TW200817002A - Amyloid-β production inhibitor comprising a proton pump inhibitor - Google Patents

Abstract

An inhibitor for production of amyloid β comprising a compound having an inhibitory activity on the proton pump (H+/K+ ATPase) is provided. The present invention is effective on preventing and/or treating neurodegenerative diseases such as Alzheimer's disease or Down syndrome based on the deposition of amyloid β.

Description

200817002 IX. Description of the invention: [Technical Field] The present invention relates to a medicament for inhibiting precipitation of a starch-like beta protein in a nerve system. More specifically, it relates to a drug having a proton pump inhibitory effect or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, which inhibits precipitation of a starch-like β in the nervous system. Or remove the precipitate to prevent and/or treat neurodegenerative diseases caused by precipitation of starch beta such as Alzheimer's disease and Down's disease. [Prior Art] Background Art Starch-like β (hereinafter referred to as Αβ) is a major constituent of plaques commonly found in the brain of patients with Alzheimer's disease (one of neurodegenerative diseases). It is generally believed that Αβ is also present in the brain of a normal person, but it is rapidly decomposed. It has been gradually found that such a protein is incidentally produced by the β secretase and γ secretase in the metabolism of the starch-like precursor protein (βΑΡΡ). Although βΑΡΡ is usually decomposed by α-secretase, Αβ is not produced at this time. There are two kinds of isomers such as Αβ1-40 and Αβ1-42(43) in Αβ, but not in the transcription level, but in the metabolic phase of βΑρρ 20 through the β-secretase and γ-secretase. The Αβ produced in the brain is almost all Αβ1-40, but the insoluble Αβ1-42(43) is easier to aggregate and precipitate. So far, it has not been known which is closely related to the pathological state. Alzheimer's disease is caused by agglutination of Αβ to form insoluble fibers, which in turn form an age spot in the brain. Αβ exerts a cytotoxic effect on nerve cells, therefore, 5 200817002, is now exploring ways to control the metabolic system of βΑΡΡ and Αβ and inhibit the production of Αβ, as a radical treatment of Alzheimer's disease, and β-secretase inhibition It is one of the most attractive methods for inhibiting Αβ production. A variety of beta-secretase inhibitors have been proposed, and Hahas et al. (C Haass 5 et al.) studied the action of liquid cell type (V-type) H +-ATPase inhibitors of Bafilomycin (BM). In the cultured cells of the Swedish-type variation βΑρρ, it was reported that ΒΜβ production was inhibited by ΒΜ (see Non-Patent Document 1). The so-called Swedish type variant βΑΡΡ is a familial Alzheimer's disease variant. One is known to have a high affinity for β-secretase and is prone to produce Αβ. In this 10-culture system, inhibition of Αβ production is considered to be ΒΜ ΒΜ inhibition. Caused by β-secretase. However, according to this report, the production of Αβ is increased in wild-type cells. It is difficult to say that V-type H + -ATPase inhibitors normally inhibit the metabolism of β ΑΡΡ. I and Lu' V-type ATPase are present in the intracellular membrane of lysosome (iyS0S0me), endosome 15 (end〇some), Golgi body, etc., and Ph control of a φ species in liquid cells And ion storage ATPase, which is very important for material storage. In particular, the v-mine, the gossip, is even called the "universal proton pump for eukaryotic cells" (Non-Patent Document 2), which exists in many tissues and cells of the human body, and maintains various physiological physiology. Functionally related, therefore, it is expected that its 20 inhibitors (such as the discussion of (4) called coffee and bafilomycin) have four effects in inhibiting cancer cell proliferation and metastasis, and also mention the possibility of treatment of Alzheimer's disease ( Patent Document 1). In addition, the mechanism by which Αβ exhibits toxicity to nerve cells is also under discussion in the study, for example, 'deduction of cell membrane depolarization with reference to Αβ. Table 6 200817002 ' 5 sees the hypothesis of cytotoxicity, and then proposes depolarization inhibitors, treatment Alzheimer's disease (Patent Document 2). Omeprazole, which is known to be a proton fruit inhibitor of gastric parietal cells, is also listed as a candidate drug, but its inhibitory effect on depolarization is not strong. It has never been recorded or implied that it can be inhibited. The production of Ap. • 5 Here, the proton pump of the parietal cells means: more in the private field. The celestial cells in the lunar wall secrete hydrogen ions (Η+) into the gastric cavity, and transport the Κ+ into the parietal cells. +/κ+ -ATPase; In general, it exists in the plasma membrane, and the ion transportability associated with the cation transport between the intracellular fluid and the extracellular fluid is ATPase (P-ATPase). Omegaprazole is a representative drug because it is widely used as a therapeutic agent for peptic ulcer because it inhibits gastric acid secretion. From the records of the above-mentioned patent publications, although it is impossible to deny that the Omera 0 sitting has the effect of alleviating the cytotoxicity of Αβ, it does not imply the depolarization inhibition of the proton pump inhibitor used as a therapeutic agent for peptic ulcer. effect. [Patent Document 1] PCT International Publication No. WO 00/50589 [Patent Document 2] PCT International Publication No. W003/068147® [Non-Patent Document 丨] Haas et al. (C. Haass et al.), J. Biol .Chem., 270(11), 6186-6192 (1995). - [Non-Patent Document 2] Finbour and 20 Harrison, Biochem. J., 324, 697_712 (1997) C invention DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION The object of the present invention is to provide a medicament which can prevent and/or treat 7 200817002 心 ! 域 域 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本disease. Another month - the purpose is to provide a method for the cause of sexual diseases, that is, to suppress hyperplasia = 手段 means of solving the problem. Protons have unexpectedly been found to be _ _ _ therapeutic drugs: sub-pump inhibitors can reduce Αβ production in cultured cells. (4) - The concentration of hemostatic in the wild type mice in which the L W and the proton pump inhibitor were decreased was determined, and the present invention was completed.

