JP6830895B2 - ストレス誘発性p−tauを低下させるトリアゾロピリジン及びトリアゾロピリミジン - Google Patents
ストレス誘発性p−tauを低下させるトリアゾロピリジン及びトリアゾロピリミジン Download PDFInfo
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- JP6830895B2 JP6830895B2 JP2017543785A JP2017543785A JP6830895B2 JP 6830895 B2 JP6830895 B2 JP 6830895B2 JP 2017543785 A JP2017543785 A JP 2017543785A JP 2017543785 A JP2017543785 A JP 2017543785A JP 6830895 B2 JP6830895 B2 JP 6830895B2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 238000002464 physical blending Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000007406 plaque accumulation Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001553 poly(ethylene glycol)-block-polylactide methyl ether Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- MICLTPPSCUXHJT-UHFFFAOYSA-M potassium;4-[3-(6-oxo-3h-purin-9-yl)propanoylamino]benzoate Chemical compound [K+].C1=CC(C(=O)[O-])=CC=C1NC(=O)CCN1C(NC=NC2=O)=C2N=C1 MICLTPPSCUXHJT-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 208000022256 primary systemic amyloidosis Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 208000030153 prolactin-producing pituitary gland adenoma Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- SCHKZZSVELPJKU-UHFFFAOYSA-N prx-03140 Chemical compound O=C1N(C(C)C)C=2SC=CC=2C(O)=C1C(=O)NCCCN1CCCCC1 SCHKZZSVELPJKU-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 229960002290 pyridostigmine Drugs 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 229940051845 razadyne Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
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- 230000003938 response to stress Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 1
- 239000003751 serotonin 6 antagonist Substances 0.000 description 1
- 206010040400 serum sickness Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940103449 simcor Drugs 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- XVFJONKUSLSKSW-JTQLQIEISA-N talsaclidine Chemical compound C1CC2[C@@H](OCC#C)CN1CC2 XVFJONKUSLSKSW-JTQLQIEISA-N 0.000 description 1
- 229950001645 talsaclidine Drugs 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 210000005196 temporal scalp Anatomy 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- VUYXVWGKCKTUMF-UHFFFAOYSA-N tetratriacontaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO VUYXVWGKCKTUMF-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012034 trail making test Methods 0.000 description 1
