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WO2008016002A1 - RÉGULATEUR DE LA PRODUCTION DE β-AMYLOÏDE CONTENANT UN INHIBITEUR DE LA POMPE À PROTONS - Google Patents

RÉGULATEUR DE LA PRODUCTION DE β-AMYLOÏDE CONTENANT UN INHIBITEUR DE LA POMPE À PROTONS Download PDF

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Publication number
WO2008016002A1
WO2008016002A1 PCT/JP2007/064872 JP2007064872W WO2008016002A1 WO 2008016002 A1 WO2008016002 A1 WO 2008016002A1 JP 2007064872 W JP2007064872 W JP 2007064872W WO 2008016002 A1 WO2008016002 A1 WO 2008016002A1
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WIPO (PCT)
Prior art keywords
lower alkoxy
compound
amyloid
pharmaceutically acceptable
solvate
Prior art date
Application number
PCT/JP2007/064872
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English (en)
Japanese (ja)
Inventor
Masayasu Okochi
Shinji Tagami
Masatoshi Takeda
Naohiro Itoh
Original Assignee
Osaka University
Juridical Foundation Osaka Industrial Promotion Organization
Shionogi & Co., Ltd.
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Filing date
Publication date
Application filed by Osaka University, Juridical Foundation Osaka Industrial Promotion Organization, Shionogi & Co., Ltd. filed Critical Osaka University
Priority to JP2008527741A priority Critical patent/JPWO2008016002A1/ja
Publication of WO2008016002A1 publication Critical patent/WO2008016002A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • 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 ⁇ 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.
  • Amyloid 0 (hereinafter referred to as ⁇ ⁇ ) is a major constituent of senile plaques frequently found in the brain of Alzheimer's disease patients, one of the neurodegenerative diseases. ⁇ 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 ⁇ -secretase during the metabolism of amyloid precursor protein (/ 3 APP). ⁇ APP is normally degraded by ⁇ -secretase, in which case ⁇ / 3 is not produced.
  • ⁇ has two isoforms, A / 3 1-40 and A / 3 1-42 (43), but they are produced at the metabolic stage of / 3 ⁇ ⁇ ⁇ ⁇ by 0 secretase and ⁇ -secretase, not at the transcriptional level. It is considered. Most of ⁇ ⁇ ⁇ / 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! / ,!
  • Alzheimer's disease A ⁇ aggregates to form insoluble fibers and deposits in the brain to form senile plaques.
  • ⁇ 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 A ⁇ and suppressing A ⁇ production.
  • ⁇ -secretase inhibition is one of the most notable methods for inhibiting ⁇ production.
  • the Swedish mutation is one of the familial Alzheimer's disease mutations of ⁇ APP, which has a high affinity for ⁇ -secretase and is known to easily produce ⁇ / 3.
  • a / 3 production in such a culture system Suppression is thought that BM inhibits ⁇ -secretase.
  • ⁇ increased ⁇ ⁇ ⁇ / 3 production in wild-type cells, and V-type H + -ATPase inhibitors generally inhibit 0 APP metabolism. I can't say that.
  • 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.
  • 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).
  • 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.
  • P—ATPase a type of ion transporting ATPase
  • the selective inhibitor suppresses gastric acid secretion and is widely used as a therapeutic agent for peptic ulcer, and omebrazole is a typical drug.
  • omebrazole is a typical drug.
  • 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)
  • An object of the present invention is to provide a medicament for preventing and / or treating neurodegenerative diseases based on A ⁇ 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 ⁇ / 3 which causes these neurodegenerative diseases.
  • 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 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.
  • FIG. 1 is a graph comparing the effects of omebrazol and lansoprazole on A / 3 production in ⁇ 293 ( ⁇ / ⁇ APPswe) cells constitutively expressing ⁇ ⁇ Swedish mutation.
  • FIG. 2 shows changes in plasma A / 3 concentration when lansoprazole was orally administered to wild-type mice.
  • 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 ⁇ -Swedish mutation.
  • the present invention provides the following.
  • an amyloid 0 production inhibitor comprising a pharmaceutically acceptable salt thereof or a solvate thereof.
  • 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.
  • amyloid / 3 production inhibitor is characterized by comprising:
  • An amyloid 0 production inhibitor comprising a compound having a proton pump inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • amyloid ⁇ production inhibitor according to any one of (1) to (4) above, which is a therapeutic agent for Alzheimer's disease.
  • 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.
  • 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.
  • 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.
  • 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.
  • the A ⁇ 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.
  • ⁇ 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 ⁇ / 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.
  • 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! /, Phenylamino, provided that compound 1 is except)
  • n or m is 2 or more, a plurality of R 1 or R 2 are different from each other! /.
  • n is 2 or 3
  • R 1 is lower alkyl, lower alkoxy, halogeno lower alkoxy or lower alkoxy lower alkoxy
  • A is
  • m is 0 or 1
  • R 2 is lower alkoxy
  • X 1 is CH
  • X 2 is CH or N (except for compound 1) or a pharmaceutically acceptable product thereof Or a solvate thereof.
  • 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.
  • 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.
  • halogen part of “halogeno lower alkoxy” is the same as the above “norogen”.
  • substituents of “optionally substituted phenylamino” include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, and acyl.
  • 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.
  • 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!
  • 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.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate
  • Acid salts acetates, propionates, lactates, maleates, fumarate, tartrate, malates, citrates, ascorbates
  • alkali metal salts such as lithium, sodium and potassium
  • alkaline earth metal salts such as calcium and magnesium
  • basic amino acid salts such as arginine and lysine.
  • 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.
  • This compound (I) is produced, for example, by the method shown below.
  • 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.
  • 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.
  • This reaction may be carried out in the presence of a suitable base as required.
  • a suitable 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.
  • 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.
  • the oxidizing agent include metachloroperbenzoic acid, peracetic acid, hydrogen peroxide, chromic acid, manganese dioxide, sodium periodate, and the like.
  • As the solvent tetrahydrofuran, dioxane, dimethylformamide, DMSO, dichloromethane, water, or a mixture thereof may be used.
  • 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.
  • 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.
  • the solvent include dichloromethane, dimethylformamide, acetone, acetonitrile, DMSO, tetrahydrofuran, or a mixture thereof.
  • This reaction may be carried out in the presence of an appropriate base as necessary.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • optically active compounds for example, (+)-mandelic acid, (1) mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (1) -1 -phenethylamine , Cinchonine, cinchonidine, brucine, etc.
  • the racemate or its salt is separated on a column for separation of optical isomers (chiral column).
  • a column for separation of optical isomers chiral column
  • 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.)
  • buffer solutions for example, phosphorus Acid buffer solution
  • organic solvent e.g. hexane, ethanol, methanolol, isopropanol, acetatenitrorole, trifanoleoacetic acid, jetylamine, etc.
  • 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).
  • 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.
  • an optical isomer is obtained by separating an optically active reagent moiety by chemical treatment such as.
  • an optically active organic acid for example, (-)- ⁇ [ ⁇ -methoxymono ⁇ - (trifluoromethyl) Diastereomers in the form of esters or amides can be obtained by subjecting them to a condensation reaction.
  • 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.
  • a gastric acid secretion inhibitor used as a therapeutic agent for peptic ulcer is preferably used. can do.
  • 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 (3 ⁇ 4 20 16; US Patent No.
  • the compound (I) of the present invention also contains tautomers as described below, for example.
  • 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.
  • 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.
  • 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.
  • the A ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • any suitable carrier known to those skilled in the art can be used for this formulation.
  • the carrier is a solid, liquid, or a mixture of solid and liquid.
  • 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.
  • the carrier is mixed with a finely divided active ingredient, and is finely ground solid. Is the body.
  • 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.
  • 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.
  • 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.
  • administration method 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.
  • parenteral administration about 0.1 mg to 3000 mg, preferably about 0.5 mg to;
  • the ⁇ 293 ( ⁇ / ⁇ APPswe) cell line which expressed the ⁇ ⁇ 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.
  • Omebrazole was purchased from Wako Pure Chemical Industries, and lansoprazole was purchased from Sigma. Tenatov. Lazonole and Rabeprazonole were purchased from 3B medical systems.
  • ⁇ ⁇ Swedish mutation constitutive expression ⁇ 293 (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 ⁇ M and mixed well.
  • DMEM Dulbecco's modified Eagle medium
  • the present invention is useful as a medicament for preventing and / or treating neurodegenerative diseases based on A ⁇ deposition such as Alzheimer's disease and Down's syndrome.

