TWI423802B - 用於治療阿茲海默症之藥劑 - Google Patents
用於治療阿茲海默症之藥劑 Download PDFInfo
- Publication number
- TWI423802B TWI423802B TW097118634A TW97118634A TWI423802B TW I423802 B TWI423802 B TW I423802B TW 097118634 A TW097118634 A TW 097118634A TW 97118634 A TW97118634 A TW 97118634A TW I423802 B TWI423802 B TW I423802B
- Authority
- TW
- Taiwan
- Prior art keywords
- salt
- disease
- hydrochloride
- winternipazole
- treating alzheimer
- Prior art date
Links
- 208000024827 Alzheimer disease Diseases 0.000 title claims description 36
- 239000003814 drug Substances 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 14
- 150000007660 quinolones Chemical class 0.000 claims description 14
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical group C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 8
- 229960004588 cilostazol Drugs 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 229940039856 aricept Drugs 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000006200 vaporizer Substances 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 1
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 1
- 206010027940 Mood altered Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012412 Presenilin-1 Human genes 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000371 effect on dementia Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000008023 pharmaceutical filler Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 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
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係關於一種用於治療阿茲海默症之藥劑，特別是，本發明係關於一種用於治療阿茲海默症之藥劑，包括以下各者作為活性成分：通式(1)之喹諾酮(carbostyril)衍生物或其鹽
[式中，A為低級伸烷基；R為環烷基；喹諾酮骨架之3及4位置間的鍵結為單鍵或雙鍵]；以及冬尼培唑(donepezil)或其鹽。
JP-63-20235-B及JP-55-35019-A揭露式(1)之喹諾酮(carbostyril)衍生物或其鹽類、及其製備方法。而且，咸知該喹諾酮衍生物(1)具有血小板聚集抑制作用、磷酸二酯酶(PDE)抑制作用、抗潰瘍作用、降血壓作用及消炎作用，而可用於作為抗血栓劑、用於改善腦循環之藥物、抗發炎劑、抗潰瘍藥物、抗高血壓藥物、止哮喘藥物、磷酸二酯酶抑制劑等。此外，咸知該化合物亦可用於作為用於治療過敏性疾病之藥劑(JP-5-320050-A)。亦知該喹諾酮衍生物(1)係用於治療阿茲海默症之藥劑(JP-2006-518732-A)。
在日本受癡呆症(dementia)之苦的病患之數量估計有1,890,000人，且其疾病盛行率於2005年估計為7.6%，因此該數目及比率隨著社會老化之進展而增加。咸知患有阿茲海默症(AD)之病患的數量佔患有癡呆症病患之總量的半數以上。
