CN105753877A - 用作治疗剂的螺-羟吲哚化合物的不对称合成 - Google Patents
用作治疗剂的螺-羟吲哚化合物的不对称合成 Download PDFInfo
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- CN105753877A CN105753877A CN201610207838.7A CN201610207838A CN105753877A CN 105753877 A CN105753877 A CN 105753877A CN 201610207838 A CN201610207838 A CN 201610207838A CN 105753877 A CN105753877 A CN 105753877A
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- compound
- enantiomter
- alkyl
- heteroaryl
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- 239000003814 drug Substances 0.000 title claims description 27
- 238000003786 synthesis reaction Methods 0.000 title abstract description 41
- 229940124597 therapeutic agent Drugs 0.000 title description 3
- 238000011282 treatment Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims description 773
- 239000000203 mixture Substances 0.000 claims description 340
- 150000003839 salts Chemical class 0.000 claims description 201
- 238000000034 method Methods 0.000 claims description 200
- -1 heteroaryl alkane Chemical class 0.000 claims description 137
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 125000003118 aryl group Chemical group 0.000 claims description 102
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 100
- 125000001072 heteroaryl group Chemical group 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 92
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 91
- 239000000460 chlorine Substances 0.000 claims description 91
- 229910052801 chlorine Inorganic materials 0.000 claims description 91
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 90
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 90
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 90
- 229910052794 bromium Inorganic materials 0.000 claims description 90
- 238000006243 chemical reaction Methods 0.000 claims description 85
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 83
- 230000008569 process Effects 0.000 claims description 82
- 150000002367 halogens Chemical class 0.000 claims description 80
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 77
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 61
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000001188 haloalkyl group Chemical group 0.000 claims description 46
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 239000000126 substance Substances 0.000 claims description 39
- 238000010511 deprotection reaction Methods 0.000 claims description 35
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 34
- 230000008859 change Effects 0.000 claims description 30
- 125000001118 alkylidene group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 238000005804 alkylation reaction Methods 0.000 claims description 19
- 230000001681 protective effect Effects 0.000 claims description 18
- 125000004450 alkenylene group Chemical group 0.000 claims description 16
- 238000007126 N-alkylation reaction Methods 0.000 claims description 15
- 239000003444 phase transfer catalyst Substances 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 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 12
- 125000004419 alkynylene group Chemical group 0.000 claims description 12
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 12
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 12
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 claims description 12
- 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 description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 11
- 238000003747 Grignard reaction Methods 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 8
- 150000001336 alkenes Chemical class 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 150000001924 cycloalkanes Chemical class 0.000 claims description 6
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 238000012546 transfer Methods 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 201000010099 disease Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 208000002193 Pain Diseases 0.000 abstract description 9
- 108010052164 Sodium Channels Proteins 0.000 abstract description 8
- 102000018674 Sodium Channels Human genes 0.000 abstract description 8
- 230000001404 mediated effect Effects 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 203
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 104
- 239000007787 solid Substances 0.000 description 79
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 34
- 239000000376 reactant Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 31
- 238000005406 washing Methods 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- 229910052799 carbon Inorganic materials 0.000 description 29
- 238000000926 separation method Methods 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 125000002541 furyl group Chemical group 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 25
- 150000002431 hydrogen Chemical class 0.000 description 25
- 238000013507 mapping Methods 0.000 description 25
- 239000000047 product Substances 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 20
- 239000003513 alkali Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000012266 salt solution Substances 0.000 description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 239000012442 inert solvent Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- 238000012545 processing Methods 0.000 description 13
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 12
- 0 *Cc1ccc(C(F)(F)F)[o]1 Chemical compound *Cc1ccc(C(F)(F)F)[o]1 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
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- 239000013078 crystal Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000003153 chemical reaction reagent Substances 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
- 230000007246 mechanism Effects 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
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- 125000001033 ether group Chemical group 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
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- 125000005605 benzo group Chemical group 0.000 description 8
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- HPARLNRMYDSBNO-UHFFFAOYSA-N 1,4-benzodioxine Chemical compound C1=CC=C2OC=COC2=C1 HPARLNRMYDSBNO-UHFFFAOYSA-N 0.000 description 7
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- 238000010790 dilution Methods 0.000 description 6
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 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 5
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 238000000151 deposition Methods 0.000 description 5
- 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 5
- 238000005516 engineering process Methods 0.000 description 5
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 239000013049 sediment Substances 0.000 description 5
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 5
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- YNHVBNGRNNVEMD-UHFFFAOYSA-N 2-(bromomethyl)-5-(trifluoromethyl)furan Chemical class FC(F)(F)C1=CC=C(CBr)O1 YNHVBNGRNNVEMD-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
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- PCVRSXXPGXRVEZ-UHFFFAOYSA-N 9-(chloromethyl)anthracene Chemical compound C1=CC=C2C(CCl)=C(C=CC=C3)C3=CC2=C1 PCVRSXXPGXRVEZ-UHFFFAOYSA-N 0.000 description 3
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- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
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- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 3
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Natural products OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
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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)
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| WO2016109795A1 (en) | 2014-12-31 | 2016-07-07 | Concert Pharmaceuticals, Inc. | Deuterated funapide and difluorofunapide |
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| 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 |
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- 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
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Also Published As
| Publication number | Publication date |
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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 |
| ES2714314T3 (es) | 2019-05-28 |
| 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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