- 229960003570 tramiprosate Drugs 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- PZJJKWKADRNWSW-UHFFFAOYSA-N trimethoxysilicon Chemical group CO[Si](OC)OC PZJJKWKADRNWSW-UHFFFAOYSA-N 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000009677 vaginal delivery Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940009349 vytorin Drugs 0.000 description 1
- PNAMDJVUJCJOIX-XVZWKFLSSA-N vytorin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1.N1([C@@H]([C@H](C1=O)CC[C@@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 PNAMDJVUJCJOIX-XVZWKFLSSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- PMBLXLOXUGVTGB-UHFFFAOYSA-N zanapezil Chemical compound C=1C=C2CCCCNC2=CC=1C(=O)CCC(CC1)CCN1CC1=CC=CC=C1 PMBLXLOXUGVTGB-UHFFFAOYSA-N 0.000 description 1
- 229950010696 zanapezil Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed 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
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本出願は、2015年2月18日出願のUSSN62/117,888の優先権及び利益を主張し、全ての目的においてその内容全体を参照により本明細書に組み込む。
[該当無し]
による化合物又は薬学的に許容されるその塩。
である、実施形態8の化合物。
である、実施形態10の化合物。
である、実施形態8の化合物。
である、実施形態10の化合物。
実施形態1〜44のいずれか一項に記載の1種若しくは複数の化合物の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物、又は薬学的に許容されるその塩若しくは溶媒和物の有効量を、前記哺乳動物に投与する工程;及び/又は
実施形態45〜47のいずれか一項に記載の製剤の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物及び薬学的に許容される担体又は賦形剤を含む製剤の有効量を、前記哺乳動物に投与する工程
を含む方法。
実施形態1〜44のいずれか一項に記載の1種若しくは複数の化合物の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物、又は薬学的に許容されるその塩若しくは溶媒和物の有効量を、前記哺乳動物に投与する工程;及び/又は
実施形態45〜47のいずれか一項に記載の製剤の有効量を前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物及び薬学的に許容される担体又は賦形剤を含む製剤の有効量を、前記哺乳動物に投与する工程
を含む方法。
実施形態1〜44のいずれか一項に記載の1種若しくは複数の化合物の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物、又は薬学的に許容されるその塩若しくは溶媒和物の有効量を、前記哺乳動物に投与する工程;及び/又は
実施形態45〜47のいずれか一項に記載の製剤の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物及び薬学的に許容される担体又は賦形剤を含む製剤の有効量を、前記哺乳動物に投与する工程
を含む方法。
実施形態1〜44のいずれか一項に記載の1種若しくは複数の化合物の有効量を前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物、又は薬学的に許容されるその塩若しくは溶媒和物の有効量を、前記哺乳動物に投与する工程;及び/又は
