ES2714314T3 - Síntesis asimétrica para compuestos de espiro-oxindol útiles como agentes terapéuticos - Google Patents
Síntesis asimétrica para compuestos de espiro-oxindol útiles como agentes terapéuticos Download PDFInfo
- Publication number
- ES2714314T3 ES2714314T3 ES13710961T ES13710961T ES2714314T3 ES 2714314 T3 ES2714314 T3 ES 2714314T3 ES 13710961 T ES13710961 T ES 13710961T ES 13710961 T ES13710961 T ES 13710961T ES 2714314 T3 ES2714314 T3 ES 2714314T3
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- Spain
- Prior art keywords
- formula
- compound
- heterocyclyl
- heteroaryl
- aryl
- Prior art date
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- 238000011914 asymmetric synthesis Methods 0.000 title description 9
- 239000003814 drug Substances 0.000 title description 5
- 229940124597 therapeutic agent Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 729
- 239000000203 mixture Substances 0.000 claims abstract description 309
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 211
- 150000003839 salts Chemical class 0.000 claims abstract description 200
- 125000003118 aryl group Chemical group 0.000 claims abstract description 195
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 179
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 176
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 170
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 169
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 157
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 124
- 238000000034 method Methods 0.000 claims abstract description 124
- -1 - R8-OR5 Chemical group 0.000 claims abstract description 123
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 117
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 117
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 116
- 125000005843 halogen group Chemical group 0.000 claims abstract description 114
- 239000001257 hydrogen Substances 0.000 claims abstract description 97
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 97
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 89
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 78
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 64
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 60
- 125000001424 substituent group Chemical group 0.000 claims abstract description 47
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 46
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 38
- 125000000262 haloalkenyl group Chemical group 0.000 claims abstract description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 33
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 30
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 27
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 27
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 25
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 25
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 22
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 20
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims abstract description 20
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 15
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960001404 quinidine Drugs 0.000 claims abstract description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 98
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 92
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 92
- 229910052794 bromium Inorganic materials 0.000 claims description 92
- 239000000460 chlorine Substances 0.000 claims description 92
- 229910052801 chlorine Inorganic materials 0.000 claims description 92
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 91
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 48
- 238000005804 alkylation reaction Methods 0.000 claims description 45
- 238000010511 deprotection reaction Methods 0.000 claims description 39
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 28
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 26
- 150000004795 grignard reagents Chemical class 0.000 claims description 22
- 239000007818 Grignard reagent Substances 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 230000004224 protection Effects 0.000 claims description 20
- 238000001953 recrystallisation Methods 0.000 claims description 15
- 230000001681 protective effect Effects 0.000 claims description 14
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 238000003747 Grignard reaction Methods 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
- 230000001012 protector Effects 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- 239000007787 solid Substances 0.000 description 80
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 43
- 239000002253 acid Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 28
- 150000002431 hydrogen Chemical group 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 238000001914 filtration Methods 0.000 description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 150000003254 radicals Chemical class 0.000 description 20
- 239000010410 layer Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002955 isolation Methods 0.000 description 15
