JPH09503491A - ムスカリン様アゴニスト活性を有するコリン作用系に作用するアザスピロ化合物 - Google Patents
ムスカリン様アゴニスト活性を有するコリン作用系に作用するアザスピロ化合物Info
- Publication number
- JPH09503491A JPH09503491A JP7504995A JP50499595A JPH09503491A JP H09503491 A JPH09503491 A JP H09503491A JP 7504995 A JP7504995 A JP 7504995A JP 50499595 A JP50499595 A JP 50499595A JP H09503491 A JPH09503491 A JP H09503491A
- Authority
- JP
- Japan
- Prior art keywords
- spiro
- methylpiperidine
- compounds
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000694 effects Effects 0.000 title claims abstract description 118
- 239000000472 muscarinic agonist Substances 0.000 title claims abstract description 22
- 230000001713 cholinergic effect Effects 0.000 title description 13
- 150000008627 azaspiro compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 277
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 33
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 27
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical group C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 21
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 19
- 210000001428 peripheral nervous system Anatomy 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 67
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 claims description 66
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 claims description 66
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 claims description 66
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 66
- -1 2-oxo-pyrrolidin-1-yl-methyl Chemical group 0.000 claims description 51
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 44
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 40
- 229940053128 nerve growth factor Drugs 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 34
- 229940091173 hydantoin Drugs 0.000 claims description 24
- 230000028327 secretion Effects 0.000 claims description 23
- 102000013498 tau Proteins Human genes 0.000 claims description 20
- 108010026424 tau Proteins Proteins 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical group CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 11
- 210000005036 nerve Anatomy 0.000 claims description 11
- 230000000508 neurotrophic effect Effects 0.000 claims description 11
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 230000012010 growth Effects 0.000 claims description 10
- 230000003551 muscarinic effect Effects 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229960002646 scopolamine Drugs 0.000 claims description 10
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 claims description 9
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 claims description 9
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 9
- 230000004071 biological effect Effects 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 230000002195 synergetic effect Effects 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 230000001976 improved effect Effects 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 7
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 229960001231 choline Drugs 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 229960002715 nicotine Drugs 0.000 claims description 7
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 claims description 7
- 229960004633 pirenzepine Drugs 0.000 claims description 7
- 125000006413 ring segment Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 6
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 6
- UBRKDAVQCKZSPO-UHFFFAOYSA-N 11-[2-[2-(diethylaminomethyl)-1-piperidinyl]-1-oxoethyl]-5H-pyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound CCN(CC)CC1CCCCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 UBRKDAVQCKZSPO-UHFFFAOYSA-N 0.000 claims description 6
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 6
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 claims description 6
- 102000005157 Somatostatin Human genes 0.000 claims description 6
- 108010056088 Somatostatin Proteins 0.000 claims description 6
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 claims description 6
- 229960004012 amifampridine Drugs 0.000 claims description 6
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 claims description 6
- 229960000793 aniracetam Drugs 0.000 claims description 6
- YBCNXCRZPWQOBR-WVHCHWADSA-N butylscopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CCCC)=CC=CC=C1 YBCNXCRZPWQOBR-WVHCHWADSA-N 0.000 claims description 6
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 6
- 229960002896 clonidine Drugs 0.000 claims description 6
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 claims description 6
- 229960004801 imipramine Drugs 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 229940067606 lecithin Drugs 0.000 claims description 6
- 235000010445 lecithin Nutrition 0.000 claims description 6
- LDMWSLGGVTVJPG-UHFFFAOYSA-N minaprine Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1NCCN1CCOCC1 LDMWSLGGVTVJPG-UHFFFAOYSA-N 0.000 claims description 6
- 229960004758 minaprine Drugs 0.000 claims description 6
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 claims description 6
- 229960001227 oxiracetam Drugs 0.000 claims description 6
- 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 claims description 6
- 229960001697 physostigmine Drugs 0.000 claims description 6
- ZULJGOSFKWFVRX-UHFFFAOYSA-N pramiracetam Chemical compound CC(C)N(C(C)C)CCNC(=O)CN1CCCC1=O ZULJGOSFKWFVRX-UHFFFAOYSA-N 0.000 claims description 6
- 229960003389 pramiracetam Drugs 0.000 claims description 6
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 6
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 6
- 229960000553 somatostatin Drugs 0.000 claims description 6
- 229960001685 tacrine Drugs 0.000 claims description 6
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 6
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 claims description 5
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 claims description 5
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 5
- 229960000836 amitriptyline Drugs 0.000 claims description 5
- 150000001768 cations Chemical group 0.000 claims description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- 229940015042 glycopyrrolate Drugs 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229960001158 nortriptyline Drugs 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 230000003248 secreting effect Effects 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 208000015114 central nervous system disease Diseases 0.000 claims description 4
- 239000003102 growth factor Substances 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 208000027232 peripheral nervous system disease Diseases 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 150000001450 anions Chemical group 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 230000001270 agonistic effect Effects 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- WAVYHSURRZBQKO-UHFFFAOYSA-N 1-cyclohexyl-4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butan-1-one Chemical compound C=1C=C(OC)C=CC=1CC(C)N(CC)CCCC(=O)C1CCCCC1 WAVYHSURRZBQKO-UHFFFAOYSA-N 0.000 claims 4
- 230000001272 neurogenic effect Effects 0.000 claims 4
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 claims 4
- 229950004117 secoverine Drugs 0.000 claims 4
- 239000007921 spray Substances 0.000 claims 4
- 230000010757 Reduction Activity Effects 0.000 claims 3
- 150000001721 carbon Chemical group 0.000 claims 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 241001061127 Thione Species 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 230000008484 agonism Effects 0.000 claims 1
- 230000000975 bioactive effect Effects 0.000 claims 1
- 238000005422 blasting Methods 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 150000003413 spiro compounds Chemical class 0.000 abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 232
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 143
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 106
- 241000700159 Rattus Species 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 94
- 239000000243 solution Substances 0.000 description 86
- 239000007787 solid Substances 0.000 description 65
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 64