大部分AD被認為是偶發性病例(sporadic case)，但是家族性AD被認為包含其中的大約10%，其可能由於基因(例如澱粉樣前體蛋白質基因、早老素-1(presenilin-1)及早老素-2)的誤義突變(missense mutation)隨著體染色體顯性遺傳而患病。特別是，婦女更容易患有AD。AD的最主要危險因子是老化。AD的疾病盛行率隨著年齡而增加，因此多數的AD為晚發性AD，其係在65歲患病或在65歲以後患病。取決於神經傳遞物質(例如乙醯膽鹼)的病症、由於澱粉樣β蛋白在腦內的積聚而形成的老年斑、異常纖維絲(包括磷酸化τ蛋白及其他物質)在神經元內的積聚、由於神經元細胞剝落而致使的腦嚴重萎縮等，AD病患可能顯示有多種病理性病況。AD的核心病徵包含記憶損傷、失語症、認知損傷、執行功能的病症、及相關的病徵；其中許多是精神異常欣快的(euphoric)。然而，AD的某些病徵顯示出不利的病況，例如缺乏動力、抑鬱症、不良情緒、來自發病初期的不健康情緒。
對AD的核心病徵而言，冬尼培唑鹽酸鹽(商品名：愛憶欣(Aricept))係廣泛地用在臨床診療(JP-2578475-B)。對相關的病徵(例如失眠、不健康情緒、及妄想症)而言，
冬尼培唑鹽酸鹽亦可用於作為緩解性治療(palliative therapy)(Japanese Journal of Psychiatric Treatment, Vol. 21, Supplement, Page. 302-305, October 15, 2006, Tsuneyoshi Ohta, Heii Arai)。然而，利用冬尼培唑鹽酸鹽之緩解性治療的效果隨著長期使用而傾向於降低。因此，由於必須長期投予藥劑，所以冬尼培唑鹽酸鹽亦有難以持續及充分壓制病理性病況的發展之問題。
如上所述，冬尼培唑鹽酸鹽(商品名：愛憶欣(Aricept®
))已廣泛地用作治療阿茲海默症之藥劑，然而，對治療阿茲海默症仍希望發展更有效的藥劑，其可抑制冬尼培唑鹽酸鹽由於長期投藥所造成之治療效果的降低。
本案發明人已透徹研究出一種用於治療阿茲海默症之新穎藥劑，且發現上述式(1)之喹諾酮衍生物，特別是6-[4-(1-環己基-1H-四唑-5-基)丁氧基]-3, 4-二氫喹諾酮(西洛他唑(cilostazol))或其鹽，及冬尼培唑或其鹽之組合或組合用藥(drug combination)對治療阿茲海默症呈現優異的協同作用(synergistic action)，然後完成本發明。特別是，本案發明人發現本發明之組合能夠呈現優異的效果以改善由於長期投予冬尼培唑鹽酸鹽而使冬尼培唑鹽酸鹽之作用降低。此外，本發明之組合或組合用藥呈現快速效能(fast-acting)及低毒性，因此可長期投予。依據安全的觀點，本發明對治療阿茲海默症亦為有用的藥劑。
本發明提供一種用於治療阿茲海默症之藥劑，包括以
下各者作為活性成分：通式(1)之喹諾酮衍生物或其鹽
[式中，A為低級伸烷基；R為環烷基；喹諾酮骨架之3及4位置間的鍵結為單鍵或雙鍵]；以及冬尼培唑(donepezil)或其鹽。
本發明亦提供一種用於治療阿茲海默症之藥劑，包括6-[4-(1-環己基-1H-四唑-5-基)丁氧基]-3, 4-二氫喹諾酮(西洛他唑)或其鹽，及冬尼培唑或其鹽作為活性成分。
本發明亦提供一種用於治療阿茲海默症之藥劑，包括喹諾酮衍生物(1)及冬尼培唑鹽酸鹽作為活性成分。
本發明亦提供一種用於治療阿茲海默症之組成物，包括上述之活性成分。
本發明亦提供一種喹諾酮衍生物(1)或其鹽、及冬尼培唑或其鹽之用途，其係用於製備治療阿茲海默症之藥劑。
本發明亦提供一種用於治療阿茲海默症之方法，該方法包括對需要該等治療之病患投予有效量之喹諾酮衍生物(1)或其鹽、及冬尼培唑或其鹽。
根據本發明，喹諾酮衍生物(1)，特別是6-[4-(1-環己基-1H-四唑-5-基)丁氧基]-3, 4-二氫喹諾酮或其鹽，及
冬尼培唑鹽酸鹽之組合對阿茲海默症呈現有效的理論性及預防性作用。
包括在組合用藥或與冬尼培唑或其鹽用作為組合物之喹諾酮衍生物係下式(1)表示之四唑基烷氧基-二氫喹諾酮衍生物或其鹽：
式中，A為低級伸烷基；R為環烷基；喹諾酮骨架之3及4位置間的鍵結為單鍵或雙鍵。
上述式(1)中，環烷基包含C3
-C8
環烷基，例如環丙基、環丁基、環戊基、環己基、環庚基、及環辛基。較佳之環烷基為環己基。低級伸烷基包含C1
-C6
伸烷基，例如亞甲基、伸乙基、伸丙基、四亞甲基、伸丁基、及伸戊基，其中，較佳之一者係四亞甲基。
較佳之喹諾酮衍生物係6-[4-(1-環己基-1H-四唑-5-基)丁氧基]-3, 4-二氫喹諾酮，其係以西洛他唑之商品名上市作為抗血小板劑。
喹諾酮衍生物(1)能藉由使用醫藥上可接受之酸來處理而易於轉換成其鹽。該酸包含，例如，無機酸類，諸如鹽酸、硫酸、磷酸、及氫溴酸；及有機酸類，諸如草酸、
順丁烯二酸、延胡索酸、蘋果酸、酒石酸、檸檬酸、及苯甲酸。
這些喹諾酮衍生物(1)及其鹽類及其製備方法係揭露在JP-55-35019-A(相關於美國專利第4,277,479號)。
其他活性成分係冬尼培唑，它的化學名稱係1-苄基-4-[(5, 6-二甲氧基二氫茚-1-酮)-2-基]甲基哌。其鹽酸鹽已上市作為治療阿茲海默症之藥劑(冬尼培唑鹽酸鹽，商品名：愛憶欣(Aricept®
))。此化合物揭露在JP-2578475-B。本發明之1-苄基-4-[(5, 6-二甲氧基二氫茚-1-酮)-2-基]甲基哌使用醫藥上可接受之酸能容易地轉換成其鹽形式。該酸包含，例如，無機酸類，諸如鹽酸、硫酸、磷酸、及氫溴酸；及有機酸類，諸如草酸、順丁烯二酸、延胡索酸、蘋果酸、酒石酸、檸檬酸、及苯甲酸。其中，其鹽酸鹽(冬尼培唑鹽酸鹽)為較佳者。
這些活性成分，即喹諾酮衍生物(1)或其鹽及冬尼培唑或其鹽可同時或不同時地共同投予或分開投予。這些成分通常能以傳統的醫藥配方使用。此外，這些成分可製備成單一劑型或個別劑型。