- 239000002798 polar solvent Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000012071 phase Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 0 Cc1cc(*(C([C@@]23c(cccc4)c4OC2)=O)I)c3cc1 Chemical compound Cc1cc(*(C([C@@]23c(cccc4)c4OC2)=O)I)c3cc1 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 235000019270 ammonium chloride Nutrition 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 239000005909 Kieselgur Substances 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
- ZWWDFMHULDPTEF-UHFFFAOYSA-N 1-benzhydrylindole-2,3-dione Chemical compound C12=CC=CC=C2C(=O)C(=O)N1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZWWDFMHULDPTEF-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
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- 125000004122 cyclic group Chemical group 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 108010052164 Sodium Channels Proteins 0.000 description 8
- 102000018674 Sodium Channels Human genes 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 7
- 230000008021 deposition Effects 0.000 description 7
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- NEBUOXBYNAHKFV-NRFANRHFSA-N (7s)-1'-[[5-(trifluoromethyl)furan-2-yl]methyl]spiro[6h-furo[2,3-f][1,3]benzodioxole-7,3'-indole]-2'-one Chemical compound O1C(C(F)(F)F)=CC=C1CN1C2=CC=CC=C2[C@@]2(C3=CC=4OCOC=4C=C3OC2)C1=O NEBUOXBYNAHKFV-NRFANRHFSA-N 0.000 description 6
- SJNKORNXURQLBJ-UHFFFAOYSA-N 1-benzhydryl-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)indol-2-one Chemical compound OC1=CC=2OCOC=2C=C1C(C1=CC=CC=C11)(O)C(=O)N1C(C=1C=CC=CC=1)C1=CC=CC=C1 SJNKORNXURQLBJ-UHFFFAOYSA-N 0.000 description 6
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- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- SVABQOITNJTVNJ-UHFFFAOYSA-N diphenyl-2-pyridylphosphine Chemical compound C1=CC=CC=C1P(C=1N=CC=CC=1)C1=CC=CC=C1 SVABQOITNJTVNJ-UHFFFAOYSA-N 0.000 description 6
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- YMRNLESIKCMDIP-LJAQVGFWSA-N (3s)-1-benzhydryl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)indol-2-one Chemical compound O=C([C@](C1=CC=CC=C11)(CO)C=2C(=CC=3OCOC=3C=2)O)N1C(C=1C=CC=CC=1)C1=CC=CC=C1 YMRNLESIKCMDIP-LJAQVGFWSA-N 0.000 description 5
- KSZGIWGOQAYVQC-QLKFWGTOSA-N (3s)-1-benzhydryl-3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)-3-(phenylmethoxymethyl)indol-2-one Chemical compound O=C([C@](C1=CC=CC=C11)(COCC=2C=CC=CC=2)C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)N1C(C=1C=CC=CC=1)C1=CC=CC=C1 KSZGIWGOQAYVQC-QLKFWGTOSA-N 0.000 description 5
- KICNGTSGLUFGHH-INIZCTEOSA-N (3s)-spiro[1h-indole-3,7'-6h-furo[2,3-f][1,3]benzodioxole]-2-one Chemical compound C1OC2=CC=3OCOC=3C=C2[C@]21C1=CC=CC=C1NC2=O KICNGTSGLUFGHH-INIZCTEOSA-N 0.000 description 5
- QXDKRULYDHLETN-UHFFFAOYSA-N 1-benzhydryl-3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)-3h-indol-2-one Chemical compound O=C1C(C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)C2=CC=CC=C2N1C(C=1C=CC=CC=1)C1=CC=CC=C1 QXDKRULYDHLETN-UHFFFAOYSA-N 0.000 description 5
- ZSGUPSLGTOBIFK-UHFFFAOYSA-N 1-benzhydryl-3-hydroxy-3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)indol-2-one Chemical compound C12=CC=CC=C2C(O)(C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)C(=O)N1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZSGUPSLGTOBIFK-UHFFFAOYSA-N 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 5
- 229910000077 silane Inorganic materials 0.000 description 5
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- MQFTXPVDQFWTFL-DHUJRADRSA-N (3s)-3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)-3-(phenylmethoxymethyl)-1-[[5-(trifluoromethyl)furan-2-yl]methyl]indol-2-one Chemical compound O1C(C(F)(F)F)=CC=C1CN1C2=CC=CC=C2[C@@](COCC=2C=CC=CC=2)(C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)C1=O MQFTXPVDQFWTFL-DHUJRADRSA-N 0.000 description 4
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- KZSVHITYIRADGH-UHFFFAOYSA-N 3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)-1-[[5-(trifluoromethyl)furan-2-yl]methyl]-3h-indol-2-one Chemical compound O1C(C(F)(F)F)=CC=C1CN1C2=CC=CC=C2C(C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)C1=O KZSVHITYIRADGH-UHFFFAOYSA-N 0.000 description 4
- MQFTXPVDQFWTFL-UHFFFAOYSA-N 3-(6-phenylmethoxy-1,3-benzodioxol-5-yl)-3-(phenylmethoxymethyl)-1-[[5-(trifluoromethyl)furan-2-yl]methyl]indol-2-one Chemical compound O1C(C(F)(F)F)=CC=C1CN1C2=CC=CC=C2C(COCC=2C=CC=CC=2)(C=2C(=CC=3OCOC=3C=2)OCC=2C=CC=CC=2)C1=O MQFTXPVDQFWTFL-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 150000005840 aryl radicals Chemical class 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 238000000746 purification Methods 0.000 description 4
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- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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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
- C07D491/12—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 three hetero rings
- C07D491/20—Spiro-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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