- 239000000556 agonist Substances 0.000 description 59
- 238000005481 NMR spectroscopy Methods 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- 239000000047 product Substances 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 47
- 238000012360 testing method Methods 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- 239000000284 extract Substances 0.000 description 38
- 239000012458 free base Substances 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 34
- 208000024827 Alzheimer disease Diseases 0.000 description 33
- 210000004556 brain Anatomy 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 33
- PHOZOHFUXHPOCK-UHFFFAOYSA-N 2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)C(CC)SC11CCN(C)CC1 PHOZOHFUXHPOCK-UHFFFAOYSA-N 0.000 description 31
- 230000002829 reductive effect Effects 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 27
- 239000011780 sodium chloride Substances 0.000 description 27
- ZSTLCHCDLIUXJE-ZGBAEQJLSA-N (2S,5S)-2-methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane] hydrate dihydrochloride Chemical compound O.Cl.Cl.C1S[C@@H](C)O[C@@]21C(CC1)CCN1C2.C1S[C@@H](C)O[C@@]21C(CC1)CCN1C2 ZSTLCHCDLIUXJE-ZGBAEQJLSA-N 0.000 description 26
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 26
- 229940079593 drug Drugs 0.000 description 24
- 230000001965 increasing effect Effects 0.000 description 24
- 208000024891 symptom Diseases 0.000 description 24
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 23
- 235000011114 ammonium hydroxide Nutrition 0.000 description 23
- 239000012528 membrane Substances 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- 238000000354 decomposition reaction Methods 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 150000003906 phosphoinositides Chemical class 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 20
- 229940114079 arachidonic acid Drugs 0.000 description 19
- 235000021342 arachidonic acid Nutrition 0.000 description 19
- 230000007062 hydrolysis Effects 0.000 description 19
- 238000006460 hydrolysis reaction Methods 0.000 description 19
- 239000011877 solvent mixture Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 238000003556 assay Methods 0.000 description 17
- 206010021113 Hypothermia Diseases 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000002631 hypothermal effect Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000004113 cell culture Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 14
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 14
- 230000009471 action Effects 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- CANZROMYQDHYHR-UHFFFAOYSA-N oxotremorine M Chemical compound C[N+](C)(C)CC#CCN1CCCC1=O CANZROMYQDHYHR-UHFFFAOYSA-N 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 206010039424 Salivary hypersecretion Diseases 0.000 description 13
- 230000004913 activation Effects 0.000 description 13
- 230000009286 beneficial effect Effects 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 208000008630 Sialorrhea Diseases 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 230000001054 cortical effect Effects 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 150000003840 hydrochlorides Chemical class 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 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 11
- 229910021529 ammonia Inorganic materials 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 238000010828 elution Methods 0.000 description 11
- 238000011534 incubation Methods 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 11
- 230000001404 mediated effect Effects 0.000 description 11
- 239000004031 partial agonist Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 101100424823 Arabidopsis thaliana TDT gene Proteins 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 208000018737 Parkinson disease Diseases 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 10
- 230000003389 potentiating effect Effects 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 206010044565 Tremor Diseases 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 230000002093 peripheral effect Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 8
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 8
- 206010012735 Diarrhoea Diseases 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000001099 ammonium carbonate Substances 0.000 description 8
- 235000012501 ammonium carbonate Nutrition 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 8
- 230000014511 neuron projection development Effects 0.000 description 8
- 230000003287 optical effect Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000012549 training Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 7
- 229960004373 acetylcholine Drugs 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 235000006408 oxalic acid Nutrition 0.000 description 7
- 230000036961 partial effect Effects 0.000 description 7
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 208000006550 Mydriasis Diseases 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- 241000906446 Theraps Species 0.000 description 6
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 6
- 230000003542 behavioural effect Effects 0.000 description 6
- STECJAGHUSJQJN-VJQRDGCPSA-N chembl3084722 Chemical compound C1([C@@H](CO)C(=O)O[C@@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-VJQRDGCPSA-N 0.000 description 6
- 238000000586 desensitisation Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 5
- 206010015150 Erythema Diseases 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 229960002317 succinimide Drugs 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 4
- 206010003591 Ataxia Diseases 0.000 description 4
- 102000017927 CHRM1 Human genes 0.000 description 4
- 101150073075 Chrm1 gene Proteins 0.000 description 4
- 108091006027 G proteins Proteins 0.000 description 4
- 102000030782 GTP binding Human genes 0.000 description 4
- 108091000058 GTP-Binding Proteins 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 206010039897 Sedation Diseases 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 230000002567 autonomic effect Effects 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 210000001638 cerebellum Anatomy 0.000 description 4
- 239000002026 chloroform extract Substances 0.000 description 4
- 230000009850 completed effect Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 4
- 238000011533 pre-incubation Methods 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000036280 sedation Effects 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000007306 turnover Effects 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 3
- HJVJWEVTPUHAFE-UHFFFAOYSA-N 2,8-dimethyl-1,3,8-triazaspiro[4.5]dec-2-ene Chemical compound C1CN(C)CCC11N=C(C)NC1 HJVJWEVTPUHAFE-UHFFFAOYSA-N 0.000 description 3
- VZSXBCQEJWUUJR-UHFFFAOYSA-N 3-ethyl-8-methyl-2-sulfanylidene-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound O=C1N(CC)C(=S)NC11CCN(C)CC1 VZSXBCQEJWUUJR-UHFFFAOYSA-N 0.000 description 3
- BVAGIEIKOUJDJC-UHFFFAOYSA-N 4-(ethylaminomethyl)-1-methylpiperidin-4-ol Chemical compound CCNCC1(O)CCN(C)CC1 BVAGIEIKOUJDJC-UHFFFAOYSA-N 0.000 description 3
- PRROBIIYGSUPNR-UHFFFAOYSA-N 4-amino-1-methylpiperidin-1-ium-4-carboxylate Chemical compound CN1CCC(N)(C(O)=O)CC1 PRROBIIYGSUPNR-UHFFFAOYSA-N 0.000 description 3
- JXUFHVUPZXLNGM-UHFFFAOYSA-N 4-hydroxy-1-methylpiperidine-4-carbonitrile Chemical compound CN1CCC(O)(C#N)CC1 JXUFHVUPZXLNGM-UHFFFAOYSA-N 0.000 description 3
- ZGSNEAYELPMHGT-UHFFFAOYSA-N 8-methyl-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-en-4-olate Chemical compound C1CN(C)CCC21C(=O)NC(=O)N2 ZGSNEAYELPMHGT-UHFFFAOYSA-N 0.000 description 3
- 229930003347 Atropine Natural products 0.000 description 3
- VMOZSZFZYQNLLP-UHFFFAOYSA-N CCCCCCC(=CC(=C)N)N Chemical compound CCCCCCC(=CC(=C)N)N VMOZSZFZYQNLLP-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000028698 Cognitive impairment Diseases 0.000 description 3
- 206010011953 Decreased activity Diseases 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 3