包括本發明之喹諾酮衍生物(1)或其鹽及冬尼培唑或其鹽之藥劑係適用於一般癡呆症，包含阿茲海默症。因此，本發明藥劑之應用包含認知損傷(例如阿茲海默型癡呆、老年性痴呆及年輕型痴呆(young-onset dementia))、以及亨丁頓舞蹈症(Huntington's disease)、匹克症(Pick' disease)、晚發型動作障礙等。
這些活性成份的劑量不被限制在特定範圍。喹諾酮衍生物(1)或其鹽可於每成人(50公斤體重)以50至200 mg/日之用量來使用，此劑量係每日投予一次或每日分成2至數次投予。冬尼培唑可於每成人(50公斤體重)以約0.1至300 mg/日，較佳約1至10 mg/日之用量來使用，此劑量通常係每日分成1至4次投予。當這些成分製備成單一劑型時，係以相對於每1重量份之喹諾酮衍生物(1)或其鹽為0.025至1.0重量份之冬尼培唑的比率將該等成分予以併入。且，該組合用藥每製劑可包含總計0.1至70%(w/w)的該等成分，但不受限於此數值。
用於本發明之組合用藥或組合的各劑型包含，例如，例示於JP-10-175864-A之劑型，且典型係口服固體劑型(例如錠劑及膠囊)、口服液體劑型(例如糖漿及酏劑)、非經腸胃劑型(例如注射劑)、及吸入劑。
本發明之製劑，例如錠劑、膠囊、用於口服投藥之液體可經習知方法製備。錠劑可經混合活性成分與傳統醫藥上之載劑(例如明膠、澱粉、乳糖、硬脂酸鎂、滑石、阿拉伯膠等)而製備。膠囊可經混合活性成分與惰性醫藥填料或稀釋劑，再利用該混合物填充硬明膠膠囊或軟膠囊而製備。口服液體製劑(例如糖漿或酏劑)係經混合活性成分與甜味劑(例如蔗糖)、保存劑(例如對羥苯甲酸甲酯、對羥苯甲酸丙酯)、著色劑、調味劑等而製備。用於非經腸胃投藥之製劑亦可經由傳統方法製備，例如經由將本發明之活性成分溶於無菌水性載劑，較佳係水或鹽水溶液而製備。適
用於非經腸胃投藥之較佳液體製劑係經由下列步驟製備：將每日劑量的如上述之活性成分溶於水中及有機溶劑中，然後再溶於具有300至5000分子量的聚乙二醇中，其中，較佳係併入潤滑劑(例如羧甲基纖維素鈉、甲基纖維素、聚乙烯吡咯啶酮、及聚乙烯醇)。較佳地，上述液體製劑可進一步包括消毒劑(例如苯甲醇、酚、乙汞硫柳酸鈉)、殺真菌劑，且進一步視需要地包括等張劑(例如蔗糖、氯化鈉)、局部麻醉劑、安定劑、緩衝劑等。鑒於維持安定性，用於非經腸胃投藥之製劑可裝入膠囊內，接著經由習知的冷凍乾燥技術移除水性介質。當使用該製劑時，可經由溶於水性介質中而恢復成液體製劑。吸入劑可經由習知方法製備。亦即，吸入劑可經由下列步驟製備：使活性化合物成為粉末或液體狀態，將該活性化合物混合入用於吸入劑的推進劑及/或載劑，再將混合物饋入適當的汽化器。通常，當活性化合物為粉末時，可使用機械式粉末汽化器，而當化合物為液體時，則可使用諸如噴霧器之汽化器。此外，吸入劑可視需要地包括界面活性劑、油、調味劑、環糊精或必要時所使用的其衍生物。
以上提及之添加劑、其製程、或其他事物之實例包括，但不限於JP-10-175864-A所揭露者。
分別對兩位患有阿茲海默症之女性(一位63歲，另一位52歲)以5mg/日之劑量投予冬尼培唑鹽酸鹽(Aricept®
)12個月及9個月。在投藥期間，對該兩位女性病患進行簡
易心智狀態檢查(mini-mental state examination (MMSE))(Journal of psychiatric research. 1975 Nov; 12(3):189-98.)，而結果係顯示在表1及第1圖。在實驗開始時(第0月)，係以與冬尼培唑鹽酸鹽之組合開始以100mg/日之劑量投予西洛他唑。此時，到當時仍持續下降中的MMSE評分係快速提升。根據上述結果，發現當冬尼培唑鹽酸鹽而投予西洛他唑可恢復由於長期投予冬尼培唑鹽酸鹽而傾向降低的冬尼培唑鹽酸鹽之效果。且亦發現，冬尼培唑鹽酸鹽及西洛他唑之組合可對癡呆症(例如阿茲海默症)提供有效的理論效果。
第1圖表示使用冬尼培唑鹽酸鹽及西洛他唑一起作為組合對阿茲海默症之理論效果。
由於本案的圖為試驗化合物的結果數據，並非本案的代表圖。故本案無指定代表圖。
Claims (5)
- 一種用於治療阿茲海默症之藥劑，包括以下各者作為活性成分：通式(1)之喹諾酮(carbostyril)衍生物或其鹽
- 如申請專利範圍第1項之藥劑，其中，該喹諾酮衍生物係6-[4-(1-環己基-1H-四唑-5-基)丁氧基]-3,4-二氫喹諾酮或其鹽。
- 如申請專利範圍第1項或第2項之藥劑，其中，該冬尼培唑之鹽係冬尼培唑鹽酸鹽。
- 一種如申請專利範圍第1項或第2項所述之喹諾酮衍生物或其鹽、及冬尼培唑或其鹽之用途，其係用於製備治療阿茲海默症之藥劑。
- 如申請專利範圍第4項之用途，其中，該冬尼培唑之鹽係冬尼培唑鹽酸鹽。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007135367 | 2007-05-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200904428A TW200904428A (en) | 2009-02-01 |
| TWI423802B true TWI423802B (zh) | 2014-01-21 |
Family
ID=39636992
