a candidate drug, but it has a strong inhibitory effect on depolarization. It is described that it suppresses A / 3 production itself. There is also a suggestion!

[0006] Here, the gastric wall cell proton pump is abundant in gastric wall cells, secretes hydrogen ions (H ⁺ ) into the gastric lumen, and transports K + into the wall cells! / H + / K + —ATPase! / Is a type of ion transporting ATPase (P—ATPase) that is generally present in the plasma membrane and is involved in cation transport between the intracellular and extracellular fluids. The selective inhibitor suppresses gastric acid secretion and is widely used as a therapeutic agent for peptic ulcer, and omebrazole is a typical drug. Descriptive power of the above patent publication The effect of omebrazol on mitigating the cytotoxicity of A / 3 cannot be denied! There is no suggestion of a depolarization inhibitory action of the amplifier inhibitor.

Patent Document 1: PCT International Publication No. WO00 / 50589

Patent Document 2: PCT International Publication No. WO03 / 068147

Non-patent literature 1: C. Haass et al., J. Biol. Chem., 270 (11), 6186-6192 (1995) Non-patent literature 2: Finnbour and Harrison, Biochem .J., 324,697- 712 (1997)

Disclosure of the invention

Problems to be solved by the invention

[0007] An object of the present invention is to provide a medicament for preventing and / or treating neurodegenerative diseases based on Aβ deposition such as Alzheimer's disease and Down's syndrome.

The object of the present invention is also to provide a method for suppressing the production of Α / 3 which causes these neurodegenerative diseases.

Means for solving the problem

[0008] The present inventors have found that a proton pump inhibitor used as a therapeutic agent for peptic ulcer unexpectedly reduces A / 3 production in cultured cells. Furthermore, the present invention was completed by confirming that the blood concentration of A / 3 was reduced in wild-type mice administered with a proton pump inhibitor.

The invention's effect

[0009] According to the present invention, not only can it be used as a prophylactic agent to suppress the progression of neurodegenerative diseases such as Alzheimer's disease and Down's syndrome, but it can also treat patients who have already had A / 3 deposition in neurons. It becomes possible.

Brief Description of Drawings

[0010] FIG. 1 is a graph comparing the effects of omebrazol and lansoprazole on A / 3 production in ΗΕΚ293 (ΗΕΚ / β APPswe) cells constitutively expressing β ΑΡΡ Swedish mutation.

[0011] FIG. 2 shows changes in plasma A / 3 concentration when lansoprazole was orally administered to wild-type mice. [0012] FIG. 3 is a graph showing the effects of lansoprazole, tenatoprazole, rabeprazole and omeprazole on A / 3 production in HEK293 (HEK / APPswe) cells constitutively expressing β-Swedish mutation.

BEST MODE FOR CARRYING OUT THE INVENTION

[0013] The present invention provides the following.

(1) Compounds having proton pump inhibitory activity (however, the following compounds:

[Chemical 1]

(Except hereinafter referred to as Compound 1))

Alternatively, an amyloid 0 production inhibitor, comprising a pharmaceutically acceptable salt thereof or a solvate thereof.

(1 ') An amyloid / 3 production inhibitor characterized by containing a proton pump inhibitor (except omebrazole).

[0014] (2) Formula (I):

(Where A is

And [0015] X ¹ and X ² are each independently CR ⁴ or N;

R ¹ is lower alkyl, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy or substituted! /, May / !, phenylamino,

R ² is a lower alkoxy, a halogeno lower alkoxy or a heterocyclic group,

R ³ is lower alkyl,

R ⁴ is hydrogen, lower alkyl, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, or has a substituent! /, May! /, Phenolamino,

n, m and p are each independently an integer of 0 to 3.

(Except for compound 1)

Or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the amyloid / 3 production inhibitor is characterized by comprising:

[0016] d) Lansoprazole, nontofu. Pantoprazole, esomepfuzo esomeprazoie, fuhepufuzonole rabeprazoie), reno pfuzano revaprazan, ilaprazole, tenatoprazole, CS-526 or a pharmaceutically acceptable salt thereof An amyloid 0 production inhibitor comprising the solvate of

(4) An amyloid 0 production inhibitor comprising a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.