- 229960000396 atropine Drugs 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 238000012875 competitive assay Methods 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- WMLCFAVGBHDOIK-UHFFFAOYSA-N ethyl 3-(2-ethoxy-2-oxoethyl)-1-azabicyclo[2.2.2]octane-3-carboxylate Chemical compound C1CC2C(CC(=O)OCC)(C(=O)OCC)CN1CC2 WMLCFAVGBHDOIK-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- OHOJRYNNXNLLOK-UHFFFAOYSA-N imidazolidine-2,4-dithione Chemical compound S=C1CNC(=S)N1 OHOJRYNNXNLLOK-UHFFFAOYSA-N 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 230000005923 long-lasting effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 229940097496 nasal spray Drugs 0.000 description 3
- 230000016273 neuron death Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 210000001747 pupil Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 3
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 description 2
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 2
- DBUISQSWQYYXLB-UHFFFAOYSA-N (4-amino-1-methylpiperidin-4-yl)methanol Chemical compound CN1CCC(N)(CO)CC1 DBUISQSWQYYXLB-UHFFFAOYSA-N 0.000 description 2
- KDTNPNBVTKTMJN-UHFFFAOYSA-N 1-acetyl-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound C1CN(C)CCC21C(=O)NC(=O)N2C(C)=O KDTNPNBVTKTMJN-UHFFFAOYSA-N 0.000 description 2
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 2
- YEEZJFPQHRGYKN-UHFFFAOYSA-N 1-ethyl-8-methyl-3-oxa-1,8-diazaspiro[4.5]decan-2-one Chemical compound CCN1C(=O)OCC11CCN(C)CC1 YEEZJFPQHRGYKN-UHFFFAOYSA-N 0.000 description 2
- RLYDPSYBQXOROH-UHFFFAOYSA-N 2,4,8-trimethyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound CN1C(=O)C(C)SC11CCN(C)CC1 RLYDPSYBQXOROH-UHFFFAOYSA-N 0.000 description 2
- YXWFAIFFILWUCS-UHFFFAOYSA-N 2,8-dimethyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one Chemical compound C1CN(C)CCC21C(=O)NC(C)=N2 YXWFAIFFILWUCS-UHFFFAOYSA-N 0.000 description 2
- IENRHKXUQYTTSN-UHFFFAOYSA-N 2,8-dimethyl-1,4-dioxa-8-azaspiro[4.5]decan-3-one Chemical compound O1C(=O)C(C)OC11CCN(C)CC1 IENRHKXUQYTTSN-UHFFFAOYSA-N 0.000 description 2
- IVCOMCSWJKKEEB-UHFFFAOYSA-N 2,8-dimethyl-1-oxa-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)C(C)OC11CCN(C)CC1 IVCOMCSWJKKEEB-UHFFFAOYSA-N 0.000 description 2
- JOKHESPDRGEKEG-UHFFFAOYSA-N 2,8-dimethyl-1-oxa-4,8-diazaspiro[4.5]decane Chemical compound O1C(C)CNC11CCN(C)CC1 JOKHESPDRGEKEG-UHFFFAOYSA-N 0.000 description 2
- RDKPCIMNMZRNEA-UHFFFAOYSA-N 2,8-dimethyl-1-oxo-1$l^{4}-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound O=S1C(C)C(=O)NC11CCN(C)CC1 RDKPCIMNMZRNEA-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- SIOXXPYXLAJRSW-UHFFFAOYSA-N 2-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)C(C)SC11CCNCC1 SIOXXPYXLAJRSW-UHFFFAOYSA-N 0.000 description 2
- CFPHMAVQAJGVPV-UHFFFAOYSA-N 2-sulfanylbutanoic acid Chemical compound CCC(S)C(O)=O CFPHMAVQAJGVPV-UHFFFAOYSA-N 0.000 description 2
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 description 2
- WGQVJSXITOHEFH-UHFFFAOYSA-N 3-ethyl-2-ethylsulfanyl-8-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one Chemical compound O=C1N(CC)C(SCC)=NC11CCN(C)CC1 WGQVJSXITOHEFH-UHFFFAOYSA-N 0.000 description 2
- DFXMJZITESLWIU-UHFFFAOYSA-N 3-ethyl-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dithione Chemical compound S=C1N(CC)C(=S)NC11CCN(C)CC1 DFXMJZITESLWIU-UHFFFAOYSA-N 0.000 description 2
- JVCUVZJRDGGVJT-UHFFFAOYSA-N 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CC)C(=O)OC11CCN(C)CC1 JVCUVZJRDGGVJT-UHFFFAOYSA-N 0.000 description 2
- SSQPQLBKDXSGED-UHFFFAOYSA-N 3-ethyl-8-methyl-1-oxa-4-thia-8-azaspiro[4.5]decan-2-one Chemical compound O1C(=O)C(CC)SC11CCN(C)CC1 SSQPQLBKDXSGED-UHFFFAOYSA-N 0.000 description 2
- NLITZISVKPYCPP-UHFFFAOYSA-N 3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(C)C(=O)NC11CCNCC1 NLITZISVKPYCPP-UHFFFAOYSA-N 0.000 description 2
- XCTPMBZCYFICBI-UHFFFAOYSA-N 4-(aminomethyl)-1-methylpiperidin-4-ol;hydrochloride Chemical compound Cl.CN1CCC(O)(CN)CC1 XCTPMBZCYFICBI-UHFFFAOYSA-N 0.000 description 2
- IKMTVQRBANTINH-UHFFFAOYSA-N 4-(aminomethyl)-1-methylpiperidin-4-ol;n-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]acetamide Chemical compound CN1CCC(O)(CN)CC1.CN1CCC(O)(CNC(C)=O)CC1 IKMTVQRBANTINH-UHFFFAOYSA-N 0.000 description 2
- HUTRESLXFRPBOW-UHFFFAOYSA-N 4-amino-1-methylpiperidine-4-carbonitrile Chemical compound CN1CCC(N)(C#N)CC1 HUTRESLXFRPBOW-UHFFFAOYSA-N 0.000 description 2
- XMFLJJRHBGGHMV-UHFFFAOYSA-N 4-amino-1-methylpiperidine-4-carboxylic acid;8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1CCC(N)(C(O)=O)CC1.C1CN(C)CCC21C(=O)NC(=O)N2 XMFLJJRHBGGHMV-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
- FTOWXCYYABFEGM-UHFFFAOYSA-N 4-methoxy-8-methyl-2-methylsulfanyl-1,3,8-triazaspiro[4.5]deca-1,3-diene Chemical compound COC1=NC(SC)=NC11CCN(C)CC1 FTOWXCYYABFEGM-UHFFFAOYSA-N 0.000 description 2
- NGNNFDYHJKDHJN-UHFFFAOYSA-N 5-aminoimidazole-2,4-dione Chemical class N=C1NC(=O)NC1=O NGNNFDYHJKDHJN-UHFFFAOYSA-N 0.000 description 2
- YNRWQRBUPXXCGI-UHFFFAOYSA-N 5-methyl-2-(1-methylpiperidin-4-yl)-1,3-thiazolidine-4-thione Chemical compound N1C(=S)C(C)SC1C1CCN(C)CC1 YNRWQRBUPXXCGI-UHFFFAOYSA-N 0.000 description 2
- ZFGWGBFPJIIWDY-UHFFFAOYSA-N 8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dithione Chemical compound C1CN(C)CCC21C(=S)NC(=S)N2 ZFGWGBFPJIIWDY-UHFFFAOYSA-N 0.000 description 2
- DCCBTJHJSAORLC-UHFFFAOYSA-N 8-methyl-2-methylsulfanyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one Chemical compound O=C1NC(SC)=NC11CCN(C)CC1 DCCBTJHJSAORLC-UHFFFAOYSA-N 0.000 description 2
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- 241001514645 Agonis Species 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- JANMPEBRKUOFDP-UHFFFAOYSA-N CN1CCC(CC1)=O.CN1CCC2(C(NC(N2)=O)=O)CC1 Chemical compound CN1CCC(CC1)=O.CN1CCC2(C(NC(N2)=O)=O)CC1 JANMPEBRKUOFDP-UHFFFAOYSA-N 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 241000723353 Chrysanthemum Species 0.000 description 2
- 235000007516 Chrysanthemum Nutrition 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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 208000014094 Dystonic disease Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010019196 Head injury Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 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 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 208000026139 Memory disease Diseases 0.000 description 2
- ZSBDPRIWBYHIAF-UHFFFAOYSA-N N-acetyl-acetamide Natural products CC(=O)NC(C)=O ZSBDPRIWBYHIAF-UHFFFAOYSA-N 0.000 description 2
- 206010068319 Oropharyngeal pain Diseases 0.000 description 2
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 201000007100 Pharyngitis Diseases 0.000 description 2
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- AMDQXGZAKPTOJZ-UHFFFAOYSA-N [4-(ethylamino)-1-methylpiperidin-4-yl]methanol Chemical compound CCNC1(CO)CCN(C)CC1 AMDQXGZAKPTOJZ-UHFFFAOYSA-N 0.000 description 2
- 229940022698 acetylcholinesterase Drugs 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 230000001022 anti-muscarinic effect Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000003376 axonal effect Effects 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- IDCNPYLLAWTFMB-UHFFFAOYSA-N dec-1-ene-4-thione Chemical compound CCCCCCC(=S)CC=C IDCNPYLLAWTFMB-UHFFFAOYSA-N 0.000 description 2
- NNFCIYWJLLJEMN-UHFFFAOYSA-N dec-2-en-4-one Chemical compound CCCCCCC(=O)C=CC NNFCIYWJLLJEMN-UHFFFAOYSA-N 0.000 description 2
- LISCNALUJKZILB-UHFFFAOYSA-N dec-3-ene-2-thione Chemical compound CC(C=CCCCCCC)=S LISCNALUJKZILB-UHFFFAOYSA-N 0.000 description 2
- WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229960004979 fampridine Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005350 fused silica glass Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229910003480 inorganic solid Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 201000003152 motion sickness Diseases 0.000 description 2
- FLEKHTYBMJLOOH-UHFFFAOYSA-N n,8-dimethyl-2-methylsulfanyl-1,3,8-triazaspiro[4.5]deca-1,3-dien-4-amine Chemical compound CNC1=NC(SC)=NC11CCN(C)CC1 FLEKHTYBMJLOOH-UHFFFAOYSA-N 0.000 description 2
- CRNIEDSCRWRAHR-UHFFFAOYSA-N n-(4-cyano-1-methylpiperidin-4-yl)acetamide Chemical compound CN1CCC(C#N)(NC(C)=O)CC1 CRNIEDSCRWRAHR-UHFFFAOYSA-N 0.000 description 2
