HRP20000555A2 - SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE - Google Patents
SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE Download PDFInfo
- Publication number
- HRP20000555A2 HRP20000555A2 HR20000555A HRP20000555A HRP20000555A2 HR P20000555 A2 HRP20000555 A2 HR P20000555A2 HR 20000555 A HR20000555 A HR 20000555A HR P20000555 A HRP20000555 A HR P20000555A HR P20000555 A2 HRP20000555 A2 HR P20000555A2
- Authority
- HR
- Croatia
- Prior art keywords
- triazolo
- compound
- phthalazine
- methylisoxazol
- methyloxy
- Prior art date
Links
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 13
- 230000019771 cognition Effects 0.000 claims description 7
- NZMJFRXKGUCYNP-UHFFFAOYSA-N α5ia Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N=NN(C)C=4)C4=CC=CC=C4C3=NN=2)=N1 NZMJFRXKGUCYNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims 1
- 230000003247 decreasing effect Effects 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000203 mixture Substances 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 206010012289 Dementia Diseases 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 206010012218 Delirium Diseases 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 208000000044 Amnesia Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000006986 amnesia Effects 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229960004381 flumazenil Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 208000031091 Amnestic disease Diseases 0.000 description 3
- 206010012374 Depressed mood Diseases 0.000 description 3
- 102000027484 GABAA receptors Human genes 0.000 description 3
- 108091008681 GABAA receptors Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- UQTJGZYAFKMABR-UHFFFAOYSA-N (4-chlorophthalazin-1-yl)hydrazine Chemical compound C1=CC=C2C(NN)=NN=C(Cl)C2=C1 UQTJGZYAFKMABR-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 description 2
- JPALNVSONHINLP-UHFFFAOYSA-N 3-(6-chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-5-methyl-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(Cl)C4=CC=CC=C4C3=NN=2)=N1 JPALNVSONHINLP-UHFFFAOYSA-N 0.000 description 2
- BNMPIJWVMVNSRD-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NO1 BNMPIJWVMVNSRD-UHFFFAOYSA-N 0.000 description 2
- SPKCNMWPMHLVKI-UHFFFAOYSA-N 5-methyl-3-[6-(2h-triazol-4-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4NN=NC=4)C4=CC=CC=C4C3=NN=2)=N1 SPKCNMWPMHLVKI-UHFFFAOYSA-N 0.000 description 2
- JNJUWXAKLRKXII-UHFFFAOYSA-N 5-methyl-3-[6-[(2-methyltriazol-4-yl)methoxy]-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC4=NN(C)N=C4)C4=CC=CC=C4C3=NN=2)=N1 JNJUWXAKLRKXII-UHFFFAOYSA-N 0.000 description 2
- VAJLZGPUVKNCRO-UHFFFAOYSA-N 5-methyl-3-[6-[(3-methyltriazol-4-yl)methoxy]-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N(N=NC=4)C)C4=CC=CC=C4C3=NN=2)=N1 VAJLZGPUVKNCRO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229960002200 flunitrazepam Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- XDDGKNRSCDEWBR-UHFFFAOYSA-N (6-bromopyridin-2-yl)methanol Chemical compound OCC1=CC=CC(Br)=N1 XDDGKNRSCDEWBR-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ODCNAEMHGMYADO-UHFFFAOYSA-N 1,4-dichlorophthalazine Chemical compound C1=CC=C2C(Cl)=NN=C(Cl)C2=C1 ODCNAEMHGMYADO-UHFFFAOYSA-N 0.000 description 1
- CBHTTYDJRXOHHL-UHFFFAOYSA-N 2h-triazolo[4,5-c]pyridazine Chemical class N1=NC=CC2=C1N=NN2 CBHTTYDJRXOHHL-UHFFFAOYSA-N 0.000 description 1
- KBXIMXGMCDDYNJ-UHFFFAOYSA-N 3-(2-trimethylsilylethoxymethyl)triazole-4-carbaldehyde Chemical compound C[Si](C)(C)CCOCN1N=NC=C1C=O KBXIMXGMCDDYNJ-UHFFFAOYSA-N 0.000 description 1
- WJSYAGTVTDLCGA-UHFFFAOYSA-N 3-(5-methyl-1,2-oxazol-3-yl)-5h-[1,2,4]triazolo[3,4-a]phthalazin-6-one Chemical compound O1C(C)=CC(C=2N3N=C(O)C4=CC=CC=C4C3=NN=2)=N1 WJSYAGTVTDLCGA-UHFFFAOYSA-N 0.000 description 1
- LBVZCSKDTGDAQW-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-3-yl)phosphanyl]-1,3-oxazolidin-2-one;hydrochloride Chemical compound [Cl-].O=C1OCCN1[PH2+]N1C(=O)OCC1 LBVZCSKDTGDAQW-UHFFFAOYSA-N 0.000 description 1
- OFIJDJZCDLBMDH-UHFFFAOYSA-N 3-[6-[(6-bromopyridin-2-yl)methoxy]-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-5-methyl-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N=C(Br)C=CC=4)C4=CC=CC=C4C3=NN=2)=N1 OFIJDJZCDLBMDH-UHFFFAOYSA-N 0.000 description 1