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Abstract

La présente invention concerne un régulateur de la production de β-amyloïde qui contient en tant que matière active un composé ayant un effet inhibiteur de la pompe à protons (H+/K+ATPase). Ledit régulateur peut être utilisé en tant que médicament de prévention et/ou de traitement des maladies neurodégénératives dépendant de la sédimentation de la β-amyloïde telles que la maladie d'Alzheimer ou le syndrome de Down.
PCT/JP2007/064872 2006-07-31 2007-07-30 RÉGULATEUR DE LA PRODUCTION DE β-AMYLOÏDE CONTENANT UN INHIBITEUR DE LA POMPE À PROTONS WO2008016002A1 (fr)

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JP2008527741A JPWO2008016002A1 (ja) 2006-07-31 2007-07-30 プロトンポンプ阻害剤を含有するアミロイドβ産生抑制剤

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102228459A (zh) * 2011-05-10 2011-11-02 江苏奥赛康药业有限公司 一种供注射用的雷贝拉唑钠组合物
WO2013031620A1 (fr) * 2011-08-26 2013-03-07 国立大学法人名古屋大学 Promoteur d'ostéogenèse et son utilisation
WO2021261471A1 (fr) * 2020-06-23 2021-12-30 国立大学法人京都大学 Substance thérapeutique pour trouble obsessionnel compulsif

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109078013A (zh) * 2018-09-28 2018-12-25 朱建友 一种泮托拉唑钠在制备治疗阿尔茨海默病药物中的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068147A2 (fr) * 2002-01-18 2003-08-21 Massachusetts Institute Of Technology Traitements de la neurotoxicite dans la maladie d'alzheimer
WO2005076987A2 (fr) * 2004-02-10 2005-08-25 Santarus, Inc. Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068147A2 (fr) * 2002-01-18 2003-08-21 Massachusetts Institute Of Technology Traitements de la neurotoxicite dans la maladie d'alzheimer
WO2005076987A2 (fr) * 2004-02-10 2005-08-25 Santarus, Inc. Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102228459A (zh) * 2011-05-10 2011-11-02 江苏奥赛康药业有限公司 一种供注射用的雷贝拉唑钠组合物
WO2013031620A1 (fr) * 2011-08-26 2013-03-07 国立大学法人名古屋大学 Promoteur d'ostéogenèse et son utilisation
CN103826632A (zh) * 2011-08-26 2014-05-28 国立大学法人名古屋大学 骨形成促进剂及其用途
JPWO2013031620A1 (ja) * 2011-08-26 2015-03-23 国立大学法人名古屋大学 骨形成促進剤及びその用途
WO2021261471A1 (fr) * 2020-06-23 2021-12-30 国立大学法人京都大学 Substance thérapeutique pour trouble obsessionnel compulsif

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JPWO2008016002A1 (ja) 2009-12-24

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