- SEASIAOAVXWYDG-UHFFFAOYSA-N n-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]acetamide Chemical compound CN1CCC(O)(CNC(C)=O)CC1 SEASIAOAVXWYDG-UHFFFAOYSA-N 0.000 description 2
- JHGJZJGWJBZWHD-UHFFFAOYSA-N n-[4-(hydroxymethyl)-1-methylpiperidin-4-yl]acetamide Chemical compound CN1CCC(CO)(NC(C)=O)CC1 JHGJZJGWJBZWHD-UHFFFAOYSA-N 0.000 description 2
- 210000004126 nerve fiber Anatomy 0.000 description 2
- 239000000842 neuromuscular blocking agent Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical group C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 2
- 150000002917 oxazolidines Chemical class 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 108010091212 pepstatin Proteins 0.000 description 2
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 229960004526 piracetam Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000009822 protein phosphorylation Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000009991 second messenger activation Effects 0.000 description 2
- 230000018448 secretion by cell Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- QQXLDOJGLXJCSE-KNVOCYPGSA-N tropinone Chemical compound C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- YYMCYJLIYNNOMK-MEKDEQNOSA-N (1r,5s)-8-azabicyclo[3.2.1]octan-3-ol Chemical group C1C(O)C[C@@H]2CC[C@H]1N2 YYMCYJLIYNNOMK-MEKDEQNOSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- PHOZOHFUXHPOCK-QMMMGPOBSA-N (2s)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)[C@H](CC)SC11CCN(C)CC1 PHOZOHFUXHPOCK-QMMMGPOBSA-N 0.000 description 1
- FCRMJSYZVAIBRC-UHFFFAOYSA-N 1,2,4,5-tetraoxane-3,6-dione Chemical compound O=C1OOC(=O)OO1 FCRMJSYZVAIBRC-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- WRADANNQOTZBDC-UHFFFAOYSA-N 1-anthracen-9-ylethanol Chemical compound C1=CC=C2C(C(O)C)=C(C=CC=C3)C3=CC2=C1 WRADANNQOTZBDC-UHFFFAOYSA-N 0.000 description 1
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 description 1
- VJCQJLZYYKTLNA-UHFFFAOYSA-N 1-methyl-4-(nitromethyl)piperidin-4-ol;hydrochloride Chemical compound Cl.CN1CCC(O)(C[N+]([O-])=O)CC1 VJCQJLZYYKTLNA-UHFFFAOYSA-N 0.000 description 1
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 1
- VFYFMNCKPJDAPV-UHFFFAOYSA-N 2,2'-(5-oxo-1,3-dioxolan-4,4-diyl)diessigs Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CC1(CC(O)=O)OCOC1=O VFYFMNCKPJDAPV-UHFFFAOYSA-N 0.000 description 1
- OQNQYANDNUXYTC-UHFFFAOYSA-N 2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-2-en-4-one Chemical compound C1CN(C)CCC21C(=O)N=C(C)O2 OQNQYANDNUXYTC-UHFFFAOYSA-N 0.000 description 1
- QUAAWVSDJQPGBI-UHFFFAOYSA-N 2,8-dimethyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)C(C)SC11CCN(C)CC1 QUAAWVSDJQPGBI-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- LFILQFFBSPEZJH-UHFFFAOYSA-N 2-ethyl-4,8-dimethyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound CN1C(=O)C(CC)SC11CCN(C)CC1 LFILQFFBSPEZJH-UHFFFAOYSA-N 0.000 description 1
- KBNXPWYPEFJHSF-UHFFFAOYSA-N 2-hydroxypropanethioic S-acid 2-sulfanylpropanoic acid Chemical group C(C(O)C)(=S)O.SC(C(=O)O)C KBNXPWYPEFJHSF-UHFFFAOYSA-N 0.000 description 1
- ZFWFRTVIIMTOLY-UHFFFAOYSA-N 2-isothiocyanato-2-methylpropane Chemical compound CC(C)(C)N=C=S ZFWFRTVIIMTOLY-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- UEKVEPQDQOYBHB-UHFFFAOYSA-N 3,8-dimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(C)C(=O)NC11CCN(C)CC1 UEKVEPQDQOYBHB-UHFFFAOYSA-N 0.000 description 1
- BAQCETYCWHELLE-UHFFFAOYSA-N 3-but-2-ynyl-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CC#CC)C(=O)NC11CCN(C)CC1 BAQCETYCWHELLE-UHFFFAOYSA-N 0.000 description 1
- OOHDXSAIMKUZKO-UHFFFAOYSA-N 3-ethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CC)C(=O)NC11CCNCC1 OOHDXSAIMKUZKO-UHFFFAOYSA-N 0.000 description 1
- FHFJNCYHQZPOSL-UHFFFAOYSA-N 3-ethyl-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CC)C(=O)NC11CCN(C)CC1 FHFJNCYHQZPOSL-UHFFFAOYSA-N 0.000 description 1
- MZQQHYDUINOMDG-UHFFFAOYSA-N 3-methyl hydantoin Natural products CN1C(=O)CNC1=O MZQQHYDUINOMDG-UHFFFAOYSA-N 0.000 description 1
- RZBCTZRJDQGMJU-UHFFFAOYSA-N 3-methyl-1-oxa-4-thia-8-azaspiro[4.5]decan-2-one Chemical compound O1C(=O)C(C)SC11CCNCC1 RZBCTZRJDQGMJU-UHFFFAOYSA-N 0.000 description 1
- JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 description 1
- JUHFGHWNBYGKCW-UHFFFAOYSA-N 4-(aminomethyl)-1-methylpiperidin-4-ol Chemical compound CN1CCC(O)(CN)CC1 JUHFGHWNBYGKCW-UHFFFAOYSA-N 0.000 description 1
- JEYBTWQZMFZEEV-UHFFFAOYSA-N 4-acetamido-1-methylpiperidine-4-carboxamide Chemical compound CN1CCC(C(N)=O)(NC(C)=O)CC1 JEYBTWQZMFZEEV-UHFFFAOYSA-N 0.000 description 1
- QFCPKLRJWIIWCX-UHFFFAOYSA-N 4-amino-1-methylpiperidine-4-carbonitrile;1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1.CN1CCC(N)(C#N)CC1 QFCPKLRJWIIWCX-UHFFFAOYSA-N 0.000 description 1
- WKKXQBIARFVHHE-UHFFFAOYSA-N 4-amino-1-methylpiperidine-4-carboxamide Chemical compound CN1CCC(N)(C(N)=O)CC1 WKKXQBIARFVHHE-UHFFFAOYSA-N 0.000 description 1
- LVSPDZAGCBEQAV-UHFFFAOYSA-N 4-chloronaphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=C(Cl)C2=C1 LVSPDZAGCBEQAV-UHFFFAOYSA-N 0.000 description 1
- KKYYHNPNRAKLJX-UHFFFAOYSA-N 4-ethylsulfanyl-8-methyl-1,3,8-triazaspiro[4.5]dec-3-ene-2-thione Chemical compound CCSC1=NC(=S)NC11CCN(C)CC1 KKYYHNPNRAKLJX-UHFFFAOYSA-N 0.000 description 1
- VMJKYXYPUPSWMA-UHFFFAOYSA-N 4-hydroxy-1-methylpiperidine-4-carboxamide Chemical compound CN1CCC(O)(C(N)=O)CC1 VMJKYXYPUPSWMA-UHFFFAOYSA-N 0.000 description 1
- WPSFOSFHXXIFDR-UHFFFAOYSA-N 5-methyl-1,3-thiazolidine Chemical compound CC1CNCS1 WPSFOSFHXXIFDR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 208000008822 Ankylosis Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 206010069632 Bladder dysfunction Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 1
- 101100354045 Caenorhabditis elegans rpn-2 gene Proteins 0.000 description 1
- 101100048435 Caenorhabditis elegans unc-18 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102100032404 Cholinesterase Human genes 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- UQABYHGXWYXDTK-UUOKFMHZSA-N GppNP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)NP(O)(O)=O)[C@@H](O)[C@H]1O UQABYHGXWYXDTK-UUOKFMHZSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 101001111439 Homo sapiens Beta-nerve growth factor Proteins 0.000 description 1
- 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 1
- 101000892360 Homo sapiens Protein AF-17 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010023198 Joint ankylosis Diseases 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 102220514786 Methyl-CpG-binding domain protein 1_F64A_mutation Human genes 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 229940086616 Monoamine oxidase B inhibitor Drugs 0.000 description 1
- 241000087624 Monoclona Species 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000756100 Muscari Species 0.000 description 1
- RHYBFKMFHLPQPH-UHFFFAOYSA-N N-methylhydantoin Natural products CN1CC(=O)NC1=O RHYBFKMFHLPQPH-UHFFFAOYSA-N 0.000 description 1
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 1
- JUMXIFURVFILEE-UHFFFAOYSA-N NC1(CCN(CC1)C)CO.C(C)(=O)NC1(CCN(CC1)C)CO Chemical compound NC1(CCN(CC1)C)CO.C(C)(=O)NC1(CCN(CC1)C)CO JUMXIFURVFILEE-UHFFFAOYSA-N 0.000 description 1
- 108091008604 NGF receptors Proteins 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 102000004659 Presynaptic Receptors Human genes 0.000 description 1
- 108010003717 Presynaptic Receptors Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 102100040638 Protein AF-17 Human genes 0.000 description 1
- VNYBTNPBYXSMOO-UHFFFAOYSA-M Pyridostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=C[N+](C)=C1 VNYBTNPBYXSMOO-UHFFFAOYSA-M 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 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 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 206010044074 Torticollis Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 description 1
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 1
- 229960004266 acetylcholine chloride Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- DXUUXWKFVDVHIK-UHFFFAOYSA-N ambenonium chloride Chemical compound [Cl-].[Cl-].C=1C=CC=C(Cl)C=1C[N+](CC)(CC)CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl DXUUXWKFVDVHIK-UHFFFAOYSA-N 0.000 description 1