実施形態45〜47のいずれか一項に記載の製剤の有効量を、前記哺乳動物に投与する工程;及び/又は
J03、J04、J05、J08、及びJ17からなる群から選択される化合物及び薬学的に許容される担体又は賦形剤を含む製剤の有効量を、前記哺乳動物に投与する工程
を含む方法。
別段の指示がない限り、化合物(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン)への参照は、示された構造名又は化学名の化学物質の、薬学的に許容されるそれらの塩、プロドラッグ、互変異性体、代替の固体形態、非共有結合性複合体、及びそれらの組合せが含まれるものと広く解釈されるべきである。
OTTR=(CIV max/Cmax)×(用量/用量IV)(Cmaxの50%を超える時間)/(薬物の最終IV除去半減期)
によって算出される。
様々な実施形態では、治療方法及び/又は予防方法は、活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩又は溶媒和物、又はそれらの類似体、誘導体、若しくはプロドラッグ)が提供されることが示される。通常、これらの方法には、所望の治療若しくは予防効果を実現するのに十分な量で、1種若しくは複数の活性薬剤を、対象に(例えば、それを必要とするヒトに)投与する工程が含まれる。
いくつかの実施形態では、活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩若しくは溶媒和物、又はそれらの類似体、誘導体、若しくはプロドラッグ)は、様々な予防的状況において利用される。したがって、例えば、いくつかの実施形態では、活性薬剤は、前アルツハイマー型認知機能障害の発生を防止する若しくは遅延させる、並びに/又は前アルツハイマー状態及び/若しくは認知機能障害の1つ若しくは複数の症状を寛解させる、並びに/又は前アルツハイマー状態及び/若しくは認知機能障害のアルツハイマー病への進行を防止する又は遅延させるために用いることができる。
軽度認識障害(MCI、初発認知症としても公知の、又は孤立性記憶障害(isolated memory impairment))は、患者の年齢及び教育について予測されるが、通常、患者の日常の活動を著しく妨げない以上に認識障害を有する個体に与えられる診断である(例えば、Petersenら(1999年)Arch.Neurol.56巻(3号):303〜308頁を参照のこと)。多くの場合、正常な老化及び認知症の間の境界又は移行段階であると考えられる。MCIは、様々な症状と共に存在し得るが、記憶喪失が主な症状である場合、これは、「健忘性MCI」と称され、アルツハイマー病のリスク因子としてしばしば示される(例えば、Grundmanら(2004年)Arch.Neurol.61巻(1号):59〜66頁;インターネットen.wikipedia.org/wiki/Mild_cognitive_impairment - cite_note-Grundman-1を参照のこと)。個体が、記憶以外のドメインにおいて機能障害がある場合、非健忘性の単一若しくは複数のドメインMCIとしてしばしば分類され、これらの個体は、他の認知症(例えば、レヴィ小体を伴う認知症)への転換の可能性が高いと考えられる。健忘性MCI患者が、アルツハイマー病についての神経病理的な基準を満たすことができず、患者は、アルツハイマー病を進展する移行段階となり得;この仮定された移行段階における患者によって、新皮質における拡散したアミロイド及び内側側頭葉内の頻繁な神経原線維タングルが実証されることが示唆される証拠がある(例えば、Petersenら(2006年)Arch.Neurol.63巻(5号):665-72を参照のこと)。
いくつかの実施形態では、活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩、溶媒和物、又は包接体、又はそれらの類似体、誘導体、若しくはプロドラッグ)は、アルツハイマー病の治療のために考えられる。かかる場合では、本明細書に記載した方法は、アルツハイマー病(AD)の発生を予防する又は遅らせるのに、対象が臨床的なAD診断に移行する場合、ADの重症度を低下させるのに及び/又はアルツハイマー病の1種又は複数の症状を緩和するのに有用である。
本明細書に記載した方法は、1種若しくは複数の活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩、溶媒和物、若しくは包接体、又はそれらの類似体、誘導体、若しくはプロドラッグ)の投与が、タウ及び/又はp-tauを低下させる、又はp-tauのストレス誘発性(例えば、コルチゾールによって誘導される)増加を防止し、例えば、軽度認識障害、アルツハイマー病、黄斑変性症等の、脳内のアミロイド沈着を特徴とする疾患の治療及び/又は予防における使用を見出すために有効であるという発見に一部基づいている。
R2は、
R1は、