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW097118634A TWI423802B (zh) | 2007-05-22 | 2008-05-21 | 用於治療阿茲海默症之藥劑 |
| TW102147146A TWI489983B (zh) | 2007-05-22 | 2008-05-21 | 用於治療阿茲海默症之藥劑 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW102147146A TWI489983B (zh) | 2007-05-22 | 2008-05-21 | 用於治療阿茲海默症之藥劑 |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US20100298375A1 (zh) |
| EP (2) | EP2937085B1 (zh) |
| JP (1) | JP5153870B2 (zh) |
| KR (1) | KR101441725B1 (zh) |
| CN (1) | CN101754758B (zh) |
| AR (1) | AR066664A1 (zh) |
| AU (1) | AU2008253977B2 (zh) |
| BR (1) | BRPI0811919A2 (zh) |
| CA (1) | CA2687289C (zh) |
| CO (1) | CO6251249A2 (zh) |
| CY (1) | CY1116683T1 (zh) |
| DK (1) | DK2157973T3 (zh) |
| ES (1) | ES2545959T3 (zh) |
| HK (2) | HK1140422A1 (zh) |
| HR (1) | HRP20150843T1 (zh) |
| HU (1) | HUE025902T2 (zh) |
| IL (1) | IL202053A (zh) |
| MX (1) | MX2009012583A (zh) |
| MY (1) | MY146407A (zh) |
| NZ (1) | NZ581099A (zh) |
| PL (1) | PL2157973T3 (zh) |
| PT (1) | PT2157973E (zh) |
| RU (1) | RU2469723C2 (zh) |
| SI (1) | SI2157973T1 (zh) |
| TW (2) | TWI423802B (zh) |
| UA (1) | UA96633C2 (zh) |
| WO (1) | WO2008143361A1 (zh) |
| ZA (1) | ZA200908202B (zh) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2135607A1 (en) | 2008-06-18 | 2009-12-23 | Pharnext | Combination of pilocarpin and methimazol for treating Charcot-MarieTooth disease and related disorders |
| US9387206B2 (en) | 2009-11-03 | 2016-07-12 | Pharnext | Therapeutic approaches for treating Alzheimer's disease |
| EP2322163A1 (en) | 2009-11-03 | 2011-05-18 | Pharnext | New therapeutics approaches for treating alzheimer disease |
| US9241933B2 (en) | 2011-03-01 | 2016-01-26 | Pharnext | Compositions for treating amyotrophic lateral sclerosis |
| KR101918745B1 (ko) | 2011-03-01 | 2018-11-15 | 파넥스트 | 바클로펜 및 아캄프로세이트에 기초한 신경 장애의 치료 |
| US10010515B2 (en) | 2011-03-01 | 2018-07-03 | Pharnext | Therapeutic approaches for treating Parkinson's disease |
| US9248111B2 (en) | 2011-03-01 | 2016-02-02 | Pharnext | Therapeutic approaches for treating parkinson's disease |
| US20150152084A1 (en) * | 2012-06-15 | 2015-06-04 | Foundation For Biomedical Research And Innovation | Prophylactic and/or therapeutic agent for mild cognitive impairment |