According to the effect of the invention, the sapphire n can be used not only as a preventive for inhibiting neurodegenerative diseases such as A (Si) and Down syndrome, but also as a patient who has produced Αβ precipitation in the nerve cell industry. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 compares the effects of omeprazole 15 and lansoprazole on Deng production in HEK293 (HEK/pAPPswe) cells, and the HEK293 (HEK/pAPPswe) cells consistently exhibit βΑρρ Sweden Type variation. Fig. 2 is a graph showing changes in the concentration of Αβ in the plasma of wild type mice when they were orally administered with a Lanso. Figure 3 compares the effects of lantra 20, tacrolimus, rabeprazole and omeprazole on Αβ production in HEK293 (HEK/APPswe) cells' and the HEK293 (HEK/APPswe) Cells consistently exhibit βΑΡΡ Swedish variants. BEST MODE FOR CARRYING OUT THE INVENTION 8 200817002 The present invention is to provide the following. (1) A starch-like β-production inhibitor containing a compound inhibiting the ', and the bell-pump pump (but the following compound (hereinafter referred to as a salt acceptable for the compound n or a solvate thereof) [Chemical 1 ^ ^ θ ^ cut 1) except) or its pharmaceuticals

Sub-pump inhibitor (but (1,) a class of powdered beta-producing inhibitors, except for the mass Omega σ sitting). 10 (2) - a type of starch-producing inhibitor containing a compound represented by hydrazine, or a salt thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(I) where, [Chemical 3]

Or ">· X1 are each independently CR4 or N; are lower alkyl, lower alkoxy, halogenated lower alkoxy, hydroxy 9 15 200817002 lower alkoxy 2 lower alkoxy lower alkoxy or Optionally, a phenylamine group having a substituent; R 2 is a lower alkoxy group, a halogenated lower alkoxy group or a heterocyclic group; R 3 is a lower alkyl group; 5 r 4 is hydrogen, a lower alkyl group, a lower alkoxy group, a halogenated lower stage An alkoxy group, a trans-lower alkoxy group, a lower alkoxy lower alkoxy group or an optionally substituted phenylamine group; and n, m and p are each independently an integer of 〇~3; Except for Compound 1. 10 (3) A starch-like P production inhibitor comprising lansoprazole, pant〇praz〇le, esomeprazole, rabeprraz〇le, Revaprazan, ilapraz®, tenatopmzole, CS-526 or such pharmaceutically acceptable salts or such solvates. (4) A starch-like β production inhibitor comprising a compound having a proton pump action or a pharmaceutically acceptable salt thereof or a solvate of a scale. (A) A starch sputum production inhibitor according to any one of the above (1), which is a therapeutic agent for Alzheimer's disease. (6) A method for inhibiting the production of a starch-like ρ, which comprises administering a compound having a proton fruit inhibitory effect or a pharmaceutically acceptable salt thereof or a solvate agent thereof. A method for producing (6')-inhibiting __, which is characterized in that a compound having a proton fruit inhibitory effect (except for compound 1) or a pharmaceutical thereof can be used in the case of Yancheng County (7), etc. Solvate (but outside Omera (10)). There is a proton pump away from the branch, and a solvate is administered. a compound for use thereof or an acceptable salt thereof, or a method for treating a proton seed, Alzheimer's disease, characterized in that the administration can be carried out as an inhibitory compound (except for Compound 1) or Pharmaceutically linked to a salt or a solvate of the same.