による化合物又はその薬学的に許容される塩、溶媒和物、若しくは包接体を含む。いくつかの実施形態では、本化合物は、J03、J04、J05、J06、J07、J08、J09、J10、JH11、J12、J15、及びJ17でない。いくつかの実施形態では、本化合物は、J03、J04、J05、J08、及びJ17でない。
である。いくつかの実施形態では、式Iの化合物において、R2は、
である。
である。いくつかの実施形態では、R7は、CH3であり、R8は、CH3である。
いくつかの実施形態では、本明細書に記載した1種若しくは複数の活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジンの薬学的に許容されるそれらの塩、溶媒和物、若しくは包接体、前記立体異性体、若しくは前記互変異性体、又はそれらの類似体、誘導体、若しくはプロドラッグ)は、それを必要とする哺乳動物に、例えば、アミロイド前駆体タンパク質の異常なプロセシングを特徴とする病態のリスクがある又はそれに罹患している哺乳動物、MCIのアルツハイマー病への進行のリスクがある哺乳動物等に投与される。いくつかの実施形態では、活性薬剤は、前アルツハイマー状態及び/若しくは認知機能障害の発生を防止する若しくは遅延させる、並びに/又は前アルツハイマー型認知機能障害の1つ若しくは複数の症状を寛解させる、並びに/又は前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する若しくは遅延させる、並びに/又は非アミロイド形成経路によりアミロイド前駆体タンパク質(APP)のプロセシングを促進するために投与される。
いくつかの実施形態では、本明細書に記載される活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩若しくは溶媒和物、又はそれらの類似体、誘導体、若しくはプロドラッグ)の「延長放出」製剤が考えられる。様々な実施形態では、かかる延長放出製剤は、高ピークの血漿レベルの静脈内の及び従来の即時放出経口剤形を避けるために設計される。
する方法は、例えば、米国特許出願公開第2004/0054164号及びその中で引用される参照において並びに米国特許出願公開第2011/0218173号及びその中で引用される参照において見出される。
本明細書に記載した延長(制御)放出経口(GI又は経粘膜)製剤の1つの利点は、固形剤形又は液体系剤形に関わらず、即放性製剤よりも長い期間の標的治療ウィンドウ内で血漿薬物濃度を維持することができる。かかる従来の即放性製剤について通常観察される高ピークの血漿レベルは、1から12時間又はそれ以上にわたって薬物の持続放出により鈍らされる。更に、薬剤が、錠剤の溶解の時間の長さの間、口腔から血流中に連続的に通過するため、血漿レベルの速やかな低下が避けられ、したがって、血漿薬物動態に、より安定したプラトーを提供する。更に、本明細書に記載した剤形は、治療の安全性を損なう、血漿中の薬物の薬物動態におけるピーク及びトラフの低下による潜在的に有害な副作用を最小限にすることにより、治療の安全性を改善することができる。
OTTR=(CIV max/Cmax)×(用量/用量IV)(Cmaxの50%を超える時間)/(薬物の最終IV消失半減期)により算出することができる。
いくつかの実施形態では、本明細書に記載した1種若しくは複数の活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩若しくは溶媒和物、又はそれらの類似体、誘導体、若しくはプロドラッグ)は、それを必要とする哺乳動物、例えば、アミロイド前駆体タンパク質の異常なプロセシングを特徴とする病態のリスクがある又はそれに罹患している哺乳動物、MCIのアルツハイマー病への進行のリスクがある哺乳動物等に投与される。いくつかの実施形態では、活性薬剤は、前アルツハイマー型認知機能障害の発生を防止する若しくは遅延させるために、及び/又は前アルツハイマー型認知機能障害の1つ若しくは複数の症状を寛解させるために、及び/又は前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する若しくは遅延させるために、及び/又は非アミロイド形成経路によりアミロイド前駆体タンパク質(APP)のプロセシングを促進するために投与される。いくつかの実施形態では、1種若しくは複数の活性薬剤は、例えば、疾患の重症度を下げるために、及び/又は疾患の1つ若しくは複数の症状を寛解させるために、及び/又は疾患の進行を遅らせるために、早期、中期、又は後期アルツハイマー病の治療のために投与される。