| WO2015100255A2 (en) * | 2013-12-23 | 2015-07-02 | Holaday John W | Disposable container for air hydration |
| WO2017199755A1 (ja) | 2016-05-19 | 2017-11-23 | 国立研究開発法人国立循環器病研究センター | 認知症の予防及び／又は治療のための薬剤 |
| HUE053636T2 (hu) | 2017-05-24 | 2021-07-28 | H Lundbeck As | 5-HT6 receptor antagonista és acetilkolin-észteráz inhibitor kombinációja Alzheimer-kór kezelésében történõ alkalmazásra ApoE4 alléleket hordozó betegek szubpopulációjában |
| CN107602523B (zh) * | 2017-09-11 | 2020-08-18 | 安徽中医药大学 | 京尼平类似物、制备方法及其应用 |
| PL237739B1 (pl) | 2018-06-06 | 2021-05-17 | Univ Gdanski | Genisteina do zastosowania do leczenia choroby Alzheimera |
| NL2024431B1 (en) | 2019-12-11 | 2021-09-07 | Sulfateq Bv | Compounds for treatment of alzheimer’s disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040229913A1 (en) * | 2002-12-13 | 2004-11-18 | Eisal Co., Ltd. | Therapeutic agent for severe Alzheimer's dementia |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5535019A (en) * | 1978-09-01 | 1980-03-11 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
| JPS5649378A (en) | 1979-08-25 | 1981-05-02 | Otsuka Pharmaceut Co Ltd | Tetrazolylalkoxycarbostyril derivative |
| FI95572C (fi) | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Menetelmä lääkeaineena käyttökelpoisen piperidiinijohdannaisten tai sen farmaseuttisen suolan valmistamiseksi |
| JP2574099B2 (ja) | 1992-05-21 | 1997-01-22 | 大塚製薬株式会社 | アレルギー疾患治療剤 |
| JPH10175864A (ja) | 1996-12-16 | 1998-06-30 | Otsuka Pharmaceut Co Ltd | 慢性閉塞性肺疾患治療剤 |
| US6428488B1 (en) * | 1997-08-28 | 2002-08-06 | Kenneth Kensey | Dual riser/dual capillary viscometer for newtonian and non-newtonian fluids |
| US6322524B1 (en) * | 1997-08-28 | 2001-11-27 | Visco Technologies, Inc. | Dual riser/single capillary viscometer |
| US6322525B1 (en) * | 1997-08-28 | 2001-11-27 | Visco Technologies, Inc. | Method of analyzing data from a circulating blood viscometer for determining absolute and effective blood viscosity |
| US6019735A (en) * | 1997-08-28 | 2000-02-01 | Visco Technologies, Inc. | Viscosity measuring apparatus and method of use |
| CA2316360C (en) * | 1998-01-16 | 2007-09-18 | Eisai Co., Ltd. | Process for production of donepezil derivative |
| US6187790B1 (en) * | 1999-03-04 | 2001-02-13 | Neal R. Cutler | Use of cilostazol for treatment of sexual dysfunction |