A compound which is inhibited by a salt or a metalloid pump or a pharmaceutically acceptable pharmaceutical composition thereof: the use of the solvate of the medicinal compound is used as a salt or a solvate thereof To manufacture drugs for inhibiting the production of sputum-like powder β. (8) a compound having a proton-inducing inhibitory effect (except for compound i) or a pharmaceutically acceptable salt thereof or a solvate of a material (but the use of Ogilvy & Mather 15) is the use of the compound or its pharmaceutically acceptable Accepting a salt or a solvate of the above to produce a drug for inhibiting the production of a starch-like β. ', (9) a compound having a proton pump inhibitory effect or a pharmaceutically acceptable salt thereof or the like The use of the solvate is the use of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for the treatment of Alzheimer's disease. (9) A proton pump inhibition The use of a compound (other than compound 1) or a pharmaceutically acceptable salt thereof, or a solvate thereof, is produced using the compound or a pharmaceutically acceptable salt thereof or a solvate thereof. A drug for treating Alzheimer's disease. 11 200817002 The Αβ production inhibitor of the present invention is a compound having a proton-inhibiting effect or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. .to a compound having a proton fruit inhibitory effect or a pharmaceutically acceptable salt or a solvate agent thereof, or a solvate agent thereof, refers to a drug which inhibits 5 drugs, the A-line-mATPase, which is present in the tree or killed In the future, there will be a cell membrane on the nerve cells of Αβ-precipitate, and play an important role in maintaining the characterization of the ionic environment inside and outside the cell. For example,

The aromatic heterocyclic compound represented by the following formula (I), a pharmaceutically acceptable salt thereof or a specific solvate thereof is used. 10【化4】

X1 and X2 are each independently CR4 or hydrazine; R1 is lower alkyl, lower alkoxy, halogenated lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy or optionally substituted Phenylamino; R2 is lower alkoxy, halogenated lower alkoxy or heterocyclic; R3 is lower alkyl; 12 200817002 R4 is hydrogen, lower alkyl, lower alkoxy, i-lower alkoxy, A hydroxy lower alkoxy group, a lower alkoxy lower alkoxy group or a phenylamine group which may have a substituent; however, except for the compound 1. Here, when η or m is 2 or more, a plurality of R1 or R2 may be optionally different from each other. Preferred are the following compounds (except compound 1) or a pharmaceutically acceptable salt thereof or a solvate thereof: in the above formula (1), η is 2 or 3, and R1 is a lower alkyl group or a lower alkoxy group. , a functional lower alkoxy group or a lower alkoxy lower alkoxy group;

m is 0 or 1, R2 is a lower alkoxy group, X1 is CH, and X2 is CH or N. Here, the "lower alkyl group" includes a linear or branched alkyl group having 1 to 10 carbon atoms (preferably having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms), and examples thereof include a methyl group. Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl , isoheptyl, n-octyl, isooctyl, n-decyl and n-kilyl. It is especially preferably a mercapto group or an ethyl group. The lower alkyl moiety of "lower alkoxy", "halogenated lower alkoxy", "hydroxyl lower alkoxy", "lower alkoxy lower alkoxy" and "lower alkoxycarbonyl" The above "lower alkyl group" has the same definition. "Halogen" contains F, Cl, Br and I. The halogen moiety in the "halogenated lower alkoxy group" is the same as the above-mentioned "halogen" 13 200817002 n 5 . The substituent in Li "optionally substituted phenylamine group" may, for example, be a halogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group or a decyl group. "Alkyl" includes an aliphatic fluorenyl group and an aroyl group having 1 to 7 carbon atoms. Specifically, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a butyl group, an isobutyl group, a pentamyl group, a neopentyl group, a hexyl group, a propylene group, a propynyl group, a mercapto propylene group can be exemplified. Sulfhydryl, Crotonoyl and benzoinyl. 10 "Heterocyclyl" includes a heterocyclic group having one or more optional hetero atoms selected from the group consisting of hydrazine, s & N, and the like, and specifically includes pyrrolyl group, imidazolyl group, oxazolyl group, pyridyl group, anthracene. Tillage, pyrimidinyl, pyridyl, triazolyl, trisyl, tetradecyl, isodecyl, sulphate, chelate, isosodium, thiazolyl, thiazepine 5 to 6 membered ring heteroaryls such as azolyl, furyl and thienyl; 15 ϋ 丨 朵 °, 异, 嗓, U 哇 基, Π 卜 卜, π 弓 朵 、, iso σ丨嗓 • 琳 基, σ 奎 琳 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基, 1 benzimidazolyl, benzotriazolyl, benzoisoxazolyl, benzoxazolyl, benzodiazolyl, benzisothiazolyl, benzoxazolyl, benzothiadiazole 20-based, benzofuranyl, isobenzofuranyl, benzoxenyl, benzotriazolyl, misobityl, oxime acridine, triazolopyridyl, imidazolium, anthracene Ploughing morphine (pyrazinopyrid Azinyl), oxazoline, quinolyl, isoindolyl, Naphthyridinyl, dihydrobenzofuranyl, tetrahydroporphyrinyl, tetrahydroisoindolyl, dihydrobenzopyrene, tetrahydrobenzo 2-ring condensation of fluorenyl group and the like 14 200817002 Heterocyclic group; anthracenyl, acridinyl, fluorenyl, thiophene, Phenoxathiinyl, porphyrin, dibenzofuranyl and imidazole Quinoline-specific 3-ring condensed heterocyclic group; diterpenoid, 〇Xymnyl, oxathioranyl, azetidinyl, thianyl, tetrahydroa thiazolidine, ° thiol, u is more than 嘻琳基, miso bite, taste 吐琳基, 吼嗤η疋基, 吼 琳 琳 、, 旅 基 base, ^ bottom base, morpholinyl, morphlin (morpj ^iino), thiomorpholinyl, thiomorpholino, dihydron-ratio® pyridine, dihydrobenzimidazolyl, tetrahydroacridinyl, tetrahydrofuranyl, tetrahydrogen 10 . A non-aromatic heterocyclic group such as a decyl group, a tetrazolyl group, a tetrahydroisodecyl group, an indoline group, a hexahydroazepinyl group or a tetrahydroazetyl group. More preferably, it is a heteroaryl or non-aromatic heterocyclic group of 5 to 6 members. When the pharmaceutically acceptable salt is an acid addition salt, a mineral acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, a carbonate, a hydrogencarbonate or a perchlorate 15 may be mentioned, an oxalate, Organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate and ascorbate; methyl acid salt, interesting ethanesulfonic acid (i- Ic add) salt, benzoate phenate and p-toluene buy acid salt and the like; acid asparagine and face amine ' _ and other acidic amino acids. In addition, when the salt is added for the test, for example, an alkali metal salt such as 20 Μ, sodium or If, a metal salt of a soil-reducing group, a basic amino acid salt such as arginine or lysine may be mentioned. The compound (1) may also be a bath composition such as water, acetonitrile, ethyl acetate, methanol or ethanol. Further, the solvent combination number of the solvate of the compound of the present invention (solvadon (4) can usually vary within the range of the synthesis method, the purification method, or the crystallization 15200817002 condition, etc. For example, the A method 5 [Chemical 7] It is said that the compound (1) having μ molecules per molecule of the compound can be produced by the following method.

