NO314999B1 - 5-substituerte-3-oksadiazolyl-1,6-naftyridin-2(1H)-on- derivater og farmasöytisk preparat inneholdende disse - Google Patents
5-substituerte-3-oksadiazolyl-1,6-naftyridin-2(1H)-on- derivater og farmasöytisk preparat inneholdende disse Download PDFInfo
- Publication number
- NO314999B1 NO314999B1 NO20000183A NO20000183A NO314999B1 NO 314999 B1 NO314999 B1 NO 314999B1 NO 20000183 A NO20000183 A NO 20000183A NO 20000183 A NO20000183 A NO 20000183A NO 314999 B1 NO314999 B1 NO 314999B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- naphthyridin
- substituted
- oxadiazol
- alkyl
- Prior art date
Links
- -1 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2 (1H) -one Chemical class 0.000 title claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 142
- 239000003814 drug Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 25
- 230000000694 effects Effects 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 102000004300 GABA-A Receptors Human genes 0.000 claims description 15
- 108090000839 GABA-A Receptors Proteins 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- ZQKMVHXJWJNEQG-UHFFFAOYSA-N 1h-1,6-naphthyridin-2-one Chemical class C1=NC=CC2=NC(O)=CC=C21 ZQKMVHXJWJNEQG-UHFFFAOYSA-N 0.000 claims description 2
- RBTIXRHVBKIRHL-UHFFFAOYSA-N 3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(3-fluorophenyl)-1H-1,6-naphthyridin-2-one Chemical compound CCC1=NOC(C=2C(NC3=CC=NC(=C3C=2)C=2C=C(F)C=CC=2)=O)=N1 RBTIXRHVBKIRHL-UHFFFAOYSA-N 0.000 claims description 2
- ZZNDEBZVDHLIAN-UHFFFAOYSA-N 3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-methoxyphenyl)-1H-1,6-naphthyridin-2-one Chemical compound CCC1=NOC(C=2C(NC3=CC=NC(=C3C=2)C=2C=CC(OC)=CC=2)=O)=N1 ZZNDEBZVDHLIAN-UHFFFAOYSA-N 0.000 claims description 2
- FYBIEHYXRQRQII-UHFFFAOYSA-N 3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-pyridin-4-yl-1H-1,6-naphthyridin-2-one Chemical compound CCC1=NOC(C=2C(NC3=CC=NC(=C3C=2)C=2C=CN=CC=2)=O)=N1 FYBIEHYXRQRQII-UHFFFAOYSA-N 0.000 claims description 2
- OWWYBYOZONVBPM-UHFFFAOYSA-N 3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methylphenyl)-1H-1,6-naphthyridin-2-one Chemical compound CC1=NOC(C=2C(NC3=CC=NC(=C3C=2)C=2C=C(C)C=CC=2)=O)=N1 OWWYBYOZONVBPM-UHFFFAOYSA-N 0.000 claims description 2
- DKNWZEDHQKSGSK-UHFFFAOYSA-N 3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-methylcyclopropyl)-1H-1,6-naphthyridin-2-one Chemical compound O1C(CC)=NC(C=2C(NC3=CC=NC(=C3C=2)C2C(C2)C)=O)=N1 DKNWZEDHQKSGSK-UHFFFAOYSA-N 0.000 claims description 2
- PZJGOWYKXCNHDD-UHFFFAOYSA-N 3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-thiophen-2-yl-1H-1,6-naphthyridin-2-one Chemical compound O1C(CC)=NC(C=2C(NC3=CC=NC(=C3C=2)C=2SC=CC=2)=O)=N1 PZJGOWYKXCNHDD-UHFFFAOYSA-N 0.000 claims description 2
- NQBWDRGDIMOHNE-UHFFFAOYSA-N 3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(2-methylphenyl)-1H-1,6-naphthyridin-2-one Chemical compound O1C(C)=NC(C=2C(NC3=CC=NC(=C3C=2)C=2C(=CC=CC=2)C)=O)=N1 NQBWDRGDIMOHNE-UHFFFAOYSA-N 0.000 claims description 2
- XLUIKMNMEGJCAN-UHFFFAOYSA-N 3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-pyridin-4-yl-1H-1,6-naphthyridin-2-one Chemical compound O1C(C)=NC(C=2C(NC3=CC=NC(=C3C=2)C=2C=CN=CC=2)=O)=N1 XLUIKMNMEGJCAN-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 31