(5) The amyloid β production inhibitor according to any one of (1) to (4) above, which is a therapeutic agent for Alzheimer's disease.

[0017] (6) A method for suppressing amyloid 0 production, comprising administering a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.

(6 ') Amyloid characterized by administration of a compound having a proton pump inhibitory effect (except for Compound 1) or a pharmaceutically acceptable salt thereof or a solvate thereof (except for omebrazole) / 3 production suppression method.

(7) a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof, or A method for treating Alzheimer's disease, comprising administering these solvates.

(7 ′) A method for treating Alzheimer's disease, comprising administering a compound having a proton pump inhibitory effect (excluding compound 1), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(8) Amyloid (Use of a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof for the production of a medicament for suppressing production.

(8 ') A compound having a proton pump inhibitory action (except for compound 1) or a pharmaceutically acceptable salt thereof or a solvate thereof (but omebrazole) for the manufacture of a medicament for suppressing amyloid / 3 production Use).

[0018] (9) Use of a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for the treatment of Alzheimer's disease.

(9 ′) Use of a compound having a proton pump inhibitory action (except for compound 1) or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for the treatment of Alzheimer's disease.

[0019] The Aβ production inhibitor of the present invention comprises a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. Here, ぅ, a compound having an inhibitory action on the proton pump, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is a neurological compound in which Α / 3 is deposited or A / 3 may be deposited in the future. H + / K + -ATPase present on the cell membrane of vesicles, which is an inhibitor of ATPase that plays an important role in maintaining homeostasis of ionic environment inside and outside the cell.

[Chemical 4

(Ri

[0020] (where A is

[Chemical 5]

And

[0021] X ¹ and X ² are each independently CR ⁴ or N;

R ² is a lower alkoxy, a halogeno lower alkoxy or a heterocyclic group,

R ³ is lower alkyl,

R ⁴ is hydrogen, lower alkyl, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy or has a substituent! /, May! /, Phenylamino, provided that compound 1 is except)

Or a pharmaceutically acceptable salt thereof, or a solvate thereof. Here, when n or m is 2 or more, a plurality of R 1 or R ² are different from each other! /.

[0022] Preferably, in the above formula (I), n is 2 or 3, R ¹ is lower alkyl, lower alkoxy, halogeno lower alkoxy or lower alkoxy lower alkoxy, and A is

[Chemical 6]

Wherein m is 0 or 1, R ² is lower alkoxy, X ¹ is CH, and X ² is CH or N (except for compound 1) or a pharmaceutically acceptable product thereof Or a solvate thereof.

Here, “lower alkyl” means carbon number;! To 10, preferably 1 to 6, more preferably Or straight-chain or branched alkyl having 1 to 3 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentinole, isopentinole, neopentinole, hexinole , Isohexynole, n-heptinole, isoheptyl, n-octyl, iso-octyl, n-nonyl, n-decyl and the like. Particularly preferred is methyl or ethyl.

The lower alkyl part of “lower alkoxy”, “halogeno lower alkoxy”, “hydroxy lower alkoxy”, “lower alkoxy lower alkoxy” and “lower alkoxycarbonyl” is the same as the above “lower alkyl”.

“Halogen” includes F, Cl, Br, and I.

The halogen part of “halogeno lower alkoxy” is the same as the above “norogen”.

Examples of the substituent of “optionally substituted phenylamino” include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, and acyl.

[0025] "Asil" includes aliphatic asil and Caroyl having 1 to 7 carbon atoms. Specific examples include honoreminole, acetyl, propionyl, butyryl, isobutyryl, valeryl, bivaloyl, hexanoyl, attalyloyl, propioroyl, methacryloyl, crotonol and benzoyl.