いくつかの実施形態では、本明細書に記載される活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記化合物、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩、溶媒和物、若しくは包接体、又はそれらの類似体、誘導体、若しくはプロドラッグ)は、MCI及び/又はADを含めた、脳内のアミロイド沈着を特徴とする疾患を治療する又は予防するために用いる、他の治療薬又はアプローチと組み合わせて用いることができる。したがって、いくつかの実施形態では、本明細書に記載される少なくとも1種の活性薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はその互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、又は前記互変異性体の薬学的に許容される塩、溶媒和物、若しくは包接体、又はその類似体、誘導体、若しくはプロドラッグ)を、少なくとも1種の追加の治療薬、場合によっては、薬学的に許容される担体又は希釈剤と共に含む医薬組成物が考えられる。いくつかの実施形態では、本明細書に記載される少なくとも活性薬剤を、少なくとも1種の追加の治療薬と併せて投与する工程を含む、治療若しくは予防方法が考えられる。
様々な実施形態では、治療の有効性は、薬剤(例えば、本明細書に記載したトリアゾロピリミジン及び/又はトリアゾロピリジン、又はそれらの互変異性体若しくは立体異性体、又は前記トリアゾロピリミジン及び/又はトリアゾロピリジン、前記立体異性体、若しくは前記互変異性体の薬学的に許容されるそれらの塩若しくは溶媒和物、又はそれらの類似体、誘導体、若しくはプロドラッグ)の投与が、薬剤又は類似体が投与された後の1つ又は複数の時点と同じパラメーターに開始される前に、疾患のパラメーターの基準となる時点の測定を比較することにより決定することができる。測定することができる例示的な1つのパラメーターは、APPプロセシング又は関連する及び関係づけられる経路のバイオマーカー(例えば、ペプチドオリゴマー)である。かかるバイオマーカーには、それだけには限らないが、血液、血漿、血清、尿、粘膜又は脳脊髄液(CSF)中のsAPPα、p3(Aβ17-42又はAβ17-40)、sAPPβ、可溶性Aβ40、及び/又は可溶性Aβ42が含まれる。
様々な実施形態では、本明細書に記載した活性薬剤(例えば、トリアゾロピリミジン及び/又はトリアゾロピリジン)は、多回若しくは単回投与容器中で密閉することができる。密閉された薬剤は、例えば、使用のために組み立てることができる構成体を含めた、キットで提供することができる。例えば、凍結乾燥した形態の活性薬剤及び適当な希釈剤は、使用前に組み合わせるための分離された構成成分として提供することができる。キットは、同時投与のための活性薬剤及び第2の治療薬を含むことができる。活性薬剤及び第2の治療薬は、別々の構成体として提供することができる。キットは、複数の容器を含むことができ、各容器は、本化合物の1種若しくは複数の単位投与量を保持する。容器は、それだけには限らないが、例えば、本明細書に記載した通り、経口投与のための錠剤、ゲルカプセル剤、徐放カプセル剤等;非経口投与のためのデポ製品、プレフィルドシリンジ、アンプル、バイアル等;及び局所投与のためのパッチ、メディパッド、クリーム等を含めた、好ましくは、所望の投与のモードに適合される。
J19の合成
J19についての例示的であるが、限定しない合成スキームを図3に示す。合成スキーム1についての試薬及び条件は、(a)2-メトキシエタノール、125℃;(b)NaNO2、DCM、酢酸、r.t;(c)THF、100oC、封管であった。
J03及び類似体の評価
後述の通り、in vitro試験を、SHSY-5Y細胞を用いて行った。これらの細胞は、タウの成熟したアイソフォームを含めた、成熟したニューロンの形態学的及び生化学的な特性を持つ細胞に分化する有用な神経モデルである。
図4に示す通り、パネルA〜C、J03は、タウを減少させ、リン酸化タウ(p-tau)は、CRFによる誘導を増加させる。初回試験では、SHSY-5Y細胞を、無血清で培養して、分化を誘導し、タウ発現を増加させた。CRFを、濃度の増加に応じて、培養物に加え、図4パネルB及びCに示す通り、タウ(パネルB)及びリン酸化タウ(パネルC)は、用量依存方式でCRFと共に増加した。この増加は、比例し、どちらも約50%であった。CRF-によって誘導されたタウを減少させたJ03(図4A)は、p-tau増加よりも増加する。CRFによるp-tauの増加は、予想通りであったが、タウの増加は、CRFが神経細胞の分化を減らすことが予測できなかった(Chenら(2004年)Proc.Natl.Acad.Sci.USA、101巻(44号):15782〜15787頁を参照のこと)、しかしながら、これによって、タウ蓄積が増加し得る。
J04(図2を参照のこと)を、トリアゾロピリジンをトリアゾロピリミジン環で置き換えた類似体として設計した。
化合物J17では(図2を参照のこと)、2つの置換基(図17中の丸で囲まれた置換基を参照のこと)を、逆転した。
J19(図2を参照のこと)は、J17に類似したJ03の類似体であり、本明細書に記載したトリアゾロピリミジンシリーズの一部である。
図28、パネルA〜Dは、CRF-によって誘導されたタウ及びp-tau変更に対するJ03及びJ19の効果を例示している。J03は、CRFの非存在下及び100nM CRFの存在下で有意に低下した(パネルA)。J19はまた、タウを減少させる傾向を示した。J03及びJ19は、CRFの存在下及び非存在下でp-tauを有意に減少した(パネルB)。p-tau/タウ比は、50及び100nM CRFでJ03及びJ19により非常に有意に減少し、CRFの非存在下で減少した(パネルC)。sAPPαについて、J03及びJ19でより高い傾向があり、100nM CRFでJ03が有意性に達した(パネルD)。