- 238000000034 method Methods 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 239000013078 crystal Substances 0.000 description 30
- 229940049706 benzodiazepine Drugs 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000000556 agonist Substances 0.000 description 15
- 230000027455 binding Effects 0.000 description 15
- 239000012528 membrane Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 150000001557 benzodiazepines Chemical class 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 239000000872 buffer Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 229940125425 inverse agonist Drugs 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000001270 agonistic effect Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 229960003529 diazepam Drugs 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- VTBHBNXGFPTBJL-UHFFFAOYSA-N 4-tert-butyl-1-sulfanylidene-2,6,7-trioxa-1$l^{5}-phosphabicyclo[2.2.2]octane Chemical compound C1OP2(=S)OCC1(C(C)(C)C)CO2 VTBHBNXGFPTBJL-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 102000027484 GABAA receptors Human genes 0.000 description 6
- 108091008681 GABAA receptors Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000009870 specific binding Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 5
- 102000005915 GABA Receptors Human genes 0.000 description 5
- 108010005551 GABA Receptors Proteins 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 230000000949 anxiolytic effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 4
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000000147 hypnotic effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000009871 nonspecific binding Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- 229940122226 Benzodiazepine receptor agonist Drugs 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 102000004310 Ion Channels Human genes 0.000 description 3
- 108090000862 Ion Channels Proteins 0.000 description 3
- QMCOPDWHWYSJSA-UHFFFAOYSA-N N-methyl-9H-pyrido[3,4-b]indole-3-carboxamide Chemical compound N1C2=CC=CC=C2C2=C1C=NC(C(=O)NC)=C2 QMCOPDWHWYSJSA-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010039966 Senile dementia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000000759 benzodiazepine receptor stimulating agent Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- GADIKQPUNWAMEB-UHFFFAOYSA-N methyl 4-ethyl-6,7-dimethoxy-9H-pyrido[5,4-b]indole-3-carboxylate Chemical compound N1C2=CC(OC)=C(OC)C=C2C2=C1C=NC(C(=O)OC)=C2CC GADIKQPUNWAMEB-UHFFFAOYSA-N 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- OGIHPFMEYMOGTB-UHFFFAOYSA-N 2-oxo-5-thiophen-2-yl-1h-1,6-naphthyridine-3-carboxylic acid Chemical compound N1=CC=C2NC(=O)C(C(=O)O)=CC2=C1C1=CC=CS1 OGIHPFMEYMOGTB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 206010043994 Tonic convulsion Diseases 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 210000003710 cerebral cortex Anatomy 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
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 230000003371 gabaergic effect Effects 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- ZJQHPWUVQPJPQT-UHFFFAOYSA-N muscimol Chemical compound NCC1=CC(=O)NO1 ZJQHPWUVQPJPQT-UHFFFAOYSA-N 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 102000027246 neurosteroid receptors Human genes 0.000 description 2
- 108091008567 neurosteroid receptors Proteins 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229960005152 pentetrazol Drugs 0.000 description 2
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- IJFNYMPUUYQPFF-UHFFFAOYSA-N 2-oxo-5-thiophen-2-yl-1h-1,6-naphthyridine-3-carbonitrile Chemical compound C=12C=C(C#N)C(=O)NC2=CC=NC=1C1=CC=CS1 IJFNYMPUUYQPFF-UHFFFAOYSA-N 0.000 description 1
- DIVYGSROKPDLPK-UHFFFAOYSA-N 2-oxo-n'-propanoyl-5-thiophen-2-yl-1h-1,6-naphthyridine-3-carbohydrazide Chemical compound N1=CC=C2NC(=O)C(C(=O)NNC(=O)CC)=CC2=C1C1=CC=CS1 DIVYGSROKPDLPK-UHFFFAOYSA-N 0.000 description 1
- YWEVENJWPJFBPQ-UHFFFAOYSA-N 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-thiophen-3-yl-1H-1,6-naphthyridin-2-one Chemical compound C=12C=C(C=3ON=C(N=3)C3CC3)C(=O)NC2=CC=NC=1C=1C=CSC=1 YWEVENJWPJFBPQ-UHFFFAOYSA-N 0.000 description 1
- SQYJMDBPAUBGKB-UHFFFAOYSA-N 3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-methyl-1H-1,6-naphthyridin-2-one Chemical compound CCC1=NOC(C=2C(NC3=CC=NC(C)=C3C=2)=O)=N1 SQYJMDBPAUBGKB-UHFFFAOYSA-N 0.000 description 1
- BPHCKZKXAHIRPD-UHFFFAOYSA-N 5-acetyl-6-methyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC(=O)C=1C=C(C#N)C(=O)NC=1C BPHCKZKXAHIRPD-UHFFFAOYSA-N 0.000 description 1
- AYUPZBQOTRFJQK-UHFFFAOYSA-N 5-methyl-2-oxo-1h-1,6-naphthyridine-3-carbonitrile Chemical compound N1C(=O)C(C#N)=CC2=C1C=CN=C2C AYUPZBQOTRFJQK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 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
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 101000773908 Archaeoglobus fulgidus (strain ATCC 49558 / DSM 4304 / JCM 9628 / NBRC 100126 / VC-16) Acetate-CoA ligase [ADP-forming] II Proteins 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 229940084657 Benzodiazepine receptor inverse agonist Drugs 0.000 description 1
- 101100257133 Caenorhabditis elegans sma-3 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000002038 Muscle Hypertonia Diseases 0.000 description 1
- HEHIEPXCABDALO-UHFFFAOYSA-N N'-hydroxy-5-(3-methoxyphenyl)-2-oxo-1H-1,6-naphthyridine-3-carboximidamide Chemical compound COC1=CC=CC(C=2C=3C=C(C(=O)NC=3C=CN=2)C(N)=NO)=C1 HEHIEPXCABDALO-UHFFFAOYSA-N 0.000 description 1
- PIFUQACRHFPZCH-UHFFFAOYSA-N N'-hydroxy-5-methyl-2-oxo-1H-1,6-naphthyridine-3-carboximidamide Chemical compound N1C(=O)C(C(N)=NO)=CC2=C1C=CN=C2C PIFUQACRHFPZCH-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000003109 amnesic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003496 anti-amnesic effect Effects 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 239000000755 benzodiazepine receptor inverse stimulating agent Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000013677 cerebrovascular dementia Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- RLZPCFQNZGINRP-UHFFFAOYSA-N n'-hydroxypropanimidamide Chemical compound CCC(N)=NO RLZPCFQNZGINRP-UHFFFAOYSA-N 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000009519 pharmacological trial Methods 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
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- DXGIRFAFSFKYCF-UHFFFAOYSA-N propanehydrazide Chemical compound CCC(=O)NN DXGIRFAFSFKYCF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 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
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20717997 | 1997-07-15 | ||
PCT/JP1998/003134 WO1999003857A1 (fr) | 1997-07-15 | 1998-07-14 | Derives de 5-substitue-3-oxadiazolyl-1,6-naphtyridin-2(1h)-one |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20000183D0 NO20000183D0 (no) | 2000-01-14 |
NO20000183L NO20000183L (no) | 2000-03-07 |
NO314999B1 true NO314999B1 (no) | 2003-06-23 |
Family
ID=16535559
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20000183A NO314999B1 (no) | 1997-07-15 | 2000-01-14 | 5-substituerte-3-oksadiazolyl-1,6-naftyridin-2(1H)-on- derivater og farmasöytisk preparat inneholdende disse |
Country Status (29)
Country | Link |
---|---|
US (2) | US6172079B1 (pt) |
EP (1) | EP1010699B1 (pt) |
JP (1) | JP3390453B2 (pt) |
KR (1) | KR100508392B1 (pt) |
CN (1) | CN1134437C (pt) |
AR (1) | AR013222A1 (pt) |
AT (1) | ATE297923T1 (pt) |
AU (1) | AU735960B2 (pt) |
BR (1) | BR9811474B1 (pt) |
CA (1) | CA2296427C (pt) |
DE (1) | DE69830595T2 (pt) |
DK (1) | DK1010699T3 (pt) |
EE (1) | EE04372B1 (pt) |
ES (1) | ES2244065T3 (pt) |
HK (1) | HK1028895A1 (pt) |
HU (1) | HUP0004671A3 (pt) |
ID (1) | ID24047A (pt) |
IL (2) | IL133512A0 (pt) |
NO (1) | NO314999B1 (pt) |
NZ (1) | NZ501814A (pt) |
PL (1) | PL191200B1 (pt) |
PT (1) | PT1010699E (pt) |
RU (1) | RU2188199C2 (pt) |
SI (1) | SI1010699T1 (pt) |
SK (1) | SK285913B6 (pt) |
TR (1) | TR200000103T2 (pt) |
TW (1) | TW486479B (pt) |
WO (1) | WO1999003857A1 (pt) |
ZA (1) | ZA985870B (pt) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI298068B (en) * | 2000-06-21 | 2008-06-21 | Dainippon Sumitomo Pharma Co | Pharmaceutical composition for schizophrenia |
TW200533371A (en) * | 2004-04-15 | 2005-10-16 | Dainippon Pharmaceutical Co | Medicament comprising a combination of an acetylcholinesterase inhibitor and a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1h)-one derivative |
CN101541311B (zh) | 2006-10-25 | 2013-01-23 | 大日本住友制药株式会社 | 不易结块的颗粒制剂 |
MX2010009207A (es) * | 2008-02-22 | 2011-03-03 | Irm Llc | Compuestos y composiciones heterociclicos como inhibidores de c-kit y pdgfr cinasa. |
WO2010002451A1 (en) * | 2008-07-01 | 2010-01-07 | Concert Pharmaceuticals, Inc. | Naphthyridin derivatives |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4415580A (en) | 1982-08-02 | 1983-11-15 | Sterling Drug Inc. | Certain 2-(1H)-pyridinones cardiotonic compositions containing same and method of using same |
US4650806A (en) * | 1985-01-14 | 1987-03-17 | Sterling Drug Inc. | Cardiotonic 5-(heterylcarbonyl)-pyridones |
US4567186A (en) * | 1985-01-14 | 1986-01-28 | Sterling Drug Inc. | 5-Heteryl-1,6-naphthyridin-2(1H)-ones, cardiotonic use thereof and intermediates therefor |
DK151890D0 (da) * | 1990-06-22 | 1990-06-22 | Ferrosan As | Heterocykliske forbindelser deres fremstilling og brug |
AU1625192A (en) * | 1991-05-31 | 1992-12-03 | Zeneca Limited | Heterocyclic derivatives |
AU664912B2 (en) * | 1992-09-02 | 1995-12-07 | Dainippon Pharmaceutical Co. Ltd. | Novel 3-oxadiazolyl-1,6-naphthyridine derivatives |
JP2002241379A (ja) * | 1997-03-21 | 2002-08-28 | Dainippon Pharmaceut Co Ltd | 3−オキサジアゾリルキノキサリン誘導体 |
-
1998
- 1998-07-03 TW TW087110767A patent/TW486479B/zh not_active IP Right Cessation
- 1998-07-03 ZA ZA985870A patent/ZA985870B/xx unknown