[0026] "Heterocyclic group" includes a heterocyclic group having one or more heteroatoms in the ring of which O, S and N forces are also arbitrarily selected, specifically pyrrolyl, imidazolyl, Pyrazolyl, Pyridinore, Pi !; Dajini, Pi !; ; Azo! ; ; ; 5- to 6-membered heteroaryl such as nore, isoxazolyl, oxazolyl, oxazazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and chenyl; indolyl, isindolyl, indazolyl, indolizinyl, indolinoline, isoindolinyl, quinolyl, isoquinolinyl Phthalajuril, quinazolinyl, naphthyridinyl, quinoxalinyl, purininole, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolinole, benzisoxazolyl, benz axazolyl, benz axadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl Benzofuryl, benzocenyl, benzotriazolinole, imidazopyridinole, pyrazo Down, birds § Zoro pyridyl, Bicyclic condensed heterocyclic groups such as imidazothiazolyl, birazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine, tetrahydrobenzozoenyl Carbazolyl, atalidinyl, xanthur, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, etc .; condensed ring heterocyclic groups; Pyrrolidininoles, pyrrolininoles, imidazo 'lisininoles, imidazo' lininoles, pyrazo 'lidininoles, pyrazo' lininoles, piperidinoles, piperazunoles, monoreholinoles, monoreforinos , Thiomonoreforinole, thiomonoreforino, dihydropyridinole, dihydrobenzimidazolyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydrobiranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroase Includes non-aromatic heterocyclic groups such as pinyl, tetrahydrodiazepinyl and the like. A 5- to 6-membered heteroaryl or non-aromatic heterocyclic group is preferable.

[0027] Pharmaceutically acceptable salts include, in the case of acid addition salts, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; Acid salts, acetates, propionates, lactates, maleates, fumarate, tartrate, malates, citrates, ascorbates, etc .; for example, methanesulfonate, isethionate Examples thereof include sulfonates such as acid salts, benzenesulfonates, p-toluenesulfonates; acidic amino acids such as aspartate and glutamate. In the case of a salt addition salt, for example, mention may be made of alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and basic amino acid salts such as arginine and lysine. .

[0028] Compound (I) may be a solvate such as water, acetonitrile, ethyl acetate, methanol, ethanol or the like. The solvation number of the solvate of the compound of the present invention can usually vary depending on the synthesis method, purification method, crystallization conditions, etc., but is, for example, in the range of 1 to 5 molecules per molecule of the compound.

[0029] This compound (I) is produced, for example, by the method shown below.

Method A [Chemical 7]

(la)

(In the formula, Y is a leaving group, and other symbols are as defined above.)

[0030] A known compound or a compound (ii) or a salt thereof obtained from a known compound by a conventional method, and a compound (III) or a salt thereof, in a suitable solvent, from about o ° c to around the boiling point of the solvent, preferably Compound (IV) can be obtained by reacting at about 20 ° C. to about 80 ° C. for about 5 minutes to about 24 hours, preferably about 30 minutes to about 3 hours. Examples of the leaving group Y of compound (III) include halogens such as chlorine and bromine, aliphatic sulfonyloxy groups such as methanesulfonyloxy group, and aromatic sulfonyloxy groups such as p-toluenesulfonyloxy group. . Further, the salts of the compounds (I I) and (III) have the same meaning as the above-mentioned “pharmaceutically acceptable salts”. Examples of the solvent include methanol, ethanol, dimethylformamide, DMSO, tetrahydrofuran, or a mixture thereof.

[0031] This reaction may be carried out in the presence of a suitable base as required. Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N, N-dimethyla Nilin, pyridine, sodium methoxide, sodium ethoxide and the like can be mentioned. About 1 to 10 equivalents, preferably about 1 to 4 equivalents, may be used with respect to the substrate.

[0032] The target compound (la) is obtained by subjecting the obtained compound (IV) to an oxidation reaction. The oxidation reaction is not particularly limited as long as it is a commonly used reaction, and using an appropriate oxidizing agent, in an appropriate solvent under ice-cooling to about 80 ° C, preferably about 0 ° C to 20 ° C, about 5 The reaction may be performed for about minutes to about 24 hours, preferably about 5 minutes to about 3 hours. Examples of the oxidizing agent include metachloroperbenzoic acid, peracetic acid, hydrogen peroxide, chromic acid, manganese dioxide, sodium periodate, and the like. About ;! to 3 equivalents, preferably about 1 to; 1. Use 5 equivalents That's fine. As the solvent, tetrahydrofuran, dioxane, dimethylformamide, DMSO, dichloromethane, water, or a mixture thereof may be used.