Wherein, Y is a leaving group, and the other symbols are the same as defined above. The compound (II) or a salt thereof and the compound (IV) or a salt thereof which can be obtained from a conventional compound according to a usual method are placed in a suitable solvent at a temperature of about 10 t to the boiling point of the solvent (suitable 2 (rc~ about 8 (rc) reaction for about 5 minutes to about 24 hours (about 3 minutes to about 3 hours), the compound state can be obtained. The leaving group γ of the compound (III) can be exemplified by chlorine And a halogen such as bromine; an aliphatic sulfomethoxy group such as a methylsulfonyloxy group; and an aromatic sulfonyloxy group such as a p-toluenesulfonyloxy group; and the salts of the compounds (II) and (III) and the foregoing The "pharmaceutically acceptable salt" has the same definition. The solvent may, for example, be decyl alcohol, ethanol, dimethylformamide, DMSO, tetrahydrofuran or a mixture thereof, etc. The reaction is only necessary as needed. The reaction may be carried out in the presence of a base, and examples thereof include sodium hydroxide, hydrogen hydroxide, potassium carbonate, sodium carbonate, triethylamine, N,N-dimethylaniline, pyridine, sodium methoxylate and ethoxylate. Sodium, etc., 20 may be used in an amount of about 1 to 10 equivalents (preferably about 1 to 4 equivalents) relative to the substrate. 16 200817002 -... The compound (ιν) is subjected to an oxidation reaction to obtain the objective compound (la). The oxidation reaction only needs to be a reaction which is usually used, and is not particularly limited, and an appropriate oxidizing agent is used in an appropriate solvent under ice cooling~ The reaction is about 5 minutes to about 24 hours (preferably about 5 minutes to about 3 hours). The oxidizing agent may, for example, be methylchloroperbenzoic acid or peracetic acid. Hydrogen peroxide, chromic acid, manganese dioxide, sodium periodate, etc., may be used in an equivalent amount (preferably about 1 to 1.5 equivalents) with respect to the substrate. The solvent is tetrahydroanthracene, dialdehyde, diterpene. Formamide, DMSO, gas, or water, or a mixture of these, etc. 10 B method [Chemical 8]

