JP5699146B2 - 縮合アミノジヒドロピリミドン誘導体 - Google Patents
縮合アミノジヒドロピリミドン誘導体 Download PDFInfo
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- JP5699146B2 JP5699146B2 JP2012521034A JP2012521034A JP5699146B2 JP 5699146 B2 JP5699146 B2 JP 5699146B2 JP 2012521034 A JP2012521034 A JP 2012521034A JP 2012521034 A JP2012521034 A JP 2012521034A JP 5699146 B2 JP5699146 B2 JP 5699146B2
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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
- 125000001424 substituent group Chemical group 0.000 claims description 394
- 150000001875 compounds Chemical class 0.000 claims description 393
- -1 3- (2-Amino-3-methyl-4-oxo-3,4,4a, 5,7,7a-hexahydrofuro [3,4-d] pyrimidin-7a-yl) -4-fluoro Phenyl Chemical group 0.000 claims description 187
- 150000003839 salts Chemical class 0.000 claims description 60
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 59
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 239000012453 solvate Substances 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 230000004770 neurodegeneration Effects 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 208000024827 Alzheimer disease Diseases 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 17
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 16
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 125000002837 carbocyclic group Chemical group 0.000 claims description 14
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 12
- 125000004916 (C1-C6) alkylcarbonyl 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
- 201000010374 Down Syndrome Diseases 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 206010044688 Trisomy 21 Diseases 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 6
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 5
- MEQQFCRSPXGDFT-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C(C23C(COC2)C(=O)N(C)C(N)=N3)=C1 MEQQFCRSPXGDFT-UHFFFAOYSA-N 0.000 claims description 5
- DUHLYQRYFBXMNZ-YZSZRTLCSA-N n-[3-[(4as,5r,7as)-2-amino-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H]([C@@H](C)OC2)C(=O)N(C)C(N)=N3)=C1 DUHLYQRYFBXMNZ-YZSZRTLCSA-N 0.000 claims description 5
- UOENZLMZWGNTFI-CKFHNAJUSA-N n-[3-[(4as,5s,7as)-2-amino-3-methyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-(difluoromethyl)pyrazine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(N)N(C([C@@H]2[C@H](OC3)C(F)(F)F)=O)C)=CC=1NC(=O)C1=CN=C(C(F)F)C=N1 UOENZLMZWGNTFI-CKFHNAJUSA-N 0.000 claims description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- DSZKHXXFYJNMRN-HPIXMPJWSA-N n-[3-[(4as,5r,7as)-2-amino-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@]23CO[C@@H]([C@H]2C(=O)N(C)C(N)=N3)C)=CC=1NC(=O)C1=CC=C(C#N)C=N1 DSZKHXXFYJNMRN-HPIXMPJWSA-N 0.000 claims description 4
- UAJVIFPKFRSETN-BFKBOQTRSA-N n-[3-[(4as,5r,7as)-2-amino-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-methylpyrazine-2-carboxamide Chemical compound C=1C=C(F)C([C@]23CO[C@@H]([C@H]2C(=O)N(C)C(N)=N3)C)=CC=1NC(=O)C1=CN=C(C)C=N1 UAJVIFPKFRSETN-BFKBOQTRSA-N 0.000 claims description 4
- KSVBULAEVSXQJV-LGZJRCCHSA-N n-[3-[(4as,5r,7as)-2-amino-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-methylpyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@]23CO[C@@H]([C@H]2C(=O)N(C)C(N)=N3)C)=CC=1NC(=O)C1=CC=C(C)C=N1 KSVBULAEVSXQJV-LGZJRCCHSA-N 0.000 claims description 4
- RUAOHUXOMQONIA-TWOQFEAHSA-N n-[3-[(4as,5s,7as)-2-amino-3-methyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(N)N(C([C@@H]2[C@H](OC3)C(F)(F)F)=O)C)=CC=1NC(=O)C1=CC=C(C#N)C=N1 RUAOHUXOMQONIA-TWOQFEAHSA-N 0.000 claims description 4
- VJNYGUADOPQFJS-YZVOILCLSA-N n-[3-[(4as,5s,7as)-2-amino-3-methyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H]([C@H](OC2)C(F)(F)F)C(=O)N(C)C(N)=N3)=C1 VJNYGUADOPQFJS-YZVOILCLSA-N 0.000 claims description 4
- NKLATUZHRNTIMW-TWOQFEAHSA-N n-[3-[(4as,5s,7as)-2-amino-3-methyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl]-4-fluorophenyl]-5-methylpyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(N)N(C([C@@H]2[C@H](OC3)C(F)(F)F)=O)C)=CC=1NC(=O)C1=CC=C(C)C=N1 NKLATUZHRNTIMW-TWOQFEAHSA-N 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- MRQCXTHJLCLJBX-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C1OCC2C(=O)N(C)C(N)=NC21C(C(=CC=1)F)=CC=1NC(=O)C1=CC=C(Cl)C=N1 MRQCXTHJLCLJBX-UHFFFAOYSA-N 0.000 claims description 3
- QSGKEECAHFOWTG-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound C1OCC2C(=O)N(C)C(N)=NC21C(C(=CC=1)F)=CC=1NC(=O)C1=CC=C(C#N)C=N1 QSGKEECAHFOWTG-UHFFFAOYSA-N 0.000 claims description 3
- RNJCOASRDMVNHK-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-ethoxypyrazine-2-carboxamide Chemical compound C1=NC(OCC)=CN=C1C(=O)NC1=CC=C(F)C(C23C(COC2)C(=O)N(C)C(N)=N3)=C1 RNJCOASRDMVNHK-UHFFFAOYSA-N 0.000 claims description 3
- VBTFXFLEBZAWFT-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C1OCC2C(=O)N(C)C(N)=NC21C(C(=CC=1)F)=CC=1NC(=O)C1=CC=C(F)C=N1 VBTFXFLEBZAWFT-UHFFFAOYSA-N 0.000 claims description 3
- OPESXDGRIQENKI-UHFFFAOYSA-N n-[3-(2-amino-3-methyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-7a-yl)-4-fluorophenyl]-5-methoxypyridine-2-carboxamide Chemical compound N1=CC(OC)=CC=C1C(=O)NC1=CC=C(F)C(C23C(COC2)C(=O)N(C)C(N)=N3)=C1 OPESXDGRIQENKI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 227
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- 238000002360 preparation method Methods 0.000 description 101
- 238000000034 method Methods 0.000 description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 96
- 239000000243 solution Substances 0.000 description 89
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 77
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- 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 54
- 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 43
- 239000002585 base Substances 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000003054 catalyst Substances 0.000 description 29
- 238000010992 reflux Methods 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 230000035484 reaction time Effects 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 22
- 239000007858 starting material Substances 0.000 description 22
- 239000002994 raw material Substances 0.000 description 21
- 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 21
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 125000006239 protecting group Chemical group 0.000 description 19
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 239000003153 chemical reaction reagent Substances 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000013065 commercial product Substances 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
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- 238000010898 silica gel chromatography Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 230000002194 synthesizing effect Effects 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000002198 insoluble material Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
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- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 11
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
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- 150000002148 esters Chemical class 0.000 description 10
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910052723 transition metal Inorganic materials 0.000 description 10
- 150000003624 transition metals Chemical class 0.000 description 10
- 239000003039 volatile agent Substances 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- 150000001350 alkyl halides Chemical class 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
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- 238000006722 reduction reaction Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
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- 150000001298 alcohols Chemical class 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000002524 organometallic group Chemical group 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
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- ZYILWLGRBAIMLH-MPSXMAJESA-N tert-butyl n-[(4as,5r,7as)-7a-(5-amino-2-fluorophenyl)-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C1([C@]23CO[C@@H]([C@H]2C(=O)N(C)C(NC(=O)OC(C)(C)C)=N3)C)=CC(N)=CC=C1F ZYILWLGRBAIMLH-MPSXMAJESA-N 0.000 description 1
- CFJXFJQRMYFGSS-CHGWPVNBSA-N tert-butyl n-[(4as,5r,7as)-7a-[2-fluoro-5-[(5-methoxypyrazine-2-carbonyl)amino]phenyl]-3,5-dimethyl-4-oxo-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H]([C@@H](C)OC2)C(=O)N(C)C(NC(=O)OC(C)(C)C)=N3)=C1 CFJXFJQRMYFGSS-CHGWPVNBSA-N 0.000 description 1
- HNKQJCICVMSQLJ-CKFHNAJUSA-N tert-butyl n-[(4as,5s,7as)-3-ethyl-7a-(2-fluoro-5-nitrophenyl)-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C1([C@]23CO[C@@H]([C@H]2C(=O)N(C(=N3)NC(=O)OC(C)(C)C)CC)C(F)(F)F)=CC([N+]([O-])=O)=CC=C1F HNKQJCICVMSQLJ-CKFHNAJUSA-N 0.000 description 1
- NSAMNCHBMLWXCJ-CKFHNAJUSA-N tert-butyl n-[(4as,5s,7as)-7a-(5-amino-2-fluorophenyl)-3-ethyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C1([C@]23CO[C@@H]([C@H]2C(=O)N(C(=N3)NC(=O)OC(C)(C)C)CC)C(F)(F)F)=CC(N)=CC=C1F NSAMNCHBMLWXCJ-CKFHNAJUSA-N 0.000 description 1
- OFGOXKLHWVZSOL-DPOKWSEZSA-N tert-butyl n-[(4as,5s,7as)-7a-[5-[[5-(difluoromethyl)pyrazine-2-carbonyl]amino]-2-fluorophenyl]-3-ethyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C=1C=C(F)C([C@]23CO[C@@H]([C@H]2C(=O)N(C(=N3)NC(=O)OC(C)(C)C)CC)C(F)(F)F)=CC=1NC(=O)C1=CN=C(C(F)F)C=N1 OFGOXKLHWVZSOL-DPOKWSEZSA-N 0.000 description 1
- WWYZCNQMQCVPIN-WOGXIUBCSA-N tert-butyl n-[(4as,5s,7as)-7a-[5-[[5-(difluoromethyl)pyrazine-2-carbonyl]amino]-2-fluorophenyl]-3-methyl-4-oxo-5-(trifluoromethyl)-5,7-dihydro-4ah-furo[3,4-d]pyrimidin-2-yl]carbamate Chemical compound C=1C=C(F)C([C@]23CO[C@@H]([C@H]2C(=O)N(C(=N3)NC(=O)OC(C)(C)C)C)C(F)(F)F)=CC=1NC(=O)C1=CN=C(C(F)F)C=N1 WWYZCNQMQCVPIN-WOGXIUBCSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 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
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- ZDGBFJBOMIFBCF-UHFFFAOYSA-N trifluoromethyl oxolane-3-carboxylate Chemical compound O1CC(CC1)C(=O)OC(F)(F)F ZDGBFJBOMIFBCF-UHFFFAOYSA-N 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
- 239000012588 trypsin Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- 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)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| GB0912777.0 | 2009-07-22 | ||
| GB0912777A GB0912777D0 (en) | 2009-07-22 | 2009-07-22 | Fused aminodihydropyrimidone derivatives |
| PCT/EP2010/060586 WO2011009897A1 (en) | 2009-07-22 | 2010-07-21 | Fused aminodihydropyrimidone derivatives |
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| JP2012533602A JP2012533602A (ja) | 2012-12-27 |
| JP5699146B2 true JP5699146B2 (ja) | 2015-04-08 |
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| CN (1) | CN102574864B (enExample) |
| AU (1) | AU2010275196B2 (enExample) |
| CA (1) | CA2768881A1 (enExample) |
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| IN (1) | IN2012DN00688A (enExample) |
| WO (1) | WO2011009897A1 (enExample) |
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| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
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| MX2009011498A (es) | 2007-04-24 | 2009-11-10 | Shionogi & Co | Derivados de aminodihidrotiazina sustituida con un grupo ciclico. |
| WO2008133273A1 (ja) | 2007-04-24 | 2008-11-06 | Shionogi & Co., Ltd. | アルツハイマー症治療用医薬組成物 |
| US20100317850A1 (en) | 2008-01-18 | 2010-12-16 | Yuichi Suzuki | Condensed aminodihydrothiazine derivative |
| AU2009258496B8 (en) | 2008-06-13 | 2014-06-26 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity |
| AU2009277485B2 (en) | 2008-07-28 | 2013-05-02 | Eisai R&D Management Co., Ltd. | Spiroaminodihydrothiazine derivatives |
| MX2011003189A (es) | 2008-09-30 | 2011-04-27 | Eisai R&D Man Co Ltd | Nuevo derivado de aminodihidrotiazina fusionada. |
| JPWO2010047372A1 (ja) | 2008-10-22 | 2012-03-22 | 塩野義製薬株式会社 | Ｂａｃｅ１阻害活性を有する２−アミノピリミジン−４−オンおよび２−アミノピリジン誘導体 |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
| US8569310B2 (en) | 2009-10-08 | 2013-10-29 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use |
| EP2485590B1 (en) | 2009-10-08 | 2015-01-07 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
| US8563543B2 (en) | 2009-10-08 | 2013-10-22 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| US8999980B2 (en) | 2009-12-11 | 2015-04-07 | Shionogi & Co., Ltd. | Oxazine derivatives |
| US8927721B2 (en) | 2010-10-29 | 2015-01-06 | Shionogi & Co., Ltd. | Naphthyridine derivative |
| WO2012057247A1 (ja) | 2010-10-29 | 2012-05-03 | 塩野義製薬株式会社 | 縮合アミノジヒドロピリミジン誘導体 |
| GB201100181D0 (en) | 2011-01-06 | 2011-02-23 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101140D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| CN106632401B (zh) | 2011-01-21 | 2020-12-29 | 卫材R&D管理有限公司 | 用于稠合氨基二氢噻嗪衍生物的合成的方法和化合物 |
| GB201101139D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| US9221839B2 (en) | 2011-04-07 | 2015-12-29 | Merck Sharp & Dohme Corp. | C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
| EP2694521B1 (en) | 2011-04-07 | 2015-11-25 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| US8883779B2 (en) | 2011-04-26 | 2014-11-11 | Shinogi & Co., Ltd. | Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them |
| AU2012298983A1 (en) | 2011-08-22 | 2014-02-27 | Merck Sharp & Dohme Corp. | 2-spiro-substituted iminothiazines and their mono-and dioxides as BACE inhibitors, compositions and their use |
| IN2014DN08922A (enExample) | 2012-04-27 | 2015-05-22 | Eisai R&D Man Co Ltd | |
| GB201212871D0 (en) | 2012-07-20 | 2012-09-05 | Eisai Ltd | Novel compounds |
| EP2912035A4 (en) | 2012-10-24 | 2016-06-15 | Shionogi & Co | DERIVATIVES OF DIHYDROOXAZINE OR OXAZEPINE HAVING BACE1 INHIBITING ACTIVITY |
| EP3626717A1 (en) | 2013-10-14 | 2020-03-25 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
| US9663486B2 (en) | 2013-10-14 | 2017-05-30 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
| US10047098B2 (en) | 2014-11-25 | 2018-08-14 | Merck Sharp & Dohme Corp. | C5-C6-oxacyclic fused iminopyrimidinone compounds as bace inhibitors, compositions, and their use |
| AU2015362790A1 (en) | 2014-12-16 | 2017-07-20 | Axovant Sciences Gmbh | Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors |
| MX2017016231A (es) | 2015-06-10 | 2018-11-29 | Axovant Sciences Gmbh | Compuestos de aminobencisoxazol como agonistas de receptores a7-nicotínicos de acetilcolina. |
| US10428062B2 (en) | 2015-08-12 | 2019-10-01 | Axovant Sciences Gmbh | Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors |
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| EP1732906A4 (en) | 2004-03-30 | 2007-11-21 | Merck & Co Inc | 2-AMINOTHIAZONE COMPOUNDS SUITABLE AS ASPARTYL PROTEASE INHIBITORS |
| PE20060664A1 (es) | 2004-09-15 | 2006-08-04 | Novartis Ag | Amidas biciclicas como inhibidores de cinasa |
| WO2006041404A1 (en) | 2004-10-15 | 2006-04-20 | Astrazeneca Ab | Substituted amino-compounds and uses thereof |
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| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| WO2012003274A1 (en) | 2010-07-01 | 2012-01-05 | Amgen Inc. | Heterocyclic compounds and their use as inhibitors of pi3k activity |
| GB201100181D0 (en) | 2011-01-06 | 2011-02-23 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101139D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101140D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| CN106632401B (zh) | 2011-01-21 | 2020-12-29 | 卫材R&D管理有限公司 | 用于稠合氨基二氢噻嗪衍生物的合成的方法和化合物 |
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2009
- 2009-07-22 GB GB0912777A patent/GB0912777D0/en not_active Ceased
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2010
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- 2010-07-21 JP JP2012521034A patent/JP5699146B2/ja not_active Expired - Fee Related
- 2010-07-21 KR KR20127004626A patent/KR20120052343A/ko not_active Ceased
- 2010-07-21 AU AU2010275196A patent/AU2010275196B2/en not_active Ceased
- 2010-07-21 CA CA2768881A patent/CA2768881A1/en not_active Abandoned
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| CA2768881A1 (en) | 2011-01-27 |
| AU2010275196B2 (en) | 2015-08-06 |
| WO2011009897A1 (en) | 2011-01-27 |
| CN102574864B (zh) | 2015-04-29 |
| US9139594B2 (en) | 2015-09-22 |
| JP2012533602A (ja) | 2012-12-27 |
| CN102574864A (zh) | 2012-07-11 |
| GB0912777D0 (en) | 2009-08-26 |
| AU2010275196A1 (en) | 2012-02-16 |
| US20120202828A1 (en) | 2012-08-09 |
| EP2456771A1 (en) | 2012-05-30 |
| IN2012DN00688A (enExample) | 2015-06-19 |
| KR20120052343A (ko) | 2012-05-23 |
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