- WIVMPMAVUMDJNQ-UHFFFAOYSA-N 3-[7-methoxy-6-(2h-triazol-4-yl)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-5-methyl-1,2-oxazole Chemical compound N12N=C(C3=NNN=C3)C=3C(OC)=CC=CC=3C2=NN=C1C=1C=C(C)ON=1 WIVMPMAVUMDJNQ-UHFFFAOYSA-N 0.000 description 1
- RYPJWVSUBZEZRG-UHFFFAOYSA-N 3-methoxy-[1,2,4]triazolo[3,4-a]phthalazine Chemical compound C1=CC=C2C=NN3C(OC)=NN=C3C2=C1 RYPJWVSUBZEZRG-UHFFFAOYSA-N 0.000 description 1
- YTGZSWOWFGVAFH-UHFFFAOYSA-N 5-methyl-3-[6-(pyridin-2-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N=CC=CC=4)C4=CC=CC=C4C3=NN=2)=N1 YTGZSWOWFGVAFH-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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229940084657 Benzodiazepine receptor inverse agonist Drugs 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- JVJPJKLSGUJUJK-UHFFFAOYSA-N [1,2,4]triazolo[3,4-a]phthalazine Chemical class C1=CC=C2C=NN3C=NN=C3C2=C1 JVJPJKLSGUJUJK-UHFFFAOYSA-N 0.000 description 1
- RFLQLCJNLFSVGT-UHFFFAOYSA-N [3-(2-trimethylsilylethoxymethyl)triazol-4-yl]methanol Chemical compound C[Si](C)(C)CCOCN1N=NC=C1CO RFLQLCJNLFSVGT-UHFFFAOYSA-N 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
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000037410 cognitive enhancement Effects 0.000 description 1
- 230000037411 cognitive enhancing Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 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
- 239000008187 granular material Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 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
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- RZLMQJSSMROKSS-UHFFFAOYSA-N trimethyl-[2-(triazol-1-ylmethoxy)ethyl]silane Chemical compound C[Si](C)(C)CCOCN1C=CN=N1 RZLMQJSSMROKSS-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Predmetni izum odnosi se na supstituirani triazolo-piridazin derivat, na njegovu uporabu u liječenju, na sastave koji ga sadrže i na postupak njegove proizvodnje.
Otkrili smo da je moguće dobiti lijekove koji imaju efekt poboljšanja spoznaje koji se mogu koristiti uz smanjeni rizik izazivanja grčeva, koji je prethodno opisan na djelomičnim ili potpunim inverznim agonistima benzodiazepinskih receptora. Poželjni su oni inverzni agonisti koji su inverzni agonisti za α5 receptor i koji su relativno slobodni od djelovanja na α1, α2 i α3 vezna mjesta na receptoru.
Europske patentne prijave 0085840 i 0134946 opisuju srodne serije derivata 1,2,4-triazolo[3,4-a]ftalazina, za koje se smatra da imaju antianksiozno djelovanje. Međutim, nema zaključaka niti hipoteza u bilo kojoj od ovih publikacija o spojevima predmetnog pronalaska, niti da spojevi opisani u prijavama imaju bilo kakva svojstva poboljšanja spoznaje.
Predmetni izum daje spoj koji je:
3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin.
Poboljšanje spoznaje dokazuje se testiranjem spoja u Morris-ovom vodenom labirintu kako je opisano u McNamara i Skelton, Psychobiology, 21:101-108. Funkcionalna efikasnost na različite receptorske podtipove može se izračunati koristeći metodu opisanu u WO-9625948.
Stoga, na primjer, spoj predmetnog pronalaska može biti korišten kod različitih poremećaja centralnog nervnog sustava. Ovi poremećaji uključuju delirij, demenciju, amneziju i druge poremećaje spoznaje. Primjeri delirija su delirij uzrokovan intoksikacijom ili apstinencijskom krizom, delirij uzrokovan višestrukom etiologijom i delirij NOS (not otherwise specifled) nepoznatog uzroka. Primjeri demencije su: demencija Alzheimer'ovog tipa s ranim pojavljivanjem, koja može biti bez komplikacija ili uz pojavu delirija, priviđenja ili depresivnih raspoloženja; demencija Alzheimer'ovog tipa, s kasnim pojavljivanjem, koja može biti bez komplikacija ili uz pojavu delirija, priviđenja ili depresivnih raspoloženja; vaskularna demencija, koja može biti bez komplikacija ili uz pojavu delirija, priviđenja ili depresivnih raspoloženja; demencija uzrokovana HIV bolesti; demencija uzrokovana povredama glave; demencija uzrokovana Parkinson-ovom bolesti; demencija uzrokovana Huntington-ovom bolesti; demencija uzrokovana Pick-ovom bolesti; demencija uzrokovana Creutzfeld-Jakob-ovom bolesti; demencija uzrokovana trajnim uzimanjem nekih supstanci ili su uzroci višestruke etiologije; i demencija NOS. Primjeri amnezije su amnezije koje su djelomično uzrokovane medicinskim stanjem ili koje su uzrokovane trajnim uzimanjem nekih supstanci ili amnezije NOS.