In the formula, Y is a leaving group, and the other symbols are the same as defined above. The compound (V) or a salt thereof and the compound (VI) or a salt thereof are placed in a suitable solvent at a temperature of from about 0 ° C to the boiling point of the solvent (preferably about 2 (TC to about 80). The reaction is about 5 minutes. The compound (lb) can be obtained in an amount of about 24 hours (about 1 hour to about 5 hours). The leaving group Y of the compound (VI) can be, for example, a halogen such as chlorine or bromine; a sulfonyloxy group; an aromatic sulfonyloxy group such as a p-toluenesulfonic acid group; and the salt of the compound (VI) are the same as defined in the above-mentioned 20 pharmaceutically acceptable salt. Methyl chloride, dimethylformamide, acetone, acetonitrile, DMSO, tetrahydrofuran or a mixture of these, etc. 17 200817002 The reaction can be carried out only in the presence of a suitable test, as required, such as hydrogen hydroxide. Sodium, hydroxide dehydration, carbonic acid unloading, sodium carbonate, triethylamine N,N-methylaniline" than hydrazine, sodium methoxylate and ethoxylated sodium, etc., relative to the use of about equivalent of About ～4 equivalents) can be used. No matter whether the 5 A method or the B method is in the presence of a compound that will become a reaction disorder When necessary, it can be pre-protected by a conventional method as needed, and then deprotected after the reaction is completed. The substance (I) contains an optical isomer, a stereoisomer, a positional isomer or a rotation In the case of a construct, these are also included in the compound of the present invention, and at the same time, they can be obtained in the form of a single product by a conventional synthetic method and a separation method. For example, S, the compound (I) is present. In the case of an optical isomer, an optical isomer which is separated from the hydrazine compound is also included in the compound of the present invention. The optical isomer can be obtained by a conventional method. Specifically, it can be optically active. The optical intermediate can be obtained by optically dividing the mixture of the final product or the mixture of the final product, and the optical isomer can be obtained by the conventional method, for example, as described in detail below. Partial recrystallization, chiral column method and non-image isomer method, etc. 1) Partial recrystallization method 20 The racemate and optically active compound (such as (+)-mandelic acid ( Mandelic acid), (-) _ amygdalin, (+) _ tartaric acid, (a) _ tartaric acid, (+) | phenethylamine, (-)-1-phenylethylamine, cinchonine, cinchonidine, horse money test (bnieine), etc.) to form a salt, which is separated by fractional recrystallization, and then obtained free optical isomers via the process of 18200817002 and 2, as required. 2) Chiral column method to racemic or The method of separating the optical isomer separation column (chiral column) for separation, for example, when using liquid chromatography, at 5 TSKgel ENANTIO__ (made by Tosoh Corporation) or the professional chemical industry Add a mixture of precursors to the chiral column such as the company's stupid AL series, and then add water, various buffers (such as Wei buffer), organic solvents (such as hexane, ethanol, methanol, isopropanol, acetonitrile). , Eryi rat acetic acid, diethylamine, etc.) made into separate or mixed miscellaneous, so that the money is opened, and it is expected to leave the forest. Further, in the case of gas chromatography, a chiral column such as (10)_chimsil_Dex CB (manufactured by GL Sciences Inc.) is separated. 3) Non-image isomer method

10 chemically reacting a mixture of racemates with an optically active reagent to form a mixture of non-image isomers, and then by conventional means of separation (such as fractional recrystallization, chromatography, etc.), etc. A method of producing an optical isomer by chemically treating a portion of the optically active reagent by a chemical reaction such as a hydrolysis reaction. For example, when the compound of the present invention has a trans group or an i, a-group amine group in the molecule, the compound is reacted with an optically active organic acid (such as (a) _mtpa methoxy-CX-(trifluoromethyl)phenylacetic acid], (i) _ Menthoxyacetic Acid 20 or the like is subjected to a condensation reaction, whereby each of the non-image isomers of the vinegar or the amine can be obtained. Alternatively, when the compound of the present invention has a carboxyl group, the compound is subjected to a condensation reaction with an optically active amine or an alcohol reagent, and each of the non-mirromeric isomers of the guanamine or acid can be obtained. The isolated non-mirror isomer can be converted to the optical isomer of the original compound by performing an acidic hydrolysis or an analytical hydrolysis reaction. Further, the proton pump-inhibiting compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof can be suitably used as a gastric acid secretion inhibitor which is used as a therapeutic drug for peptic ulcer. 5 Specifically, for example, omeprazole (U.S. Patent Nos. 4,545,431 and 6,666,213), lansoprazole (lansopmzole; U.S. Patent No. 4,628,098), and Pantoprazole (U.S. Patent Nos. 4,555,518 and 4,758,579) are exemplified. , Esso-American Patent No. 4,738,974), rabeprazole (U.S. Patent No. 5,045,552), Revapl 10 (Respalazan; U.S. Patent Nos. 5,705,531, 6,252,076 and 5,990,311), ilaprazole; Patent No. 5,703,097) and Tetrolazole (tenatoprazole; U.S. Patent No. 4,808,596), etc.; Agro-pyrolopyridazine derivatives of AGN-201904 and CS-526 (U.S. Patent No. 6,063,782), etc., which may be based on One of the patent publications described in the foregoing is readily available. In addition, other salts or solvates which are pharmaceutically acceptable are equally suitable for use. For example, the compound (1) of the present invention also contains the following tautomers.