- 229960004302 ambenonium chloride Drugs 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 230000003942 amyloidogenic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- OJHAHQJRQIOCFK-UHFFFAOYSA-N azane;chloroform;methanol Chemical compound N.OC.ClC(Cl)Cl OJHAHQJRQIOCFK-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008238 biochemical pathway Effects 0.000 description 1
- GERIGMSHTUAXSI-UHFFFAOYSA-N bis(8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 4-phenyl-2,3-dihydro-1h-naphthalene-1,4-dicarboxylate Chemical group CN1C(C2)CCC1CC2OC(=O)C(C1=CC=CC=C11)CCC1(C(=O)OC1CC2CCC(N2C)C1)C1=CC=CC=C1 GERIGMSHTUAXSI-UHFFFAOYSA-N 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- DXHPZXWIPWDXHJ-UHFFFAOYSA-N carbon monosulfide Chemical compound [S+]#[C-] DXHPZXWIPWDXHJ-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- PIPAJLPNWZMYQA-KNCRFDSUSA-N chembl1187724 Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(CO)C1=CC=CC=C1 PIPAJLPNWZMYQA-KNCRFDSUSA-N 0.000 description 1
- FUFVKLQESJNNAN-RIMUKSHESA-M chembl1200851 Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(O)C1=CC=CC=C1 FUFVKLQESJNNAN-RIMUKSHESA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- PTRFNEDHQMAOKK-UHFFFAOYSA-N decane-2-thione Chemical compound CCCCCCCCC(C)=S PTRFNEDHQMAOKK-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- BXKDSDJJOVIHMX-UHFFFAOYSA-N edrophonium chloride Chemical compound [Cl-].CC[N+](C)(C)C1=CC=CC(O)=C1 BXKDSDJJOVIHMX-UHFFFAOYSA-N 0.000 description 1
- 229960002406 edrophonium chloride Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- KBVGZIFNIBCBKH-UHFFFAOYSA-N ethanol iodomethane Chemical compound IC.CCO KBVGZIFNIBCBKH-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VBZCVIBBTVSYSO-UHFFFAOYSA-N ethyl propanimidate Chemical compound CCOC(=N)CC VBZCVIBBTVSYSO-UHFFFAOYSA-N 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108700039708 galantide Proteins 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 229960003246 homatropine methylbromide Drugs 0.000 description 1
- 102000057063 human MAPT Human genes 0.000 description 1
- 102000046917 human NGF Human genes 0.000 description 1
- 150000001469 hydantoins Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002933 hypercholinergic effect Effects 0.000 description 1
- 230000001025 hypocholinergic effect Effects 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000018197 inherited torticollis Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000020121 low-fat milk Nutrition 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- BQDBKDMTIJBJLA-UHFFFAOYSA-N metopimazine Chemical compound C12=CC(S(=O)(=O)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCC(C(N)=O)CC1 BQDBKDMTIJBJLA-UHFFFAOYSA-N 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000897 modulatory effect Effects 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 229960001499 neostigmine bromide Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 239000000181 nicotinic agonist Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- GSWAOPJLTADLTN-UHFFFAOYSA-N oxidanimine Chemical compound [O-][NH3+] GSWAOPJLTADLTN-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 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
- 102000020233 phosphotransferase Human genes 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960002151 pyridostigmine bromide Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000008584 quinuclidines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000012501 relaxation of skeletal muscle Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002483 superagonistic effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 108010021724 tonin Proteins 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- C07D471/10—Spiro-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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式I、II、III、IV、V、VI、VII、VIII及びIX の化合物並びにそれらの医薬上許される塩、三級窒素原子を有する前記化合物か ら構造上誘導される四級化合物、鏡像体及びラセミ体。 (式中、Xは>O、>S又は>NR°であり;Tは−C(Q)=又は−N=であ り;Yは>C=O、>C=S、>C=NR°、>C=CRR’、>CRR’、> CHOR”、>O、>S又は>NR°であり;Zは>O、>S、>C=O、>C =S、>C=NR°、>C=CRR’、>CRR’、>CHOR”又は>NR° であり;Wは>O、>S、>C=O、>C=S、>C=NR°、>C=CRR’ 、>CHOR”又は>NR°であり;Q及びQ’は夫々独立にOR、SR、NR R’及びRから選ばれ;X’及びZ’は夫々独立に>C=O、>C=S及び>C =CRR’から選ばれ;R、R’、R”、R°、R*及びR’”は夫々独立にH 、C1-6アルキル、C1-6アルコキシ、C2-6ヒドロキシアルキル、C2-6アルケニル、 C2-6アルキニル、フェニル及び1個、2個又は3個のフェニル により置換されたC1-6アルキルから選ばれ、またR”及びR°は独立にC1-6アル カノイルから選ばれてもよく;かつ環Aはスピロ−炭素原子と一緒になって1個 又は2個の環窒素原子を含むブリッジされ、又はブリッジされていない環を構成 し、環Aは好ましくは構造式K、L、M、N、P及びS、即ち、 (式中、夫々のこのような構造は置換されておらず、又はC1-6アルキル及びヒド ロキシルから選ばれた1〜3個の置換基により置換されており、構造式K及びL において、そのブリッジは一端で1位に結合され、かつ他端で4位又は5位に結 合されており、mは1、2又は3であり、かつn及びpは、n+pが1〜3であ ることを条件として、夫々独立に0、1、2又は3であり、R1は水素、C1-6ア ルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、1〜6個のハ ロゲン原子により置換されたC1-6アルキル、ヒドロキシ−C1-6アルキル、C1-6ア ルコキシ、C1-6アルキルチオ、C1-6アルコキシ−C1-6アルキル、カルボキシ−C1 -6 アルキル、(C1-6アルコキシ)カルボニル−C1-6アルキル、アミノ−C1-6アル キル、モノ−(C1-6アルキル)アミノ−C1-6アルキル、ジ−(C1-6アルキル)ア ミノ−C1-6アルキル、2−オキソ−ピロリジン−1−イル−メチル、アリール、 ジアリールメチロール、1〜2個のアリール基により置換されたC1-6アルキル、 C1-6アルカノイル及びアリールカルボニルから選ばれ;かつアリールは未置換フ ェニル又はハロゲン、C1-6アルキル、C1-6アルコキシ及びCF3から選ばれた1 〜3個の置換基により置換されたフェニルを表し、かつR2及びR3は独立にC1-4 アルキルから選ばれる) の群の中から選ばれ、 但し、示された5員環がスピロ−炭素原子の他に少なくとも1個の環炭素原子を 含むこと、二つの隣接環原子が同時に酸素原子ではないこと、かつ(ia)式Iにお いて、−W−Z−Y−X−が−C(=O)−NH−C(=O)−N(アルキル) −、−C(=O)−NH−C(=O)−NH−、−O−C(=O)−CRR’− O−又は-O−C(=O)−CRR’−S−ではないこと、(Ib)式Iにおいて、 環AがN−置換されていてもよいピペリジン環である場合、−W−Z−Y−X− が−NR°−CRR’−CRR’−O−、−NR°−C(=O)−CRR’−O −、−NR°−CRR’−CRR’−S−、又は−NR°−C(=O)−CRR ’−S−ではないこと、(Ic)式Iにおいて、−W−Z−Y−X−が−C(=O) −NH−C(=O)−である場合、環Aがキヌクリジン環ではないこと、(ii)式 Iにおいて、−W−Z−Y−X−が−NH−C(=O)−N(Ph)−NH−、 −NH−N(Ph)−C(=O)−NH−、−NR°−NR°−C(=O)−N R°−、又は−NR°−NR°−C(=S)−NR°−である場合、環AがN− メチルピペリジン環ではなく、そして−W−Z−Y−X−が−NR°−NR°− C(=S)−NR°−である場合、環Aがまた未置換ピペリジン環ではないこと 、(iiia)式III において、環Aは二つのフェニル基により置換されていなくても よいこと、(iiib)式III において、QがNRR’であり、かつWがC=Oである 場合、Xは0ではないこと、(iv)式VIにおいて、YがCRR’であり、かつX= Z=O又はS、又はX及びZの一方がOであり、かつ他方がSである場合、R* 及びR’”の少なくとも一つがHではないこと、(v)式VIにおいて、YがCRR ’であり、XがO又はSであり、かつ環AがN−置換されていてもよいピペリジ ン環である場合、ZがN−CHO以外のNR°であること、(vi)式VIにおいて、 XがOであり、YがNR°であり、かつZがC=O又はC=Sである場合、環A がブリッジされた環であり、又はR*及びR’”の少なくとも一つがHではない こと、(vii)式VIにおいて、−X−Y−Z−が−O−C(=O)−NH−、−O −C(=S)−NH−、−O−NR°−C(=O)−又は−O−NR°−C(= S)−であり、かつR°がH又はアルキルである場合、環Aがピペリジン環では ないこと、(viii)式VII において、ZがOである場合、QがSR又はNRR’で あり、又はR*及びR’”の少なくとも一つがHではないこと、(ix)式VIIIに おいて、XがO又はSである場合、QがSRであり、又はR*及びR’”の少な くとも一つがHではないこと、また(x)式IXにおいて、−X’−Y−Z’−が− C(=O)−NR°−C(=O)−であり、かつR°がH又はアルキルである場 合、環Aがピペリジン環ではないことを条件とする) 2.1−メチル−ピペリジン−4−スピロ−5’−(3’エチルヒダントイン) ;1−メチルピペリジン−4−スピロ−5’−(1’−アセチルヒダントイン) ;ピペリジン−4−スピロ−5’−(3’−エチルヒダントイン);1−メチル ピペリジン−4−スピロ−5’−(3’−メチルヒダントイン);ピペリジン− 4−スピロ−5’−(3’−メチルヒダントイン);1−メチルピペリジン−4 −スピロ−5’−(3’−プロパルギルヒダントイン);1−メチルピペリジン −4−スピロ−4’−(2’,5’−ビス(メチルチオ)4’H−イミダゾール );1−メチルピペリジン−4−スピロ−5’−(3’−エチル−4’−チオヒ ダントイン);1−メチルピペリジン−4−スピロ−5’(4’−メチルチオ− 3’−イミダゾリン−2’−チオン);1−メチルピペリジン−4−スピロ−5 ’−(2’,4’−ジチオヒダントイン);1−メチルピペリジン−4−スピロ −5’−(3’−エチル−2’,4’−ジチオヒダントイン);1−メチルピペ リジン−4−スピロ−5’−(4’−エチルチオ−3’−イミダゾリン−2’− チオン);1−メチルピペリジン−4−スピロ−4’−(1’−エチル−2’− エチルチオ−2’−イミダゾリン−5’−チオン);1−メチルピペリジン−4 −スピロ−5’−(2’−チオヒダントイン);1−メチルピペリジン−4−ス ピロ−5’−(2’−チオ−4’−β−ヒドロキシエチルイミノヒダントイン) ;1−メチルピペリジン−4−スピロ−5’−(オキサゾリジン−2’−チオン );N−メチル−ノルトロパン−3−スピロ−5’−(3’−メチルヒダントイ ン);N−メチルノルトロパン−3−スピロ−5’−(3’−エチルヒダントイ ン);1−メチルピペリジン−4−スピロ−5’−(3’−エチルオキサゾリジ ン−2’−オン);1−メチル−1−ピペリジン−4−スピロ−4’−(3’− エチルオキサゾリジン−2’−オン);2−N−メチル−スピロ−(1,3−ス クシンイミド4,3’)キヌクリジン;2−N−エチルスピロ−(1,3−スク シンイミド4,3’)キヌクリジン;1−メチルピペリジン−4−スピロ−5’ −(オキサ ゾリジン−2’,4’−ジオン);1−メチルピペリジン−4−スピロ−5’− (3’−エチルオキサゾリジン−2’,4’−ジオン);1−メチルピペリジン −4−スピロ−4’−(2’−メチル−2’−チアゾリン);N−メチルノルト ロパン−3−スピロ−5’−ヒダントイン;1−メチルピペリジン−4−スピロ −4’(5’)−(2’−メチル−2’−イミダゾリン);1−メチルピペリジ ン−4−スピロ−5’−(2’−メチル−2’−オキサゾリン−4’−オン); 1−メチルピペリジン−4−スピロ−4’(5’)−[2’−メチル−4’H( 5’H)−イミダゾール−5’(4’)−オン];1−メチルピペリジン−4− スピロ−4’−(2’−メチルチオ−5’−メトキシ−4’H−イミダゾール) ;1−メチルピペリジン−4−スピロ−4’−(2’−メチルチオ−5’−アミ ノ−4’H−イミダゾール);1−メチルピペリジン−4−スピロ−4’−(2 ’−メチルチオ−5’−アミノメチル−4’Hイミダゾール;1−メチルピペリ ジン−4−スピロ−4’−(2’,5’−ビス(アミノメチル)−4’H−イミ ダゾール)から選ばれる請求の範囲第1項に記載の化合物。 3.下記の分子寸法を有し、この場合、 rはその最も安定な配座のこのような化合物中の環A(又はA’)のN*とし て特定される非二重結合窒素原子のカチオン形態に相当するアニオンの位置によ り特定される基準点であり、 X*は式I〜IX、又はX〜XIIIのいずれかを有する示された5員環中の環ヘテ ロ原子を特定し、このような環ヘテロ原子はスピロ炭素原子に隣接する位置にあ り、 Z*は示された5員環中のX*から一つおいてその隣の環原子を特定し、かつ Q*は示された5員環中の原子X*とZ*の間の環原子に結合された側鎖の末端 炭素原子又は窒素原子を特定し、側鎖水素原子はこの目的のために無視され、 このような分子寸法は実質的に下記の値、即ち、二面角r-X*-Q*-Z*=-54°〜- 170°;かつ分子距離r-N*=3.0 Å(基準距離)、r-X*=5.7〜6.75Å、r-Q*=7. 9〜8.90Å、x-Q*=2.4〜2.8 Åを有し、 そしてこうして特定された分子寸法を有するこのような化合物がムスカリン様 アゴニスト活性を有することを特徴とする請求の範囲第1項に記載の化合物。 