Claims (14)
- 下記式:
- S鏡像異性体又はR鏡像異性体である、請求項1に記載の化合物。
- 請求項1又は2に記載の化合物及び薬学的に許容される担体又は賦形剤を含む、医薬製剤。
- 請求項1又は2に記載の化合物を含む薬剤であって、
哺乳動物においてp-tauを減少させる又は哺乳動物におけるp-tauの増加を抑制する若しくは防止するため;及び/又は
哺乳動物において非アミロイド形成経路によるアミロイド前駆体タンパク質(APP)のプロセシングを促進するため;及び/又は
前アルツハイマー状態及び/若しくは認知機能障害の発生を予防する若しくは遅延させる、並びに/又は前アルツハイマー状態及び/若しくは認知機能障害の1つ若しくは複数の症状を寛解させる、又は哺乳動物における前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する又は遅延させるため;及び/又は
前アルツハイマー状態及び/若しくは前アルツハイマー型認知機能障害、又はアルツハイマー病の処置のため;及び/又は
アルツハイマー病の1つ若しくは複数の症状を寛解させる、及び/又はアルツハイマー病を逆転させる、及び/又は哺乳動物においてアルツハイマー病の進行の速度を低減するために使用するための、薬剤。 - 下記式:
哺乳動物においてp-tauを減少させる又は哺乳動物におけるp-tauの増加を抑制する若しくは防止するため;及び/又は
哺乳動物において非アミロイド形成経路によるアミロイド前駆体タンパク質(APP)のプロセシングを促進するため;及び/又は
前アルツハイマー状態及び/若しくは認知機能障害の発生を予防する若しくは遅延させる、並びに/又は前アルツハイマー状態及び/若しくは認知機能障害の1つ若しくは複数の症状を寛解させる、又は哺乳動物における前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する又は遅延させるため;及び/又は
前アルツハイマー状態及び/若しくは前アルツハイマー型認知機能障害、又はアルツハイマー病の処置のため;及び/又は
アルツハイマー病の1つ若しくは複数の症状を寛解させる、及び/又はアルツハイマー病を逆転させる、及び/又は哺乳動物においてアルツハイマー病の進行の速度を低減するために使用するための、医薬組成物。 - 前アルツハイマー状態及び/若しくは前アルツハイマー型認知機能障害、又はアルツハイマー病の処置に使用するための、請求項5に記載の医薬組成物。
- 前記化合物が、S鏡像異性体又はR鏡像異性体である、請求項5または6に記載の医薬組成物。
- 前アルツハイマー状態及び/若しくは前アルツハイマー型認知機能障害、又はアルツハイマー病を治療するための、請求項5から7のいずれか一項に記載の医薬組成物。
- 哺乳動物におけるp-tauの増加を抑制する若しくは防止するために使用するための、請求項5から8のいずれか一項に記載の医薬組成物。
- 下記式:
哺乳動物においてp-tauを減少させる又は哺乳動物におけるp-tauの増加を抑制する若しくは防止するため;及び/又は
哺乳動物において非アミロイド形成経路によるアミロイド前駆体タンパク質(APP)のプロセシングを促進するための、医薬組成物。 - 哺乳動物においてp-tauを減少させる又は哺乳動物におけるp-tauの増加を抑制する若しくは防止するための、請求項10に記載の医薬組成物。
- 前アルツハイマー状態及び/若しくは認知機能障害の発生を予防する若しくは遅延させる、並びに/又は前アルツハイマー状態及び/若しくは認知機能障害の1つ若しくは複数の症状を寛解させる、又は哺乳動物における前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する又は遅延させるため;及び/又は
前アルツハイマー状態及び/若しくは前アルツハイマー型認知機能障害、又はアルツハイマー病の処置に使用するため;及び/又は
アルツハイマー病の1つ若しくは複数の症状を寛解させる、及び/又はアルツハイマー病を逆転させる、及び/又は哺乳動物においてアルツハイマー病の進行の速度を低減するために使用するための、請求項10または11に記載の医薬組成物。 - 前記化合物が、S鏡像異性体又はR鏡像異性体である、請求項10から12のいずれか一項に記載の医薬組成物。
- 前アルツハイマー状態の発生を予防する若しくは遅延させる、並びに/又は前アルツハイマー状態の1つ若しくは複数の症状を寛解させる、又は哺乳動物における前アルツハイマー状態若しくは認知機能障害のアルツハイマー病への進行を防止する又は遅延させるため;及び/又は
前アルツハイマー状態の処置に使用するための、請求項10から13のいずれか一項に記載の医薬組成物。
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