The inhibitor of sputum production can be a pharmaceutical composition, and is particularly effective for treating or preventing a neurodegenerative disease caused by Αβ precipitation. These two diseases can be exemplified by Alzheimer's type dementia (Alzheimer's disease, Alzheimer's type old 2008 200817002 dementia, etc.), Down's syndrome 'memory disorder, Pri〇ndisease (Jia Creutzfeldt-Jakob disease, etc., mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, brain amyloid vascular disorders, other degenerative dementia, vascular degeneration mixed dementia, with Parkinson Dementia caused by 5's disease, dementia with progressive supranuclear nerve palsy, dementia associated with degeneration of cortical basal ganglia, generalized Lewy body type Alzheimer's disease, age-related macular degeneration, Parkinson's disease Disease and spleen vascular disease (Amyloid gossip "...also", etc. Preferably, in order to inhibit Alzheimer's type dementia (especially Alzheimer's disease) or for treatment purposes, it can be prescribed 10-port or parenteral administration. When administered orally, the Αβ production inhibitor of the present invention can be used as a usual preparation, for example, a solid agent such as a tablet, a powder, a granule or a capsule; a liquid; an oily suspension Turbidity agent; syrup and _( _Liquid in any of the liquid preparations. When it is administered orally, it can be used as an aqueous or oily suspension injection 15 or a nasal spray. Any conventional excipients and binders can be used at the time of preparation. An aqueous solvent, an oily solvent, an emulsifier, a suspending agent, a preservative, a stabilizer, etc. The preparation of the present invention can be combined (e.g., mixed) with a therapeutically effective amount of a compound and a pharmaceutically acceptable carrier or diluent. In this case, 20 components which are known and easily available can be used and can be produced by a known method. When the pharmaceutical composition of the present invention is produced, the active ingredient is mixed with a carrier or diluted with a carrier, or can be charged. In the form of a capsule, bag, paper or other container. When the carrier acts as a diluent, the system acts as a solid, semi-solid or liquid material acting as a medium, which can be made into a spinning agent and a pellet 21 200817002 , powders, oral preparations, elixirs, suspensions, emulsions, solutions, troches, aerosols (solids in liquid media) and ointments, for example, less than 10% active compound. In terms of A suitable carrier can be used for the preparation. In such a preparation, the carrier is a solid, a liquid, or a mixture of a solid and a liquid. For example, when intravenously administered, the compound of the active ingredient is dissolved in 4% glucose/ In a 0.5% aqueous solution of sodium citrate. The solid preparation contains powder, lozenge and capsules. The solid carrier is a kind of perfume, slip agent, dissolving agent, suspending agent, binding agent, tablet disintegrating agent and capsule even if used as a perfume. The material of the agent is also useful in one or more substances. The tablet for oral administration contains corn starch, alginic acid and other disintegrants, and/or gelatin, locust and other binding agents, and stearin. A slip agent such as magnesium sulfate, stearic acid or talc, and a suitable excipient such as a carbonated mother, sodium carbonate, lactose or squaric acid. In the case of a powder, the carrier is mixed with the finely pulverized active ingredient, and 15 is a finely pulverized solid. In the case of a tablet, the active ingredient is mixed in a suitable ratio with a carrier having the desired combination and solidified to the desired shape and size. The powders and lozenges contain from about 1% to about 99% by weight of the active ingredient of the present invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax and Coco fat. Liquid preparations include suspensions, emulsions, syrups and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent or a mixture of the two. The active ingredient can be dissolved in a suitable organic solvent such as an aqueous solution of propylene glycol. The finely pulverized activity 22 200817002 can also be dispersed in aqueous starch, sodium carboxymethyl cellulose solution, or a suitable oil to make other compositions. The dosage and administration method of the compound of the present invention are different depending on the age, body weight, state and type and degree of the disease of the patient. Generally, when the oral administration is 5 ♦ and the medicine is administered, the adult is about mgjmgwOOOOmg per 曰. 5mg~3000 mg) 'If you need to take the drug in divided doses. In addition, when administered parenterally, the adult doses about 0.1 mg to 3000 mg per day, and preferably about 0.5 mg to 1000 mg. [Example 1] ® The effects of the present invention were tested as follows. 10 Test Example 1 Αβ quantification in HEK293 (HEK/pAPPswe) cells with constant expression of βΑΡΡ Swedish variant (comparative effect of Ogilvy saliva and lansola saliva) with 10% fetal bovine serum and 200 pg/mL Hybrexco's modified 15 Eagle medium (DMEM) was cultured in a hygromycin-modified 15 Eagle medium (DMEM) to express a βK-Swedish variant HEK293 (HEK/pAPPswe) cell line. The cells were seeded at 200 pL/well in a 96 well polystyrene petri dish to make 2 x 104 cells/well. The culture medium was exchanged at approximately 70% confluence while adding the compound. The chosol, razol (50 mM stock solution in DMSO) was added to a final concentration of 5 ΟμΜ 20 and omeprazole (100 mM stock solution in DMSO) to a final concentration of 300 μM and mixed well. After culturing overnight at 37 ° C (about 16 hours), the culture supernatant was recovered 1 μ μί, and Αβ40 was measured using the HTRF method (曰本Schering, #62B40PEC). The method was carried out in accordance with the manufacturer's recommended Pr〇t〇e〇l (the method described in the instruction manual). However, the Αβ sample was obtained from the sample attached to the 40β40 ELISA kit (#KHB3482) of Biotrans, Inc., 23 200817002 * ...1. The concentration of Αβ in the culture supernatant of the same concentration of DMSO (〇·5% dmSO) as the compound was used as the control group, and the percentage relative to the control group (% relative to the control group, % 〇fc 〇ntr〇l) to represent the result. 