4.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、下記の成分(i)及び(ii):(i)少なくとも一種の医薬上許される希 釈剤、担体又はアジュバント; (ii)フィゾスチグミン、テトラヒドロアミノアクリジン、コリン、レシチン、ピ ラセタム、アニラセタム、プラミラセタム、オキシラセタム、4−アミノピリジ ン、3,4−ジアミノピリジン、ソマトスタチン、ピレンゼピン、N−メチルア トロピン、N−ブチルスコポラミン、スコポラミン、クロニジン、クアンファミ シン、プロパンセリン、メタンセリン、グリコピロレート、トロペンジリウム、 ノルトリプチリン、アミトリプチリン、イミプラミン、ミナプリン、セコベリン 、AFDX-116、ニコチン、アラプロクレート、ジメリジン、デプレニル及び神経成 長因子からなる群から選ばれた少なくとも一種の更に別の薬理活性化合物 の少なくとも一種と一緒に、前記疾患を治療するのに使用するのに有効な量の請 求の範囲第1項〜第3項のいずれか一項に記載の少なくとも一種の化合物(それ らの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導される 四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を含むこと を特徴とする医薬組成物。 5.経口投与、直腸投与、非経口投与又は経皮投与、或いはガス注入もしくは鼻 内スプレーによる投与に適した形態であり、また経皮投与の場合、その組成物が 追加成分として、低分子量の脂肪酸を含んでいてもよい請求の範囲第4項に記載 の医薬組成物。 6.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、少なくとも一種の医薬上許される希釈剤、担体又はアジュバント 、及び更に別の薬理活性化合物としての神経成長因子と一緒に、前記疾患を治療 するのに使用するのに有効な量の請求の範囲第1項〜第3項のいずれか一項に記 載の少なくとも一種の化合物(それらの医薬上許される塩、三級窒素原子を有す る前記化合物から構造上誘導される四級化合物、並びにこのような化合物の鏡像 体及びラセミ体を含む)を含み、但し、前記の少なくとも一種の化合物が神経成 長因子の神経成長活性を促進する量で存在することを条件とする医薬組成物。 7.1−メチルピペリジン−4−スピロ−5’−(2’−チオン−3’−エチル ヒダントイン); 1−メチルピペリジン−4−スピロ−5’−(2’−チオン−3’−t−ブチル ヒダントイン); 1−メチルピペリジン−4−スピロ−5’−(3’−t−ブチルヒダントイン) ; 1−プロパルギルピペリジン−4−スピロ−5’−(3’−エチルヒダントイン ); 1−メチルピペリジン−4−スピロ−5’−[3’−(4−ピロリジノ−2−ブ チニル)ヒダントイン]; 1−メチルピペリジン−4−スピロ−5’−[3’−(2−ブチニル)−ヒダン トイン]; ピペリジン−4−スピロ−5’−(3’−プロパルギルヒダントイン); 2−メチル−1,4−チアゾリジン−3−オン−スピロ[5,3’]−キヌクリ ジン; 1−メチルピペリジン−4−スピロ−4’(5’)−(2’−メチルチオ−2’ −イミダゾリン−5’(4’)−オン); 1−メチルピペリジン−4−スピロ−4’−(1’−エチル−2’−エチルチオ −2’−イミダゾリン−5’−オン); 1−メチルピペリジン−4−スピロ−4’−(1’−エチル−2’−イミダゾリ ン−5’−オン) から選ばれる請求の範囲第1項に記載の化合物。 8.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、下記の成分(i)及び(ii):(i)少なくとも一種の医薬上許される希 釈剤、担体又はアジュバント; (ii)フィゾスチグミン、テトラヒドロアミノアクリジン、コリン、レシチン、ピ ラセタム、アニラセタム、プラミラセタム、オキシラセタム、4−アミノピリジ ン、3,4−ジアミノピリジン、ソマトスタチン、ピレンゼピン、N−メチルア トロピン、N−ブチルスコポラミン、スコポラミン、クロニジン、クアンファミ シン、プロパンセリン、メタンセリン、グリコピロレート、トロペンジリウム、 ノルトリプチリン、アミトリプチリン、イミプラミン、ミナプリン、セコベリン 、AFDX-116、ニコチン、アラプロクレート、ジメリジン、デプレニル及び神経成 長 因子からなる群から選ばれた少なくとも一種の更に別の薬理活性化合物の少なく とも一種と一緒に、前記疾患を治療するのに使用するのに有効な量の請求の範囲 第7項に記載の少なくとも一種の化合物(それらの医薬上許される塩、三級窒素 原子を有する前記化合物から構造上誘導される四級化合物、並びにこのような化 合物の鏡像体及びラセミ体を含む)を含むことを特徴とする医薬組成物。 9.経口投与、直腸投与、非経口投与又は経皮投与、或いはガス注入もしくは鼻 内スプレーによる投与に適した形態であり、また経皮投与の場合、その組成物が 追加成分として、低分子量の脂肪酸を含んでいてもよい請求の範囲第8項に記載 の医薬組成物。 10.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、少なくとも一種の医薬上許される希釈剤、担体又はアジュバント 、及び更に別の薬理活性化合物としての神経成長因子と一緒に、前記疾患を治療 するのに使用するのに有効な量の請求の範囲第7項に記載の少なくとも一種の化 合物(それらの医薬上許される塩、三級窒素原子を有する前記化合物から構造上 誘導される四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む) を含み、但し、前記の少なくとも一種の化合物が神経成長因子の神経成長活性を 促進する量で存在することを条件とする医薬組成物。 11.(a)ムスカリン様アゴニスト活性、(b)神経栄養様活性又はNGF との相乗活性 、(c)アミロイド前駆体タンパク質(APP)分泌活性及びβ−アミロイド低下活性、 (d)脱リン酸化τタンパク質の比率を増大する活性、及び(e)NGF 様活性から選ば れた生物活性を有する医薬品の製造に使用するための請求の範囲第1項に記載の 式(I)の化合物(医薬上許される塩、三級窒素原子を有する前記化合物から構造 上誘導される四級化合物、これらの鏡像体及びラセミ体を含む)(式中、−W− Z−Y−X−は−NR°−CRR’−CRR’O−、−O−C(=O)−CRR ’−O−、−O−C(=O)−CRR’−S−、−NR°−C(=O)−CRR ’−O−、−NR°−CRR’−CRR’−S(=O)q−、又は−NR°−C (=O)−CRR’−S(=O)q−であり、qは0、1又は2であり、かつR 、R’及びR°は請求の範囲第1項に記載された意味を有する)。 12.1−メチルピペリジン−4−スピロ−5’−(2’−メチル−1’,4’− オキサゾリジン−3’−オン);1−メチルピペリジン−4−スピロ−5’−( 2’−メチル−1’,4’−チアゾリジン−3’−オン);1−メチルピペリジ ン−4−スピロ−5’−(2’,4’−ジ−メチル−1’,4−チアゾリジン− 3’−オン);1−メチルピペリジン−4−スピロ−5’−(2’−エチル−1 ’,4’−チアゾリジン−3’−オン);1−メチルピペリジン−4−スピロ− 5’−(2’−エチル−4−メチル−1’,4’−チアゾリジン−3’−オン) ;ピペリジン−4−スピロ−5’−(3’−メチル−1’4’−オキサチオラン −2’−オン);ピペリジン−4−スピロ−5’−(2’−メチル−1’,4’ −チアゾリジン−3’−オン);1−メチルピペリジン−4−スピロ−5’−( 2’−メチル−3’−オキソ−1’,4’−チアゾリジン−1’−オキシド); 1−メチルピペリジン−4−スピロ−5’−(3’−メチル−1’,4’−オキ サチオラン−2’−オン);1−メチルピペリジン−4−スピロ−2’−(5’ −メチル−1’,3’−オキサゾリジン);1−メチルピペリジン−4−スピロ −2’−(4’−エチル−1’,3’−オキサゾリジン);1−メチルピペリジ ン−4−スピロ−5’−(3’−エチル−1’,4’−オキサチオラン−2’− オン);1−メチルピペリジン−4−スピロ−5’−(2’−メチル−1’,4 ’−チアゾリジン−3’−オン);1−メチルピペリジン−4−スピロ−5’− (2’−エチル−1’,4’−チアゾリジン−3’−オン);1−メチルピペリ ジン−4−スピロ−2’−(5’−メチル−1’,3’−ジオキソラン−4’− オン);1−メチルピペリジン−4−スピロ−5’−(2’−メチル−1’,4 ’−チアゾリジン−3’−チオン)から選ばれる請求の範囲第11項に記載の化合 物。 13.d−及び1−1−メチルピペリジン−4−スピロ−5’−(2’−メチル− 1’,4’−チアゾリジン−3’−オン)並びにd−及び1−1−メチルピペリ ジン−4−スピロ−5’−(2’−エチル−1’,4’−チアゾリジン−3’− オン)から選ばれた分離された右旋性鏡像体及び左旋性鏡像体。 14.下記の成分(i)及び(ii): (i)少なくとも一種の医薬上許される希釈剤、担体又はアジュバント; (ii)フィゾスチグミン、テトラヒドロアミノアクリジン、コリン、レシチン、ピ ラセタム、アニラセタム、プラミラセタム、オキシラセタム、4−アミノピリジ ン、3,4−ジアミノピリジン、ソマトスタチン、ピレンゼピン、N−メチルア トロピン、N−ブチルスコポラミン、スコポラミン、クロニジン、クアンファミ シン、プロパンセリン、メタンセリン、グリコピロレート、トロペンジリウム、 ノルトリプチリン、アミトリプチリン、イミプラミン、ミナプリン、セコベリン 、AFDX-116、ニコチン、アラプロクレート、ジメリジン、デプレニル及び神経成 長因子からなる群から選ばれた少なくとも一種の更に別の薬理活性化合物 の少なくとも一種と一緒に、請求の範囲第11項に記載の生物活性を有する量の請 求の範囲第11項〜第13項のいずれか一項に記載の少なくとも一種の化合物(それ らの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導される 四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を含むこと を特徴とする医薬組成物。 15.経口投与、直腸投与、非経口投与又は経皮投与、或いはガス注入もしくは鼻 内スプレーによる投与に適した形態であり、また経皮投与の場合、その組成物が 追加成分として、低分子量の脂肪酸を含んでいてもよい請求の範囲第14項に記載 の医薬組成物。 16.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、少なくとも一種の医薬上許される希釈剤、担体又はアジュバント 、及び更に別の薬理活性化合物としての神経成長因子と一緒に、ムスカリン様ア ゴニスト活性量の請求の範囲第11項〜第13項のいずれかに記載の少なくとも一種 の化合物(それらの医薬上許される塩、三級窒素原子を有する前記化合物から構 造上誘導される四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含 む)を含み、但し、前記の少なくとも一種の化合物が神経成長因子の神経成長活 性を促進する量で存在することを条件とする医薬組成物。 17.請求の範囲第1項に記載の式I、II、III、IV、V、VI、VII、VIII及びIXの 化合物、並びにそれらの医薬上許される塩、三級窒素原子を有する前記化合物か ら構造上誘導される四級化合物、鏡像体及びラセミ体であって、 更に、又は別に、 部分CRR’において、R及びR’がそれらが結合される炭素原子と一緒にな って3〜6の環員を有する飽和炭素環を形成してもよく、かつ 構造式(K)、(L)、(M)、(N)、(P)及び(S)において、環炭素原子に結合された水 素原子が、水素を除いて請求の範囲第1項に特定される置換基R1により置換さ れていてもよい前記化合物。 18.下記の分子寸法を有し、この場合、 rはその最も安定な配座のこのような化合物中の環A(又はA’)のN*とし て特定される非二重結合窒素原子のカチオン形態に相当するアニオンの位置によ り特定される基準点であり、 X*は式I〜IX、又はX〜XIIIのいずれかを有する示された5員環中の環ヘテ ロ原子を特定し、このような環ヘテロ原子はスピロ炭素原子に隣接する位置にあ り、 Z*は示された5員環中のX*から一つおいてその隣の環原子を特定し、かつ Q*は示された5員環中の原子X*とZ*の間の環原子に結合された側鎖の末端 炭素原子又は窒素原子を特定し、側鎖水素原子はこの目的のために無視され、 このような分子寸法は実質的に下記の値、即ち、二面角r-X*-Q*-Z*=-54°〜- 170°;かつ分子距離r-N*=3.0 Å(基準距離)、r-X*=5.7〜6.75Å、r-Q*=7. 9〜8.90Å、x-Q*=2.4〜2.8 Åを有し、 そしてこうして特定された分子寸法を有する前記化合物がムスカリン様アゴニ スト活性を有することを特徴とする請求の範囲第17項に記載の化合物。 19.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、下記の成分(i)及び(ii): (i)少なくとも一種の医薬上許される希釈剤、担体又はアジュバント; (ii)フィゾスチグミン、テトラヒドロアミノアクリジン、コリン、レシチン、ピ ラセタム、アニラセタム、プラミラセタム、オキシラセタム、4−アミノピリジ ン、3,4−ジアミノピリジン、ソマトスタチン、ピレンゼピン、N−メチルア トロピン、N−ブチルスコポラミン、スコポラミン、クロニジン、クアンファミ シン、プロパンセリン、メタンセリン、グリコピロレート、トロペンジリウム、 ノルトリプチリン、アミトリプチリン、イミプラミン、ミナプリン、セコベリン 、AFDX-116、ニコチン、アラプロクレート、ジメリジン、デプレニル及び神経成 長因子からなる群から選ばれた少なくとも一種の更に別の薬理活性化合物 の少なくとも一種と一緒に、前記疾患を治療するのに使用するのに有効な量の請 求の範囲第17項及び第18項のいずれか一項に記載の少なくとも一種の化合物(そ れらの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導され る四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を含むこ とを特徴とする医薬組成物。 20.経口投与、直腸投与、非経口投与又は経皮投与、或いはガス注入もしくは鼻 内スプレーによる投与に適した形態であり、また経皮投与の場合、その組成物が 追加成分として、低分子量の脂肪酸を含んでいてもよい請求の範囲第19項に記載 の医薬組成物。 21.哺乳類の中枢神経系及び末梢神経系の疾患を治療するのに使用される医薬組 成物であって、少なくとも一種の医薬上許される希釈剤、担体又はアジュバント 、及び更に別の薬理活性化合物としての神経成長因子と一緒に、前記疾患を治療 するのに使用するのに有効な量の請求の範囲第17項及び第18項のいずれか一項に 記載の少なくとも一種の化合物(それらの医薬上許される塩、三級窒素原子を有 する前記化合物から構造上誘導される四級化合物、並びにこのような化合物の鏡 像体及びラセミ体を含む)を含み、但し、前記の少なくとも一種の化合物が神経 成長因子の神経成長活性を促進する量で存在することを条件とする医薬組成物。 22.哺乳類の中枢神経系及び末梢神経系の疾患の治療方法であって、このような 疾患を有する哺乳類に、このような疾患を治療するのに使用するのに有効な量の 請求の範囲第1項〜第3項のいずれか一項に記載の少なくとも一種の化合物(そ れらの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導され る四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を投与す ることを特徴とする治療方法。 23.前記化合物が、(a)ムスカリン様アゴニスト活性、(b)神経栄養様活性又はNG F との相乗活性、(c)アミロイド前駆体タンパク質(APP)分泌活性及びβ−アミロ イド低下活性、(d)脱リン酸化τタンパク質の比率を増大する活性、及び(e)NGF 様活性から選ばれた生物活性を有する請求の範囲第22項に記載の方法。 24.哺乳類の中枢神経系及び末梢神経系の疾患の治療方法であって、このような 疾患を有する哺乳類に、このような疾患を治療するのに使用するのに有効な量の 請求の範囲第7項に記載の少なくとも一種の化合物(それらの医薬上許される塩 、三級窒素原子を有する前記化合物から構造上誘導される四級化合物、並びにこ のような化合物の鏡像体及びラセミ体を含む)を投与することを特徴とする治療 方法。 25.前記化合物が、(a)ムスカリン様アゴニスト活性、(b)神経栄養様活性又はNG Fとの相乗活性、(c)アミロイド前駆体タンパク質(APP)分泌活性及びβ−アミロ イド低下活性、(d)脱リン酸化τタンパク質の比率を増大する活性、及び(e)NGF 様活性から選ばれた生物活性を有する請求の範囲第24項に記載の方法。 26.(a)ムスカリン様アゴニスト活性、(b)神経栄養様活性又はNGFとの相乗活性 、(c)アミロイド前駆体タンパク質(APP)分泌活性及びβ−アミロイド低下活性、 (d)脱リン酸化τタンパク質の比率を増大する活性、及び(e)NGF 様活性から選ば れた生物活性を有する化合物による治療を受けやすいと診断される哺乳類の疾患 の治療方法であって、このような哺乳類に、このような生物活性の状況に有効な 量の請求の範囲第11項〜第13項のいずれかに記載の少なくとも一種の化合物(そ れらの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導され る四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を投与す ることを特徴とする治療方法。 27.哺乳類の中枢神経系及び末梢神経系の疾患の治療方法であって、このような 疾患を有する哺乳類に、このような疾患を治療するのに使用するのに有効な量の 請求の範囲第17項及び第18項のいずれか一項に記載の少なくとも一種の化合物( それらの医薬上許される塩、三級窒素原子を有する前記化合物から構造上誘導さ れる四級化合物、並びにこのような化合物の鏡像体及びラセミ体を含む)を投与 することを特徴とする治療方法。 28.前記化合物が、(a)ムスカリン様アゴニスト活性、(b)神経栄養様活性又はNG F との相乗活性、(c)アミロイド前駆体タンパク質(APP)分泌活性及びβ−アミロ イド低下活性、(d)脱リン酸化τタンパク質の比率を増大する活性、及び(e)NGF 様活性から選ばれた生物活性を有する請求の範囲第27項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/094,855 | 1993-07-20 | ||