[0033] Method B

[Chemical 8]

(V) (VI) (lb)

(In the formula, Y is a leaving group, and other symbols are as defined above.)

[0034] Compound (V) or a salt thereof and Compound (VI) or a salt thereof in a suitable solvent at about 0 ° C to around the boiling point of the solvent, preferably at about 20 ° C to about 80 ° C, for about 5 minutes. It is possible to obtain the compound (lb) by reacting for about 24 hours, preferably about 1 hour to about 5 hours. Examples of the leaving group Y of compound (VI) include halogens such as chlorine and bromine, aliphatic sulfonyloxy groups such as methanesulfonyloxy groups, and aromatic sulfonyloxy groups such as p-toluenesulfonyloxy groups. . The salts of the compounds (V) and (VI) are the same as the pharmaceutically acceptable salts described above. Examples of the solvent include dichloromethane, dimethylformamide, acetone, acetonitrile, DMSO, tetrahydrofuran, or a mixture thereof.

[0035] This reaction may be carried out in the presence of an appropriate base as necessary. Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N, N-dimethyla Nilin, pyridine, sodium methoxide, sodium ethoxide and the like can be mentioned. About 1 to 10 equivalents, preferably about 1 to 4 equivalents, may be used with respect to the substrate. In both methods A and B, when a functional group that hinders the reaction is present in compound (I), it may be protected in advance by a known method if desired, and then deprotected after completion of the reaction.

[0036] When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these are also included as the compound of the present invention, and are known per se known synthesis methods and separation methods. Thus, each can be obtained as a single product. For example, when compound (I) has an optical isomer, an optical isomer resolved from the compound is also included in the compound of the present invention. The optical isomer can be produced by a method known per se. Specifically, an optically active synthetic intermediate is used, or a final racemic mixture is prepared by a conventional method. To give an optical isomer.

[0037] As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like described in detail below are used.

1) Fractional recrystallization method

Racemates and optically active compounds (for example, (+)-mandelic acid, (1) mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (1) -1 -phenethylamine , Cinchonine, cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step.

[0038] 2) Chiral column method

In this method, the racemate or its salt is separated on a column for separation of optical isomers (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as TSKgel ENANTIO— OVM (manufactured by Tosoichi Co., Ltd.) or the CHIRAL series manufactured by Daicel Chemical Industries, Ltd., and water, various buffer solutions (for example, phosphorus Acid buffer solution) and organic solvent (e.g. hexane, ethanol, methanolol, isopropanol, acetatenitrorole, trifanoleoacetic acid, jetylamine, etc.)

The optical isomers are separated. Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

[0039] 3) Diastereomer method

The racemic mixture is converted into a diastereomer mixture by chemical reaction with an optically active reagent, and this is converted into a single substance through normal separation means (for example, fractional recrystallization, chromatography, etc.), followed by hydrolysis reaction. In this method, an optical isomer is obtained by separating an optically active reagent moiety by chemical treatment such as. For example, when the compound of the present invention has hydroxy or 1,2 secondary amino acid in the molecule, the compound and an optically active organic acid (for example, (-)-ΜΤΡΑ [α-methoxymono α- (trifluoromethyl) Diastereomers in the form of esters or amides can be obtained by subjecting them to a condensation reaction. On the other hand, when the compound of the present invention has a carboxyl group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Separated 'One is converted to the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis.

[0040] Further, as the compound having a proton pump inhibitory action of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof, a gastric acid secretion inhibitor used as a therapeutic agent for peptic ulcer is preferably used. can do.

Specifically, omebrazole (om mark razole; U.S. Pat. Nos. 4,255,431 and 6,166,213), lansoprazole; U.S. Pat. No. 4,628,098, U.S. patent, pantoprazole; U.S. Pat. No. 4758579), Esomeprazole (esom sign razole; U.S. Patent 47 38974), Rabebrazole (rab sign razole; U.S. Patent No. 5045552), Revaprazan (revapr azan; U.S. Pat. No. 5750531, No. 6252076, No. 5990311) Iloprazole (¾ ₂₀ 16; US Patent No. 5703097), Tenatoprazole (US Pat. No. 4808596), etc., AGN-201904, and pyropyridazine derivatives such as CS-526 (US Patent No. 6063782), etc. These can be easily obtained based on the description of the patent gazette described together, and other pharmaceutically acceptable salts or solvates are also preferably used. And leave by force.

[0041] The compound (I) of the present invention also contains tautomers as described below, for example.

[Chemical 9]

[0042] The A / 3 production inhibitor of the present invention is effective for treating or preventing a pharmaceutical composition, particularly a neurodegenerative disease based on A / 3 deposition. Examples of such diseases include Alzheimer-type dementia (Alzheimer's disease, Alzheimer-type senile dementia, etc.), Down's syndrome, memory impairment, prion disease (Kreuzfeld 'Jakob's disease, etc.) Cerebral amyloid angiopathy, other degenerative dementia, mixed dementia with vascular degeneration, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with cortical basal ganglia degeneration, small diffuse Lewy Body type Alzheimer's disease, age-related macular degeneration, parki Nonson disease, amyloid angiopathy and the like. Preferably, it may be formulated for oral or parenteral administration in order to suppress the progression of Alzheimer's dementia, especially Alzheimer's disease, or for therapeutic purposes.

[0043] In the case of oral administration, the Aβ production inhibitor of the present invention is an ordinary preparation such as a solid preparation such as a tablet, powder, granule or capsule; a liquid agent; an oily suspension; or a syrup or elixir. It can also be used as a liquid dosage form such as an agent or any dosage form. In the case of parenteral administration, it can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.

[0044] The formulations of the present invention are manufactured by combining (eg, mixing) a therapeutically effective amount of a compound with a pharmaceutically acceptable carrier or diluent, in which case the well-known and readily available ingredients Is manufactured by a known method.

In preparing the pharmaceutical compositions of the invention, the active ingredient is mixed with the carrier, or diluted with the carrier, or placed in a carrier that is in the form of a capsule, sash, paper, or other container. . When the carrier acts as a diluent, the carrier is a solid, semi-solid, or liquid material that acts as a medium, such as tablets, pills, powders, mouthpieces, elixirs, suspensions, emulsions, Can be made into solutions, syrups, aerosols (solids in liquid media), ointments, eg containing up to 10% active compound.

[0045] Any suitable carrier known to those skilled in the art can be used for this formulation. In such formulations, the carrier is a solid, liquid, or a mixture of solid and liquid. For example, the compound of the active ingredient is dissolved in 4% dextrose / 0.5% sodium quenate aqueous solution for intravenous injection. Solid formulations include powders, tablets and capsules. A solid carrier is one or more substances that can also serve as a flavoring agent, lubricant, solubilizer, suspending agent, binder, tablet disintegrant, or capsule. Tablets for oral administration consist of corn starch, alginic acid and other disintegrants, and / or binders such as gelatin, acacia, and lubricants such as magnesium stearate, stearic acid, talc, Contains suitable excipients such as ratatoses and calcium phosphate.

[0046] In powders, the carrier is mixed with a finely divided active ingredient, and is finely ground solid. Is the body. In tablets, the active ingredients are mixed in the appropriate proportions with a carrier having the necessary binding properties and consolidated into the desired shape and size. Powders and tablets contain from about 1 to about 99 weight percent of the active ingredient of the present invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, ratatoose, pectin, dextrin, starch, gelatin, tragacanth gum, methinoresenololose, sodium strength noroxymethinoresenololose, low melting wax, Cocoa butter.

[0047] Liquid formulations include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent, or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for example an aqueous propylene glycol solution. Other compositions may be made by spraying the active ingredients with aqueous starch, sodium-powered l-poxymethylcellulose solution, or a suitable oil.

The dose of the compound in the present invention varies depending on the administration method, the patient's age, body weight, condition, and the type and degree of the disease. Usually, in the case of oral administration, about 0.1 mg to 10,000 mg per day for an adult; Preferably, about 0.5 mg to 3000 mg may be administered in divided portions if necessary. In the case of parenteral administration, about 0.1 mg to 3000 mg, preferably about 0.5 mg to;

Example 1

[0048] The effects of the present invention were tested as in the following examples.

Test example 1

β 定量 Quantification of A β in ΗΕΚ293 (ΗΕΚ / β APPswe) cells constitutively expressing the Swedish mutation (comparative efficacy of omeprazole and lansoprazole)

The ΗΕΚ293 (ΗΕ / β APPswe) cell line, which expressed the β ΑΡΡ Swedish mutation constitutively, was cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 10% calf serum and 200 g / mL hygromycin. Cells were seeded at a density of 2 × 10 ⁴ cells / well in a 96-well polystyrene culture dish at 200 LI well. At approximately 70% confluence, the compound was added at the same time as the medium change. Lansoprazole (50 mM stock solution in DMSO) at a final concentration of 50 M and omebrazole (lOO mM stock solution in DMSO) at a final concentration of 300 μm. Added to M and mixed well.ー晚 (about 16 hours) After culturing at 37 ° C, 100 μL of the culture supernatant was collected and A / 340 was measured using the HTRF method (Nippon Schering # 62B40PEC). The method was performed according to the manufacturer's recommended protocol (the method described in the package insert). However, the A β standard was attached to the Biosource Α β 40 Eliser Kit (# ΚΗΒ 3482)! The results are the same as the applied DMSO concentration of these compounds. 0.5% DMSO in the culture supernatant 濃度 / 3 concentration as a control, not as a percentage (% of control) relative to this.

[0049] Cell survival was evaluated using the WST method. 10 L of WST reagent (Nacalai Tesque # 07553-44) was added to the 96-well polystyrene culture dish after the culture supernatant was collected for Aβ measurement, and cultured at 37 ° C for 3 hours. The measurement was performed according to the manufacturer's recommended protocol (the method described in the package insert). The results are shown as a percentage (% of control,% of control) to the survival rate in culture supernatant of 0.5% DMSO treatment. As a result, both lansoprazole and omebrazole inhibited A / 3 production under conditions different from cytotoxicity. Lansoprazole showed the same effect at a lower concentration than omebrazole, and lansoprazole was found to be extremely strong / active compared to omebrazole (see Fig. 1).

[0050] Test Example 2

Effects on plasma Aβ content in wild-type mice (CD-I)

Wild-type mice (CD-1 (ICR), male, 8 weeks old) were purchased from Nippon Chisuriba Corporation. 0.5% methylcellulose was used as the solvent, and the lansoprazole-administered group (each n = 8) was orally administered at 100 mg / kg or 200 mg / kg, and laparotomy was performed under halothane anesthesia 2 hours after administration. Blood was collected from a vein. In the lansoprazole non-administration group (base, n = 8), 0.5% methylcellulose was orally administered at 10 mL / kg, and blood was collected 2 hours after administration. Blood was collected with a 1 mL syringe containing 10 L of 0.25 M EDTA and collected in a 1.5 mL Eppendorf tube. Centrifugation was performed at 9600 g at 4 ° C for 10 minutes, and the supernatant was collected to prepare plasma. Plasma was stored frozen at -80 ° C until Aβ measurement. Aβ measurement was performed using Wako Pure Chemical Industries Ltd. β 40 Eraser Kit (# 294-625901). The plasma sample is diluted 4 times with the standard diluent supplied with the ELISA kit, and the manufacturer's recommended protocol (method described in the package insert) Went according to. The results are shown as a percentage of the plasma A / 3 content of the compound non-administered group (base) (% of control,% of control).

As a result, lansoprazole 200 mg / kg, a significant decrease in plasma-containing A / 3 was observed in the group 2 hours after administration [p = 0.0241, Dunnett's test] (see Fig. 2).

[0051] Test Example 3

β 定量 Quantification (IC value measurement) in HEK293 (HEK / APPswe) cells constitutively expressing β ΑΡΡ Swedish mutation

50

Omebrazole was purchased from Wako Pure Chemical Industries, and lansoprazole was purchased from Sigma. Tenatov. Lazonole and Rabeprazonole were purchased from 3B medical systems.