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| US201261623336P | 2012-04-12 | 2012-04-12 | |
| PCT/US2013/030219 WO2013154712A1 (en) | 2012-04-12 | 2013-03-11 | Asymmetric syntheses for spiro-oxindole compounds useful as therapeutic agents |
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| ES2714314T3 true ES2714314T3 (es) | 2019-05-28 |
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| MX (1) | MX2014012266A (enExample) |
| WO (1) | WO2013154712A1 (enExample) |
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| JO3032B1 (ar) | 2008-10-17 | 2016-09-05 | Xenon Pharmaceuticals Inc | مركبات سبيرو – اوكسندول وإستعمالاتها كعوامل علاجية. |
| AR077252A1 (es) | 2009-06-29 | 2011-08-10 | Xenon Pharmaceuticals Inc | Enantiomeros de compuestos de espirooxindol y sus usos como agentes terapeuticos |
| KR20120099429A (ko) | 2009-10-14 | 2012-09-10 | 제논 파마슈티칼스 인크. | 스피로-옥스인돌 화합물의 합성 방법 |
| WO2011106729A2 (en) | 2010-02-26 | 2011-09-01 | Xenon Pharmaceuticals Inc. | Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents |
| HK1205114A1 (en) | 2012-04-12 | 2015-12-11 | Xenon Pharmaceuticals Inc. | Asymmetric syntheses for spiro-oxindole compounds useful as therapeutic agents |
| WO2016109795A1 (en) | 2014-12-31 | 2016-07-07 | Concert Pharmaceuticals, Inc. | Deuterated funapide and difluorofunapide |
| WO2016127068A1 (en) | 2015-02-05 | 2016-08-11 | Teva Pharmaceuticals International Gmbh | Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound |
| WO2017180248A1 (en) * | 2016-04-15 | 2017-10-19 | William Marsh Rice University | Enantioenriched viridicatumtoxin b analogs |
| WO2017214442A1 (en) | 2016-06-08 | 2017-12-14 | President And Fellows Of Harvard College | Methods and compositions for reducing tactile dysfunction and anxiety associated with autism spectrum disorder, rett syndrome, and fragile x syndrome |
| JP2019518058A (ja) * | 2016-06-16 | 2019-06-27 | ゼノン・ファーマシューティカルズ・インコーポレイテッドＸｅｎｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | スピロ−オキシインドール化合物の固体状態形 |
| US10100060B2 (en) | 2016-06-16 | 2018-10-16 | Xenon Pharmaceuticals Inc. | Asymmetric synthesis of funapide |
| CN108395438A (zh) * | 2018-04-03 | 2018-08-14 | 陕西科技大学 | 一类具有抗菌活性的靛红母核螺环化合物及其合成方法 |
| US12252457B2 (en) | 2018-05-22 | 2025-03-18 | President And Fellows Of Harvard College | Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment |
| EP3801512A4 (en) | 2018-05-29 | 2022-01-19 | President and Fellows of Harvard College | COMPOSITIONS AND METHODS TO REDUCE TACTILE DYSFUNCTION, ANXIETY AND SOCIAL DISABILITIES |
| US12077512B2 (en) | 2019-03-25 | 2024-09-03 | President And Fellows Of Harvard College | Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment |
| US11345681B1 (en) | 2020-06-05 | 2022-05-31 | Kinnate Biopharma Inc. | Inhibitors of fibroblast growth factor receptor kinases |
| US12552808B2 (en) | 2020-09-03 | 2026-02-17 | Amgen Inc. | Diol desymmetrization by nucleophilic aromatic substitution |
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-
2013
- 2013-03-11 HK HK15105599.7A patent/HK1205114A1/xx unknown
- 2013-03-11 HK HK15105598.8A patent/HK1205113A1/xx unknown
- 2013-03-11 KR KR1020147031580A patent/KR20150002794A/ko not_active Withdrawn
- 2013-03-11 ES ES13710961T patent/ES2714314T3/es active Active
- 2013-03-11 CN CN201610207838.7A patent/CN105753877A/zh active Pending
- 2013-03-11 MX MX2014012266A patent/MX2014012266A/es unknown
- 2013-03-11 EP EP13710961.7A patent/EP2838902B1/en active Active
- 2013-03-11 US US13/794,147 patent/US9487535B2/en active Active
- 2013-03-11 WO PCT/US2013/030219 patent/WO2013154712A1/en not_active Ceased
- 2013-03-11 JP JP2015505723A patent/JP6195609B2/ja active Active
- 2013-03-11 CN CN201380030552.0A patent/CN104350057A/zh active Pending
- 2013-03-11 CA CA2869547A patent/CA2869547A1/en active Pending
- 2013-03-11 AU AU2013246485A patent/AU2013246485A1/en not_active Abandoned
- 2013-03-11 EA EA201491854A patent/EA201491854A1/ru unknown
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2014
- 2014-10-06 IL IL235006A patent/IL235006A0/en unknown
- 2014-10-09 ZA ZA2014/07334A patent/ZA201407334B/en unknown
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2015
- 2015-06-12 HK HK16114577.4A patent/HK1226389A1/zh unknown
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2016
- 2016-09-14 US US15/265,549 patent/US20170066777A1/en not_active Abandoned
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| AU2013246485A1 (en) | 2014-10-16 |
| US9487535B2 (en) | 2016-11-08 |
| EA201491854A1 (ru) | 2015-03-31 |
| HK1205113A1 (en) | 2015-12-11 |
| JP2015516389A (ja) | 2015-06-11 |
| HK1226389A1 (zh) | 2017-09-29 |
| JP6195609B2 (ja) | 2017-09-13 |
| EP2838902B1 (en) | 2018-12-05 |
| WO2013154712A1 (en) | 2013-10-17 |
| CN105753877A (zh) | 2016-07-13 |
| CA2869547A1 (en) | 2013-10-17 |
| IL235006A0 (en) | 2014-12-31 |
| ZA201407334B (en) | 2017-05-31 |
| KR20150002794A (ko) | 2015-01-07 |
| EP2838902A1 (en) | 2015-02-25 |
| US20130274483A1 (en) | 2013-10-17 |
| US20170066777A1 (en) | 2017-03-09 |
| MX2014012266A (es) | 2014-12-05 |
| HK1205114A1 (en) | 2015-12-11 |
| CN104350057A (zh) | 2015-02-11 |
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