US08/094,855 US5534520A (en) | 1990-04-10 | 1993-07-20 | Spiro compounds containing five-membered rings |
PCT/GB1994/001543 WO1995003303A2 (en) | 1993-07-20 | 1994-07-15 | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH09503491A true JPH09503491A (ja) | 1997-04-08 |
JP3802050B2 JP3802050B2 (ja) | 2006-07-26 |
Family
ID=22247578
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP50499595A Expired - Fee Related JP3802050B2 (ja) | 1993-07-20 | 1994-07-15 | ムスカリン様アゴニスト活性を有するコリン作用系に作用するアザスピロ化合物 |
Country Status (25)
Country | Link |
---|---|
US (1) | US5534520A (ja) |
EP (1) | EP0711292B1 (ja) |
JP (1) | JP3802050B2 (ja) |
KR (1) | KR100341683B1 (ja) |
CN (1) | CN1129942B (ja) |
AT (1) | ATE212347T1 (ja) |
AU (1) | AU696530B2 (ja) |
BG (1) | BG62774B1 (ja) |
BR (1) | BR9407088A (ja) |
CA (1) | CA2167584C (ja) |
CZ (1) | CZ295929B6 (ja) |
DE (1) | DE69429724T2 (ja) |
DK (1) | DK0711292T3 (ja) |
ES (1) | ES2171458T3 (ja) |
FI (1) | FI113777B (ja) |
HU (1) | HU224638B1 (ja) |
IL (1) | IL110340A (ja) |
NO (1) | NO310075B1 (ja) |
NZ (1) | NZ268637A (ja) |
PL (1) | PL178931B1 (ja) |
PT (1) | PT711292E (ja) |
RO (1) | RO117851B1 (ja) |
RU (1) | RU2129555C1 (ja) |
WO (1) | WO1995003303A2 (ja) |
ZA (1) | ZA945284B (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005517682A (ja) * | 2001-12-28 | 2005-06-16 | アカディア ファーマシューティカルズ,インコーポレーテッド | モノアミン受容体調節因子としてのスピロアザ環式化合物 |
JP2005530742A (ja) * | 2002-05-03 | 2005-10-13 | イスラエル インスティチュート フォー バイオロジカル リサーチ | 中枢及び末梢神経系障害を治療するための方法及び組成物、並びにそれらに有用な新規の化合物 |
JP2007509038A (ja) * | 2003-10-03 | 2007-04-12 | ノバルティス アクチエンゲゼルシャフト | 特定の置換スピロ環ラクタムおよび医薬品としてのその使用 |
JP2009541392A (ja) * | 2006-06-30 | 2009-11-26 | ウニヴェルシタ’ デリ ストゥディ ディ ミラノ | アルファ7受容体サブタイプ選択的なニコチン性アゴニスト、その製造方法およびそれの医薬組成物 |
JP2012515763A (ja) * | 2009-01-26 | 2012-07-12 | イスラエル インスティトゥート フォー バイオロジカル リサーチ | 複素二環スピロ化合物 |
JP2019529389A (ja) * | 2016-10-05 | 2019-10-17 | エヌエスシー セラピューティクス ゲーエムベーハー | ムスカリン性アセチルコリン受容体アゴニストの結晶性多形 |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5852029A (en) * | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
EP0618917B1 (en) * | 1991-11-25 | 1997-03-26 | American Home Products Corporation | 1'-amino-2- (benzothiazolyl)methyl]spiro isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones and analogs thereof useful as aldose reductase inhibitors |
EP0777671B1 (en) * | 1994-08-24 | 2000-04-26 | Astra Aktiebolag | Spiro-azabicyclic compounds useful in therapy |
FR2725206B1 (fr) * | 1994-09-29 | 1996-12-06 | Roussel Uclaf | Nouvelles imidazolidines substituees par un heterocycle, leur procede et des intermediaires de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant |
NZ320963A (en) | 1995-09-29 | 1999-08-30 | Lilly Co Eli | Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation |
DE59712592D1 (de) | 1996-04-02 | 2006-05-04 | Bayer Cropscience Ag | Substituierte phenylketoenole als schädlingsbekämpfungsmittel und herbizide |
EP0932401A1 (en) * | 1996-07-01 | 1999-08-04 | Sepracor, Inc. | Methods and compositions for treating urinary incontinence using enantiomerically enriched (r,r)-glycopyrrolate |
US8048875B1 (en) * | 1997-02-24 | 2011-11-01 | S.L.A. Pharma Ag | Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker |
CA2281755C (en) | 1997-02-24 | 2006-11-07 | Michael Albert Kamm | Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker |
ATE254618T1 (de) | 1997-05-30 | 2003-12-15 | Neurosearch As | Spiro chinuclidin-derivate, ihre herstellung und verwendung |
TW402591B (en) * | 1997-07-11 | 2000-08-21 | Janssen Pharmaceutica Nv | Monocyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives |
WO1999064043A1 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Muscarinic receptor antagonists |
ES2194402T3 (es) | 1998-06-12 | 2003-11-16 | Hoffmann La Roche | Derivados de di - o triaza-espiro(4,5)decano.. |
DK0963987T3 (da) * | 1998-06-12 | 2002-12-30 | Hoffmann La Roche | Spiro(piperidin-4,1'-pyrrolo(3,4-c)pyrrol) |
US6353006B1 (en) | 1999-01-14 | 2002-03-05 | Bayer Corporation | Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents |
US6693202B1 (en) | 1999-02-16 | 2004-02-17 | Theravance, Inc. | Muscarinic receptor antagonists |
WO2001066546A1 (fr) * | 2000-03-09 | 2001-09-13 | Mitsubishi Pharma Corporation | Composes spiro, leur procede de preparation et leur utilisation comme medicaments |
DE10130020A1 (de) | 2001-06-25 | 2003-12-04 | Gruenenthal Gmbh | Substituierte 1-Oxa-2,8-diaza-spiro[4.5]dec-2-en-derivate |
DE10210195B4 (de) * | 2002-03-07 | 2005-12-15 | Schwarz Pharma Ag | Verwendung von 1,3-Diazaspiro-[4,5]decan-2,4-dithion zur Behandlung von Schmerz |
US7700603B2 (en) * | 2003-12-15 | 2010-04-20 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7763609B2 (en) * | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7592348B2 (en) * | 2003-12-15 | 2009-09-22 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
JP2008515989A (ja) * | 2004-10-13 | 2008-05-15 | メルク エンド カムパニー インコーポレーテッド | アルツハイマー病を治療するためのβ−セクレターゼ阻害薬として有用なスピロピペリジン化合物 |
EP1824853A4 (en) * | 2004-12-09 | 2010-06-09 | Virochem Pharma Inc | NEW SPIROTROPAN COMPOUNDS AND METHOD FOR MODULATING THE ACTIVITY OF THE CHEMOKIN RECEPTOR |
US7960403B2 (en) * | 2004-12-09 | 2011-06-14 | Virochem Pharma Inc. | Spirotropane compounds and methods for the modulation of chemokine receptor activity |
CN101238124A (zh) * | 2005-07-18 | 2008-08-06 | 默克公司 | 用于治疗阿尔茨海默氏病的螺哌啶β-分泌酶抑制剂 |
EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
US7678363B2 (en) * | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
US20100298342A1 (en) * | 2006-09-07 | 2010-11-25 | Merck & Co., Inc. | Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's Disease |
EP2068872A1 (en) | 2006-09-08 | 2009-06-17 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
JP2010508272A (ja) * | 2006-10-30 | 2010-03-18 | メルク エンド カムパニー インコーポレーテッド | アルツハイマー病を治療するためのスピロピペリジンβセクレターゼ阻害剤 |
EP2061771A1 (en) * | 2006-12-12 | 2009-05-27 | Schering Corporation | Aspartyl protease inhibitors containing a tricyclic ring system |
MX2009006228A (es) | 2006-12-12 | 2009-06-22 | Schering Corp | Inhibidores de aspartil proteasa. |
US7863291B2 (en) * | 2008-04-23 | 2011-01-04 | Bristol-Myers Squibb Company | Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands |
US9034891B2 (en) | 2009-01-26 | 2015-05-19 | Israel Institute For Biological Research | Bicyclic heterocyclic spiro compounds |
EP2485920B1 (en) | 2009-10-08 | 2016-04-27 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
WO2011044184A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
US8563543B2 (en) | 2009-10-08 | 2013-10-22 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
MX2012004560A (es) * | 2009-10-29 | 2012-05-08 | Bristol Myers Squibb Co | Compuestos de quinuclidina como ligandos del receptor de acetilcolina nicotinico alfa-7. |
EP2694521B1 (en) | 2011-04-07 | 2015-11-25 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2012138734A1 (en) | 2011-04-07 | 2012-10-11 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9499502B2 (en) | 2011-04-13 | 2016-11-22 | Merck Sharp & Dohme Corp. | 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use |
EP2747769B1 (en) | 2011-08-22 | 2017-08-02 | Merck Sharp & Dohme Corp. | 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use |
ES2716049T3 (es) | 2012-07-13 | 2019-06-07 | Pain Therapeutics Inc | Un método para inhibir la fosforilación de tau |
WO2014062549A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2014062553A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
CA2894919A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | C5,c6 oxacyclic-fused iminothiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9489013B2 (en) | 2012-12-20 | 2016-11-08 | Merck Sharp & Dohme Corp. | C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use |
WO2014099788A1 (en) | 2012-12-21 | 2014-06-26 | Merck Sharp & Dohme Corp. | C5-spiro iminothiadiazine dioxides as bace inhibitors |
EP2968353B1 (en) | 2013-03-15 | 2018-12-19 | Merck Sharp & Dohme Corp. | C2-azaspiro iminothiazine dioxides as bace inhibitors |
US9433604B2 (en) | 2013-10-08 | 2016-09-06 | Pain Therapeutics Inc. | Method for inhibiting growth of cancer cells |