Izum isto tako daje farmaceutske sastave koji sadrže spojeve ovog pronalaska i farmaceutski prihvatljivi nosač. Poželjno, ovi sastavi su u obliku jedinične doze kao što su tablete, pilule, kapsule, prašci, granule, sterilne parenteralne otopine ili suspenzije, aerosoli u raspršivaču ili tekući sprejevi, kapi, ampule, transdermalni flasteri, auto-injectori ili supozitoriji; za oralnu, parenteralnu, intranazalnu, sublingvalnu ili rektalnu primjenu, ili za primjenu inhalacijom ili insuflacijom. Za pripravu krutih sastava kao što su tablete, glavni aktivni sastojak je miješan s farmaceutskim nosačem, npr. uobičajenim sastojcima tableta kao što su škrob, laktoza, sukroza, sorbitol, talk, stearinska kiselina, magnezij stearat, dikalcij fosfat ili gume ili surfaktanti kao što su sorbitan monooleat, polietilen glikol, i druga farmaceutska otapala, npr. voda da se dobiju čvrsti preformulirani sastavi, koji sadržavaju homogenu smjesu spoja predmetnog pronalaska, ili njegovu farmaceutski prihvatljivu sol. Kada nazivamo ove preformulirane sastave homogenima, to znači da je aktivni sastojak dispergiran ravnomjerno kroz sastav, tako da sastav može biti raspodijeljen u jednako efikasne oblike jediničnih doza kao što su tablete, pilule i kapsule. Ovi kruti preformulirani sastavi se zatim razdijele u forme jediničnih doza, tipovi kojih su gore opisani, sadržavaju od 0.1 do oko 500 mg aktivnog sastojaka predmetnog pronalaska. Tipične forme jedinične doze sadržavaju od 1 do 100 mg, na primjer 1, 2, 5, 10, 25, 50 ili 100 mg, aktivnog sastojka. Tablete ili pilule novog sastava mogu biti presvučene ili spojene da omoguće formu doziranja s produljenim djelovanjem. Na primjer, tableta ili pilula može se sastojati od unutarnje doze i komponente vanjske doze, tako da ova druga obuhvaća prvu. Dvije komponente mogu biti odvojene enteričnim slojem koji odoljeva dezintegraciji u želucu i omogućava unutarnjoj komponenti da prijeđe netaknuta u duodenum ili da se oslobađa uz odgodu. Razni materijali mogu se koristiti za takve enteričke slojeve ili omotače, kao što su polimeričke kiseline i smjese polimeričkih kiselina kao što su shellac, cetil alkohol i celulozni acetat.
Tekući oblici u kojima se novi sastavi predmetnog pronalaska mogu pripravljati za oralno davanje ili injekcijom uključuju vodene otopine, sirupe s umjetnim aromama, vodene ili uljne suspenzije, i emulzije sa jestivim uljima kao što su pamučno ulje, sezamovo ulje, kokosovo ulje ili ulje kikirikija, kao i eliksire i slične farmaceutske nosače. Pogodni disperzivni ili suspenzivni agensi za vodene suspenzije uključuju sintetske i prirodne smole kao što su tragakant, akacija, alginati, dekstran, natrij karboksimetilceluloza, metilceluloza, polivinil-pirolidon ili želatina.
Predmetni pronalazak nadalje omogućava korištenje spoja predmetnog pronalaska u proizvodnji lijeka za poticanje spoznaje, poželjno kod ljudi oboljelih od dementnih bolesti kao što je Alzheimerova bolest.
Za poticanje spoznaje, pogodna razina doziranja je od oko 0.01 do 250 mg/kg dnevno, poželjno oko 0.01 na 100 mg/kg dnevno, i naročito oko 0.01 do 5 mg/kg tjelesne težine dnevno. Spoj se može davati u režimu od 1 do 4 puta dnevno. U nekim slučajevima, međutim, mogu se koristit doze izvan ovih okvira.
Poželjno je da je spoj predmetnog pronalaska usitnjen, na primjer koristeći tučak ili njegov industrijski ekvivalent, do veličine čestica od 1 do 10 μM, i poželjno manje od 5 μM, prije formulacije. Spoj može biti usitnjen metodama znanim u struci ili nanoziran, na primjer po metodi opisanoj u US-5145684.
Predmetni pronalazak također daje postupak za proizvodnju spoja predmetnog pronalaska, reagiranjem metilirajućeg reagensa, kao što je litij heksametildisilazid sa 3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazinom.
Reakcija se odvija u otapalu kao što je DMF, općenito na temperaturi ispod 0°C sa zagrijavanjem do sobne temperature i općenito pod inertnim plinom kao što je dušik. Reakcijska smjesa je općenito ostavljena 4-12 sati. Željeni produkt je općenito pročišćen od drugih reakcijskih produkta konvencionalnim tehnikama separacije kao što je preparativni HPLC.
Za vrijeme gore navedenih sintetskih sekvenci može biti potrebno i/ili poželjno zaštiti osjetljive ili reaktivne grupe molekula. Ovo se može postići konvencionalnim zaštitnim grupama, kao što su one opisane u Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; i T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Zaštitne grupe mogu biti uklonjene u pogodnoj daljnjoj fazi koristeći metode poznate u struci.
Spojevi u skladu s ovim pronalaskom potencijalno inhibiraju vezivanje [3H]-flumazenila na vezivnu lokaciju benzodiazepina ljudskih GABAA receptora sa α5 podjedinicom stabilno ekspresiranom u Ltk- stanicama.
Reagensi
• Fosfat-puferirana slana otopina (PBS).
• Testni pufer: 10 mM KH2PO4, 100 mM KCl, pH 7.4 na sobnoj temperaturi.
• [3H]-Flumazenil (18 nM za α1β3γ2 stanice; 18 nM za stanice α2β3γ2; 10 nM za α3β3γ2 stanice; 10 nM za α5β3γ2 stanice) u testnom puferu.
• Flunitrazepam 100 μM u testnom puferu.
• Stanice resuspendirane u testnom puferu (1 posuda na 10 ml).
Žetva Stanica
Supernatant je odvojen od stanica. PBS (približno 20 ml)je dodan. Stanice su ostrugane i stavljene u 50 ml epruvetu za centrifugiranje. Postupak je ponovljen sa daljnjih 10 ml PBS tako da je većina stanica uklonjena. Stanice su istaložene centrifugiranjem u trajanju 20 min na 3000 rpm u stolnoj centrifugi, i zatim smrznute po želji. Kuglice su resuspendirane u 10 ml pufera po posudi (25 cm x 25 cm) stanica.
Test
Može se izvesti u dubokim pločicama s 96-jažica ili u epruvetama. Svaka epruveta sadrži:
• 300 μl testnog pufera.
• 50 μl [3H]-flumazenila (krajnja koncentracija za α1β3γ2: 1.8 nM; za α2β3γ2: 1.8 nM; za α3β3γ2: 1.0 nM; za α5β3γ2: 1.0 nM).
• 50 μl pufera ili topivog nosača (npr. 10% DMSO) ako je spoj otopljen u 10% DMSO (ukupno); testni spoj ili flunitrazepam (da se odredi ne-specifično vezivanje), 10 μM krajnja koncentracija.
• 100 μ1 stanica.
Testovi su inkubirani 1 sat na 40°C, zatim flltrirani koristeći ili Tomtec ili Brandel stanični harvester na GF/B filtere, praćeno 3 x 3 ml ispiranjem ledenim testnim puferom. Filteri su osušeni i izbrojeni scintilacijskim brojačem za tekućine. Očekivane vrijednosti za ukupno vezivanje su 3000-4000 dpm za ukupan broj i manje od 200 dpm za ne-specifično vezivanje, ako se koristi scintilacijski brojač za tekućine, ili 1500-2000 dpm za ukupno brojanje i manje od 200 dpm za ne-specifično vezivanje, ako se broji sa meltilex scintilantorom za krutine. Vezivni parametri su određeni ne-linearnom analizom metodom regresije, gdje se inhibicijska konstanta Ki može izračunati za testni spoj.
Spoj u skladu sa ovim pronalaskom potencijalno inhibira vezivanje [3H]-flumazenila na benzodiazepin vezivnu lokaciju ljudskih GABAA receptora sa α5 podjedinicom stabilno ekspresiranom u Ltk- stanice.
Spoj pratećeg Primjera je testiran kako je gore navedeno i nađena je vrijednost Ki za pomak [3H]Ro 15-1788 od α5 podjedinice ljudskog GABAA receptora od 100 nM ili manje.
Spoj predmetnog pronalaska dokazano potiče spoznaju u testu vodenog labirinta štakora (Morris, Learning i Motivation, 1981, 12, 239ff). Nadalje detalji metodologije za dokazivanje da predmetni spojevi poboljšavaju spoznaju mogu se naći u WO-9625948. Ovo je dokazano pri minimalnoj efektivnoj dozi od 0.3mg/kg, na kojoj spoj predmetnog pronalaska zauzima 40% receptora. Isto je dokazano pri dozama od 3mg/kg.
Spoj predmetnog pronalaska može biti pripravljen kako je opisano u sljedećim Primjerima. Precizni detalji reakcijskih uvjeta i očigledne modifikacije reakcijskog postupka su poznati stručnim osobama.
Međuprodukt 1
6-kloro-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3,4-a]ftalazina)
a) 1-kloro-4-hidrazinoftalazin
1,4-dikloroftalazin (20. Og, 0.100 mol)je dodan u kipuću otopinu hidrazin monohidrata (37.3 ml, 0.765 mol) u etanolu (500 ml) i smjesa zagrijavana na refluksu za 0.5 h. Smjesa je ohlađena na sobnoj temperaturi i krutina sakupljena filtracijom i isprana s eterom. Materijal je uzet sa n-butanolom i otopinom amonija (sp. gr. 0.91) i zagrijavanje do otapanja krutine. Organski sloj je odvojen, otparen in vacuo i ostatak azeotropiran sa ksilenom (x2) i osušen in vacuo da se dobije naslovni-hidrazin (11.5 g, 59%),
1H NMR (250 MHz, d6DMSO) δ 7.84 - 8.04 (3H, m, Ar-H), 8.20 (1H, m, Ar-H); MS (ES+) m/e 194 [MH]+.
b) 5-metilizoksazol-3-karboksilna kiselina
Smjesa acetonilacetona (10g, 88 mmol) i dušične kiseline (sp. gr. 1.42) / voda (2:3) (50 ml) je oprezno dodavana na refluksu pod strujom dušika i ključala 1h. Otopina je ohlađena na sobnoj temperaturi i odstajala preko noći. Rezultirajuća krutina je sakupljena filtracijom, isprana sa ohlađenom vodom (2x7 ml) i heksanom, i osušena in vacuo da se dobije naslovna-kiselina (4.4g, 40%),
1H NMR (CDCl3) δ 2.50 (3H, d, J = 0.8Hz, Me), 6.41 (1H, d, J = 0.8Hz, Ar-H).
c) 6-kloro-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3,4-a]ftalazin
5-metilizoksazol-3-karboksilna kiselina (5.24 g, 41.3 mmol), bis(2-okso-3-oksazolidinil)fosfin klorid (10.5 g, 41.2 mmol) i trietilamin (11.5 ml, 82.5 mmol) su dodani sukcesivno u mješanu suspenziju 1-kloro-4-hidrazinoftalazina (8.00 g, 41.2 mmol) u diklorometanu (1 l) na 0°C pod dušikom. Smjesa je miješana na 0°C 2h i ostavljen na sobnoj temperaturi preko noći. Otapalo je otpareno in vacuo, ostatak trituriran s vodom i krutina profiltrirana, isprana s heksanom i osušena in vacuo da se dobije ketohidrazin (11 g), MS (ES+) m/e 304 [MH]+. Otopina ketohidrazina (11 g) i trietilamin hidroklorida (2.2 g, 20% w/w) u ksilenu (500 ml) je zagrijavana na refluksu 3 h. Smjesa je ohlađena na sobnoj temperaturi i otapalo otpareno in vacuo. Ostatak je otopljen u diklorometanu, ispran s vodom (x 2), osušen (MgSO4) i otparen in vacuo, i krutina rekristalizirana (diklorometan/heksan) da se dobije naslovni-spoj (6.8 g, 58%),
1H NMR (360MHz, CDCl3) δ 2.59 (3H, s, Me), 6.90 (1H, s, Ar-H), 7.95 (1H, m, Ar-H), 8.07 (1H, m, Ar-H), 8.34 (1H, m, Ar-H), 8.78 (1H, s, Ar-H); MS (ES+) m/e 286 [MH]+.
Referentni primjer 1
3-(5-metilizoksazol-3-il)-6-(2-piridil)metiloksi-1,2,4-triazolo [3,4-a]ftalazin
Natrij hidrid (244 mg 60% disperzija u ulju, 6.10 mmol)je dodan u miješanu otopinu 2-piridilkarbinola (470 mg, 4.27 mmol) u DMF (60 ml) na sobnoj temperaturi., pod dušikom i smjesa je miješana 0.25 h. Nakon tog vremena, Međuprodukt 1 (1160 mg, 4.07 mmol)je dodan i smjesa miješana 2h. Otapalo je uklonjeno in vacuo i ostatak otopljen u diklorometanu, ispran s vodom (x2), osušen (MgSO4) i otparen in vacuo. Brzom kromatografijom na silika gelu, eluirano sa 3% metanol/diklorometan, praćeno s rekristalizacijom (diklorometan/heksan) dobiven je naslovni-produkt (640 mg, 44%), mp 234 - 236 °C;
1H NMR (360 MHz, CDCl3) δ 2.59 (3H, d, J = 0.8Hz, Me), 5.77 (2H, s, CH2), 6.82 (1H, d, J-0.8Hz, Ar-H), 7.30 (1H, m, Ar-H), 7.74 - 7.85 (3H, m, Ar-H), 7.95 (1H, m, Ar-H), 8.33 (1H, d, J = 7.8Hz, Ar-H), 8.64 - 8.72 (2H, m, Ar-H); MS (ES+) m/e 359 [MH]+;
Anal. nađeno C 62.93; H, 3.56; N, 22.94. C19H14N6O2 0.05 (CH2Cl2)
zahtjeva C 63.10; H, 3.92; N, 23.17%.
Referentni primjer 2
6-(6-bromopiridin-2-il)metiloksi-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3,4-a]ftalazin
Naslovni-spoj je pripravljen od Međuprodukta 1 i 2-bromopiridin-6-metanola (Tetrahedron Lett., 1996, 50, 2537) po postupku opisanom za Referentni Primjer 1. Produkt je izoliran dodavanjem vode u reakcijsku smjesu i rezultirajući precipitat je profiltriran. Brza kromatografija na silika gelu, eluirano sa etil acetatom, i rekristalizacijom (etil acetate-metanol) dala je naslovni-ftalazin, mp 247.5 - 249 °C;
1H NMR (360 MHz, CDCl3) δ 2.61 (3H, d, J = 0.7 Hz, Me), 5.73 (2H, s, CH2), 6.82 (1H, d, J = 0.7 Hz, Ar-H), 7.48 (1H, d, J = 7.8 Hz, Ar-H), 7.63 (1H, t, J = 7.7 Hz, Ar-H), 7.76 (1H, d, J = 7.4 Hz, Ar-H), 7.84 (1H, t, J = 8.4 Hz, Ar-H), 7.98 (1H, t, J = 8.4 Hz, Ar-H), 8.31 (1H, d, J = 8.5 Hz, Ar-H), 8.70 (1H, d, Ar-H); MS (ES+) m/e 437 [MH]+;
Anal. nađeno C, 52.27; H, 2.85; N, 19.14. C19H13N6O Br. 0.1 (H2O)
zahtjeva C, 51.98; H, 3.03; N, 18.60%.
Međuprodukt 2
6-hidroksi-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3,4-a]ftalazin
Otopina natrij hidroksida (0.67 g, 17 mmol) u vodi (7.5 ml)je dodana u miješanu otopinu Međuprodukta 1 (1.0 g, 3.5 mmol) u dioksanu (37.5 ml) i smjesa zagrijavana na refluksu 4 h. Otapalo je otpareno in vacuo i ostatak podijeljen između vode i dietil etera. Vodeni sloj je odvojen, ispran sa eterom (x 1) i zatim zakiseljen sa 2N klorovodičnom kiselinom do postizanja pH2. Krutina koja je istaložena iz otopine je profiltrirana i vodeni filtrat ekstrahiran s diklorometanom (x 3). Kombinirani ekstrakti su osušeni (MgSO4) i otpareni in vacuo i kombiniranjem sa talogom se dobije naslovni-produkt (0.45 g, 48%),
1H NMR (250 MHz, d6-DMSO) δ 2.58 (3H, d, J = 0.7 Hz, Me), 7.07 (1H, d, J = 0.9 Hz, Ar-H), 7.94 (1H, m, Ar-H), 8.08 (1H, m, Ar-H), 8.24 (1H, d, J = 7.4 Hz, Ar-H), 8.54 (1H, d, J = 7.4 Hz, Ar-H), 13.32 (1H, br s, NH); MS (ES+) m/e 268 [MH]+.
Referentni primjer 3
3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin
a) 5-formil-1-[2-(trimetilsilil)etoksi]metil-1,2,3-triazol
n-butil litij (6.8ml 1.6M otopina u heksanima, 10.9mmol)je dodana u kapima tijekom 0.08h u miješanu otopinu 1-[2-(trimetil-silil)etoksi]metil-1,2,3-triazola (J. Heterocycl. Chem., 1992, 29, 1203) (2.077g, 10.42mmol) u THF (30ml) na -78°C pod dušikom. Otopina je puštena da se zagrije do -60°C tijekom 0.67h, zatim ponovno ohlađena na -78°C i dodan je DMF (0.9ml, 11.6mmol). Smjesa je puštena da se zagrije do sobne temperature i miješana 16.5h. Dodana je zasićena otopina amonij klorida (50ml) i reakcijska smjesa ekstrahirana sa dietil eterom (3 x 80ml). Kombinirani etarski ekstrakti su osušeni (MgSO4), otpareni in vacuo, i ostatak kromatografiran na silika gelu, eluirano sa 30% etil acetat/heksan, da se dobije naslovni-triazol (1.713g, 72%),
1H NMR (360 MHz, CDCl3) δ 0.01 (9H, s, Me3Si), 0.92-0.99 (2H, m, CH2), 3.64-3.69 (2H, m, CH2), 6.05 (2H, s, CH2), 8.31 (1H, s, Ar-H), 10.12 (1H, s, CHO).
b) 5-hidroksimetil-1-[2-(trimetilsilil)etoksi]metil-1,2,3-triazol
Natrij borohidrid (0.284g, 7.51mmol)je dodan u miješanu otopinu prethodnog triazola (1.704g, 7.495mmol) u metanolu (8ml) na 0°C, pod dušikom. Smjesa je miješana na 0°C 0.5h i na sobnoj temperaturi 0.5h. Voda je dodana i smjesa podijeljena između diklorometana i zasićene slane otopine. Vodeni sloj je odvojen i nadalje ekstrahiran sa diklorometanom (x2). Kombinirani organski slojevi su osušeni ((MgSO4) i otpareni in vacuo i ostatak kromatografiran na silika gelu, eluirano sa 70% etil acetat/heksan, da se dobije naslovni-produkt (1.34g, 78%),
1H NMR (360 MHz, CDCl3) δ 0.00 (9H, s, Me3Si), 0.90-0.95 (2H, m, CH2), 3.58-3.63 (2H, m, CH2), 4.84 (2H, s, CH2), 5.80 (2H, s, CH2), 7.68 (1H,s,Ar-H).
c) 3-(5-metilizoksazol-3-il)-6-{1-[2-(trimetilsilil)etoksi]metil-1,2,3-triazol-5-il}metiloksi-1,2,4-triazolo[3,4-a]ftalazin
Naslovni-spoj je pripravljen od Međuprodukta 1 i prethodnog alkohola prema postupku opisanom za primjer 10, 360 MHz (360 MHz, CDCl3) δ 0.00 (9H, s, Me3Si), 0.88-0.93 (2H, m, CH2), 2.63 (3H, s, Me), 3.61-3.66 (2H, m, CH2), 5.92 (2H, s, CH2), 5.97 (2H, s, CH2), 6.89 (1H, s, Ar-H), 7.86 (1H, m, Ar-H), 8.02 (1H, t, J = 7.7 Hz, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (1H, d, J = 8.0 Hz, Ar-H), 8.76 (1H, d, J = 8.0 Hz, Ar-H); MS (ES+) m/e 479 [MH]+.
d) 3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin
Smjesa prethodnog produkta, etanola (10 ml) i 2N HCl (20 ml) je zagrijavana na 50°C 15.25h. Otopina je bazificirana do pH 12 sa zasićenom otopinom natrij karbonata i otapala su otparena in vacuo. Ostatak je azeotropiran sa etanolom (x2) i kromatografiran na silika gelu, eluirano sa 0-4% metanol/diklorometan (gradijent eluacije), da se dobije naslovni-produkt,
1H NMR (400 MHz, CDCl3) δ 2.65 (3H, s, Me), 5.73 (2H, s, CH2), 7.02 (1H, s, Ar-H), 7.87 (1H, U = 7.8 Hz, Ar-H), 7.99-8.03 (2H, m, 2 of Ar-H), 8.24 (1H, d, J = 8.2 Hz, Ar-H) 8.72 (1H, d, J = 7.9 Hz, Ar-H); MS (ES+) m/e 349 [MH]+.
Primjer 1
3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin, 3-(5-metilizoksazol-3-il)-6-(2-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin i 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin
Litij heksametildisilazid (1.63ml of 1M otopina u THF, 1.63mmol) je dodan u kapima u miješanu otopinu 3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazina (241mg, 0.626mmol) pripravljenu kao u Referentnom Primjeru 3, u DMF (50ml) na -31°C, pod dušikom. Smjesa je zagrijana do -23°C tijekom 1.5h, metiljodid (0.10 ml, 1.6 mmol) dodan u kapima i reakcijska smjesa ostavljena da se zagrije do sobne temperature preko noći. Voda je dodana i otapalo otpareno in vacuo. Ostatak je podijeljen između diklorometana i vode i vodena faza izdvojena i re-ekstrahirana sa diklorometanom (x1). Kombinirani organski ekstrakti su isprani slanom otopinom (x1), osušeni (MgSO4) i otpareni in vacuo. Kromatografija ostatka na silika gelu, eluirano sa 0-5% metanol/diklorometan (gradijent eluacije), praćeno s preparativnom HPLC (YMC Sil kolona, 250 x 20mm) eluirano sa 5% metanol/l-klorobutan, izdvojilo je izomere triazola:
Manje polarni izomer (HPLC sustav otapala): 3-(5-metilizoksazol-3-il)-6-(2-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin
1H NMR (400 MHz, CDCl3) δ 2.59 (3H, s, Me), 4.21 (3H, s, Me), 5.73 (2H, s, CH2), 6.89 (1H, s, Ar-H), 7.79 (1H, m, Ar-H), 7.94 (1H, m, Ar-H), 8.10 (1H, s, Ar-H), 8.22 (1H, d, J = 8.0 Hz, Ar-H), 8.67 (1H, d, J = 8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+.
Izomer srednjeg polariteta: 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin 1H NMR (400MHz, CDCl3) δ 2.60 (3H, s, Me), 4.09 (3H, s, Me), 5.78 (2H, s, CH2), 6.90 (1H, d, J = 0.8 Hz, Ar-H), 7.80 (1H, m, Ar-H), 7.94 (1H, m, Ar-H), 8.25 (1H, d, J = 8.0 Hz, Ar-H), 8.65 (1H, d, J = 8.0 Hz, Ar-H), 8.73 (1H, s, Ar-H);
MS (ES+) m/e 363 [MH]+.
Više polarni izomer (HPLC sustav otapala): 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin
1H NMR (400 MHz, CDCl3) δ 2.56 (3H, s, Me), 4.19 (3H, s, Me), 5.76 (2H, s, CH2), 6.82 (1H, s, Ar-H), 7.80 (1H, m, Ar-H), 7.96 (1H, m, Ar-H), 8.04 (1H, s, Ar-H), 8.12 (1H, d, J = 8.8 Hz, Ar-H), 8.67 (1H, d, J = 8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+.
Claims (5)
1. 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin.
2. Farmaceutski sastav, naznačen time, da sadrži spoj kako je opisan u zahtjevu 1 i farmaceutski prihvatljivi nosač.
3. 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]ftalazin, naznačen time, da se koristi kao metoda liječenja ljudi ili životinja.
4. Korištenje spoja iz zahtjeva 1, naznačeno time, da je za proizvodnju lijeka za poticanje spoznaje.
5. Metoda poboljšanja spoznaje kod subjekta, koji pati od smanjenja spoznaje, naznačena time, da se sastoji od davanja tom subjektu količine spoja iz zahtjeva 1, koja poboljšava spoznaju.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9803992.8A GB9803992D0 (en) | 1998-02-25 | 1998-02-25 | Therapeutic agents |
| PCT/GB1998/001307 WO1998050385A1 (en) | 1997-05-08 | 1998-05-06 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
| GBGB9824896.6A GB9824896D0 (en) | 1998-11-12 | 1998-11-12 | Therapeutic compound |
| PCT/GB1999/000485 WO1999043677A1 (en) | 1998-02-25 | 1999-02-17 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20000555A2 true HRP20000555A2 (en) | 2001-08-31 |
Family
ID=27269184
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20000555A HRP20000555A2 (en) | 1998-02-25 | 2000-08-25 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1070066A1 (hr) |
| JP (1) | JP2002504554A (hr) |
| CN (1) | CN1291194A (hr) |
| AU (1) | AU746719B2 (hr) |
| BG (1) | BG104705A (hr) |
| CA (1) | CA2317416A1 (hr) |
| EA (1) | EA002824B1 (hr) |
| HR (1) | HRP20000555A2 (hr) |
| HU (1) | HUP0100647A3 (hr) |
| NZ (1) | NZ505695A (hr) |
| PL (1) | PL341975A1 (hr) |
| SK (1) | SK12772000A3 (hr) |
| TR (1) | TR200002469T2 (hr) |
| WO (1) | WO1999043677A1 (hr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9821179D0 (en) * | 1998-09-30 | 1998-11-25 | Merck Sharp & Dohme | Therapeutic use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI81350C (fi) * | 1982-01-18 | 1990-10-10 | Lepetit Spa | Analogfoerfarande foer framstaellning av nya, farmakologiskt aktiva 6-substituerade s-triatsolo/3,4-a/ ftalazinderivat. |
| AU724076B2 (en) * | 1996-07-25 | 2000-09-14 | Merck Sharp & Dohme Limited | Substituted triazolo pyridazine derivatives as inverse agonists of the GABAAalpha5 receptor subtype |
| WO1998050385A1 (en) * | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
-
1999
- 1999-02-17 CA CA002317416A patent/CA2317416A1/en not_active Abandoned
- 1999-02-17 PL PL99341975A patent/PL341975A1/xx not_active Application Discontinuation
- 1999-02-17 HU HU0100647A patent/HUP0100647A3/hu unknown
- 1999-02-17 TR TR2000/02469T patent/TR200002469T2/xx unknown
- 1999-02-17 SK SK1277-2000A patent/SK12772000A3/sk unknown
- 1999-02-17 EA EA200000878A patent/EA002824B1/ru not_active IP Right Cessation
- 1999-02-17 JP JP2000533432A patent/JP2002504554A/ja not_active Withdrawn
- 1999-02-17 WO PCT/GB1999/000485 patent/WO1999043677A1/en not_active Application Discontinuation
- 1999-02-17 CN CN99803190A patent/CN1291194A/zh active Pending
- 1999-02-17 AU AU25368/99A patent/AU746719B2/en not_active Ceased
- 1999-02-17 EP EP99905069A patent/EP1070066A1/en not_active Withdrawn
- 1999-02-17 NZ NZ505695A patent/NZ505695A/en unknown
-
2000
- 2000-08-22 BG BG104705A patent/BG104705A/bg unknown
- 2000-08-25 HR HR20000555A patent/HRP20000555A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EA200000878A1 (ru) | 2001-02-26 |
| TR200002469T2 (tr) | 2000-12-21 |
| AU746719B2 (en) | 2002-05-02 |
| PL341975A1 (en) | 2001-05-07 |
| WO1999043677A1 (en) | 1999-09-02 |
| HUP0100647A2 (hu) | 2001-09-28 |
| NZ505695A (en) | 2002-03-01 |
| SK12772000A3 (sk) | 2001-03-12 |
| CN1291194A (zh) | 2001-04-11 |
| HUP0100647A3 (en) | 2003-03-28 |
| JP2002504554A (ja) | 2002-02-12 |
| EA002824B1 (ru) | 2002-10-31 |
| AU2536899A (en) | 1999-09-15 |
| CA2317416A1 (en) | 1999-09-02 |
| EP1070066A1 (en) | 2001-01-24 |
| BG104705A (bg) | 2001-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69807074T2 (de) | Substituierte 1,2,4-triazolo[3,4,-a]phthalazin-derivate als gaba-alpha 5-liganden | |
| JP2003513015A (ja) | ポリ（ａｄｐ−リボース）ポリメラーゼの三環系阻害剤 | |
| EA002755B1 (ru) | Производные триазолопиридазина в качестве лигандов для гамк рецепторов | |
| JP2000515851A (ja) | ＧＡＢＡ▲下Ａα５▼レセプターサブタイプの逆アゴニストとしての置換のあるトリアゾロピリダジン誘導体 | |
| US6313125B1 (en) | Therapeutically active 1,2,4-triazolo[4.,3-B] pyridazine derivatives as ligands for GABA receptors | |
| IE921945A1 (en) | Imidazodiazepines | |
| JPH07258260A (ja) | イミダゾジアゼピン | |
| US5700796A (en) | Tricyclic benzazepine vasopressin antagonists | |
| DE69907923T2 (de) | Triazolopyridazinderivate zur verbesserung der kognitiven funktionen | |
| US6949549B2 (en) | Imidazolophthalazine derivatives as ligands for GABAA receptors | |
| JP2003516994A (ja) | 認知能力を向上させるための置換１，２，３−トリアゾロ［１，５−ａ］キナゾリン | |
| JP2002501069A (ja) | Ｇａｂａ受容体のためのリガンドとしてのトリアゾロ−ピリダジン誘導体 | |
| HRP20000555A2 (en) | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE | |
| US6613766B1 (en) | Pentaaza-cyclopental[a]naphthalene derivatives as ligands for GABAa α5 receptors | |
| US6448249B1 (en) | Substituted 1,2,4-triazolo[3,4-A]phthalazine derivatives as GABAα5 ligands | |
| JP2003514909A (ja) | 認識能力増強用ピラゾロ〔１，５−ｄ〕〔１，２，４〕トリアジン | |
| US6444666B1 (en) | Triazolopyridazine Derivatives for treating anxiety and enhancing cognition | |
| US20030153562A1 (en) | Imidazolophthalazine derivatives as ligands for gabaa receptors | |
| CA2631034A1 (en) | Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents | |
| US7022724B2 (en) | Cognition enhancing derivatives of isoxazole triazoloindane GABA-A α5 receptor subunit ligands | |
| HRP980584A2 (en) | SUBSTITUTED 1,2,4-TRIAZOLO/3,4-a/ PHTHALAZINE | |
| MXPA00008320A (en) | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE | |
| MXPA97005061A (en) | Hidroximetilimidazodiazepinas and its east |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| ODRP | Renewal fee for the maintenance of a patent |
Payment date: 20020217 Year of fee payment: 4 |
|
| ARAI | Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application | ||
| OBST | Application withdrawn |