5 Evaluation of cell survival was performed using the WST method. After the culture supernatant for the Αβ measurement was collected, 1 μM!^ iwsm. (NACALAITESQuE, INC, #07553_44) was added to a 96-well polystyrene culture dish, and cultured at 37 ° C for 3 hours. The measurement is carried out in accordance with the manufacturer's recommended Pr〇t〇e〇1 (the method described in the attached instructions). The results are expressed as a percentage of the culture supernatant treated with respect to 0.5% DMSO (% relative to the control group % '% of control). As a result, both lansoprazole and omeprazole inhibited Αβ production by deviating from cytotoxicity. Lansoprazole showed the same effect at a lower concentration than omeprazole, and it was found that lansoprazole was extremely active compared to omeprazole (see Fig. 1). Test Example 2 Effect of plasma containing Αβ in wild type mice (CD-1) Wild type mice (CD-1 (ICR), male, 8 weeks old) were purchased from Japan's Chaer's / Can be. Luo agent used 0. 5% methylcellulose, lansoprazole drug group (n = 8 each) 20 series at 10 〇 mg / kg or 200 mg / kg oral administration, 2 hours after administration of difluorobromide After laparotomy under halothane anesthesia, blood was collected from the large vein. For the non-administered group of lansoprazole (base agent, oral administration of 0·5/〇methylcellulose was carried out at 10 mL/kg, and blood was collected 2 hours after administration. The lmL syringe containing 1 〇 0.25 Μ EDTA was used. Blood collection, recovery in 丨.5 micro-dissociation 24 200817002 • heart tube (four) teacher *). - Centrifugal separation was carried out for 1 minute at 960 Qg, and the supernatant was recovered and plasma was prepared. Before the plasma was measured by Deng, 8 〇 <t cold-camped AP test system was used by 光β40 Elisa kit (#294_625901). Plasma samples were diluted 4-fold with standard dilutions 5 attached to the misa kit' and were performed according to the manufacturer's recommended pr〇t〇e〇1 (attached to the instructions for use). The percentage of plasma Αβ content relative to the non-administered group (base) of the compound (% relative to the control group, % 〇f(7), r〇i) showed no results. _ As a result, in the group of 200 mg/kg of proxastrobin and 2 hours after administration, it was found that 10 plasma contained Αβ significantly decreased [p=〇〇241, Dmmett's test] (refer to the second Figure). Test Example 3 Αβ quantification in HEK293 (HEK/Appswe) cells with constant β ΑΡΡ Swedish type variation (assay 1 (^ value) 15 Omega 嗤 from the Wako Pure Chemical Industries, and purchased from Sigma Saliva. Tetopraz and rabeprazole were purchased from 3B medical systems, and were treated with 10% fetal bovine serum and 200 pg/mL hygromycin. HEK293 (HEK/pAPPswe) cell line with constant expression of βΑΡΡ Swedish variant was cultured in Dulbecco's modified 20 Eagle medium (DMEM). The cells were seeded at 2 mL/well in a Petri dish of 6 wells. Become i.5><105 cells/well. Exchange the culture solution at approximately 70% confluence while adding the compound. Add each test compound (50 mM stock solution in DMSO) to a final concentration of 500, 25 200817002 • 300, 180, 108', 64·8, 38.88 μΜ, and uniformly mixed. After culturing overnight at 37 ° C (about 16 hours), 1 mL of the culture supernatant was recovered, and Αβ40 was measured by HTRF method (Schering Co., Ltd., #62B40PEC, Japan). The manufacturer's recommended protocol attached ) Is described in the description of the method. However, the '5 AP sample was obtained from the sample attached to BioSource's Αβ40 ELISA kit (# KHB3482). The concentration of Αβ in the culture supernatant of the same concentration as the DMSO to which the compounds were applied (1% DMS〇) was used as a control group, and the percentage relative thereto (% relative to the control group, % 〇fc〇ntr〇) 1) The results are not shown. 10 Cell survival assessment was performed using the WST method. After the culture supernatant for Αβ measurement was collected, 2 〇|liL 2WSTSt (NACALAITESQUE, INc, #〇7553_44) was added to a 6-well polystyrene culture dish, and cultured at w37 °C for 3 hours. The measurement is carried out in accordance with the manufacturer's recommended pr〇t〇c〇i (attached to the instruction manual §). The results are expressed as a percentage of the survival rate in the culture supernatant treated with respect to 1% DMS (relative to the percentage of the control group, % 〇fC〇ntr〇1). The IC5 〇 W value of each test compound for inhibition of Αβ production was calculated. As a result, it was confirmed that each of the test compounds showed a strong inhibitory activity against cytotoxicity by inhibiting the conditions of cytotoxicity, _ Μ ° ° 4 'Tetuo H, and Rebela reading Ogilre oxime 20 (see ^ and Figure 3). 26 200817002 [Table 1] Αβ production inhibits cell survival inhibition (μΜ) (μΜ) Omeprazole 236.9 > 500 Lansoprazole 99.7 595.65 Rabeprazole 90.6 > 500 Tetoprazole 125.7 > 500 Example 1 A tablet containing the following ingredients is produced.

Compound of formula (I) 10 mg 5 Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg Stearic acid 5 mg 150 mg 10 The compound of formula (I), lactose, microcrystalline cellulose, CMC-Na (carboxyl

Methylcellulose sodium salt) was sieved through 60 mesh and mixed. Further, magnesium stearate was further mixed at the end of the mixing to obtain a mixed powder for tableting. The mixture was directly ingot, and a 150 mg tablet was obtained. Example 2 15 The following ingredients were warmed and mixed, and then sterilized to prepare an injection. Compound of formula (1) 3 mg of nonionic surfactant 15 mg of purified water for injection 1 ml Industrial Applicability 20 The present invention can be used for preventing and/or treating Alzheimer's disease and Down's syndrome, etc. 27 200817002 It is very useful for drugs for neurodegenerative diseases caused by Αβ precipitation. [Simplified illustration] Figure 1 compares the effects of omeprazole and lansoprazole on Αβ production in HEK293 (HEK/pAPPswe) cells, and the HEK293 5 (HEK/pAPPswe) cells are consistently expressed. ΑΡΡ ΑΡΡ Swedish variant. Fig. 2 is a graph showing changes in the concentration of Αβ in the plasma of wild type mice when orally administered lansoprazole. Figure 3 compares the effects of lanprasor, temseroprazole, rabeprazole, and omeprazole on Αβ production in HEK293 (HEK/APPswe) cells, and the HEK293 (HEK/APPswe) The cell constants exhibit a βΑρρ Swedish variant. [Main component symbol description] (none)

28

Claims (1)

200817002 X. Patent application: L A starch-like β-production inhibitor containing a proton pump inhibitor (except for the following compounds) or a pharmaceutically acceptable salt thereof or a solvate thereof. 【化1】 2. A bactericidal beta production inhibitor comprising a compound of the formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof; 10 In the formula, Α is [Chemical 3] X1 and X2 are each independently CR4 or N; R1 is lower alkyl, lower alkoxy, dentate lower alkoxy, hydroxy lower alkyl alkoxy, lower alkoxy lower alkoxy or optionally substituted Phenylamino; 29 15 200817002 R 2 is a lower alkoxy group, a halogenated lower alkoxy group or a heterocyclic group R 3 is a lower alkyl group; R 4 is hydrogen, a lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group And a hydroxyl lower alkoxy group, a lower alkoxy lower alkoxy group or a phenylamine group which may have a substituent; and each of η, m and p is independently an integer of 〇~3; 【化4】 3. A variety of starch beta production inhibitors, including lansoprazole, pandoprazole, esomepmzole, rabepraz〇le, thunder Prassan (revapmzan), prajolazole (five), tetoprazole 10 15 (tenatoprazole), CS_526 or such pharmaceutically acceptable salts or such solvates. 4. 5. Type, powder p produces an inhibitor comprising a proton pumping compound or a pharmaceutically acceptable salt thereof or a solvate thereof. For example, the anti-starch beta production inhibitor of any of the four items of the fourth aspect of the invention is a therapeutic agent for Alzheimer's disease. A method for inhibiting the production of a salt-free compound, which is characterized in that a compound which inhibits the action of a drug or a pharmaceutically acceptable salt thereof or a solvate of the above-mentioned 30 20 200817002 or the like. A method for treating Alzheimer's disease, which comprises administering a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof. 5. The use of a compound having a proton pump inhibitory effect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, using the compound or a pharmaceutically acceptable salt thereof or a solvent thereof The substance is used to manufacture a drug for inhibiting the production of starch-like β. A use of a proton pump inhibiting compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a compound or a pharmaceutically acceptable salt thereof or a solvate thereof To make drugs for the treatment of Alzheimer's disease. 31