| US6294192B1 (en) * | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
| US6267985B1 (en) * | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
| US6484565B2 (en) * | 1999-11-12 | 2002-11-26 | Drexel University | Single riser/single capillary viscometer using mass detection or column height detection |
| US6458804B1 (en) * | 2001-01-26 | 2002-10-01 | R.T. Alamo Venturesi, Llc | Methods for the treatment of central nervous system disorders in certain patient groups |
| TW200301135A (en) * | 2001-12-27 | 2003-07-01 | Otsuka Maryland Res Inst Inc | Pharmaceutical compositions comprising a multifunctional phosphodiesterase inhibitor and an adenosine uptake inhibitor |
| IL150509A (en) * | 2002-07-01 | 2007-07-04 | Joseph Kaspi | Pharmaceutical preparations containing donafazil hydrochloride |
| US6743806B2 (en) * | 2002-10-23 | 2004-06-01 | Otsuka Pharmaceutical Company, Limited | Active oxygen scavenger |
| FR2848452B1 (fr) * | 2002-12-12 | 2007-04-06 | Aventis Pharma Sa | Application des inhibiteurs de recapture intestinale des acides biliaires pour la prevention et le traitement de la maladie d'alzheimer |
| TWI323660B (en) * | 2003-02-25 | 2010-04-21 | Otsuka Pharma Co Ltd | Pten inhibitor or maxi-k channels opener |
-
2008
- 2008-05-21 PL PL08764779T patent/PL2157973T3/pl unknown
- 2008-05-21 SI SI200831493T patent/SI2157973T1/sl unknown
- 2008-05-21 CA CA2687289A patent/CA2687289C/en not_active Expired - Fee Related
- 2008-05-21 DK DK08764779.8T patent/DK2157973T3/en active
- 2008-05-21 BR BRPI0811919-8A2A patent/BRPI0811919A2/pt not_active IP Right Cessation
- 2008-05-21 MX MX2009012583A patent/MX2009012583A/es active IP Right Grant
- 2008-05-21 JP JP2010509026A patent/JP5153870B2/ja not_active Expired - Fee Related
- 2008-05-21 PT PT87647798T patent/PT2157973E/pt unknown
- 2008-05-21 KR KR1020097026651A patent/KR101441725B1/ko active IP Right Grant
- 2008-05-21 HU HUE08764779A patent/HUE025902T2/en unknown
- 2008-05-21 EP EP15164200.6A patent/EP2937085B1/en active Active
- 2008-05-21 US US12/599,962 patent/US20100298375A1/en not_active Abandoned
- 2008-05-21 NZ NZ581099A patent/NZ581099A/en not_active IP Right Cessation
- 2008-05-21 RU RU2009147456/15A patent/RU2469723C2/ru not_active IP Right Cessation