EP3083575B1 (en) | 2013-12-18 | 2021-11-03 | Merck Sharp & Dohme Corp. | C-6 spirocarbocyclic iminothiadiazine dioxides as bace inhibitors, compositions, and their use |
US10307409B2 (en) | 2015-03-06 | 2019-06-04 | Chase Pharmaceuticals Corporation | Muscarinic combinations and their use for combating hypocholinergic disorders of the central nervous system |
WO2016144727A1 (en) * | 2015-03-06 | 2016-09-15 | Chase Pharmaceuticals Corporation | Peripheral-anticholinergic muscarinic agonist combination |
WO2017044693A1 (en) | 2015-09-11 | 2017-03-16 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
EP3768261A1 (en) | 2018-03-22 | 2021-01-27 | NSC THERAPEUTICS GmbH | Compounds and methods for use in the treatment of microglia-mediated disorders |
US20230348493A1 (en) * | 2020-05-12 | 2023-11-02 | Beijing Greatway Pharmaceutical Technology Co., Ltd. | Compound for adjusting activity of nmda receptor, and pharmaceutical composition and use thereof |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3161644A (en) * | 1962-06-22 | 1964-12-15 | Res Lab Dr C Janssen N V | 1-benzyl-4-substituted piperidines |
JPS4917534B1 (ja) * | 1970-10-06 | 1974-05-01 | ||
BE790675A (fr) * | 1971-10-29 | 1973-04-27 | Science Union & Cie | Nouveaux derives de l'oxa-1 diaza-3,8 spiro (4,5) decane |
EP0189370A3 (de) * | 1985-01-16 | 1988-01-27 | Sandoz Ag | Spiro-dioxolane, -dithiolane und -oxothiolane |
US4855290A (en) * | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
EP0273659A1 (en) * | 1986-12-27 | 1988-07-06 | Takeda Chemical Industries, Ltd. | Azaspiro compounds, their production and use |
JPS63208590A (ja) * | 1987-02-24 | 1988-08-30 | Yamanouchi Pharmaceut Co Ltd | ヘテロ環式スピロ化合物及びその製造法 |
IL87234A (en) * | 1987-08-13 | 1992-02-16 | Israel Inst Biolog Res | Optical isomers of 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine,their preparation and pharmaceutical compositions containing them |
ES2074441T3 (es) * | 1987-10-05 | 1995-09-16 | Yamanouchi Pharma Co Ltd | Compuestos espiro heterociclicos y su preparacion. |
US4876260A (en) * | 1987-10-28 | 1989-10-24 | State Of Israel, Israel Institute Of Biological Research | Oxathiolanes |
JPH02164882A (ja) * | 1988-12-20 | 1990-06-25 | Yamanouchi Pharmaceut Co Ltd | スピロ化合物及びその中間体 |
JPH02247183A (ja) * | 1989-03-20 | 1990-10-02 | Yamanouchi Pharmaceut Co Ltd | ヘテロ環スピロ化合物 |
YU150489A (sh) * | 1989-08-10 | 1992-12-21 | W.L. Gore & Co. Gmbh. | Uređaj za ispitivanje odevnih predmeta na nepromočivost |
IL97726A (en) * | 1990-04-10 | 1994-12-29 | Israel Inst Biolog Res | Pharmaceutical preparations containing compounds with bridged and unbridged heterocyclic groups connected via spiro-atop with oxazoline and thiazoline groups, and sharp compounds |
US5073560A (en) * | 1990-07-20 | 1991-12-17 | Fisons Corporation | Spiro-isoxazolidine derivatives as cholinergic agents |
TW201312B (en) * | 1991-04-09 | 1993-03-01 | Israel State | Spiro bridged and unbridged heterocyclic compounds |
-
1993
- 1993-07-20 US US08/094,855 patent/US5534520A/en not_active Expired - Lifetime
-
1994
- 1994-07-15 RO RO96-00099A patent/RO117851B1/ro unknown
- 1994-07-15 ES ES94921036T patent/ES2171458T3/es not_active Expired - Lifetime
- 1994-07-15 NZ NZ268637A patent/NZ268637A/en not_active IP Right Cessation
- 1994-07-15 PT PT94921036T patent/PT711292E/pt unknown
- 1994-07-15 KR KR1019960700296A patent/KR100341683B1/ko not_active IP Right Cessation
- 1994-07-15 DE DE69429724T patent/DE69429724T2/de not_active Expired - Lifetime
- 1994-07-15 BR BR9407088A patent/BR9407088A/pt not_active Application Discontinuation
- 1994-07-15 HU HU9600126A patent/HU224638B1/hu not_active IP Right Cessation
- 1994-07-15 DK DK94921036T patent/DK0711292T3/da active
- 1994-07-15 EP EP94921036A patent/EP0711292B1/en not_active Expired - Lifetime
- 1994-07-15 IL IL11034094A patent/IL110340A/xx not_active IP Right Cessation
- 1994-07-15 AT AT94921036T patent/ATE212347T1/de not_active IP Right Cessation
- 1994-07-15 RU RU96103370A patent/RU2129555C1/ru not_active IP Right Cessation
- 1994-07-15 WO PCT/GB1994/001543 patent/WO1995003303A2/en active IP Right Grant
- 1994-07-15 AU AU71915/94A patent/AU696530B2/en not_active Ceased
- 1994-07-15 PL PL94312684A patent/PL178931B1/pl not_active IP Right Cessation
- 1994-07-15 CN CN94192839XA patent/CN1129942B/zh not_active Expired - Fee Related
- 1994-07-15 JP JP50499595A patent/JP3802050B2/ja not_active Expired - Fee Related
- 1994-07-15 CZ CZ1996182A patent/CZ295929B6/cs not_active IP Right Cessation
- 1994-07-15 CA CA002167584A patent/CA2167584C/en not_active Expired - Fee Related
- 1994-07-19 ZA ZA945284A patent/ZA945284B/xx unknown
-
1996
- 1996-01-17 FI FI960238A patent/FI113777B/fi active
- 1996-01-18 NO NO960225A patent/NO310075B1/no not_active IP Right Cessation
- 1996-02-19 BG BG100370A patent/BG62774B1/bg unknown
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005517682A (ja) * | 2001-12-28 | 2005-06-16 | アカディア ファーマシューティカルズ,インコーポレーテッド | モノアミン受容体調節因子としてのスピロアザ環式化合物 |
US7727999B2 (en) | 2001-12-28 | 2010-06-01 | Acadia Pharmaceuticals Inc. | Spiroazacyclic compounds as monoamine receptor modulators |
JP2005530742A (ja) * | 2002-05-03 | 2005-10-13 | イスラエル インスティチュート フォー バイオロジカル リサーチ | 中枢及び末梢神経系障害を治療するための方法及び組成物、並びにそれらに有用な新規の化合物 |
JP2010184946A (ja) * | 2002-05-03 | 2010-08-26 | Israel Inst For Biological Research | 中枢及び末梢神経系障害を治療するための方法及び組成物、並びにそれらに有用な新規の化合物 |
JP2007509038A (ja) * | 2003-10-03 | 2007-04-12 | ノバルティス アクチエンゲゼルシャフト | 特定の置換スピロ環ラクタムおよび医薬品としてのその使用 |
JP2009541392A (ja) * | 2006-06-30 | 2009-11-26 | ウニヴェルシタ’ デリ ストゥディ ディ ミラノ | アルファ7受容体サブタイプ選択的なニコチン性アゴニスト、その製造方法およびそれの医薬組成物 |
JP2012515763A (ja) * | 2009-01-26 | 2012-07-12 | イスラエル インスティトゥート フォー バイオロジカル リサーチ | 複素二環スピロ化合物 |
JP2015172098A (ja) * | 2009-01-26 | 2015-10-01 | イスラエル インスティトゥート フォー バイオロジカル リサーチ | 複素二環スピロ化合物又はその薬学的に許容される塩、これらの化合物を含む医薬組成物、および哺乳類のアルツハイマー病及びインスリン抵抗性症候群及び2型糖尿病を治療するための薬剤の調整における、これらの化合物の利用 |
JP2019529389A (ja) * | 2016-10-05 | 2019-10-17 | エヌエスシー セラピューティクス ゲーエムベーハー | ムスカリン性アセチルコリン受容体アゴニストの結晶性多形 |
JP2022119840A (ja) * | 2016-10-05 | 2022-08-17 | エヌエスシー セラピューティクス ゲーエムベーハー | ムスカリン性アセチルコリン受容体アゴニストの結晶性多形 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH09503491A (ja) | ムスカリン様アゴニスト活性を有するコリン作用系に作用するアザスピロ化合物 | |
US5852029A (en) | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity | |
TWI450900B (zh) | 橋聯雜環化合物及使用方法 | |
JP5815644B2 (ja) | オキサジアゾール誘導体およびそれらの代謝型グルタミン酸受容体増強剤としての使用 | |
KR101675174B1 (ko) | 이환형 헤테로사이클릭 스피로 화합물 | |
HUT65771A (en) | Process for producing substituted 3-amino-quinuclidine derivatives and pharmaceutical compositions containing them | |
JP2010529117A (ja) | 代謝型グルタミン酸受容体オキサジアゾールリガンドおよびそれらの増強剤としての使用 | |
JP2011510932A (ja) | 新規2,3,4,5−テトラヒドロ−1H−ピリド[4,3−b]インドール化合物およびその使用方法 | |
TW200400192A (en) | Chemical compounds | |
US20130109711A1 (en) | Novel compounds | |
AU623205B2 (en) | N-pyridinyl-9h-carbazol-9-amines, a process their preparation and their use as medicaments | |
AU655071B2 (en) | Neuroleptic 2-substituted perhydro-1-H-pyrido(1,2a) pyrazines | |
KR100222238B1 (ko) | 스피로 교상 및 비교상 헤테로고리 화합물 | |
KR20010092424A (ko) | 신규 형태의 축합 피리다지논 화합물 | |
WO2012152854A1 (en) | Metabotropic glutamate receptor modulators | |
NZ624872B2 (en) | Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives | |
NO304522B1 (no) | AnologifremgangsmÕte for fremstilling av terapeutisk aktive heterocykliske forbindelser |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20040427 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20040614 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20040727 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20050823 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20051124 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20060116 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060223 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20060418 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20060427 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100512 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110512 Year of fee payment: 5 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120512 Year of fee payment: 6 |
|
LAPS | Cancellation because of no payment of annual fees |