β ΑΡΡ Swedish mutation constitutive expression ΗΕΚ293 (HEK / APPswe) cell line was cultured in Dulbecco's modified Eagle medium (DMEM) containing 10% calf serum and 200 ag / mL hygromycin. Cells were seeded at 2 mL I well in a 6-well polystyrene culture dish at 1.5 × 10 ⁵ cells / well. At approximately 70% confluence, the compound was added at the same time as the medium was changed. Each test compound (50 mM stock solution in DMSO) was added to a final concentration of 500, 300, 180, 108, 64.8, 38.88 μM and mixed well. -晚 (about 16 hours) After culturing at 37 ° C, 1 mL of the culture supernatant was collected, and A / 340 was measured using the HTRF method (Japan Schering # 62B40P EC). The method was performed according to the manufacturer's recommended protocol (the method described in the package insert). However, as the A β standard, the standard attached to Biosource A / 3 40 Eliza Kit (# KHB3482) was used. The results were expressed as percentages (% of control,% of control), with the A / 3 concentration in the culture supernatant of 1% DMSO being the same as the applied DMSO concentration of these compounds as the control.

[0052] Cell survival was evaluated using the WST method. A Twenty WST reagents (Nacalai Tesque # 07553-44) were added to a 6-well polystyrene culture dish after collecting the culture supernatant for measurement, and cultured at 37 ° C for 3 hours. The measurement was performed according to the manufacturer's recommended protocol (the method described in the package insert). The results are shown as a percentage of the survival rate in the culture supernatant treated with 1% DMSO (% of control). The IC value for A / 3 production inhibition of each test compound was calculated. As a result, it was confirmed that each test compound suppressed A / 3 production under conditions different from cytotoxicity, and that lansoprazole, tenatoprazole, and rabebrazol showed stronger! / ヽ Aβ production inhibitory activity than omebrazole. (See Table 1 and Figure 3).

[table 1]

Example 1 Component Compound represented by formula (I) 10 mg

Lactose 90 mg

Microcrystalline cellulose 30 mg

CMC-Na 15 mg

Magnesium stearate 5 mg

Manufacture tablets containing less than 150 mg of ingredients.

Pass the compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethyl cellulose sodium salt) through a 60 mesh sieve and mix. Mix the powdered magnesium stearate to obtain a mixed powder for tableting. Directly press this mixed powder to obtain a 150mg tablet.

Ingredient Compound represented by formula (I) 3 mg

Nonionic surfactant 15 mg

Purified water for injection 1 ml

[0054] Example 2

The following ingredients are heated and mixed and then sterilized to give an injection.

Industrial applicability

[0055] The present invention is useful as a medicament for preventing and / or treating neurodegenerative diseases based on Aβ deposition such as Alzheimer's disease and Down's syndrome.

Claims

Claims Compounds having proton pump inhibitory activity (however, the following compounds:

[Chemical 1]

except for)

Formula (I):

[Chemical 2]

(Where A is

And

X ¹ and X ² are each independently CR ⁴ or N;

R ² is a lower alkoxy, a halogeno lower alkoxy or a heterocyclic group,

R ³ is lower alkyl, R is hydrogen, lower alkyl, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy or having a substituent! /, May! /, Phenolamino,

n, m and p are each independently an integer of 0 to 3.

However, the following compounds:

[Chemical 4]

except for)

[3] lansoprazole, pantoprazoie, esomephun

(esomeprazole), fubefuzonole rabeprazole, renopufuken (revaprazan, ifapfol (ilaprazole), tenatoprazole, CS-526 or a pharmaceutically acceptable salt thereof or a solvate thereof An amyloid / 3 production inhibitor characterized by the above.

[4] An amyloid 0 production inhibitor comprising a compound having a proton pump action or a pharmaceutically acceptable salt thereof or a solvate thereof.

[5] The amyloid 0 production inhibitor according to any one of claims 1 to 4, which is a therapeutic agent for Alzheimer's disease.

[6] A method for suppressing amyloid / 3 production, comprising administering a compound having a proton pump inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[7] A method for treating Alzheimer's disease, comprising administering a compound having a proton pump inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[8] Amyloid (Use of a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof for the production of a medicament for suppressing production. [9] Use of a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for the treatment of Alzheimer's disease.