- 1998-07-14 TR TR2000/00103T patent/TR200000103T2/xx unknown
- 1998-07-14 PT PT98931076T patent/PT1010699E/pt unknown
- 1998-07-14 WO PCT/JP1998/003134 patent/WO1999003857A1/ja active IP Right Grant
- 1998-07-14 AT AT98931076T patent/ATE297923T1/de not_active IP Right Cessation
- 1998-07-14 AU AU81294/98A patent/AU735960B2/en not_active Ceased
- 1998-07-14 JP JP50689699A patent/JP3390453B2/ja not_active Expired - Fee Related
- 1998-07-14 NZ NZ501814A patent/NZ501814A/en unknown
- 1998-07-14 EP EP98931076A patent/EP1010699B1/en not_active Expired - Lifetime
- 1998-07-14 ID IDW991683A patent/ID24047A/id unknown
- 1998-07-14 ES ES98931076T patent/ES2244065T3/es not_active Expired - Lifetime
- 1998-07-14 BR BRPI9811474-3A patent/BR9811474B1/pt not_active IP Right Cessation
- 1998-07-14 US US09/462,412 patent/US6172079B1/en not_active Expired - Fee Related
- 1998-07-14 HU HU0004671A patent/HUP0004671A3/hu unknown
- 1998-07-14 KR KR10-2000-7000388A patent/KR100508392B1/ko not_active IP Right Cessation
- 1998-07-14 RU RU2000103445/04A patent/RU2188199C2/ru not_active IP Right Cessation
- 1998-07-14 EE EEP200000029A patent/EE04372B1/xx not_active IP Right Cessation
- 1998-07-14 CN CNB988072262A patent/CN1134437C/zh not_active Expired - Fee Related
- 1998-07-14 DK DK98931076T patent/DK1010699T3/da active
- 1998-07-14 IL IL13351298A patent/IL133512A0/xx active IP Right Grant
- 1998-07-14 CA CA002296427A patent/CA2296427C/en not_active Expired - Fee Related
- 1998-07-14 SI SI9830774T patent/SI1010699T1/xx unknown
- 1998-07-14 SK SK53-2000A patent/SK285913B6/sk not_active IP Right Cessation
- 1998-07-14 PL PL338085A patent/PL191200B1/pl not_active IP Right Cessation
- 1998-07-14 DE DE69830595T patent/DE69830595T2/de not_active Expired - Fee Related
- 1998-07-15 AR ARP980103452A patent/AR013222A1/es active IP Right Grant
-
1999
- 1999-12-14 IL IL133512A patent/IL133512A/en not_active IP Right Cessation
-
2000
- 2000-01-14 NO NO20000183A patent/NO314999B1/no not_active IP Right Cessation
- 2000-09-01 US US09/654,782 patent/US6277993B1/en not_active Expired - Fee Related
- 2000-12-21 HK HK00108261A patent/HK1028895A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3704106B1 (en) | Alkene compounds as farnesoid x receptor modulators | |
JPH11513679A (ja) | 薬剤活性キナゾリン化合物 | |
JP2002241379A (ja) | 3−オキサジアゾリルキノキサリン誘導体 | |
TW200916469A (en) | Multi-cyclic compounds | |
TW200815414A (en) | Inhibitors of C-FMS kinase | |
EP3704112B1 (en) | Alkene spirocyclic compounds as farnesoid x receptor modulators | |
NO314999B1 (no) | 5-substituerte-3-oksadiazolyl-1,6-naftyridin-2(1H)-on- derivater og farmasöytisk preparat inneholdende disse | |
DE69907923T2 (de) | Triazolopyridazinderivate zur verbesserung der kognitiven funktionen | |
CN115348962A (zh) | 作为GABAAα5受体调节剂的萘啶及吡啶并[3,4-c]哒嗪衍生物 | |
NO301011B1 (no) | 3-oksadiazolyl-5,6,7,8-tetrahydro-1,6-naftyridinderivater | |
Ohashi | Discovery of Novel Hedgehog Signaling Inhibitor | |
JPH11279176A (ja) | 1,2,4−オキサジアゾリルキノロン誘導体 | |
MXPA00000558A (en) | 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1h)-one derivatives | |
大橋知洋 | Discovery of Novel Hedgehog Signaling Inhibitor | |
CZ200046A3 (cs) | Deriváty 5-substituovaného-3~oxadiazoIyl-l,6- naftyridin-2(lH)-onu |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |