KR20120052343A - 융합된 아미노디하이드로피리미돈 유도체 - Google Patents
융합된 아미노디하이드로피리미돈 유도체 Download PDFInfo
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- KR20120052343A KR20120052343A KR20127004626A KR20127004626A KR20120052343A KR 20120052343 A KR20120052343 A KR 20120052343A KR 20127004626 A KR20127004626 A KR 20127004626A KR 20127004626 A KR20127004626 A KR 20127004626A KR 20120052343 A KR20120052343 A KR 20120052343A
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- South Korea
- Prior art keywords
- group
- substituents selected
- compound
- fluorophenyl
- amino
- Prior art date
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- GVBYERGPDQXKMZ-UHFFFAOYSA-N 3-amino-1,6-dihydropyrimidin-2-one Chemical class NN1C=CCNC1=O GVBYERGPDQXKMZ-UHFFFAOYSA-N 0.000 title description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 238000004519 manufacturing process Methods 0.000 claims abstract description 45
- 239000012453 solvate Substances 0.000 claims abstract description 45
- 125000005843 halogen group Chemical group 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 21
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 20
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 19
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 18
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 17
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims abstract description 16
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 102100021257 Beta-secretase 1 Human genes 0.000 claims abstract 2
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 404
- 125000001424 substituent group Chemical group 0.000 claims description 359
- 238000000034 method Methods 0.000 claims description 183
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 62
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 claims description 15
- 125000002837 carbocyclic group Chemical group 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 11
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 11
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 10
- 201000010374 Down Syndrome Diseases 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 6
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 6
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 102000014303 Amyloid beta-Protein Precursor Human genes 0.000 claims description 3
- 108010079054 Amyloid beta-Protein Precursor Proteins 0.000 claims description 3
- 206010012289 Dementia Diseases 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000007026 protein scission Effects 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 235000013601 eggs Nutrition 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 16
- 229940124597 therapeutic agent Drugs 0.000 abstract description 10
- 230000003449 preventive effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 228
- -1 aminodihydropyrimidone compound Chemical class 0.000 description 195
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- 239000000243 solution Substances 0.000 description 102
- 239000002904 solvent Substances 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 79
- 230000008569 process Effects 0.000 description 79
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 74
- 238000002360 preparation method Methods 0.000 description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 55
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- 239000000203 mixture Substances 0.000 description 47
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- 239000002585 base Substances 0.000 description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 33
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 239000003054 catalyst Substances 0.000 description 29
- 238000010992 reflux Methods 0.000 description 29
- 230000035484 reaction time Effects 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 22
- 239000002994 raw material Substances 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 19
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 16
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 230000002194 synthesizing effect Effects 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 0 CC(*)(C([C@@]1(C=C(CCCCC2)CCCCC2NC(C2CCCCCCCC2)=O)N=C(N)N2*)C2=O)OC1=* Chemical compound CC(*)(C([C@@]1(C=C(CCCCC2)CCCCC2NC(C2CCCCCCCC2)=O)N=C(N)N2*)C2=O)OC1=* 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 238000007254 oxidation reaction Methods 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 229910052723 transition metal Inorganic materials 0.000 description 10
- 150000003624 transition metals Chemical class 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 239000003039 volatile agent Substances 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- UYWJPTNAOQSWOS-UHFFFAOYSA-N 5-(difluoromethyl)pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=C(C(F)F)C=N1 UYWJPTNAOQSWOS-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 230000006872 improvement Effects 0.000 description 8
- 239000002198 insoluble material Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- YVGVOPNUEFTVQO-UHFFFAOYSA-N 5-methoxypyrazine-2-carboxylic acid Chemical compound COC1=CN=C(C(O)=O)C=N1 YVGVOPNUEFTVQO-UHFFFAOYSA-N 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 150000001298 alcohols Chemical class 0.000 description 7
- 150000001350 alkyl halides Chemical class 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 125000002524 organometallic group Chemical group 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000012258 stirred mixture Substances 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 5
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 5
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000001537 neural effect Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000012799 strong cation exchange Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- HRLVPHGCEGTVLK-UHFFFAOYSA-N 5-cyanopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)C=N1 HRLVPHGCEGTVLK-UHFFFAOYSA-N 0.000 description 4
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- ZGOVNGSQBPQXIL-CJBNDPTMSA-N tert-butyl n-[(3s,4r,5r)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-methyloxolan-3-yl]carbamate Chemical compound OC[C@@H]1[C@@H](C)OC[C@@]1(NC(=O)OC(C)(C)C)C1=CC=CC=C1F ZGOVNGSQBPQXIL-CJBNDPTMSA-N 0.000 description 1
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (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 |
|---|---|---|---|
| GB0912777.0 | 2009-07-22 | ||
| GB0912777A GB0912777D0 (en) | 2009-07-22 | 2009-07-22 | Fused aminodihydropyrimidone derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20120052343A true KR20120052343A (ko) | 2012-05-23 |
Family
ID=41058390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR20127004626A Ceased KR20120052343A (ko) | 2009-07-22 | 2010-07-21 | 융합된 아미노디하이드로피리미돈 유도체 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US9139594B2 (https=) |
| EP (1) | EP2456771A1 (https=) |
| JP (1) | JP5699146B2 (https=) |
| KR (1) | KR20120052343A (https=) |
| CN (1) | CN102574864B (https=) |
| AU (1) | AU2010275196B2 (https=) |
| CA (1) | CA2768881A1 (https=) |
| GB (1) | GB0912777D0 (https=) |
| IN (1) | IN2012DN00688A (https=) |
| WO (1) | WO2011009897A1 (https=) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| RU2416603C9 (ru) | 2005-10-25 | 2012-06-20 | Сионоги Энд Ко., Лтд. | Производные аминодигидротиазина |
| EP2151435A4 (en) | 2007-04-24 | 2011-09-14 | Shionogi & Co | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| EP2147914B1 (en) | 2007-04-24 | 2014-06-04 | Shionogi&Co., Ltd. | Aminodihydrothiazine derivatives substituted with cyclic groups |
| RU2476431C2 (ru) | 2008-01-18 | 2013-02-27 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Конденсированное производное аминодигидротиазина |
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-
2009
- 2009-07-22 GB GB0912777A patent/GB0912777D0/en not_active Ceased
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2010
- 2010-07-21 KR KR20127004626A patent/KR20120052343A/ko not_active Ceased
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- 2010-07-21 US US13/386,199 patent/US9139594B2/en not_active Expired - Fee Related
- 2010-07-21 CN CN201080034140.0A patent/CN102574864B/zh not_active Expired - Fee Related
- 2010-07-21 JP JP2012521034A patent/JP5699146B2/ja not_active Expired - Fee Related
- 2010-07-21 EP EP20100734143 patent/EP2456771A1/en not_active Withdrawn
- 2010-07-21 AU AU2010275196A patent/AU2010275196B2/en not_active Ceased
- 2010-07-21 IN IN688DEN2012 patent/IN2012DN00688A/en unknown
- 2010-07-21 WO PCT/EP2010/060586 patent/WO2011009897A1/en not_active Ceased
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| WO2011009897A1 (en) | 2011-01-27 |
| AU2010275196B2 (en) | 2015-08-06 |
| CN102574864A (zh) | 2012-07-11 |
| CN102574864B (zh) | 2015-04-29 |
| JP5699146B2 (ja) | 2015-04-08 |
| AU2010275196A1 (en) | 2012-02-16 |
| JP2012533602A (ja) | 2012-12-27 |
| GB0912777D0 (en) | 2009-08-26 |
| US20120202828A1 (en) | 2012-08-09 |
| CA2768881A1 (en) | 2011-01-27 |
| US9139594B2 (en) | 2015-09-22 |
| EP2456771A1 (en) | 2012-05-30 |
| IN2012DN00688A (https=) | 2015-06-19 |
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