- 2008-05-21 CN CN2008800167568A patent/CN101754758B/zh not_active Expired - Fee Related
- 2008-05-21 WO PCT/JP2008/059763 patent/WO2008143361A1/en active Application Filing
- 2008-05-21 AU AU2008253977A patent/AU2008253977B2/en not_active Ceased
- 2008-05-21 MY MYPI20094815A patent/MY146407A/en unknown
- 2008-05-21 UA UAA200913247A patent/UA96633C2/uk unknown
- 2008-05-21 TW TW097118634A patent/TWI423802B/zh not_active IP Right Cessation
- 2008-05-21 TW TW102147146A patent/TWI489983B/zh not_active IP Right Cessation
- 2008-05-21 AR ARP080102154A patent/AR066664A1/es unknown
- 2008-05-21 ES ES08764779.8T patent/ES2545959T3/es active Active
- 2008-05-21 EP EP08764779.8A patent/EP2157973B1/en active Active
-
2009
- 2009-11-11 IL IL202053A patent/IL202053A/en not_active IP Right Cessation
- 2009-11-20 ZA ZA200908202A patent/ZA200908202B/xx unknown
- 2009-12-21 CO CO09145995A patent/CO6251249A2/es active IP Right Grant
-
2010
- 2010-07-13 HK HK10106804.1A patent/HK1140422A1/zh not_active IP Right Cessation
-
2015
- 2015-08-07 HR HRP20150843TT patent/HRP20150843T1/hr unknown
- 2015-09-14 CY CY20151100797T patent/CY1116683T1/el unknown
-
2016
- 2016-03-23 HK HK16103366.2A patent/HK1215384A1/zh not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040229913A1 (en) * | 2002-12-13 | 2004-11-18 | Eisal Co., Ltd. | Therapeutic agent for severe Alzheimer's dementia |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI423802B (zh) | 用於治療阿茲海默症之藥劑 | |
| EP3992183A1 (en) | Method for treating idiopathic pulmonary fibrosis | |
| US20100160372A1 (en) | Treatment of proteinopathies using a farnesyl transferase inhibitor | |
| JP2014185161A (ja) | シロスタゾールを含むカルボスチリル誘導体の脂肪肝治療剤 | |
| US20150258107A1 (en) | Methods and compositions for treating depression | |
| AU2007212349A1 (en) | 4-acylaminopyridine derivative mediated neurogenesis | |
| SK22004A3 (sk) | Farmaceutická kompozícia na moduláciu cholínergnej funkcie a použitie kombinácie NRPA zlúčeniny a antiemetického/antinauzeózneho činidla na výrobu liečiva | |
| AU2016220049A1 (en) | Triazolopyridines and triazolopyrimidines that lower stress-induced p-tau | |
| WO2024050527A2 (en) | Intranasal dihydropyridine compositions and methods | |
| WO2023123468A1 (zh) | 心脑血管药物及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |