JP2016515617A - Multifunctional quinoline derivatives as anti-neurodegenerative agents - Google Patents
Multifunctional quinoline derivatives as anti-neurodegenerative agents Download PDFInfo
- Publication number
- JP2016515617A JP2016515617A JP2016506301A JP2016506301A JP2016515617A JP 2016515617 A JP2016515617 A JP 2016515617A JP 2016506301 A JP2016506301 A JP 2016506301A JP 2016506301 A JP2016506301 A JP 2016506301A JP 2016515617 A JP2016515617 A JP 2016515617A
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- JP
- Japan
- Prior art keywords
- compound
- quinolin
- undecan
- chloro
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title abstract description 6
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title abstract 2
- 230000002555 anti-neurodegenerative effect Effects 0.000 title 1
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 14
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 12
- -1 Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 10-decyl ester Chemical class 0.000 claims description 203
- 150000001875 compounds Chemical class 0.000 claims description 144
- 229910052739 hydrogen Inorganic materials 0.000 claims description 136
- 239000001257 hydrogen Substances 0.000 claims description 135
- 150000002431 hydrogen Chemical class 0.000 claims description 71
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 67
- 239000000460 chlorine Substances 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 229940002612 prodrug Drugs 0.000 claims description 17
- 239000000651 prodrug Substances 0.000 claims description 17
- 229960000583 acetic acid Drugs 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- DUTUOHKWXVMGNH-UHFFFAOYSA-N 11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC=C(Cl)C2=C1 DUTUOHKWXVMGNH-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 10
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 claims description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000002207 metabolite Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims description 7
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 7
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- PUNQNSYNZQFQNY-UHFFFAOYSA-N 11-(5-bromo-8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=CC=C(Br)C2=C1 PUNQNSYNZQFQNY-UHFFFAOYSA-N 0.000 claims description 6
- SGZSPKGQRHIKGA-UHFFFAOYSA-N 15-(5-chloro-8-propan-2-yloxyquinolin-2-yl)pentadecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCCCCO)N=C2C(OC(C)C)=CC=C(Cl)C2=C1 SGZSPKGQRHIKGA-UHFFFAOYSA-N 0.000 claims description 6
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 6
- 125000005237 alkyleneamino group Chemical group 0.000 claims description 6
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- JCRQQQUHRPKCRV-UHFFFAOYSA-N 1-bromo-2-methylidenecyclopropane Chemical compound BrC1CC1=C JCRQQQUHRPKCRV-UHFFFAOYSA-N 0.000 claims description 4
- QDFLURPUBPBKKM-UHFFFAOYSA-N 10-(8-ethoxyquinolin-2-yl)decan-1-ol Chemical compound C1=C(CCCCCCCCCCO)N=C2C(OCC)=CC=CC2=C1 QDFLURPUBPBKKM-UHFFFAOYSA-N 0.000 claims description 4
- KNMDDAXPYDLLIX-UHFFFAOYSA-N 10-(8-methoxyquinolin-2-yl)decan-1-ol Chemical compound C1=C(CCCCCCCCCCO)N=C2C(OC)=CC=CC2=C1 KNMDDAXPYDLLIX-UHFFFAOYSA-N 0.000 claims description 4
- IZXRCUJAVJTCGS-UHFFFAOYSA-N 10-(8-phenylmethoxyquinolin-2-yl)decan-1-ol Chemical compound C12=NC(CCCCCCCCCCO)=CC=C2C=CC=C1OCC1=CC=CC=C1 IZXRCUJAVJTCGS-UHFFFAOYSA-N 0.000 claims description 4
- DTZCJXTYHRNEGW-UHFFFAOYSA-N 10-(8-propan-2-yloxyquinolin-2-yl)decan-1-ol Chemical compound C1=C(CCCCCCCCCCO)N=C2C(OC(C)C)=CC=CC2=C1 DTZCJXTYHRNEGW-UHFFFAOYSA-N 0.000 claims description 4
- FAXMCVQBQVXHPF-UHFFFAOYSA-N 10-[8-(cyclopropylmethoxy)quinolin-2-yl]decan-1-ol Chemical compound C12=NC(CCCCCCCCCCO)=CC=C2C=CC=C1OCC1CC1 FAXMCVQBQVXHPF-UHFFFAOYSA-N 0.000 claims description 4
- ZVAGGISDAZTVCA-UHFFFAOYSA-N 11-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=C(Cl)C=C(Cl)C2=C1 ZVAGGISDAZTVCA-UHFFFAOYSA-N 0.000 claims description 4
- TYUAMFMDMBTOAX-UHFFFAOYSA-N 11-(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=C(Cl)C=C(Cl)C2=C1 TYUAMFMDMBTOAX-UHFFFAOYSA-N 0.000 claims description 4
- HVZFCSBJWIFSLN-UHFFFAOYSA-N 11-(5,7-dichloro-8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=C(Cl)C=C(Cl)C2=C1 HVZFCSBJWIFSLN-UHFFFAOYSA-N 0.000 claims description 4
- IMNGNXYZKMGVQH-UHFFFAOYSA-N 11-(5,8-dimethoxyquinolin-2-yl)undecan-1-ol Chemical compound OCCCCCCCCCCCC1=CC=C2C(OC)=CC=C(OC)C2=N1 IMNGNXYZKMGVQH-UHFFFAOYSA-N 0.000 claims description 4
- LJMXQCJIJHNVOK-UHFFFAOYSA-N 11-(5-bromo-8-ethoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=CC=C(Br)C2=C1 LJMXQCJIJHNVOK-UHFFFAOYSA-N 0.000 claims description 4
- WNQKPJOOPFCOQV-UHFFFAOYSA-N 11-(5-bromo-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC=C(Br)C2=C1 WNQKPJOOPFCOQV-UHFFFAOYSA-N 0.000 claims description 4
- LKUGDHVUJLNVHW-UHFFFAOYSA-N 11-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-1-ol Chemical compound N1=C(CCCCCCCCCCCO)C=CC2=C(Cl)C(OC)=CC(OC)=C21 LKUGDHVUJLNVHW-UHFFFAOYSA-N 0.000 claims description 4
- WQSJHONVNUFWRH-UHFFFAOYSA-N 11-(5-chloro-8-ethoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=CC=C(Cl)C2=C1 WQSJHONVNUFWRH-UHFFFAOYSA-N 0.000 claims description 4
- IXVFETHYNWFHOK-UHFFFAOYSA-N 11-(5-chloro-8-phenylmethoxyquinolin-2-yl)undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(Cl)=CC=C1OCC1=CC=CC=C1 IXVFETHYNWFHOK-UHFFFAOYSA-N 0.000 claims description 4
- FYQUGONYSHQSTJ-UHFFFAOYSA-N 11-(5-chloro-8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=CC=C(Cl)C2=C1 FYQUGONYSHQSTJ-UHFFFAOYSA-N 0.000 claims description 4
- JJSKSFLNWNKRMW-UHFFFAOYSA-N 11-(5-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC=C(F)C2=C1 JJSKSFLNWNKRMW-UHFFFAOYSA-N 0.000 claims description 4
- CQBXYBQSALOEBB-UHFFFAOYSA-N 11-(5-fluoro-8-phenylmethoxyquinolin-2-yl)undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(F)=CC=C1OCC1=CC=CC=C1 CQBXYBQSALOEBB-UHFFFAOYSA-N 0.000 claims description 4
- FTPKEEXWINXUCI-UHFFFAOYSA-N 11-(5-fluoro-8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=CC=C(F)C2=C1 FTPKEEXWINXUCI-UHFFFAOYSA-N 0.000 claims description 4
- LZVSCMAMYLHWNG-UHFFFAOYSA-N 11-(5-methyl-8-phenylmethoxyquinolin-2-yl)undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(C)=CC=C1OCC1=CC=CC=C1 LZVSCMAMYLHWNG-UHFFFAOYSA-N 0.000 claims description 4
- COGPNFVLPBPPRA-UHFFFAOYSA-N 11-(5-methyl-8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=CC=C(C)C2=C1 COGPNFVLPBPPRA-UHFFFAOYSA-N 0.000 claims description 4
- RUYKCINGJGFMCL-UHFFFAOYSA-N 11-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC(Cl)=C(OC)C2=C1 RUYKCINGJGFMCL-UHFFFAOYSA-N 0.000 claims description 4
- DDPZFECNKXBAOO-UHFFFAOYSA-N 11-(6-chloro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC(Cl)=CC2=C1 DDPZFECNKXBAOO-UHFFFAOYSA-N 0.000 claims description 4
- HCJKYRSYCCJYME-UHFFFAOYSA-N 11-(6-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC(F)=CC2=C1 HCJKYRSYCCJYME-UHFFFAOYSA-N 0.000 claims description 4
- JCVPBCQTMYDXHR-UHFFFAOYSA-N 11-(6-methyl-8-phenylmethoxyquinolin-2-yl)undecan-1-ol Chemical compound C=12N=C(CCCCCCCCCCCO)C=CC2=CC(C)=CC=1OCC1=CC=CC=C1 JCVPBCQTMYDXHR-UHFFFAOYSA-N 0.000 claims description 4
- BSTNBTHKKUUYCF-UHFFFAOYSA-N 11-(7-chloro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=C(Cl)C=CC2=C1 BSTNBTHKKUUYCF-UHFFFAOYSA-N 0.000 claims description 4
- KQZYBQHNLMYCRH-UHFFFAOYSA-N 11-(7-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=C(F)C=CC2=C1 KQZYBQHNLMYCRH-UHFFFAOYSA-N 0.000 claims description 4
- NKCMZNWCXWMWNJ-UHFFFAOYSA-N 11-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=CC=C(F)C2=C1 NKCMZNWCXWMWNJ-UHFFFAOYSA-N 0.000 claims description 4
- OVHZDWBSSFYVFG-UHFFFAOYSA-N 11-(8-ethoxy-5-methylquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=CC=C(C)C2=C1 OVHZDWBSSFYVFG-UHFFFAOYSA-N 0.000 claims description 4
- YSTDGIZKOZZGCU-UHFFFAOYSA-N 11-(8-ethoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OCC)=CC=CC2=C1 YSTDGIZKOZZGCU-UHFFFAOYSA-N 0.000 claims description 4
- DNVCFEZJAFKCHG-UHFFFAOYSA-N 11-(8-methoxy-5-methylquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC=C(C)C2=C1 DNVCFEZJAFKCHG-UHFFFAOYSA-N 0.000 claims description 4
- FEEWHEOAQJJUCN-UHFFFAOYSA-N 11-(8-methoxy-6-methylquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC(C)=CC2=C1 FEEWHEOAQJJUCN-UHFFFAOYSA-N 0.000 claims description 4
- KKWIRVPVMYONCW-UHFFFAOYSA-N 11-(8-methoxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC)=CC=CC2=C1 KKWIRVPVMYONCW-UHFFFAOYSA-N 0.000 claims description 4
- LWVFCXGUYBPGHU-UHFFFAOYSA-N 11-(8-phenylmethoxyquinolin-2-yl)undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C=CC=C1OCC1=CC=CC=C1 LWVFCXGUYBPGHU-UHFFFAOYSA-N 0.000 claims description 4
- HNEDCYJFLCCYGE-UHFFFAOYSA-N 11-(8-propan-2-yloxyquinolin-2-yl)undecan-1-ol Chemical compound C1=C(CCCCCCCCCCCO)N=C2C(OC(C)C)=CC=CC2=C1 HNEDCYJFLCCYGE-UHFFFAOYSA-N 0.000 claims description 4
- TWMYJYAVNZRURW-UHFFFAOYSA-N 11-[5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(Cl)=CC(Cl)=C1OCC1CC1 TWMYJYAVNZRURW-UHFFFAOYSA-N 0.000 claims description 4
- BUSXDPBVPUCIME-UHFFFAOYSA-N 11-[5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(Br)=CC=C1OCC1CC1 BUSXDPBVPUCIME-UHFFFAOYSA-N 0.000 claims description 4
- FGRGXDRULKADDB-UHFFFAOYSA-N 11-[5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(Cl)=CC=C1OCC1CC1 FGRGXDRULKADDB-UHFFFAOYSA-N 0.000 claims description 4
- AKTPETRXUNSGEU-UHFFFAOYSA-N 11-[8-(cyclopropylmethoxy)-5-fluoroquinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(F)=CC=C1OCC1CC1 AKTPETRXUNSGEU-UHFFFAOYSA-N 0.000 claims description 4
- CJIPXNXLHWBBFJ-UHFFFAOYSA-N 11-[8-(cyclopropylmethoxy)-5-methylquinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C(C)=CC=C1OCC1CC1 CJIPXNXLHWBBFJ-UHFFFAOYSA-N 0.000 claims description 4
- AOINQWHDIWBEEN-UHFFFAOYSA-N 11-[8-(cyclopropylmethoxy)quinolin-2-yl]undecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCO)=CC=C2C=CC=C1OCC1CC1 AOINQWHDIWBEEN-UHFFFAOYSA-N 0.000 claims description 4
- IILBBARQDQWEKG-UHFFFAOYSA-N 11-[8-(trifluoromethoxy)quinolin-2-yl]undecan-1-ol Chemical compound C1=CC=C(OC(F)(F)F)C2=NC(CCCCCCCCCCCO)=CC=C21 IILBBARQDQWEKG-UHFFFAOYSA-N 0.000 claims description 4
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- ZYDRTJDJYPYWBT-UHFFFAOYSA-N 12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCO)N=C2C(OC)=CC=C(F)C2=C1 ZYDRTJDJYPYWBT-UHFFFAOYSA-N 0.000 claims description 4
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- DENCELAFXAZVGU-UHFFFAOYSA-N 12-(8-phenylmethoxyquinolin-2-yl)dodecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCCO)=CC=C2C=CC=C1OCC1=CC=CC=C1 DENCELAFXAZVGU-UHFFFAOYSA-N 0.000 claims description 4
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- CFRJBTGJWCIKCH-UHFFFAOYSA-N 12-[8-(cyclopropylmethoxy)quinolin-2-yl]dodecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCCO)=CC=C2C=CC=C1OCC1CC1 CFRJBTGJWCIKCH-UHFFFAOYSA-N 0.000 claims description 4
- GQPUZFPFJHPWMW-UHFFFAOYSA-N 13-(8-ethoxyquinolin-2-yl)tridecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCCO)N=C2C(OCC)=CC=CC2=C1 GQPUZFPFJHPWMW-UHFFFAOYSA-N 0.000 claims description 4
- YTJXLKZSEQIRGW-UHFFFAOYSA-N 13-(8-methoxyquinolin-2-yl)tridecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCCO)N=C2C(OC)=CC=CC2=C1 YTJXLKZSEQIRGW-UHFFFAOYSA-N 0.000 claims description 4
- ZMKCKFHLLPDEOK-UHFFFAOYSA-N 13-(8-phenylmethoxyquinolin-2-yl)tridecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCCCO)=CC=C2C=CC=C1OCC1=CC=CC=C1 ZMKCKFHLLPDEOK-UHFFFAOYSA-N 0.000 claims description 4
- LVSDZRSGUUCVIC-UHFFFAOYSA-N 13-(8-propan-2-yloxyquinolin-2-yl)tridecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCCO)N=C2C(OC(C)C)=CC=CC2=C1 LVSDZRSGUUCVIC-UHFFFAOYSA-N 0.000 claims description 4
- BLHPNMZDUKSSQY-UHFFFAOYSA-N 13-[8-(cyclopropylmethoxy)quinolin-2-yl]tridecan-1-ol Chemical compound C12=NC(CCCCCCCCCCCCCO)=CC=C2C=CC=C1OCC1CC1 BLHPNMZDUKSSQY-UHFFFAOYSA-N 0.000 claims description 4
- LLJSVNZKSLXPLF-UHFFFAOYSA-N 15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-1-ol Chemical compound C1=C(CCCCCCCCCCCCCCCO)N=C2C(OCC)=CC=C(Cl)C2=C1 LLJSVNZKSLXPLF-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- HQFYIDOMCULPIW-UHFFFAOYSA-N n-methylprop-2-yn-1-amine Chemical compound CNCC#C HQFYIDOMCULPIW-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000006764 neuronal dysfunction Effects 0.000 description 1
- 230000007511 neuronal proliferation Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004932 phenoxathinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
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- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
新規のキノリン誘導体を開示する。また、その合成及び神経変性疾患を治療するための使用も開示する。【選択図】図6Novel quinoline derivatives are disclosed. Also disclosed is its synthesis and use for treating neurodegenerative diseases. [Selection] Figure 6
Description
発明の背景
米国特許第7,439,243号及び7,452,888号は、アルツハイマー病を含むCNS疾患の治療に有効な一連のキノリン誘導体を記載している。米国特許第7,009,053号は、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋萎縮性側索硬化症、脳卒中、虚血、外傷性脳損傷、脊髄損傷又は骨関節炎の治療に有効な一連のキノリン誘導体を記載している。
BACKGROUND OF THE INVENTION US Pat. Nos. 7,439,243 and 7,452,888 describe a series of quinoline derivatives that are effective in the treatment of CNS diseases including Alzheimer's disease. U.S. Pat. It is described.
発明の開示
一つの態様では、本発明は、化学式(I)
R1は、水素、(C1-C8)アルキル、(C1-C8)アルキレン(C3-C8)シクロアルキル、(C1-C8)ハロアルキル又は(C1-C8)アルキレン(C6-C20)アリールであり;
R2は、水素又はハロゲンであり;
R3は水素、ハロゲン、(C1-C8)アルキル又は(C1-C8)アルコキシであり;
R4は、水素、ハロゲン、(C1-C8)アルキル、(C1-C8)アルコキシ又は(C1-C8)ハロアルキルであり;
R5は、水素又は(C1-C20)アルカノールであり;
R6は、水素であり;
R7は、水素、(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルキル、(C1-C8)アルキレン(C1-C6)アルキルアミノ(C1-C6)アルキニル、(C1-C8)アルキレンアミノ(C1-C20)アルカノール又は(C1-C8)アルキレンアミノ(C1-C20)アルカノール(C1-C8)アルキレン置換(C3-C20)ヘテロアリールである、化合物又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物に関する。
In one aspect, the present invention provides compounds of formula (I)
R 1 is hydrogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkylene (C 3 -C 8 ) cycloalkyl, (C 1 -C 8 ) haloalkyl or (C 1 -C 8 ) alkylene (C 6 -C 20 ) aryl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, (C 1 -C 8 ) alkyl or (C 1 -C 8 ) alkoxy;
R 4 is hydrogen, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy or (C 1 -C 8 ) haloalkyl;
R 5 is hydrogen or (C 1 -C 20 ) alkanol;
R 6 is hydrogen;
R 7 is hydrogen, (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkyl, (C 1 -C 8 ) alkylene (C 1 -C 6 ) alkylamino (C 1 -C 6 ) alkynyl, (C 1 -C 8) is alkyleneamino (C 1 -C 20) alkanols or (C 1 -C 8) alkylene amino (C 1 -C 20) alkanols (C 1 -C 8) alkylene-substituted (C 3 -C 20) heteroaryl , Or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof.
別の態様においては、本発明は、上述の化合物を調製する方法に関するものであって、上記方法は、(1)
化学式(II)
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素である、化合物と、臭化ベンジル、ヨウ化メチル、ヨウ化エチル、2-ブロモプロパン又は臭化メチレンシクロプロピルとを塩基性溶液中において約室温から約80℃にて反応させて、化学式(III)
R1は、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2又はベンジルであり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素である、化合物を取得するステップと、
(2)
化学式(III)の化合物とリチウムビス(トリメチルシリル)アミド及び臭化(C1C20)アルカノールとをテトラヒドロフラン中において0℃にて反応させて化学式(I)
R1は、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2又はベンジルであり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである若しくはR3はClであり、R4はOCH3である;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OHである、化合物を取得するステップと、
(3)
化学式(I)の化合物であって、R1は、ベンジルである化合物と加圧水素ガスとパラジウム炭素とをメタノール中において室温にて、又は、三塩化ホウ素とをジクロロメタン中において0℃にて反応させて、化学式(I)
R1、R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R1、R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R1、R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R1、R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである;
又は
R2、R4はClであり、R1、R3、R5、R6は他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OHである、化合物を取得するステップ
又は
(4)
化学式(I)の化合物であって、
R1、R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり、
R7は(CH2)11OHである、化合物とN-クロロスクシンイミドとをジクロロメタン中において室温にて反応させて、化学式(I)の化合物であって
R1、R3、R5及びR6は、他と関係なくそれぞれ水素であり、
R2及びR4は、他と関係なくそれぞれ塩素であり、
R7は、(CH2)11OHである、化合物を得るステップ
又は
(5)
化学式(I)の化合物であって、
R1はメチルであり、
R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり、
R7は(CH2)11OH、(CH2)12OH又は(CH2)13OHである、化合物と濃塩酸、ICl3及び氷酢酸とを反応させて化学式(I)の化合物であって、
R1はメチルであり、
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、
R4はClであり、
R7は(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OH、(CH2)10OCOCH3、(CH2)11OCOCH3、(CH2)12OCOCH3、(CH2)13OCOCH3である、化合物を得るステップ
又は
(6)
2-アミノフェノールとメチルビニルケトンとを塩酸中において反応させて、化学式(INT-1)
(7)
化学式(INT-1)の化合物とヨウ化メチル、ヨウ化エチル、2-ブロモプロパン、臭化メチレンシクロプロピル又は臭化ベンジルとを塩基性溶液中において反応させて化学式(III)
R10は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルである、化合物を得るステップと、
(8)
化学式(III)の化合物であって、
R10は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルである化合物と、リチウムビス(トリメチルシリル)アミド及び10-ブロモ-1-デカノール又は11-ブロモ-1-ウンデカノールとをテトラヒドロフラン中において0℃にて反応させて化学式(I)の化合物であって、
R1は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルであり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物を取得するステップと、
(9)
化学式(I)の化合物であって、
R1は、ベンジルであり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物と加圧水素ガスとパラジウム炭素とをメタノール中において室温にて反応させて化学式(I)の化合物であって、
R1は、水素であり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物を取得するステップ
又は
(10)
2-トリフルオロメトキサナリン(trifluoromethoxyanaline)とクロトンアルデヒドとを反応させて2-メチル-8-トリフルオメトキシキノリン(trifluormethoxyquinoline)を取得し、リチウムビス(トリメチルシリル)アミド及び臭化(C1C20)アルカノールを用いてテトラヒドロフラン中において0℃にて処理して化学式(I)の化合物であって、
R1は、トリフルオロメチル(trifluoromethyl)であり;
R2、R3、R4、R5及びR7は、他と関係なくそれぞれ水素であり;
R7は、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH又は(CH2)15OHである、化合物を取得するステップ
又は
(11)
化学式(IV)
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物と二酸化セレンとをジオキサン中において高温にて反応させて化学式(VI)
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物を得るステップと、
(12)
化学式(VI)の化合物であって、
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物とN-メチルプロパルギルアミン(methylpropagylamine)とを反応させて化学式(I)の化合物であって、
R1は水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり、
R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり;
R7は、CH2N(CH3)CH2C≡CHである化合物を取得するステップ
又は
(13)
化学式(VI)の化合物であって
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物と2(ピペラジン(piperazin)-1-イル)エタノールとを反応させて化学式(I)の化合物であって、
R1は水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり、
R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり;
R7は、CH2(N(CH2CH2)2N)CH2CH2OHである、化合物を取得するステップ
又は
(14)
化学式(VI)の化合物とアミノ(C1-C20)アルカノールとを反応させて化学式(I)の化合物であって、
R1は、水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、CH2NH(CH2)8OH又はCH2N((CH2)6OH)CH2(8-メトキシキノリン-2-イル)である、化合物を取得するステップと、を有する。
In another aspect, the invention relates to a method of preparing the above-described compound, the method comprising (1)
Chemical formula (II)
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl;
Or
R 2 , R 4 is Cl, and R 3 , R 5 , R 6 are each independently hydrogen, the compound, benzyl bromide, methyl iodide, ethyl iodide, 2-bromopropane or bromide Methylenecyclopropyl is reacted in a basic solution at about room temperature to about 80 ° C. to obtain a chemical formula (III)
R 1 is CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl;
Or
R 2 , R 4 is Cl, and R 3 , R 5 , R 6 are each independently hydrogen, obtaining a compound;
(2)
A compound of formula (III) is reacted with lithium bis (trimethylsilyl) amide and bromide (C 1 C 20 ) alkanol in tetrahydrofuran at 0 ° C. to give a compound of formula (I)
R 1 is CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 , R 4 is Cl or R 3 is Cl and R 4 is OCH 3 ;
Or
R 2 , R 4 are Cl, and R 3 , R 5 , R 6 are each independently hydrogen;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, the compound A step to obtain,
(3)
R 1 is a compound of the formula (I), wherein R 1 is reacted with a compound of benzyl, pressurized hydrogen gas and palladium carbon in methanol at room temperature or with boron trichloride at 0 ° C. in dichloromethane. Chemical formula (I)
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
Or
R 1 , R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 1 , R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 1 , R 2 , R 5 , R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl;
Or
R 2 , R 4 are Cl, and R 1 , R 3 , R 5 , R 6 are each hydrogen independently of the others;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, the compound Step to get or
(Four)
A compound of formula (I) comprising:
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
R 7 is (CH 2 ) 11 OH, wherein a compound of formula (I) is reacted with N-chlorosuccinimide in dichloromethane at room temperature.
R 1 , R 3 , R 5 and R 6 are each independently hydrogen,
R 2 and R 4 are each independently chlorine,
R 7 is (CH 2 ) 11 OH
(Five)
A compound of formula (I) comprising:
R 1 is methyl
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
R 7 is (CH 2 ) 11 OH, (CH 2 ) 12 OH or (CH 2 ) 13 OH, a compound of the formula (I) obtained by reacting a compound with concentrated hydrochloric acid, ICl 3 and glacial acetic acid. ,
R 1 is methyl
R 2 , R 3 , R 5 and R 6 are each independently hydrogen,
R 4 is Cl;
R 7 is (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, (CH 2 ) 10 OCOCH 3 , (CH 2 ) 11 OCOCH 3 , (CH 2 ) 12 OCOCH 3 , (CH 2 ) 13 OCOCH 3
(6)
Reaction of 2-aminophenol and methyl vinyl ketone in hydrochloric acid gives the chemical formula (INT-1)
(7)
A compound of the formula (INT-1) is reacted with methyl iodide, ethyl iodide, 2-bromopropane, methylenecyclopropyl bromide or benzyl bromide in a basic solution to give a chemical formula (III)
Obtaining a compound wherein R 10 is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl;
(8)
A compound of formula (III),
R 10 is a compound of methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl and lithium bis (trimethylsilyl) amide and 10-bromo-1-decanol or 11-bromo-1-undecanol in tetrahydrofuran. A compound of formula (I) reacted at
R 1 is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH to obtain a compound;
(9)
A compound of formula (I) comprising:
R 1 is benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH, a compound of the formula (I) obtained by reacting a compound, pressurized hydrogen gas and palladium carbon in methanol at room temperature,
R 1 is hydrogen;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH
(Ten)
2-Trifluoromethoxyquinoline is obtained by reacting trifluoromethoxyanaline with trifluoromethoxyanaline to obtain lithium bis (trimethylsilyl) amide and bromide (C 1 C 20 ) alkanol A compound of formula (I) treated at 0 ° C. in tetrahydrofuran with
R 1 is trifluoromethyl;
R 2 , R 3 , R 4 , R 5 and R 7 are each independently hydrogen,
R 7 is (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH or (CH 2 ) 15 OH
(11)
Chemical formula (IV)
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl, the compound of formula (VI) is reacted with selenium dioxide at high temperature in dioxane.
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl to obtain a compound;
(12)
A compound of formula (VI),
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl, a compound of formula (I) obtained by reacting a compound with N-methylpropagylamine (methylpropagylamine),
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ,
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is a step of obtaining a compound in which CH 2 N (CH 3 ) CH 2 C≡CH or
(13)
A compound of formula (VI)
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl, a compound of formula (I) by reacting a compound with 2 (piperazin-1-yl) ethanol,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ,
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 2 OH
(14)
A compound of formula (I) obtained by reacting a compound of formula (VI) with an amino (C 1 -C 20 ) alkanol,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 has CH 2 NH (CH 2 ) 8 OH or CH 2 N ((CH 2 ) 6 OH) CH 2 (8-methoxyquinolin-2-yl) to obtain a compound.
別の態様においては、本発明は、治療上効果的な量の上述の化合物、又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物、及び、医薬的に許容可能な希釈液又はキャリアを含む組成物に関する。 In another aspect, the invention provides a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof, and pharmaceutically It relates to a composition comprising an acceptable diluent or carrier.
更に別の態様においては、本発明は、上述の化合物、又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物、及び、医薬的に許容可能な希釈液又はキャリアを含む、神経変性疾患を治療するのに用いられる組成物に関する。 In yet another aspect, the invention provides a compound as described above, or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof, and a pharmaceutically acceptable diluent or It relates to a composition used to treat a neurodegenerative disease, comprising a carrier.
更に他の態様において、本発明は、神経変性疾患を治療するための医薬品の製造における上述の化合物の使用に関する。一実施形態として、上記医薬品は、アルツハイマー病を治療するためのものである。 In yet another aspect, the invention relates to the use of a compound as described above in the manufacture of a medicament for treating a neurodegenerative disease. In one embodiment, the medicament is for treating Alzheimer's disease.
これらの態様及び他の態様は、以下の図面に関連する好適な実施形態に関する以下の記述から明らかになるだろう。但し、その中の変更形態及び修正形態は、開示する新規の概念の精神と範囲から逸脱することなく作用し得るものである。 These and other aspects will become apparent from the following description of preferred embodiments in connection with the following drawings. However, changes and modifications therein can operate without departing from the spirit and scope of the disclosed novel concept.
添付の図面は、本発明の1又は複数の実施形態を例示して、明細書と共に本発明の原理を説明するのに役立つ。可能限り、同じ参照番号を図面の全体にわたって使用して、実施形態における同一又は類似の構成要素を指す。 The accompanying drawings illustrate one or more embodiments of the invention and, together with the description, serve to explain the principles of the invention. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like components in the embodiments.
発明の詳細な説明単数形「a」、「an」、及び「the」は、前後の文脈で別途明確な指示がない限り、複数を言及することが含まれる。 DETAILED DESCRIPTION OF THE INVENTION The singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
2つの文字又はシンボル間にないダッシュ("-")は、部分又は置換基の結合ポイントを示すために用いている。例えば、部分-CONH2は、炭素原子を通じて結合する。 A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent. For example, the moiety —CONH 2 is bonded through a carbon atom.
「アミノ」という用語は、-NH2を指す。アミノ基は、本明細書において「置換」という用語により規定されている通り、任意に置換することができる。「アルキルアミノ」という用語は、-NR2を指し、少なくとも一つのRはアルキルであり、もう一つのRはアルキルまたは水素である。「アシルアミノ」という用語は、N(R)C(=O)Rを指し、各Rは、互いに独立して、水素、アルキルまたはアリールである。 The term “amino” refers to —NH 2 . The amino group can be optionally substituted as defined herein by the term “substituted”. The term “alkylamino” refers to —NR 2 wherein at least one R is alkyl and the other R is alkyl or hydrogen. The term “acylamino” refers to N (R) C (═O) R, wherein each R, independently of one another, is hydrogen, alkyl or aryl.
「アルキル」という用語は、通常、第二級、第三級又は環状炭素原子を含むC1-C18炭化水素を指す。メチル、エチル、1-プロピル、2-プロピル、1-ブチル、2-メチル-1-プロピル(イソブチル、-CH2CH(CH3)2)、2-ブチル(sec-ブチル、-CH(CH3)CH2CH3)、2-メチル-2-プロピル(tert-ブチル、-C(CH3)3)、1-ペンチル、2-ペンチル、3-ペンチル、2-メチル-2-ブチル、3-メチル-2-ブチル、3-メチル-1-ブチル、2-メチル-1-ブチル、1-ヘキシル、2-ヘキシル、3-ヘキシル、2-メチル-2-ペンチル、3-メチル-2-ペンチル、4-メチル-2-ペンチル、3-メチル-3-ペンチル、2-メチル-3-ペンチル、2,3-ジメチル-2-ブチル、3,3-ジメチル-2-ブチルが例である。アルキルは、これより前に記載し例示した通り、一価の炭化水素ラジカルか二価の炭化水素ラジカル(すなわち、アルキレン)であってもよい。アルキルは、1又は複数のアルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRyおよび/またはCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。アルキルは、1又は複数の非ペルオキシドオキシ(-O-)、チオ(-S-)、イミノ(-N(H)-)、メチレンジオキシ(-OCH2O-)、カルボニル(-C(=O)-)、カルボキシ(-C(=O)O-)、カルボニルジオキシ(-OC(=O)O-)、カルボキシラト(-OC(=O)-)、イミノ(C=NH)、スルフィニル(SO)またはスルホニル(SO2)を任意に割り込ませることができる。加えて、アルキルは、任意に少なくとも部分的に不飽和であってもよく、それによって、アルケニルがもたらされる。 The term “alkyl” usually refers to a C 1 -C 18 hydrocarbon containing secondary, tertiary or cyclic carbon atoms. Methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (isobutyl, -CH 2 CH (CH 3) 2), 2- butyl (sec-butyl, -CH (CH 3 ) CH 2 CH 3 ), 2-methyl-2-propyl (tert-butyl, -C (CH 3 ) 3 ), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3- Methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, Examples are 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl. Alkyl may be a monovalent hydrocarbon radical or a divalent hydrocarbon radical (ie, alkylene), as described and exemplified earlier. Alkyl is one or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trimethyl Fluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyl Oxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, Isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (where each R x and R y is independently of one another H, alkyl, alkenyl, aryl, hetero Optionally substituted by aryl, heterocycle, cycloalkyl or hydroxy). Alkyl, one or more non-peroxide oxy (-O-), thio (-S-), imino (-N (H) -), methylenedioxy (-OCH 2 O-), carbonyl (-C (= O)-), carboxy (-C (= O) O-), carbonyldioxy (-OC (= O) O-), carboxylato (-OC (= O)-), imino (C = NH), Sulfinyl (SO) or sulfonyl (SO 2 ) can optionally be interrupted. In addition, alkyl may optionally be at least partially unsaturated, thereby providing alkenyl.
「アルキレン」という用語は、親アルカンの同一又は異なる炭素原子由来の2つの水素原子を除去することによって誘導された2つの一価のラジカル中心を有する、1-18個の炭素原子の飽和、分岐、直鎖又は環状炭化水素ラジカルを指す。典型的なアルキレンラジカルには、メチレン(-CH2-)、1,2-エチレン(-CH2CH2-)、1,3-プロピレン(-CH2CH2CH2-)、1,4-ブチレン(-CH2CH2CH2CH2-)等が挙げられるが、これらに限定されるものではない。アルキレンは、は、1又は複数のアルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRyおよび/またはCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。加えて、アルキレンは、1又は複数の非ペルオキシドオキシ(-O-)、チオ(-S-)、イミノ(-N(H)-)、メチレンジオキシ(-OCH2O-)、カルボニル(-C(=O)-)、カルボキシ(-C(=O)O-)、カルボニルジオキシ(-OC(=O)O-)、カルボキシラト(-OC(=O)-)、イミン(C=NH)、スルフィニル(SO)またはスルホニル(SO2)を任意に割り込ませることができる。さらに、アルキレンは、任意に少なくとも部分的に不飽和であってもよく、それによって、アルケニレンがもたらされる。 The term “alkylene” is a saturated, branched, 1-18 carbon atom with two monovalent radical centers derived by removing two hydrogen atoms from the same or different carbon atoms of the parent alkane. , Refers to a straight or cyclic hydrocarbon radical. Typical alkylene radicals include methylene (—CH 2 —), 1,2-ethylene (—CH 2 CH 2 —), 1,3-propylene (—CH 2 CH 2 CH 2 —), 1,4- Examples thereof include butylene (—CH 2 CH 2 CH 2 CH 2 —), but are not limited thereto. Alkylene is one or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl , Trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino , Benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate , Isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (each R x and R y independently of one another is H, alkyl, alkenyl, Optionally substituted by aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy). In addition, alkylene, one or more non-peroxide oxy (-O-), thio (-S-), imino (-N (H) -), methylenedioxy (-OCH 2 O-), carbonyl (- C (= O)-), carboxy (-C (= O) O-), carbonyldioxy (-OC (= O) O-), carboxylate (-OC (= O)-), imine (C = NH), sulfinyl (SO) or sulfonyl (SO 2 ) can optionally be interrupted. Furthermore, the alkylene may optionally be at least partially unsaturated, thereby providing alkenylene.
「アルキニル」という用語は、完全な不飽和な点(即ち、炭素-炭素、sp三重結合)を有するモノラジカル分岐又は非分岐炭化水素鎖を指す。一実施形態として、アルキニル基は、2から10の炭素原子又は2〜6の炭素原子を有することができる。別の実施形態において、アルキニル基は、2から4の炭素原子を有することができる。この用語は、例えば、エチニル、1-プロピニル、2-プロピニル、1-ブチニル、2-ブチニル、3-ブチニル、1-ヘキシニル、2-ヘキシニル、3-ヘキシニル、1-オクチニル等の基が例示される。アルキニルは、置換されていないものであってもよく置換されたものであってもよい。 The term “alkynyl” refers to a monoradical branched or unbranched hydrocarbon chain having a fully unsaturated point (ie, carbon-carbon, sp triple bond). In one embodiment, the alkynyl group can have 2 to 10 carbon atoms or 2 to 6 carbon atoms. In another embodiment, an alkynyl group can have 2 to 4 carbon atoms. This term is exemplified by groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1-octynyl and the like. . Alkynyl may be unsubstituted or substituted.
「アルコキシ」という用語は、アルキル-O-基を指し、アルキルは、本願明細書において規定されるものである。好ましいアルコキシ基には、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、tert-ブトキシ、sec-ブトキシ、n-ペントキシ、n-ヘキソキシ、1,2-ジメチルブトキシ等が挙げられる。アルコキシは、1又は複数のハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRyおよび/またはCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。 The term “alkoxy” refers to an alkyl-O— group, where alkyl is as defined herein. Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like. Alkoxy is one or more halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy Carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, Benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyana Isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (each R x and R y independently of one another is H, alkyl, alkenyl, aryl, hetero Optionally substituted by aryl, heterocycle, cycloalkyl or hydroxy).
「アルカノール」という用語は、一般式ROHの化合物を指し、Rは、本願明細書において規定される通り、アルキルである。 The term “alkanol” refers to a compound of the general formula ROH, where R is alkyl as defined herein.
「アリール」という用語は、単環(例えば、フェニル)又は多重縮合(融合)環を有する6から20個の炭素原子の不飽和芳香族炭素環化学式基を指し、少なくとも一つの環は、芳香族(例えば、ナフチル、ジヒドロフェナントレニル、フルオレニル又はアントリル)である。好ましいアリールには、フェニル、ナフチル等が含まれる。アリールは、任意に二価のラジカルとすることができ、それによって、アリーレンがもたらされる。アリールは、1又は複数のアルキル、アルケニル、アルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRy及び/又はCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。 The term `` aryl '' refers to an unsaturated aromatic carbocyclic chemical group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (Eg naphthyl, dihydrophenanthrenyl, fluorenyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Aryl can optionally be a divalent radical, leading to arylene. Aryl is one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, tri Fluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl, Benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carba Moyl, carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (each R x and R y independently of one another is H, alkyl, alkenyl , Aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy).
「アリールオキシ」及び「アリールアルコキシ」という用語は、それぞれ、酸素原子に結合したアリール基と、アルキル部分で酸素原子に結合したアラルキル基を指す。例として、フェノキシ、ナフチルオキシ及びベンジルオキシを挙げられるがこれらに限られものではない。 The terms “aryloxy” and “arylalkoxy” refer to an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy.
「炭素環」という用語は、単環として3〜8の炭素原子、ニ環として7〜12の炭素原子及び多環として最高約30の炭素原子を有する、飽和、不飽和、芳香族環を指す。単環炭素環は典型的に3〜6個の環原子を有し、更により典型的には、5または6個の環原子を有する。二環炭素環は、7から12個の環原子(例えば、ビシクロ[4,5]、[5,5]、[5,6]又は[6,6]系として構成するもの)、または、ビシクロ[5,6]若しくは[6,6]系として構成される9若しくは10個の環原子を有する。炭素環の例には、シクロプロピル、シクロブチル、シクロペンチル、1-シクロペント-1-エニル、1-シクロペント-2-エニル、1-シクロペント-3-エニル、シクロヘキシル、1-シクロヘキサ-1-エニル、1-シクロヘキサ-2-エニル、1-シクロヘキサ-3-エニル、フェニル、スピリル(spiryl)及びナフチルが挙げられる。炭素環は、上記の通り、任意にアルキル基の代わりに用いることができる。 The term “carbocycle” refers to a saturated, unsaturated, aromatic ring having from 3 to 8 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicycle and up to about 30 carbon atoms as a polycycle. . Monocyclic carbocycles typically have 3 to 6 ring atoms, and still more typically have 5 or 6 ring atoms. Bicyclic carbocycles are 7 to 12 ring atoms (eg, those configured as bicyclo [4,5], [5,5], [5,6] or [6,6] systems) or bicyclo It has 9 or 10 ring atoms configured as a [5,6] or [6,6] system. Examples of carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex And cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl. A carbocycle can optionally be used in place of an alkyl group, as described above.
ある置換基が1つの原子か、特定の一体性をもつ複数の原子か、「結合」に特定される場合、置換基が「結合」であるときには、特定の置換基と直ぐ近くに隣接している複数の基は、化学的に適した結合構成によって各々が直接接続している構成と言える。 When a substituent is a single atom, a plurality of atoms with a particular unity, or specified as a “bond”, when the substituent is a “bond”, it is immediately adjacent to the specific substituent. It can be said that the plurality of groups are directly connected by a chemically suitable bond structure.
「シクロアルキル」という用語は、単環又は多重縮合環を有する3〜20個の炭素原子の環状アルキル基を指す。かかるシクロアルキル基は、一例として、単環構造(例えばシクロプロピル、シクロブチル、シクロペンチル、シクロオクチル等)又は多重環構造(例えばアダマンタニル等)が含まれる。シクロアルキルは、1又は複数のアルキル、アルケニル、アルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRy及び/又はCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。シクロアルキルは、任意に少なくとも部分的に不飽和であってもよく、それによって、シクロアルケニルがもたらされる。加えて、シクロアルキルは、ニ価のラジカルであってもよく、それによって、シクロアルキレンがもたらされる。 The term “cycloalkyl” refers to cyclic alkyl groups of 3 to 20 carbon atoms having a single ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc.) or multiple ring structures (eg, adamantanyl, etc.). Cycloalkyl is one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, Trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl , Benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, Carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (where each R x and R y are independently of each other H, alkyl, alkenyl , Aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy). Cycloalkyls may optionally be at least partially unsaturated, thereby providing cycloalkenyl. In addition, cycloalkyl may be a divalent radical, thereby providing cycloalkylene.
「効果的な量」という用語は、有益又は所望の結果を成し遂げるのに十分な量を指す。所定の投与に関する効果的な量は、製薬技術における通常の技量の範囲内で充分に決定できる。 The term “effective amount” refers to an amount sufficient to achieve a beneficial or desired result. The effective amount for a given administration can be determined well within the ordinary skill in the pharmaceutical arts.
「ハロ」という用語は、フルオロ、クロル、ブロモ及びヨードを指す。同様に、「ハロゲン」という用語は、フッ素、塩素、臭素及びヨウ素を指す。 The term “halo” refers to fluoro, chloro, bromo and iodo. Similarly, the term “halogen” refers to fluorine, chlorine, bromine and iodine.
「ハロアルキル」という用語は、1-4個のハロ基によって置換されたアルキルを指すものであり、それは同じであっても異なるものであってもよい。代表的なハロアルキル基としては、トリフルオロメチル、3-フルオロドデシル、12,12,12-トリフルオロドデシル、2-ブロモオクチル、3-ブロモ-6-クロロヘプチル等が挙げられる。 The term “haloalkyl” refers to an alkyl substituted by 1-4 halo groups, which may be the same or different. Representative haloalkyl groups include trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl and the like.
「ヘテロアリール」という用語は、単環化学式、二環化学式、又は三環化学式環系であって、1、2又は3つの芳香族環を有し且つ芳香族環に少なくとも一つの窒素、酸素又は硫黄原子を有するものであり、それらは、置換されていないものであったり置換されたものであったりすることができる。ヘテロアリールは、任意に二価のラジカルであってもよく、それによって、ヘテロアリーレンがもたらされる。ヘテロアリール基の例として、2H-ピロリル、3H-インドリル、4H-キノリジニル、4nH-カルバゾリル、アクリジニル、ベンゾ[b]チエニル、ベンゾチアゾリル、(β-カルボリニル、カルバゾリル、クロメニル、シンナオリニル(cinnaolinyl)、ジベンゾ[b,d]フラニル、フラザニル、フリル、イミダゾリル、イミジゾリル(imidizolyl)、インダゾリル、インドリシニル(indolisinyl)、インドリル、イソベンゾフラニル、イソインドリル、イソキノリル、イソチアゾリル、イソオキサゾリル、ナフチリジニル、ナフト
[2,3-b]、オキサゾリル、ペリミジニル(perimidinyl)、フェナントリジニル、フェナントロリニル、フェナルサジニル、フェナジニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、フタラジニル、プテリジニル、プリニル、ピラニル、ピラジニル、ピラゾリル、ピリダジニル、ピリジル、ピリミジニル、ピリミジニル、ピロリル、キナゾリニル、キノリル、キノキサリニル、チアジアゾリル、チアントレニル、チアゾリル、チエニル、トリアゾリル及びキサンテニルが挙げられるが、これらに限定されるものではない。一実施形態として、「ヘテロアリール」という用語は、非ペルオキシド酸素、硫黄及びN(Z)の群から独立して選択される1、2、3又は4つのヘテロ原子と炭素を含む5又は6個の環原子を含む単環化学式芳香族環を意味するものであって、Zは、無しか、H、O、アルキル、フェニル又はベンジルである。他の実施形態において、ヘテロアリールは、オルト縮合二環化学式ヘテロ環であって約8〜10個の環原子から誘導されたもの、特にベンズ-誘導体かプロピレン縮合によって誘導されたもの、又はそのテトラメチレンジラジカルを意味する。
The term “heteroaryl” is a monocyclic, bicyclic, or tricyclic chemical ring system having 1, 2 or 3 aromatic rings and at least one nitrogen, oxygen or Those having a sulfur atom, which can be unsubstituted or substituted. Heteroaryl may optionally be a divalent radical, thereby providing a heteroarylene. Examples of heteroaryl groups include 2H-pyrrolyl, 3H-indolyl, 4H-quinolidinyl, 4nH-carbazolyl, acridinyl, benzo [b] thienyl, benzothiazolyl, (β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo [b , d] furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolicinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naphtho
[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenalsadinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl , Pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiantenyl, thiazolyl, thienyl, triazolyl and xanthenyl. In one embodiment, the term “heteroaryl” refers to 5 or 6 containing 1, 2, 3 or 4 heteroatoms and carbon independently selected from the group of non-peroxide oxygen, sulfur and N (Z). And Z is none, H, O, alkyl, phenyl or benzyl. In other embodiments, the heteroaryl is an ortho-fused bicyclic chemical heterocycle derived from about 8-10 ring atoms, particularly those derived from benz-derivatives or propylene condensation, or its tetra Means methylene diradical.
ヘテロアリールは、1又は複数のアルキル、アルケニル、アルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRy及び/又はCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。 Heteroaryl is one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, Trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl , Benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, Carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (where each R x and R y are independently of each other H, alkyl, alkenyl , Aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy).
「ヘテロ環」または「ヘテロサイクリル」という用語は、酸素、窒素及び硫黄のグループから選択される少なくとも一つのヘテロ原子であって、任意に、アルキルまたはC(=O)ORbによって置換されているものを含む飽和又は部分的不飽和環系であって、Rbは、水素またはアルキルである。典型的には、ヘテロ環は、酸素、窒素及び硫黄のグループから選択される1又は複数のヘテロ原子を含む単環化学式、二環化学式又は三環化学式基である。ヘテロ環基は、上記環に結合したオキソ基(=O)を含むこともできる。ヘテロ環基の非限定的な例としては、1,3-ジヒドロベンゾフラン、1,3-ジオキソラン、1,4-ジオキサン、1,4-ジチアン、2H-ピラン、2-ピラゾリン、4H-ピラン、クロマニル、イミダゾリジニル、イミダゾリニル、インドリニル、イソクロマニル、イソインドリニル、モルフォリン、ピペラジニル、ピペリジン、ピペリジル、ピラゾリジン、ピラゾリジニル、ピラゾリニル、ピロリジン、ピロリン、キニクリジン及びチオモルホリンが挙げられる。ヘテロ環は、任意に二価のラジカルであってもよく、それによって、ヘテロシクレン(heterocyclene)がもたらされる。ヘテロ環は、1又は複数のアルキル、アルケニル、アルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート(isocyannato)、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRyおよび/またはCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)によって任意に置換することができる。 The term “heterocycle” or “heterocyclyl” is at least one heteroatom selected from the group of oxygen, nitrogen and sulfur, optionally substituted by alkyl or C (═O) OR b . Saturated or partially unsaturated ring systems, including those in which R b is hydrogen or alkyl. Typically, the heterocycle is a monocyclic, bicyclic or tricyclic chemical group containing one or more heteroatoms selected from the group of oxygen, nitrogen and sulfur. The heterocyclic group may also contain an oxo group (═O) bonded to the ring. Non-limiting examples of heterocyclic groups include 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazolin, 4H-pyran, chromanyl Imidazolidinyl, imidazolinyl, indolinyl, isochrominyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quiniclidine and thiomorpholine. The heterocycle may optionally be a divalent radical, thereby providing a heterocyclene. A heterocycle is one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, Trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl, benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl , Benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carba Moyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (each R x and R y independently of one another is H, alkyl, alkenyl , Aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy).
窒素複素環化学式化合物及びヘテロアリールの例には、ピロール、イミダゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、インドリジン、イソインドール、インドール、インダゾール、プリン、キノリジン、イソキノリン、キノリン、フタラジン、ナフチルピリジン、キノキサリン、キナゾリン、シンノリン、プテリジン、カルバゾール、カルボリン、フェナントリジン、アクリジン、フェナントロリン、イソチアゾール、フェナジン、イソオキサゾール、フェノキサジン、フェノサイアジン、イミダゾリジン、イミダゾリン、ピペリジン、ピペラジン、インドリン、モルホリノ、ピペリジニル、テトラヒドロフラニル等と、ヘテロ環を含むN-アルコキシ-窒素が挙げられるが、これらに限定されるものではない。 Examples of nitrogen heterocyclic chemical compounds and heteroaryl include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, Quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, Non-limiting examples include tetrahydrofuranyl and the like, and N-alkoxy-nitrogen containing a heterocycle.
「水和物」という用語は、溶媒分子が水である複合体をいう。 The term “hydrate” refers to the complex where the solvent molecule is water.
「個体」、「宿主」、「対象」及び「患者」という用語は、互いに置換可能に使用され、哺乳動物に関連するが、これに限定されず、サル及びヒトを含む霊長類が含まれる。 The terms “individual”, “host”, “subject” and “patient” are used interchangeably and relate to, but are not limited to, mammals, including primates including monkeys and humans.
「代謝産物」という用語は、親薬物からインビボ又はインビトロで生産される化学式(I)の任意の化合物又はそのプロドラッグを指す。 The term “metabolite” refers to any compound of formula (I) or a prodrug thereof produced in vivo or in vitro from a parent drug.
本願明細書に記載されている化合物の医薬的に許容可能な塩は、従来の化学的な方法によって親化合物から合成することができ、それらは、塩基性又は酸性的な部分を含んでいる。一般的には、かかる塩は、これらの化合物の遊離酸または塩基の形態と、適切な塩基または酸の化学当量とを、水若しくは有機溶媒中又は2つの混合物(一般には、エーテル、酢酸エチル、エタノール、イソプロパノールまたはアセトニトリルのような非水溶媒が好ましい)中で反応させて調製することができる。多くの適切な塩類の一覧は、Remington:The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins, (2005)にある。 The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound by conventional chemical methods and contain a basic or acidic moiety. In general, such salts produce the free acid or base form of these compounds and the appropriate base or chemical equivalent of the acid in water or an organic solvent or a mixture of the two (generally ether, ethyl acetate, Non-aqueous solvents such as ethanol, isopropanol or acetonitrile are preferred). A list of many suitable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams & Wilkins, (2005).
医薬的に許容可能なプロドラッグは、代謝(例:加水分解又は酸化)されて、化学式(I)の化合物を形成する化合物を指す。プロドラッグの代表例には、活性化合物の機能的な部分において生物学的に不安定な保護基を有する化合物が挙げられる。プロドラッグには、活性化合物を生産するために、酸化、還元、アミノ化、脱アミノ化、ヒドロキシル化、脱ヒドロキシル化、加水分解、脱加水分解(dehydrolyzed)、アルキル化、脱アルキル化、アシル化、脱アシル化、リン酸化及び脱リン酸化され得る化合物が含まれる。 A pharmaceutically acceptable prodrug refers to a compound that is metabolized (eg, hydrolyzed or oxidized) to form a compound of formula (I). Representative examples of prodrugs include compounds that have biologically labile protecting groups in the functional part of the active compound. Prodrugs can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated to produce the active compound. Compounds that can be deacylated, phosphorylated and dephosphorylated are included.
プロドラッグは、従来技術において知られている方法を使用して、化学式(I)の化合物から容易に調製することができる。例えば、Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309 323 (1985);Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3):165 182 (1981);及びBundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985);Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172 178, 949 982 (1995)を参照。 Prodrugs can be readily prepared from compounds of formula (I) using methods known in the art. For example, Notari, RE, "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112: 309 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6 (3): 165 182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, NY (1985); Burger's See Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172 178, 949 982 (1995).
「溶媒和物」という用語は、溶質(本発明においては、化学式Iの化合物又はその塩若しくは生理的に機能的な誘導体)と溶媒によって形成される化学当量が可変的な複合体を指す。かかる溶媒は、本発明の目的に関して言えば、溶質の生物活性を妨げてはならない。適切な溶媒に関する非制限的な例には、水、メタノール、エタノール及び酢酸が挙げられるが、これらに限定されるものではない。好ましくは、使用する溶媒は、医薬的に許容可能な溶媒である。適切な医薬的に許容可能な溶媒に関する非制限的な例には、水、エタノール及び酢酸が挙げられる。 The term “solvate” refers to a complex with variable chemical equivalents formed by a solute (in the present invention, a compound of formula I or a salt or physiologically functional derivative thereof) and a solvent. Such a solvent should not interfere with the biological activity of the solute for the purposes of the present invention. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
「室温」という用語は、約20℃から約30℃の範囲の温度を指す。 The term “room temperature” refers to a temperature in the range of about 20 ° C. to about 30 ° C.
「置換」又は「置換された」という用語は、明示した原子の1又は複数の水素が、明示された基から選択されたものと置き換えられることを示すものを意図する。但し、明示された原子の通常の原子価を超えず、そして、置換の結果、安定化合物になる。適切な明示された基には、例えば、アルキル、アルケニル、アルキリデニル(alkylidenyl)、アルケニリデニル(alkenylidenyl)、アルコキシ、ハロ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル、アルカノイル、アルコキシカルボニル、アミノ、イミノ、アルキルアミノ、アシルアミノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、カルボキシ、カルボキシアルキル、ケト、チオキソ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、シアノ、アセトアミド、アセトキシ、アセチル、ベンズアミド、ベンゼンスルフィニル、ベンゼンスルホンアミド、ベンゼンスルホニル、ベンゼンスルホニルアミノ、ベンゾイル、ベンゾイルアミノ、ベンゾイルオキシ、ベンジル、ベンジルオキシ、ベンジルオキシカルボニル、ベンジルチオ、カルバモイル、カルバメート、イソシアナート、スルファモイル、スルフィナモイル、スルフィノ、スルホ、スルホアミノ、チオスルホ、NRxRyおよび/またはCOORx(各Rx及びRyは、互いに独立して、H、アルキル、アルケニル、アリール、ヘテロアリール、ヘテロ環、シクロアルキル又はヒドロキシのいずれかである)が挙げられる。置換基がオキソ(すなわち、=O)またはチオキソ(すなわち、=S)基であると、原子上の2つの水素は置き換えられる。 The term “substituted” or “substituted” is intended to indicate that one or more hydrogens of a specified atom is replaced with one selected from a specified group. However, the normal valence of the specified atom is not exceeded, and the substitution results in a stable compound. Suitable explicit groups include, for example, alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy Carbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamide, acetoxy, acetyl, benzamide, benzenesulfinyl , Benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, Benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y and / or COOR x (where each R x and R y are independently of each other) , H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy). When the substituent is an oxo (ie, ═O) or thioxo (ie, ═S) group, the two hydrogens on the atom are replaced.
「治療すること」又は「治療する」又は「治療」という用語は、所望の薬理学的及び/又は生理的効果を得ることを指す。上記効果は、疾患若しくはその症状を完全にか部分的に予防する観点から予防的であるとしてもよく、及び/又は、疾患若しくは疾患に起因する悪影響を部分的にか完全に治癒する観点から治療的であるとしてもよい。 The term “treating” or “treating” or “treatment” refers to obtaining a desired pharmacological and / or physiological effect. The above effect may be preventive from the viewpoint of completely or partially preventing the disease or its symptoms and / or treatment from the viewpoint of partially or completely curing the adverse effects caused by the disease or disease. It may be good.
本発明は、金属キレート化、活性酸素種の消去、抗凝集、神経突起伸長及びニューロン増殖の特性を有する多機能キノリン誘導体に関する。それらは、酸化的ストレスによって誘導されるニューロン毒性又は機能不全を伴う神経変性疾患及びミスフォールディングタンパク質凝集と関連した他の障害を治療するために有効である。動物のモデルにおいて、1〜100mg/kg、好ましくは1〜10mg/kgのキノリン誘導体(B3又はC12)(i.p.で毎日)は、有意な毒性を引き起こすことなくマウスの記憶を向上させることがわかった。 The present invention relates to multifunctional quinoline derivatives having properties of metal chelation, elimination of reactive oxygen species, anti-aggregation, neurite outgrowth and neuronal proliferation. They are effective for treating neurodegenerative diseases with neuronal toxicity or dysfunction induced by oxidative stress and other disorders associated with misfolded protein aggregation. In animal models, 1-100 mg / kg, preferably 1-10 mg / kg quinoline derivatives (B3 or C12) (daily with ip) were found to improve mouse memory without causing significant toxicity. .
一つの態様においては、本発明は、化学式(I)
R1は、水素、(C1-C8)アルキル、(C1-C8)アルキレン(C3-C8)シクロアルキル、(C1-C8)ハロアルキル又は(C1-C8)アルキレン(C6-C20)アリールであり;
R2は、水素又はハロゲンであり;
R3は水素、ハロゲン、(C1-C8)アルキル又は(C1-C8)アルコキシであり;
R4は、水素、ハロゲン、(C1-C8)アルキル、(C1-C8)アルコキシ又は(C1-C8)ハロアルキルであり;
R5は、水素又は(C1-C20)アルカノールであり;
R6は、水素であり;
R7は、水素、(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルキル、(C1-C8)アルキレン(C1-C6)アルキルアミノ(C1-C6)アルキニル、(C1-C8)アルキレンアミノ(C1-C20)アルカノール又は(C1-C8)アルキレンアミノ(C1-C20)アルカノール(C1-C8)アルキレン置換(C3-C20)ヘテロアリールである、化合物又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物に関するものである。
In one embodiment, the present invention provides compounds of formula (I)
R 1 is hydrogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkylene (C 3 -C 8 ) cycloalkyl, (C 1 -C 8 ) haloalkyl or (C 1 -C 8 ) alkylene (C 6 -C 20 ) aryl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, (C 1 -C 8 ) alkyl or (C 1 -C 8 ) alkoxy;
R 4 is hydrogen, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy or (C 1 -C 8 ) haloalkyl;
R 5 is hydrogen or (C 1 -C 20 ) alkanol;
R 6 is hydrogen;
R 7 is hydrogen, (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkyl, (C 1 -C 8 ) alkylene (C 1 -C 6 ) alkylamino (C 1 -C 6 ) alkynyl, (C 1 -C 8) is alkyleneamino (C 1 -C 20) alkanols or (C 1 -C 8) alkylene amino (C 1 -C 20) alkanols (C 1 -C 8) alkylene-substituted (C 3 -C 20) heteroaryl , Or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof.
本発明の一実施形態において、
R1は、水素、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2、CF3又はベンジルであり;
R2は、水素、F又はClであり;
R3は、水素、F、Cl、CH3又はOCH3であり;
R4は、水素、F、Cl、Br、CH3、OCH3又はCF3であり;
R5は、水素、(CH2)11OH又は(CH2)12OHであり;
R6は、水素であり;
R7は、水素、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)14OH、(CH2)15OH、CH2(N(CH2CH2)2N)CH2CH2OH、CH2(N(CH2CH2)2N)CH2CH3、CH2N(CH3)CH2C≡CH、CH2NH(CH2)8OH又はCH2N((CH2)6OH)CH2(8-メトキシキノリン-2-イル)である。
In one embodiment of the invention,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CF 3 or benzyl;
R 2 is hydrogen, F or Cl;
R 3 is hydrogen, F, Cl, CH 3 or OCH 3 ;
R 4 is hydrogen, F, Cl, Br, CH 3 , OCH 3 or CF 3 ;
R 5 is hydrogen, (CH 2 ) 11 OH or (CH 2 ) 12 OH;
R 6 is hydrogen;
R 7 is hydrogen, (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 14 OH, (CH 2 ) 15 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 2 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 3 , CH 2 N (CH 3 ) CH 2 C≡CH, CH 2 NH (CH 2 ) 8 OH or CH 2 N ((CH 2 ) 6 OH) CH 2 (8-methoxyquinolin-2-yl).
本発明の別の実施形態において、
R1は、水素、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2、CH2CH(CH2)2、CF3又はベンジルであり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)14OH、(CH2)15OH、CH2(N(CH2CH2)2N)CH2CH2OH又はCH2N(CH3)CH2C≡CHである。
In another embodiment of the invention,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 , CF 3 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 14 OH, (CH 2 ) 15 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 2 OH or CH 2 N (CH 3 ) CH 2 C≡CH.
本発明の別の実施形態において、
R1は、水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり;
R2、R3、R5及びR6は、他と関係なくそれぞれ水素であり;
R4は、CH3、F、Cl、Br、CF3又はOCH3であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OH、(CH2)10OCOCH3、(CH2)11OCOCH3、(CH2)12OCOCH3、(CH2)13OCOCH3、CH2NH(CH2)8OH、CH2(N(CH2CH2)2N)CH2CH2OH、CH2(N(CH2CH2)2N)CH2CH3又はCH2N(CH3)CH2C≡CHである。
In another embodiment of the invention,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 5 and R 6 are each independently hydrogen;
R 4 is CH 3 , F, Cl, Br, CF 3 or OCH 3 ;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, (CH 2 ) 10 OCOCH 3 , (CH 2 ) 11 OCOCH 3 , (CH 2 ) 12 OCOCH 3 , (CH 2 ) 13 OCOCH 3 , CH 2 NH (CH 2 ) 8 OH, CH 2 (N (CH 2 CH 2 ) 2 N ) CH 2 CH 2 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 3 or CH 2 N (CH 3 ) CH 2 C≡CH.
本発明の別の実施形態において、
R1は、水素、CH3、CH2CH3、CH(CH2)2又はCH2CH(CH2)2であり;
R2、R4は、他と関係なくそれぞれClであり;
R3、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、(CH2)11OH、CH2NH(CH2)8OH又はCH2N(CH3)CH2C≡CHである。
In another embodiment of the invention,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 2 ) 2 or CH 2 CH (CH 2 ) 2 ;
R 2 and R 4 are each Cl independently of the others;
R 3 , R 5 and R 6 are each independently hydrogen,
R 7 is (CH 2 ) 11 OH, CH 2 NH (CH 2 ) 8 OH, or CH 2 N (CH 3 ) CH 2 C≡CH.
本発明の別の実施形態において、
R1は、水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2、CH(CH3)2又はベンジルであり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである。
In another embodiment of the invention,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 , CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH.
本発明の別の実施形態において、
R1は、CH3であり;
R2、R5及びR6は、他と関係なくそれぞれ水素であり;
R3及びR4は、他と関係なくそれぞれOCH3又はClであり;
R7は、(CH2)11OHである。
In another embodiment of the invention,
R 1 is CH 3 ;
R 2 , R 5 and R 6 are each independently hydrogen;
R 3 and R 4 are each independently OCH 3 or Cl;
R 7 is (CH 2 ) 11 OH.
本発明の別の実施形態において、上記化合物は、
9-(8-(ベンジルオキシ)キノリン-2-イル)ノナン-1-オール、
10-(8-(ベンジルオキシ)キノリン-2-イル)デカン-1-オール、
11-(8-(ベンジルオキシ)キノリン-2-イル)ウンデカン-1-オール、
12-(8-(ベンジルオキシ)キノリン-2-イル)ドデカン-1-オール、
13-(8-(ベンジルオキシ)キノリン-2-イル)トリデカン-1-オール、
14-((8-(ベンジルオキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(ベンジルオキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(8-(ベンジルオキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-6-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-5-クロロキノリン-2-イル)ウンデカン-1-オール、
2-(9-ヒドロキシノニル)キノリン-8-オール、
2-(10-ヒドロキシデシル)キノリン-8-オール、
2-(11-ヒドロキシウンデシル)キノリン-8-オール、
2-(12-ヒドロキシウンデシル)キノリン-8-オール、
2-(13-ヒドロキシトリデシル)キノリン-8-オール、
2-(14-(-ヒドロキシテトラデシル)キノリン-8-オール、
2-(15-ヒドロキシペンタデシル)キノリン-8-オール、
2-(11-ヒドロキシウンデシル)-5-メチルキノリン-8-オール、
2-(11-ヒドロキシウンデシル)-6-メチルキノリン-8-オール、
5-クロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール、
9-(8-メトキシキノリン-2-イル)ノナン-1-オール、
10-(8-メトキシキノリン-2-イル)デカン-1-オール、
11-(8-メトキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-メトキシキノリン-2-イル)ドデカン-1-オール、
13-(8-メトキシキノリン-2-イル)トリデカン-1-オール、
14-((8-メトキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-メトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-メトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(5-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
12-(5-フルオロ-8-メトキシキノリン-2-イル)ドデカン-1-オール、
9-(5-クロロ-8-メトキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-メトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(8-メトキシ-5-(トリフルオロメチル)キノリン-2-イル)ウンデカン-1-オール、
11-(5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(8-メトキシ-6-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(6-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(6-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(7-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(7-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5-クロロ-6,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(6-クロロ-5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-エトキシキノリン-2-イル)ノナン-1-オール、
10-(8-エトキシキノリン-2-イル)デカン-1-オール、
11-(8-エトキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-エトキシキノリン-2-イル)ドデカン-1-オール、
13-(8-エトキシキノリン-2-イル)トリデカン-1-オール、
14-((8-エトキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-エトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-エトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-エトキシ-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-エトキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-エトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-イソプロポキシキノリン-2-イル)ノナン-1-オール、
10-(8-イソプロポキシキノリン-2-イル)デカン-1-オール、
11-(8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-イソプロポキシキノリン-2-イル)ドデカン-1-オール、
13-(8-イソプロポキシキノリン-2-イル)トリデカン-1-オール、
14-((8-イソプロポキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-イソプロポキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(5-フルオロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-イソプロポキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール、
10-(8-(シクロプロピルメトキシ)キノリン-2-イル)デカン-1-オール、
11-(8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
12-(8-(シクロプロピルメトキシ)キノリン-2-イル)ドデカン-1-オール、
13-(8-(シクロプロピルメトキシ)キノリン-2-イル)トリデカン-1-オール、
14-((8-(シクロプロピルメトキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(8-(シクロプロピルメトキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(シクロプロピルメトキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
5,7-ジクロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール、
10-(5-クロロ-8-メトキシキノリン-2-イル)デカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 10-デシルエステル、
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 11-ウンデシルエステル、
12-(5-クロロ-8-メトキシキノリン-2-イル)ドデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 12-ドデシルエステル、
13-(5-クロロ-8-メトキシキノリン-2-イル)トリデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 13-トリデシルエステル、
11-(8-メトキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-エトキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-イソプロポキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-(シクロプロピルメトキシ)キノリン-4-(-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)キノリン-4-(-イル)ウンデカン-1-オール、
12-(8-(ベンジルオキシ)キノリン-4-(-イル)ドデカン-1-オール、
4-((11-ヒドロキシウンデシル)キノリン-8-オール、
4-((12-ヒドロキシウンデシル)キノリン-8-オール、
9-(8-(トリフルオロメトキシ)キノリン-2-イル)ノナ-1-オール、
11-(8-(トリフルオロメトキシ)キノリン-2-イル)ウンデカン-1-オール、
14-((8-(トリフルオロメトキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(トリフルオロメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
2-((4-((2-ヒドロキシエチル)ピペラジン(piperazin)-1-イル)メチル)キノリン-8-オール、
2-(4-(((5-クロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-エトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタン、
2-(4-(((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール、
5-クロロ-2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール、
N((5-クロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-エトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
8-((5-クロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-エトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-イソプロポキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール、
及び
6-(ビス((8-メトキシキノリン-2-イル)メチル)アミノ)ヘキサン-1-オールからなる群より選択される。
In another embodiment of this invention the compound is
9- (8- (benzyloxy) quinolin-2-yl) nonan-1-ol,
10- (8- (benzyloxy) quinolin-2-yl) decan-1-ol,
11- (8- (benzyloxy) quinolin-2-yl) undecan-1-ol,
12- (8- (benzyloxy) quinolin-2-yl) dodecan-1-ol,
13- (8- (benzyloxy) quinolin-2-yl) tridecan-1-ol,
14-((8- (benzyloxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (benzyloxy) quinolin-2-yl) pentadecan-1-ol,
11- (8- (benzyloxy) -5-methylquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -6-methylquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -5-fluoroquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -5-chloroquinolin-2-yl) undecan-1-ol,
2- (9-hydroxynonyl) quinolin-8-ol,
2- (10-hydroxydecyl) quinolin-8-ol,
2- (11-hydroxyundecyl) quinolin-8-ol,
2- (12-hydroxyundecyl) quinolin-8-ol,
2- (13-hydroxytridecyl) quinolin-8-ol,
2- (14-(-hydroxytetradecyl) quinolin-8-ol,
2- (15-hydroxypentadecyl) quinolin-8-ol,
2- (11-hydroxyundecyl) -5-methylquinolin-8-ol,
2- (11-hydroxyundecyl) -6-methylquinolin-8-ol,
5-chloro-2- (11-hydroxyundecyl) quinolin-8-ol,
9- (8-methoxyquinolin-2-yl) nonan-1-ol,
10- (8-methoxyquinolin-2-yl) decan-1-ol,
11- (8-methoxyquinolin-2-yl) undecan-1-ol,
12- (8-methoxyquinolin-2-yl) dodecan-1-ol,
13- (8-methoxyquinolin-2-yl) tridecan-1-ol,
14-((8-methoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-methoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-methoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (5-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
12- (5-fluoro-8-methoxyquinolin-2-yl) dodecan-1-ol,
9- (5-chloro-8-methoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-methoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (8-methoxy-5- (trifluoromethyl) quinolin-2-yl) undecan-1-ol,
11- (5,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (8-methoxy-6-methylquinolin-2-yl) undecan-1-ol,
11- (6-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (6-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (7-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (7-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (5-chloro-6,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (6-chloro-5,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-methoxyquinolin-2-yl) undecan-1-ol,
9- (8-ethoxyquinolin-2-yl) nonan-1-ol,
10- (8-ethoxyquinolin-2-yl) decan-1-ol,
11- (8-ethoxyquinolin-2-yl) undecan-1-ol,
12- (8-ethoxyquinolin-2-yl) dodecan-1-ol,
13- (8-ethoxyquinolin-2-yl) tridecan-1-ol,
14-((8-ethoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-ethoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-ethoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (8-ethoxy-5-fluoroquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8-ethoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-ethoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-ethoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-ethoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-ethoxyquinolin-2-yl) undecan-1-ol,
9- (8-isopropoxyquinolin-2-yl) nonan-1-ol,
10- (8-isopropoxyquinolin-2-yl) decan-1-ol,
11- (8-isopropoxyquinolin-2-yl) undecan-1-ol,
12- (8-isopropoxyquinolin-2-yl) dodecan-1-ol,
13- (8-isopropoxyquinolin-2-yl) tridecan-1-ol,
14-((8-isopropoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-isopropoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (5-fluoro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8-isopropoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-isopropoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-isopropoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
9- (8- (cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol,
10- (8- (cyclopropylmethoxy) quinolin-2-yl) decan-1-ol,
11- (8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
12- (8- (cyclopropylmethoxy) quinolin-2-yl) dodecan-1-ol,
13- (8- (cyclopropylmethoxy) quinolin-2-yl) tridecan-1-ol,
14-((8- (cyclopropylmethoxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol,
11- (8- (cyclopropylmethoxy) -5-methylquinolin-2-yl) undecan-1-ol,
11- (8- (cyclopropylmethoxy) -5-fluoroquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol,
11- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
15- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
5,7-dichloro-2- (11-hydroxyundecyl) quinolin-8-ol,
10- (5-chloro-8-methoxyquinolin-2-yl) decan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 10-decyl ester,
11- (5-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 11-undecyl ester,
12- (5-chloro-8-methoxyquinolin-2-yl) dodecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 12-dodecyl ester,
13- (5-chloro-8-methoxyquinolin-2-yl) tridecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 13-tridecyl ester,
11- (8-methoxyquinolin-4-(-yl) undecan-1-ol,
11- (8-ethoxyquinolin-4-(-yl) undecan-1-ol,
11- (8-isopropoxyquinolin-4-(-yl) undecan-1-ol,
11- (8- (cyclopropylmethoxy) quinolin-4-(-yl) undecan-1-ol,
11- (8- (benzyloxy) quinolin-4-(-yl) undecan-1-ol,
12- (8- (benzyloxy) quinolin-4-(-yl) dodecan-1-ol,
4-((11-hydroxyundecyl) quinolin-8-ol,
4-((12-hydroxyundecyl) quinolin-8-ol,
9- (8- (trifluoromethoxy) quinolin-2-yl) non-1-ol,
11- (8- (trifluoromethoxy) quinolin-2-yl) undecan-1-ol,
14-((8- (trifluoromethoxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (trifluoromethoxy) quinolin-2-yl) pentadecan-1-ol,
2-((4-((2-hydroxyethyl) piperazin-1-yl) methyl) quinolin-8-ol,
2- (4-(((5-chloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8-ethoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8-isopropoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethane,
2- (4-(((5,7-dichloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2-((methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol,
5-chloro-2-((methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol,
N ((5-chloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8-ethoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8-isopropoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5,7-dichloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
8-((5-chloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8-ethoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8-isopropoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol,
8-((5,7-dichloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol,
as well as
Selected from the group consisting of 6- (bis ((8-methoxyquinolin-2-yl) methyl) amino) hexan-1-ol.
別の態様においては、本発明は、上述の化合物又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物、及び、医薬的に許容可能な希釈液又はキャリアを含む、神経変性疾患を治療する際に使用するための組成物に関する。 In another aspect, the invention provides a compound as described above or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof, and a pharmaceutically acceptable diluent or carrier. The present invention relates to a composition for use in treating neurodegenerative diseases.
本発明の一実施形態において、上記神経変性疾患は、アルツハイマー病、筋萎縮性側索硬化症(ALS)、白内障、認知障害、脳虚血脳卒中、脳性麻痺、脳卒中、出血性脳卒中、クロイツフェルトヤコブ病、海綿状脳症、狂牛病、痴呆、うつ病、ダウン症候群、てんかん、外傷性てんかん、前頭側頭認知症、ジルドラトゥレット症候群、ハレルフォルデンスパッツ病、ハンチントン舞踏病、レビー小体病、パーキンソン病、認知障害、学習障害、黄斑部変性、記憶障害、多発硬化、多系統萎縮症、運動ニューロン疾患、ピック病、進行性核上性麻痺、仮性痴呆、網膜症、老人性痴呆、精神分裂症一過性低酸素誘導性神経変性、痛み、脳外傷、及び脊髄損傷からなる群より選択される。 In one embodiment of the present invention, the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), cataract, cognitive impairment, cerebral ischemic stroke, cerebral palsy, stroke, hemorrhagic stroke, Creutzfeldt Jacob. Disease, spongiform encephalopathy, mad cow disease, dementia, depression, Down's syndrome, epilepsy, traumatic epilepsy, frontotemporal dementia, Zirdra Tourette's syndrome, Hallelfolden spats disease, Huntington's chorea, Lewy body disease, Parkinson's disease, cognitive impairment, learning impairment, macular degeneration, memory impairment, multiple sclerosis, multiple system atrophy, motor neuron disease, Pick's disease, progressive supranuclear palsy, pseudodementia, retinopathy, senile dementia, schizophrenia Selected from the group consisting of transient hypoxia-induced neurodegeneration, pain, brain trauma, and spinal cord injury.
化学
実施例1
(8-ベンジルオキシキノール-2-イル)及び(8-ヒドロキシキノール-2-イル)アルキルアルコールの調製
Preparation of (8-benzyloxyquinol-2-yl) and (8-hydroxyquinol-2-yl) alkyl alcohols
試薬及び条件:
(a) BnBr、KOH、EtOH、還流、15時間;(b) 1) LHMDS、THF、0℃、1時間;2) Br(CH2)n-1OH、室温、16から36時間;(c) H2、Pd/C、MeOH、室温、6から10時間;(d) BCl3、CH2Cl2、0℃から室温、3時間。
Reagents and conditions:
(a) BnBr, KOH, EtOH, reflux, 15 hours; (b) 1) LHMDS, THF, 0 ° C., 1 hour; 2) Br (CH 2 ) n-1 OH, room temperature, 16-36 hours; (c ) H 2 , Pd / C, MeOH, room temperature, 6 to 10 hours; (d) BCl 3 , CH 2 Cl 2 , 0 ° C. to room temperature, 3 hours.
方法:
ベンジル化は、G. Serratriceら[Tetrahedron, 1996, 52, 4659-4672]に記載通りに実行した。臭化ベンジル(6.45g、37.7mmol)を、還流条件下で、60mlのEtOH中の2-メチルキナルジン(5.0g、31.4mmol)及びKOH(1.95g、34.8mmol)の撹拌溶液に加えた。15時間後、反応混合物をろ過して、ろ液を減圧下で除去した。残留物を、Hex/EA(6:1)にてフラッシュカラムクロマトグラフィーによって精製し、ヘキサン中において再結晶化して、中間体を得た。LHMDS(2.2〜2.5当量)を、20mlのTHF中の(1当量)の撹拌溶液を用いて0℃で1時間処理した。対応するBr(CH2)n-1OH(1.0〜1.2当量)を反応混合物に加えて、温度を15時間以上から36時間、室温(RT)に戻した。溶媒を減圧下で除去した。茶色の油状残留物を、Hex/EA(3:1〜2:1)又はDCM/EA(15:1〜9:1)にてフラッシュカラムクロマトグラフィーによって精製し、ヘキサン/EAにて再結晶化して一連の化合物Aを得た。一連の化合物Aのベンジル基の除去は、10%Pd/Cの存在下において、室温で6から10時間、水素下で実施した。反応混合物をろ過して取り除き、ろ液を、Hex/EA(4:1〜3:1)にてフラッシュカラムクロマトグラフィーによって精製して一連の化合物Bを得た。20mlのCH2Cl2中のA11(0.65g、1.4mmol)の撹拌溶液に1MのBCl3(2.8ml、2.8mmol)を加え、3時間、氷浴とした。反応混合物を氷浴に注いで、50mlのCH2Cl2によって抽出した。有機層を減圧濃縮して、フラッシュカラムクロマトグラフィー(EA)によって精製し、産物(0.31g、60%)を得た。
Method:
Benzylation was performed as described in G. Serratrice et al. [Tetrahedron, 1996, 52, 4659-4672]. Benzyl bromide (6.45 g, 37.7 mmol) was added to a stirred solution of 2-methylquinaldine (5.0 g, 31.4 mmol) and KOH (1.95 g, 34.8 mmol) in 60 ml EtOH under reflux conditions. After 15 hours, the reaction mixture was filtered and the filtrate was removed under reduced pressure. The residue was purified by flash column chromatography on Hex / EA (6: 1) and recrystallized in hexane to give an intermediate. LHMDS (2.2-2.5 eq) was treated with a stirred solution of (1 eq) in 20 ml THF at 0 ° C. for 1 h. In addition the corresponding Br and (CH 2) n-1 OH (1.0~1.2 eq) to the reaction mixture, 36 hours a temperature from above 15 hours, returned to room temperature (RT). The solvent was removed under reduced pressure. The brown oily residue was purified by flash column chromatography with Hex / EA (3: 1 to 2: 1) or DCM / EA (15: 1 to 9: 1) and recrystallized with hexane / EA. A series of compounds A were obtained. Removal of the benzyl group of Compound A was carried out under hydrogen in the presence of 10% Pd / C for 6 to 10 hours at room temperature. The reaction mixture was filtered off and the filtrate was purified by flash column chromatography on Hex / EA (4: 1-3: 1) to give a series of compounds B. To a stirred solution of A11 (0.65 g, 1.4 mmol) in 20 ml CH 2 Cl 2 was added 1M BCl 3 (2.8 ml, 2.8 mmol) and placed in an ice bath for 3 hours. The reaction mixture was poured into an ice bath and extracted with 50 ml CH 2 Cl 2 . The organic layer was concentrated under reduced pressure and purified by flash column chromatography (EA) to give the product (0.31 g, 60%).
9-(8-(ベンジルオキシ)キノリン-2-イル)ノナン-1-オール(A1)
収率(YD): 53%。1H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 6.8 Hz, 2H), 7.31 ~ 7.41 (m, 5H), 7.29 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.6, 2.0 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 6.8 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.28-1.42 (br, 11H); MS. m/z 400.0, [M+Na]+。
9- (8- (Benzyloxy) quinolin-2-yl) nonan-1-ol (A1)
Yield (YD): 53%. 1 H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 6.8 Hz, 2H), 7.31 to 7.41 (m, 5H), 7.29 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.6, 2.0 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 6.8 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.28-1.42 (br, 11H); MS. M / z 400.0, [M + Na] + .
10-(8-(ベンジルオキシ)キノリン-2-イル)デカン-1-オール(A2)
YD: 41%。1H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.32-7.42 (m, 5H), 7.28 (t, J = 7.2 Hz, 1H), 7.14 (dd, J = 7.6, 1.2 Hz, 1H), 5.38 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 2H), 1.29-1.40 (br, 13H) ; MS. m/z 414.0, [M+Na]+。
10- (8- (Benzyloxy) quinolin-2-yl) decan-1-ol (A2)
YD: 41%. 1 H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.32-7.42 (m, 5H), 7.28 (t, J = 7.2 Hz, 1H), 7.14 (dd, J = 7.6, 1.2 Hz, 1H), 5.38 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 2H), 1.29-1.40 (br, 13H); MS. M / z 414.0, [M + Na] + .
11-(8-(ベンジルオキシ)キノリン-2-イル)ウンデカン-1-オール(A3)
YD: 42%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.27-7.39 (m, 6H), 7.02 (d, J = 7.6 Hz, 1H), 5.46 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 8 Hz, 2H), 1.84 (q, J = 7.6 Hz, 3H), 1.56 (t, J = 7.2 Hz, 2H), 1.29-1.46 (m, 12H); MS. m/z 428.3, [M+Na]+。
11- (8- (Benzyloxy) quinolin-2-yl) undecan-1-ol (A3)
YD: 42%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.27-7.39 (m, 6H), 7.02 (d, J = 7.6 Hz, 1H), 5.46 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 8 Hz, 2H), 1.84 (q, J = 7.6 Hz, 3H), 1.56 (t, J = 7.2 Hz, 2H), 1.29-1.46 (m, 12H); MS. M / z 428.3, [M + Na] + .
12-(8-(ベンジルオキシ)キノリン-2-イル)ドデカン-1-オール(A4)
YD: 44%。 1H NMR (400 MHz, d4-MeOD) δ8.13 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.31-7.40 (m, 5H), 7.26 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 7.6, 0.8 Hz, 1H), 5.37 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H), 1.49 (quin, J = 7.2 Hz, 2H), 1.25-1.41 (m, 17H); MS. m/z 442.3, [M+Na]+。
12- (8- (Benzyloxy) quinolin-2-yl) dodecan-1-ol (A4)
YD: 44%. 1 H NMR (400 MHz, d4-MeOD) δ8.13 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.31-7.40 (m, 5H), 7.26 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 7.6, 0.8 Hz, 1H), 5.37 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H), 1.49 (quin, J = 7.2 Hz, 2H), 1.25-1.41 (m, 17H); MS. M / z 442.3, [M + Na] + .
13-(8-(ベンジルオキシ)キノリン-2-イル)トリデカン-1-オール(A5)
YD: 40%。1H NMR (400 MHz, CDCl3) δ7.95 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.19-7.30 (m, 5H), 6.93 (d, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.46 (t, J = 6.8 Hz, 2H), 1.19-1.38 (br, 19H); MS. m/z 456.3, [M+Na]+。
%.
13- (8- (Benzyloxy) quinolin-2-yl) tridecan-1-ol (A5)
YD: 40%. 1 H NMR (400 MHz, CDCl 3 ) δ7.95 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.19-7.30 (m, 5H), 6.93 (d, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.46 (t, J = 6.8 Hz, 2H), 1.19-1.38 (br, 19H); MS. M / z 456.3, [M + Na] + .
%.
14-(8-(ベンジルオキシ)キノリン-2-イル)テトラデカン-1-オール(A6)
YD: 51%。 1H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.33-7.42 (m, 5H), 7.28 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 6.8 Hz, 1H), 5.38 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 2H), 1.22-1.41 (br, 21H); MS. m/z 447.3, [M+H]+。
14- (8- (Benzyloxy) quinolin-2-yl) tetradecan-1-ol (A6)
YD: 51%. 1 H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.33-7.42 (m, 5H), 7.28 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 6.8 Hz, 1H), 5.38 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H) , 1.50 (quin, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 2H), 1.22-1.41 (br, 21H); MS. M / z 447.3, [M + H] + .
15-(8-(ベンジルオキシ)キノリン-2-イル)ペンタデカン-1-オール(A7)
YD: 42%。 1H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.35-7.43 (m, 5H), 7.28-7.33 (m, 1H), 7.15 (dd, J = 7.6, 1.6 Hz, 1H), 5.39 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.22-1.41 (br, 23H); MS. m/z 462.3, [M+H]+。
15- (8- (Benzyloxy) quinolin-2-yl) pentadecan-1-ol (A7)
YD: 42%. 1 H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.35-7.43 (m, 5H), 7.28-7.33 ( m, 1H), 7.15 (dd, J = 7.6, 1.6 Hz, 1H), 5.39 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.22-1.41 (br, 23H); MS. M / z 462.3, [M + H] + .
11-(8-(ベンジルオキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール(A8)
YD: 47%。 1H NMR (400 MHz, d4-MeOD) δ8.30 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.26-7.36 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.36 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.55 (s, 3H), 1.80 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. m/z 420.3, [M+H]+。
11- (8- (Benzyloxy) -5-methylquinolin-2-yl) undecan-1-ol (A8)
YD: 47%. 1 H NMR (400 MHz, d4-MeOD) δ8.30 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.26 -7.36 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.36 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H) , 3.00 (t, J = 7.6 Hz, 2H), 2.55 (s, 3H), 1.80 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. M / z 420.3, [M + H] + .
11-(8-(ベンジルオキシ)-6-メチルキノリン-2-イル)ウンデカン-1-オール(A9)
YD: 40%。 1H NMR (400 MHz, d4-MeOD) δ8.03 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.33-7.37 (m, 3H), 7.26-7.30 (m, 1H), 7.16 (s, 1H), 7.00 (d, J = 1.2 Hz, 2H), 5.36 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.40 (s, 3H), 1.76 (q, J = 7.6 Hz, 2H), 1.56 (t, J = 7.2 Hz, 2H), 1.29-1.46 (m, 15H); MS. m/z 442.3, [M+Na]+。
11- (8- (Benzyloxy) -6-methylquinolin-2-yl) undecan-1-ol (A9)
YD: 40%. 1 H NMR (400 MHz, d4-MeOD) δ8.03 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.33-7.37 (m, 3H), 7.26-7.30 ( m, 1H), 7.16 (s, 1H), 7.00 (d, J = 1.2 Hz, 2H), 5.36 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.40 (s, 3H), 1.76 (q, J = 7.6 Hz, 2H), 1.56 (t, J = 7.2 Hz, 2H), 1.29-1.46 (m, 15H); MS.m / z 442.3, [M + Na] + .
11-(8-(ベンジルオキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール(A10)
YD: 43%。 1H NMR (400 MHz, CDCl3) δ8.28 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.33-7.40 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 6.89 ~ 6.98 (m, 2H), 5.42 (s, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 8 Hz, 2H), 1.83 (q, J = 7.6 Hz, 2H), 1.51-1.54 (m, 2H), 1.21-1.45 (m, 15H); MS. m/z 446.2, [M+Na]+。
11- (8- (Benzyloxy) -5-fluoroquinolin-2-yl) undecan-1-ol (A10)
YD: 43%. 1 H NMR (400 MHz, CDCl 3 ) δ8.28 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.33-7.40 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 6.89 to 6.98 (m, 2H), 5.42 (s, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 8 Hz, 2H), 1.83 (q , J = 7.6 Hz, 2H), 1.51-1.54 (m, 2H), 1.21-1.45 (m, 15H); MS. M / z 446.2, [M + Na] + .
11-(8-(ベンジルオキシ)-5-クロロキノリン-2-イル)ウンデカン-1-オール(A11)
YD: 43%。 H NMR (400 MHz, d4-MeOD) δ8.48 (d, J = 8.8 Hz, 1H), 7.52-7.57 (m, 3H), 7.46 (d, J = 8.4 Hz, 1H), 7.35 ~ 7.39 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. m/z 462.2, [M+Na]+。
11- (8- (Benzyloxy) -5-chloroquinolin-2-yl) undecan-1-ol (A11)
YD: 43%. H NMR (400 MHz, d4-MeOD) δ8.48 (d, J = 8.8 Hz, 1H), 7.52-7.57 (m, 3H), 7.46 (d, J = 8.4 Hz, 1H), 7.35 to 7.39 (m , 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.03 (t , J = 7.6 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS.m / z 462.2, [ M + Na] + .
2-(9-ヒドロキシノニル)キノリン-8-オール(B1)
YD: 85%。 1H NMR (400 MHz, d4-MeOD) δ7.86 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.03-7.13 (m, 3H), 3.50 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), 1.58 (quin, J = 6.8 Hz, 2H), 1.44 (quin, J = 6.8 Hz, 2H), 1.10-1.20 (m, 11H); HRMS (ESI): Calcd for [C18H25NO2-Na]+: 310.1778, Found: 310.1779。
2- (9-Hydroxynonyl) quinolin-8-ol (B1)
YD: 85%. 1 H NMR (400 MHz, d4-MeOD) δ7.86 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.03-7.13 (m, 3H), 3.50 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), 1.58 (quin, J = 6.8 Hz, 2H), 1.44 (quin, J = 6.8 Hz, 2H), 1.10-1.20 (m, 11H); HRMS (ESI): Calcd for [C 18 H 25 NO 2 -Na] +: 310.1778, Found: 310.1779.
2-(10-ヒドロキシデシル)キノリン-8-オール(B2)
YD: 85%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.26-7.28 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 3.60 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.53 (quin, J = 6.8 Hz, 2H), 1.27-1.33 (br, 14H); MS. m/z 302.2, [M+H]+。
2- (10-Hydroxydecyl) quinolin-8-ol (B2)
YD: 85%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.26-7.28 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 3.60 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.53 (quin, J = 6.8 Hz, 2H), 1.27-1.33 (br, 14H); MS. M / z 302.2, [M + H] + .
2-(11-ヒドロキシウンデシル)キノリン-8-オール(B3)
YD: 77%。 1H NMR (400 MHz, CDCl3) δ8.04 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.27-7.31 (m, 2H), 7.14 (dd, J = 1.2, 7.6 Hz, 1H), 3.64 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 1.83 (quin, J = 7.8 Hz, 2H), 1.55 (m, 2H), 1.28-1.36 (br, 17H); 1 MS. m/z 316.2, [M+H]+。
2- (11-Hydroxyundecyl) quinolin-8-ol (B3)
YD: 77%. 1 H NMR (400 MHz, CDCl 3 ) δ8.04 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.27-7.31 (m, 2H), 7.14 (dd, J = 1.2, 7.6 Hz, 1H), 3.64 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 1.83 (quin, J = 7.8 Hz, 2H), 1.55 (m, 2H ), 1.28-1.36 (br, 17H); 1 MS. M / z 316.2, [M + H] + .
2-(12-ヒドロキシウンデシル)キノリン-8-オール(B4)
YD: 76%。 1H NMR (400 MHz, CDCl3) δ8.03 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.25-7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.29-1.38 (br, 18H); MS. m/z 330.3, [M+H]+。
2- (12-Hydroxyundecyl) quinolin-8-ol (B4)
YD: 76%. 1 H NMR (400 MHz, CDCl 3 ) δ8.03 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.25-7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.29-1.38 (br, 18H); MS. M / z 330.3, [M + H] + .
2-(13-ヒドロキシトリデシル)キノリン-8-オール(B5)
YD: 84%。 1H NMR (400 MHz, CDCl3) δ8.03 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26-7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.25-1.34 (br, 20H); MS. m/z 344.3, [M+H]+。
2- (13-Hydroxytridecyl) quinolin-8-ol (B5)
YD: 84%. 1 H NMR (400 MHz, CDCl 3 ) δ8.03 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26-7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.25-1.34 (br, 20H); MS. M / z 344.3, [M + H] + .
2-(14-ヒドロキシテトラデシル)キノリン-8-オール(B6)
YD: 87%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25-7.29 (m, 2H), 7.12 (d, J = 7.2 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.24-1.34 (br, 24H); MS. m/z 358.3, [M+H]+。
2- (14-Hydroxytetradecyl) quinolin-8-ol (B6)
YD: 87%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25-7.29 (m, 2H), 7.12 (d, J = 7.2 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.24-1.34 (br, 24H); MS. M / z 358.3, [M + H] + .
2-(15-ヒドロキシペンタデシル)キノリン-8-オール(B7)
YD: 83%。 1H NMR (400 MHz, CDCl3) δ8.04 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.26-7.29 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 7.2 Hz, 2H), 1.24-1.37 (br, 24H); MS. m/z 372.3, [M+H]+。
2- (15-Hydroxypentadecyl) quinolin-8-ol (B7)
YD: 83%. 1 H NMR (400 MHz, CDCl 3 ) δ8.04 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.26-7.29 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.2 Hz, 2H), 1.54 (quin, J = 7.2 Hz, 2H), 1.24-1.37 (br, 24H); MS. M / z 372.3, [M + H] + .
2-(11-ヒドロキシウンデシル)-5-メチルキノリン-8-オール(B8)
YD: 83%。 1H NMR (400 MHz, d4-MeOD) δ8.26 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 3.2 Hz, 1H), 3.52 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.53 (s, 3H), 1.81 (quin, J = 7.2 Hz, 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 330.3, [M+H]+。
2- (11-Hydroxyundecyl) -5-methylquinolin-8-ol (B8)
YD: 83%. 1 H NMR (400 MHz, d4-MeOD) δ8.26 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 3.2 Hz, 1H), 3.52 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.53 (s, 3H), 1.81 (quin, J = 7.2 Hz , 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. M / z 330.3, [M + H] + .
2-(11-ヒドロキシウンデシル)-6-メチルキノリン-8-オール(B9)
YD: 83%。 1H NMR (400 MHz, d4-MeOD) δ7.99 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.51 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 2.41 (s, 3H), 1.77 (quin, J = 6.4 Hz, 2H), 1.49 (quin, J = 6.8 Hz, 2H), 1.25-1.37 (m, 19H); MS. m/z 352.2, [M+Na]+。
2- (11-Hydroxyundecyl) -6-methylquinolin-8-ol (B9)
YD: 83%. 1 H NMR (400 MHz, d4-MeOD) δ7.99 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 1H) , 3.51 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 2.41 (s, 3H), 1.77 (quin, J = 6.4 Hz, 2H), 1.49 (quin, J = 6.8 Hz, 2H), 1.25-1.37 (m, 19H); MS. M / z 352.2, [M + Na] + .
5-クロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール(B10)
1H NMR (400 MHz, d4-MeOD) δ8.39 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.51 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.35 (m, 15H); MS. m/z 350.2, [M+H]+。
5-Chloro-2- (11-hydroxyundecyl) quinolin-8-ol (B10)
1 H NMR (400 MHz, d4-MeOD) δ8.39 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.51 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.50 (quin , J = 6.8 Hz, 2H), 1.27-1.35 (m, 15H); MS. M / z 350.2, [M + H] + .
実施例2
(8-メトキシキノール-2-イル)アルキルアルコールの調製
Preparation of (8-methoxyquinol-2-yl) alkyl alcohol
試薬及び条件:
(a) MeI、K2CO3、アセトン、室温、10時間;(b) 1) LHMDS、THF、0℃、1時間;2) Br(CH2)n-1OH、室温、12から30時間。
Reagents and conditions:
(a) MeI, K 2 CO 3 , acetone, room temperature, 10 hours; (b) 1) LHMDS, THF, 0 ° C., 1 hour; 2) Br (CH 2 ) n-1 OH, room temperature, 12 to 30 hours .
方法:
ヨウ化メチル(10.8g、76.3mmol)を、10時間室温で、30mlのアセトン中の2-メチルキナルジン(1.0g、6.3mmol)及びK2CO3(5.0g、36.2mmol)の撹拌溶液に加えた。反応混合物をろ過して、ろ液を減圧下で除去した。残留物を、Hex/EA(3:1)にてフラッシュカラムクロマトグラフィーによって精製し、ヘキサン/EAを用いて再結晶化して、中間体として8-メトキシ-2-メチルキノリン(methylauinoline)を得た。LHMDS(2.2〜2.5当量)を、20mlのTHF中の中間体(1当量)の撹拌溶液を用いて0℃で1時間処理した。対応するBr(CH2)n-1OH(1.0〜1.2当量)を反応混合物に加えて、12時間以上から30時間、室温に戻した。溶媒を減圧下で除去した。茶色の油状残留物を、Hex/EA又はDCM/EAにてフラッシュカラムクロマトグラフィーによって精製し、Hex/EAにて再結晶化して一連の化合物Cを得た。
Method:
Methyl iodide (10.8 g, 76.3 mmol) was added to a stirred solution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K 2 CO 3 (5.0 g, 36.2 mmol) in 30 ml acetone at room temperature for 10 hours. added. The reaction mixture was filtered and the filtrate was removed under reduced pressure. The residue was purified by flash column chromatography on Hex / EA (3: 1) and recrystallized using hexane / EA to give 8-methoxy-2-methylquinoline as an intermediate . LHMDS (2.2-2.5 eq) was treated with a stirred solution of the intermediate (1 eq) in 20 ml of THF at 0 ° C. for 1 h. The corresponding Br (CH 2) n-1 OH (1.0~1.2 eq) was added to the reaction mixture, 30 hours or more 12 hours, the temperature was returned to room temperature. The solvent was removed under reduced pressure. The brown oily residue was purified by flash column chromatography on Hex / EA or DCM / EA and recrystallized on Hex / EA to give a series of compounds C.
9-(8-メトキシキノリン-2-イル)ノナン-1-オール(C1)
YD: 50%。 1H NMR (400 MHz, CDCl3) δ8.05 (d, J = 8.4 Hz, 1H), 7.33-7.42 (m, 3H), 7.04 (d, J = 6.8 Hz, 1H), 4.08 (s, 3H), 3.62 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 1.79 (br, 2H), 1.53 (br, 2H), 1.30-1.42 (br, 11H); MS. m/z 324.0, [M+Na]+。
9- (8-Methoxyquinolin-2-yl) nonan-1-ol (C1)
YD: 50%. 1 H NMR (400 MHz, CDCl 3 ) δ8.05 (d, J = 8.4 Hz, 1H), 7.33-7.42 (m, 3H), 7.04 (d, J = 6.8 Hz, 1H), 4.08 (s, 3H ), 3.62 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 1.79 (br, 2H), 1.53 (br, 2H), 1.30-1.42 (br, 11H); MS m / z 324.0, [M + Na] + .
10-(8-メトキシキノリン-2-イル)デカン-1-オール(C2)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.60 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 8 Hz, 2H), 1.52 (quin, J = 6.8 Hz, 2H), 1.30-1.43 (br, 12H); MS. m/z 316.2, [M+H]+。
10- (8-methoxyquinolin-2-yl) decan-1-ol (C2)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.60 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 8 Hz, 2H), 1.52 (quin, J = 6.8 Hz, 2H), 1.30-1.43 (br, 12H); MS. m / z 316.2, [M + H] + .
11-(8-メトキシキノリン-2-イル)ウンデカン-1-オール(C3)
YD: 42%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31-7.34 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.31-1.42 (br, 15H); MS. m/z 352.2, [M+Na]+。
11- (8-methoxyquinolin-2-yl) undecan-1-ol (C3)
YD: 42%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31-7.34 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.31-1.42 (br, 15H); MS. M / z 352.2, [M + Na] + .
12-(8-メトキシキノリン-2-イル)ドデカン-1-オール(C4)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.30-7.32 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.36-1.41 (m, 2H), 1.24-1.33 (br, 16H); MS. m/z 344.3, [M+H]+。
12- (8-Methoxyquinolin-2-yl) dodecan-1-ol (C4)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.30-7.32 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.36-1.41 (m, 2H), 1.24-1.33 (br, 16H); MS. M / z 344.3, [M + H] + .
13-(8-メトキシキノリン-2-イル)トリデカン-1-オール(C5)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 8 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz , 2H), 1.36-1.43 (br, 19H); MS. m/z 358.3, [M+H]+。
13- (8-Methoxyquinolin-2-yl) tridecan-1-ol (C5)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 8 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.36-1.43 (br, 19H); MS. M / z 358.3, [M + H] + .
14-(8-メトキシキノリン-2-イル)テトラデカン-1-オール(C6)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.4 Hz, 1H), 7.31-7.38 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz , 2H), 1.23-1.40 (br, 21H); MS. m/z 394.3, [M+Na]+。
14- (8-Methoxyquinolin-2-yl) tetradecan-1-ol (C6)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.4 Hz, 1H), 7.31-7.38 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H ), 3.61 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.23-1.40 (br, 21H); MS. M / z 394.3, [M + Na] + .
15-(8-メトキシキノリン-2-イル)ペンタデカン-1-オール(C7)
YD: 31%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz , 2H), 1.32-1.43 (br, 23H); MS. m/z 408.3, [M+H]+。
15- (8-Methoxyquinolin-2-yl) pentadecan-1-ol (C7)
YD: 31%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H ), 3.63 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.54 (quin, J = 6.8 Hz, 2H), 1.32-1.43 (br, 23H); MS. M / z 408.3, [M + H] + .
11-(8-メトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール(C8)
YD: 30%。 1H NMR (400 MHz, d4-MeOD) δ8.29 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.0, 0.8 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 2.56 (s, 3H), 1.76 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 7.2 Hz, 2H), 1.27-1.40 (br, 15H); MS. m/z 366.2, [M+Na]+。
11- (8-Methoxy-5-methylquinolin-2-yl) undecan-1-ol (C8)
YD: 30%. 1 H NMR (400 MHz, d4-MeOD) δ8.29 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.0, 0.8 Hz, 1H) , 7.01 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 2.56 (s, 3H) , 1.76 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 7.2 Hz, 2H), 1.27-1.40 (br, 15H); MS. M / z 366.2, [M + Na] + .
11-(5-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C9)
1H NMR (400 MHz, d4-MeOD) δ8.34 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 3.2 Hz, 1H), 4.02 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.81 (quin, J = 7.2 Hz, 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 370.2, [M+Na]+。
11- (5-Fluoro-8-methoxyquinolin-2-yl) undecan-1-ol (C9)
1 H NMR (400 MHz, d4-MeOD) δ8.34 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 3.2 Hz, 1H), 4.02 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.81 (quin, J = 7.2 Hz , 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. M / z 370.2, [M + Na] + .
12-(5-フルオロ-8-メトキシキノリン-2-イル)ドデカン-1-オール(C10)
YD: 38%。 1H NMR (400 MHz, d4-MeOD) δ8.36 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.4, 4.8 Hz, 1H), 4.04 (s, 3H), 3.53 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 7.2 Hz, 2H), 1.28-1.42 (m, 17H); MS. m/z 384.2, [M+Na]+。
12- (5-Fluoro-8-methoxyquinolin-2-yl) dodecan-1-ol (C10)
YD: 38%. 1 H NMR (400 MHz, d4-MeOD) δ8.36 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.4, 4.8 Hz, 1H), 4.04 (s, 3H), 3.53 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 7.2 Hz, 2H), 1.28-1.42 (m, 17H); MS. M / z 384.2, [M + Na] + .
9-(5-クロロ-8-メトキシキノリン-2-イル)ノナン-1-オール(C11)
YD: 38%。 1H NMR (400 MHz, d4-MeOD) δ8.47 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.30-1.37 (m, 11H); MS. m/z 336.2, [M+H]+。
9- (5-Chloro-8-methoxyquinolin-2-yl) nonan-1-ol (C11)
YD: 38%. 1 H NMR (400 MHz, d4-MeOD) δ 8.47 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz , 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.30-1.37 (m, 11H); MS. M / z 336.2, [M + H] + .
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C12)
YD: 35%。 1H NMR (400 MHz, d4-MeOD) δ8.46 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.6 Hz, 2H), 1.49 (quin, J = 6.8 Hz, 2H), 1.27-1.38 (br, 15H); MS. m/z 386.2, [M+Na]+。
11- (5-Chloro-8-methoxyquinolin-2-yl) undecan-1-ol (C12)
YD: 35%. 1 H NMR (400 MHz, d4-MeOD) δ8.46 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.6 Hz , 2H), 1.49 (quin, J = 6.8 Hz, 2H), 1.27-1.38 (br, 15H); MS. M / z 386.2, [M + Na] + .
15-(5-クロロ-8-メトキシキノリン-2-イル)ペンタデカン-1-オール(C13)
YD: 39%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.44 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4, 4.0 Hz, 1H), 4.03 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.22-1.38 (m, 23H); MS. m/z 442.3, [M+Na]+。
15- (5-Chloro-8-methoxyquinolin-2-yl) pentadecan-1-ol (C13)
YD: 39%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.44 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H ), 7.01 (dd, J = 8.4, 4.0 Hz, 1H), 4.03 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin , J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.22-1.38 (m, 23H); MS. M / z 442.3, [M + Na] + .
11-(5-ブロモ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C14)
YD: 46%。 1H NMR (400 MHz, CDCl3) δ8.40 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.55 (quin, J = 6.8 Hz , 2H), 1.30-1.45 (br, 15H); MS. m/z 430.2, [M+Na]+。
11- (5-Bromo-8-methoxyquinolin-2-yl) undecan-1-ol (C14)
YD: 46%. 1 H NMR (400 MHz, CDCl 3 ) δ8.40 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.91 ( d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.55 (quin, J = 6.8 Hz, 2H), 1.30-1.45 (br, 15H); MS. M / z 430.2, [M + Na] + .
11-(8-メトキシ-5-(トリフルオロメチル)キノリン-2-イル)ウンデカン-1-オール(C15)
YD: 36%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.40 (dq, J = 10.4, 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.11 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.43 (m, 15H); MS. m/z 420.2, [M+Na]+。
11- (8-methoxy-5- (trifluoromethyl) quinolin-2-yl) undecan-1-ol (C15)
YD: 36%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.40 (dq, J = 10.4, 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz , 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.11 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.78 (quin , J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.43 (m, 15H); MS. M / z 420.2, [M + Na] + .
11-(5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール(C16)
YD: 31%; 1H NMR (400 MHz, d4-MeOD) δ8.46 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.73 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.35 (br, 15H); MS. m/z 360.2, [M+H]+。
11- (5,8-Dimethoxyquinolin-2-yl) undecan-1-ol (C16)
YD: 31%; 1 H NMR (400 MHz, d4-MeOD) δ8.46 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz , 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz , 2H), 1.73 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.35 (br, 15H); MS.m / z 360.2, [M + H] + .
11-(8-メトキシ-6-メチルキノリン-2-イル)ウンデカン-1-オール(C17)
YD: 41%。 1H NMR (400 MHz, CDCl3) δ7.96 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.06 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.50 (s, 3H), 1.79 (quin, J = 8.0 Hz, 2H), 1.55 (quin, J = 6.8 Hz, 2H), 1.27-1.41 (br, 15H); MS. m/z 366.2, [M+Na]+。
11- (8-Methoxy-6-methylquinolin-2-yl) undecan-1-ol (C17)
YD: 41%. 1 H NMR (400 MHz, CDCl 3 ) δ7.96 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.06 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.50 (s, 3H), 1.79 (quin, J = 8.0 Hz, 2H), 1.55 (quin, J = 6.8 Hz, 2H), 1.27-1.41 (br, 15H); MS. M / z 366.2, [M + Na] + .
11-(6-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C18)
YD: 41%; 1H NMR (400 MHz, d4-MeOD) δ8.12 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 9.2, 2.4 Hz, 1H), 7.01 (dd, J = 10.8, 2.8 Hz, 1H), 4.06 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.75 (quin, J = 7.6 Hz, 2H), 1.48 (quin, J = 7.2 Hz, 2H), 1.19-1.35 (m, 15H); MS. m/z 348.2, [M+H]+。
11- (6-Fluoro-8-methoxyquinolin-2-yl) undecan-1-ol (C18)
YD: 41%; 1 H NMR (400 MHz, d4-MeOD) δ8.12 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 9.2, 2.4 Hz, 1H), 7.01 (dd, J = 10.8, 2.8 Hz, 1H), 4.06 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H) , 1.75 (quin, J = 7.6 Hz, 2H), 1.48 (quin, J = 7.2 Hz, 2H), 1.19-1.35 (m, 15H); MS. M / z 348.2, [M + H] + .
11-(6-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C19)
YD: 39%; 1H NMR (400 MHz, d4-MeOD) δ8.11 (d, J = 8.4 Hz, 1H), 7.44-7.47 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 4.05 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.36 (br, 15H); MS. m/z 360.2, [M+H]+。
11- (6-Chloro-8-methoxyquinolin-2-yl) undecan-1-ol (C19)
YD: 39%; 1 H NMR (400 MHz, d4-MeOD) δ8.11 (d, J = 8.4 Hz, 1H), 7.44-7.47 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H) , 4.05 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.36 (br, 15H); MS. M / z 360.2, [M + H] + .
11-(7-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C20)
YD: 32%; 1H NMR (400 MHz, d4-MeOD) δ8.20 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 5.6 Hz, 1H), 7.39 (dd, J = 8.8, 1.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 1.2 Hz, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.29-1.42 (m, 15H); MS. m/z 348.2, [M+H]+。
11- (7-Fluoro-8-methoxyquinolin-2-yl) undecan-1-ol (C20)
YD: 32%; 1 H NMR (400 MHz, d4-MeOD) δ8.20 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 5.6 Hz, 1H), 7.39 (dd, J = 8.8, 1.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 1.2 Hz, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.29-1.42 (m, 15H); MS.m / z 348.2, (M + H ] + .
11-(7-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C21)
YD: 17%; 1H NMR (400 MHz, d4-MeOD) δ8.20 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.42 (br, 15H); MS. m/z 360.2, [M+H]+。
11- (7-Chloro-8-methoxyquinolin-2-yl) undecan-1-ol (C21)
YD: 17%; 1 H NMR (400 MHz, d4-MeOD) δ8.20 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.8 Hz , 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.82 (quin , J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.28-1.42 (br, 15H); MS. M / z 360.2, [M + H] + .
11-(5-クロロ-6,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール(C22)
YD: 32%; 1H NMR (400 MHz, d4-MeOD) δ8.40 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz , 2H), 1.27-1.34 (br, 15H); MS. m/z 394.2, [M+H]+。
11- (5-Chloro-6,8-dimethoxyquinolin-2-yl) undecan-1-ol (C22)
YD: 32%; 1 H NMR (400 MHz, d4-MeOD) δ8.40 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.27-1.34 (br, 15H); MS. m / z 394.2, [M + H] + .
11-(6-クロロ-5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール(C23)
YD: 35%; 1H NMR (400 MHz, d4-MeOD) δ8.38 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz , 2H), 1.34-1.41 (br, 15H); MS. m/z 394.2, [M+H]+。
11- (6-Chloro-5,8-dimethoxyquinolin-2-yl) undecan-1-ol (C23)
YD: 35%; 1 H NMR (400 MHz, d4-MeOD) δ8.38 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.34-1.41 (br, 15H); MS. m / z 394.2, [M + H] + .
11-(5,7-ジクロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(C24)
YD: 40%。 1H NMR (400 MHz, CDCl3) δ8.40 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.19 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.55 (quin, J = 6.8 Hz , 2H), 1.27-1.40 (br, 15H); MS. m/z 420.2, [M+Na]+。
11- (5,7-Dichloro-8-methoxyquinolin-2-yl) undecan-1-ol (C24)
YD: 40%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.19 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.55 ( quin, J = 6.8 Hz, 2H), 1.27-1.40 (br, 15H); MS. m / z 420.2, [M + Na] + .
実施例3
(8-エトキシキノール-2-イル)及び(8-イソプロポキシキノール-2-イル)アルキルアルコールの調製
Preparation of (8-ethoxyquinol-2-yl) and (8-isopropoxyquinol-2-yl) alkyl alcohols
試薬及び条件:
(a) ヨウ化エチル又は2-ブロモプロパン、K2CO3、DMF、60℃、14時間;(b) 1) LHMDS、THF、0℃、1時間;2) Br(CH2)n-1OH、室温、12から30時間。
Reagents and conditions:
(a) Ethyl iodide or 2-bromopropane, K 2 CO 3 , DMF, 60 ° C., 14 hours; (b) 1) LHMDS, THF, 0 ° C., 1 hour; 2) Br (CH 2 ) n-1 OH, room temperature, 12-30 hours.
方法:
ヨウ化エチル(3.9g、25.0mmol)又は2-ブロモプロパン(2.4g、19.2mmol)を、14時間60℃で、30mlのDMF中の2-メチルキナルジン(3.0g、18.8mmol)及びK2CO3(6.5g、47mmol; 5.2g、37.6mmol)の撹拌溶液に加えた。反応混合物を、H2O(200ml)によってクエンチして、EtOAc(50ml X 2)によって抽出した。有機層を、減圧蒸発によって濃縮した。残留物を、Hex/EA(6:1)にてフラッシュカラムクロマトグラフィーによって精製し、ヘキサン/EAを用いて再結晶化して、固体の中間体として8-エトキシ-2-メチルキノリン(2.75g、78%)と、液状の8-イソプロポキシ-2-メチルキノリン(2.92g、77%)を得た。LHMDS(2.2当量)を、THF溶液中の種々の中間体の撹拌溶液を用いて0℃で1時間処理した。対応するBr(CH2)n-1OH(1.1〜1.2当量)を反応混合物に加えて、12時間以上から30時間、室温に戻した。溶媒を減圧下で除去した。茶色の油状残留物を、Hex/EA又はDCM/EAにてフラッシュカラムクロマトグラフィーによって精製し、ヘキサン/EAにて再結晶化して化合物D及びEを得た。
Method:
Ethyl iodide (3.9 g, 25.0 mmol) or 2-bromopropane (2.4 g, 19.2 mmol) was added 14 hours at 60 ° C. with 2-methylquinaldine (3.0 g, 18.8 mmol) and K 2 in 30 ml DMF. To a stirred solution of CO 3 (6.5 g, 47 mmol; 5.2 g, 37.6 mmol). The reaction mixture was quenched with H 2 O (200 ml) and extracted with EtOAc (50 ml X 2). The organic layer was concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on Hex / EA (6: 1) and recrystallized using hexane / EA to give 8-ethoxy-2-methylquinoline (2.75 g, 78%) and liquid 8-isopropoxy-2-methylquinoline (2.92 g, 77%). LHMDS (2.2 eq) was treated with a stirred solution of various intermediates in THF solution at 0 ° C. for 1 h. The corresponding Br (CH 2) n-1 OH (1.1~1.2 eq) was added to the reaction mixture, 30 hours or more 12 hours, the temperature was returned to room temperature. The solvent was removed under reduced pressure. The brown oily residue was purified by flash column chromatography with Hex / EA or DCM / EA and recrystallized with hexane / EA to give compounds D and E.
9-(8-エトキシキノリン-2-イル)ノナン-1-オール(D1)
YD: 45%。 1H NMR (400 MHz, CDCl3) δ8.07 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 4.35 (q, J = 6.8 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.11 (br, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.52-1.64 (m, 5H), 1.26-1.46 (br, 11H); MS. m/z 338.0, [M+Na]+。
9- (8-Ethoxyquinolin-2-yl) nonan-1-ol (D1)
YD: 45%. 1 H NMR (400 MHz, CDCl 3 ) δ8.07 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 4.35 (q, J = 6.8 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.11 (br, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.52-1.64 (m, 5H), 1.26-1.46 (br, 11H); MS. m / z 338.0, [M + Na] + .
10-(8-エトキシキノリン-2-イル)デカン-1-オール(D2)
YD: 36%。 1H NMR (400 MHz, d4-MeOD) δ8.16 (d, J = 8.4 Hz, 1H), 7.38-7.44 (m, 3H), 7.14 (dd, J = 7.2, 1.6 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 7.6 Hz, 3H), 1.50 (t, J = 7.6 Hz, 2H), 1.30-1.43 (br, 13H); MS. m/z 352.0, [M+Na]+。
10- (8-Ethoxyquinolin-2-yl) decan-1-ol (D2)
YD: 36%. 1 H NMR (400 MHz, d4-MeOD) δ8.16 (d, J = 8.4 Hz, 1H), 7.38-7.44 (m, 3H), 7.14 (dd, J = 7.2, 1.6 Hz, 1H), 4.29 ( q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 7.6 Hz, 3H), 1.50 (t, J = 7.6 Hz, 2H), 1.30-1.43 (br, 13H); MS. M / z 352.0, [M + Na] + .
11-(8-エトキシキノリン-2-イル)ウンデカン-1-オール(D3)
YD: 43%。 1H NMR (400 MHz, CDCl3) δ8.03 (d, J = 7.6 Hz, 1H), 7.31-7.41 (m, 3H), 7.04 (d, J = 7.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.06 (br, 2H), 1.81 (quin, J = 8.0 Hz, 2H), 1.51-1.61(m, 6H), 1.38-1.51 (br, 14H); MS. m/z 344.3, [M+H]+。
11- (8-Ethoxyquinolin-2-yl) undecan-1-ol (D3)
YD: 43%. 1 H NMR (400 MHz, CDCl 3 ) δ8.03 (d, J = 7.6 Hz, 1H), 7.31-7.41 (m, 3H), 7.04 (d, J = 7.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.06 (br, 2H), 1.81 (quin, J = 8.0 Hz, 2H), 1.51-1.61 (m, 6H), 1.38-1.51 (br, 14H); MS. m / z 344.3, [M + H] + .
12-(8-エトキシキノリン-2-イル)ドデカン-1-オール(D4)
YD: 33%。1H NMR (400 MHz, CDCl3) δ8.03 (d, J = 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H),, 1.53-1.62 (m, 5H), 1.27-1.42 (br, 17H); MS. m/z 380.3, [M+Na]+。
12- (8-Ethoxyquinolin-2-yl) dodecan-1-ol (D4)
YD: 33%. 1 H NMR (400 MHz, CDCl 3 ) δ8.03 (d, J = 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.53-1.62 (m, 5H), 1.27-1.42 (br, 17H); MS. M / z 380.3, [M + Na] + .
13-(8-エトキシキノリン-2-イル)トリデカン-1-オール(D5)
YD: 43%。 1H NMR (400 MHz, CDCl3) δ8.04 (d, J = 8.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.34 (q, J = 6.8 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 1.82 (quin, J = 7.6 Hz, 2H), 1.52-1.62 (m, 5H), 1.19-1.46 (br, 19H); MS. m/z 394.0, [M+Na]+。
13- (8-Ethoxyquinolin-2-yl) tridecan-1-ol (D5)
YD: 43%. 1 H NMR (400 MHz, CDCl 3 ) δ8.04 (d, J = 8.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.34 (q, J = 6.8 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 1.82 (quin, J = 7.6 Hz, 2H), 1.52-1.62 (m, 5H ), 1.19-1.46 (br, 19H); MS. M / z 394.0, [M + Na] + .
14-(8-エトキシキノリン-2-イル)テトラデカン-1-オール(D6)
YD: 35%。 1H NMR (400 MHz, CDCl3) δ8.00 (d, J = 8.4 Hz, 1H), 7.28-7.35 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.52-1.60 (m, 5H), 1.24-1.41 (br, 21H); MS. m/z 408.3, [M+Na]+。
14- (8-Ethoxyquinolin-2-yl) tetradecan-1-ol (D6)
YD: 35%. 1 H NMR (400 MHz, CDCl 3 ) δ8.00 (d, J = 8.4 Hz, 1H), 7.28-7.35 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.52-1.60 (m, 5H ), 1.24-1.41 (br, 21H); MS. M / z 408.3, [M + Na] + .
15-(8-エトキシキノリン-2-イル)ペンタデカン-1-オール(D7)
YD: 33%。 1H NMR (400 MHz, d4-MeOD) δ8.21 (d, J = 8.4 Hz, 1H), 7.40-7.47 (m, 3H), 7.17 (dd, J = 7.2, 1.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 6.8 Hz, 3H), 1.51 (quin, J = 6.8 Hz, 2H), 1.26-1.43 (br, 23H); MS. m/z 400.4, [M+Na]+。
15- (8-Ethoxyquinolin-2-yl) pentadecan-1-ol (D7)
YD: 33%. 1 H NMR (400 MHz, d4-MeOD) δ8.21 (d, J = 8.4 Hz, 1H), 7.40-7.47 (m, 3H), 7.17 (dd, J = 7.2, 1.6 Hz, 1H), 4.30 ( q, J = 7.2 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 6.8 Hz, 3H), 1.51 (quin, J = 6.8 Hz, 2H), 1.26-1.43 (br, 23H); MS. M / z 400.4, [M + Na] + .
11-(8-エトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール(D8)
YD: 34%。 1H NMR (400 MHz, CDCl3) δ8.20 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.31 (q, J = 6.8 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 8.0 Hz, 2H), 2.57 (s, 3H), 1.83 (quin, J = 7.6 Hz, 2H), 1.83 (t, J = 7.6 Hz, 3H), 1.57 (quin, J = 7.2 Hz, 2H), 1.41-1.45 (m, 2H), 1.28-1.33 (br, 13H); MS. m/z 380.2, [M+Na]+。
11- (8-Ethoxy-5-methylquinolin-2-yl) undecan-1-ol (D8)
YD: 34%. 1 H NMR (400 MHz, CDCl 3 ) δ8.20 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.94 ( d, J = 8.0 Hz, 1H), 4.31 (q, J = 6.8 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 8.0 Hz, 2H), 2.57 (s, 3H), 1.83 (quin, J = 7.6 Hz, 2H), 1.83 (t, J = 7.6 Hz, 3H), 1.57 (quin, J = 7.2 Hz, 2H), 1.41-1.45 (m, 2H), 1.28- 1.33 (br, 13H); MS. M / z 380.2, [M + Na] + .
11-(8-エトキシ-5-フルオロキノリン-2-イル)ウンデカン-1-オール(D9)
YD: 49%。 1H NMR (400 MHz, d4-MeOD) δ8.33 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.12 (t, J = 9.2 Hz, 1H), 7.05 (dd, J = 8.4, 4.8 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H), 1.48-1.52 (m, 2H), 1.28-1.46 (br, 15H); MS. m/z 384.2, [M+Na]+。
11- (8-Ethoxy-5-fluoroquinolin-2-yl) undecan-1-ol (D9)
YD: 49%. 1 H NMR (400 MHz, d4-MeOD) δ8.33 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.12 (t, J = 9.2 Hz, 1H), 7.05 (dd, J = 8.4, 4.8 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H), 1.48-1.52 (m, 2H), 1.28-1.46 (br, 15H); MS.m / z 384.2, (M + Na] + .
9-(5-クロロ-8-エトキシキノリン-2-イル)ノナン-1-オール(D10)
YD: 34%。 1H NMR (400 MHz, d4-MeOD) δ8.47 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.6 Hz, 2H), 1.56 (t, J = 6.8 Hz, 3H), 1.48-1.51 (m, 2H), 1.31-1.46 (br, 11H); MS. m/z 350.2, [M+H]+。
9- (5-Chloro-8-ethoxyquinolin-2-yl) nonan-1-ol (D10)
YD: 34%. 1 H NMR (400 MHz, d4-MeOD) δ 8.47 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.76 (quin , J = 7.6 Hz, 2H), 1.56 (t, J = 6.8 Hz, 3H), 1.48-1.51 (m, 2H), 1.31-1.46 (br, 11H); MS.m / z 350.2, (M + H ] + .
11-(5-クロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール(D11)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ8.35 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.4, 3.6 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 8.0 Hz, 2H), 1.45-1.54(m, 5H), 1.19-1.39 (br, 15H); MS. m/z 400.2, [M+Na]+。
11- (5-Chloro-8-ethoxyquinolin-2-yl) undecan-1-ol (D11)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ8.35 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.4, 3.6 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.76 ( quin, J = 8.0 Hz, 2H), 1.45-1.54 (m, 5H), 1.19-1.39 (br, 15H); MS. m / z 400.2, [M + Na] + .
15-(5-クロロ-8-エトキシキノリン-2-イル)ペンタデカン-1-オール(D12)
YD: 38%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.47 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 6.8 Hz, 3H), 1.49 (quin, J = 6.8 Hz, 2H), 1.25-1.41 (br, 23H); MS. m/z 434.3, [M+H]+。
15- (5-Chloro-8-ethoxyquinolin-2-yl) pentadecan-1-ol (D12)
YD: 38%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.47 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H ), 7.08 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.57 (t, J = 6.8 Hz, 3H), 1.49 (quin, J = 6.8 Hz, 2H), 1.25-1.41 (br, 23H); MS.m / z 434.3, [M + H] + .
11-(5-ブロモ-8-エトキシキノリン-2-イル)ウンデカン-1-オール(D13)
YD: 33%。1H NMR (400 MHz, d4-MeOD) δ 8.41 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.56 (t, J = 7.2 Hz, 3H), 1.47-1.57 (m, 2H), 1.27-1.39 (br, 15H); MS. m/z 444.2, [M+Na]+。
11- (5-Bromo-8-ethoxyquinolin-2-yl) undecan-1-ol (D13)
YD: 33%. 1 H NMR (400 MHz, d4-MeOD) δ 8.41 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.04 ( d, J = 8.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.56 (t, J = 7.2 Hz, 3H), 1.47-1.57 (m, 2H), 1.27-1.39 (br, 15H); MS.m / z 444.2, [M + Na] + .
11-(5,7-ジクロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール(D14)
YD: 34%。 1H NMR (400 MHz, d4-MeOD) δ8.43 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.39 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.45-1.49 (m, 5H), 1.27-1.36 (br, 15H); MS. m/z 434.2, [M+Na]+。
11- (5,7-Dichloro-8-ethoxyquinolin-2-yl) undecan-1-ol (D14)
YD: 34%. 1 H NMR (400 MHz, d4-MeOD) δ8.43 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.39 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.45-1.49 (m, 5H) , 1.27-1.36 (br, 15H); MS. M / z 434.2, [M + Na] + .
9-(8-イソプロポキシキノリン-2-イル)ノナン-1-オール(E1)
YD: 28%。 1H NMR (400 MHz, d4-MeOD) δ 8.07 (d, J = 8.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.31-7.33 (m, 2H), 7.09 (d, J = 7.2 Hz, 1H), 4.79 (m, 1H), 3.49 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 1.71 (quin, J = 7.6 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d, J = 6 Hz, 6H), 1.20-1.35 (br, 11H); MS. m/z 330.2, [M+H]+。
9- (8-Isopropoxyquinolin-2-yl) nonan-1-ol (E1)
YD: 28%. 1 H NMR (400 MHz, d4-MeOD) δ 8.07 (d, J = 8.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.31-7.33 (m, 2H), 7.09 (d, J = 7.2 Hz , 1H), 4.79 (m, 1H), 3.49 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 1.71 (quin, J = 7.6 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d, J = 6 Hz, 6H), 1.20-1.35 (br, 11H); MS. m / z 330.2, [M + H] + .
10-(8-イソプロポキシキノリン-2-イル)デカン-1-オール(E2)
YD: 36%。 1H NMR (400 MHz, d4-MeOD) δ 8.14 (d, J = 8.8 Hz, 1H), 7.40-7.43 (m, 1H), 7.37-7.39 (m, 2H), 7.16 (dd, J = 6.8, 2.0 Hz, 1H), 4.83 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.77 (quin, J = 7.2 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d, J = 6 Hz, 6H), 1.20-1.35 (br, 11H); MS. m/z 366.0, [M+Na]+。
10- (8-Isopropoxyquinolin-2-yl) decan-1-ol (E2)
YD: 36%. 1 H NMR (400 MHz, d4-MeOD) δ 8.14 (d, J = 8.8 Hz, 1H), 7.40-7.43 (m, 1H), 7.37-7.39 (m, 2H), 7.16 (dd, J = 6.8, 2.0 Hz, 1H), 4.83 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.77 (quin, J = 7.2 Hz, 2H), 1.45 -1.49 (m, 2H), 1.41 (d, J = 6 Hz, 6H), 1.20-1.35 (br, 11H); MS. M / z 366.0, [M + Na] + .
11-(8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール(E3)
YD: 45 %。 1H NMR (400 MHz, CDCl3) δ7.99 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 4.4 Hz, 2H), 7.24-7.27 (m, 1H), 7.09 (t, J = 4.4 Hz, 1H), 4.82 (sept, J = 6 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.51-1.56 (m, 2H), 1.47 (d, J = 6 Hz, 6H), 1.33-1.43 (br, 15H); MS. m/z 380.3, [M+Na]+。
11- (8-Isopropoxyquinolin-2-yl) undecan-1-ol (E3)
YD: 45%. 1 H NMR (400 MHz, CDCl 3 ) δ7.99 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 4.4 Hz, 2H), 7.24-7.27 (m, 1H), 7.09 (t, J = 4.4 Hz, 1H), 4.82 (sept, J = 6 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.51-1.56 (m, 2H), 1.47 (d, J = 6 Hz, 6H), 1.33-1.43 (br, 15H); MS. M / z 380.3, [M + Na] + .
12-(8-イソプロポキシキノリン-2-イル)ドデカン-1-オール(E4)
YD: 34 %。 1H NMR (400 MHz, CDCl3) δ8.05 (d, J = 7.6 Hz, 1H), 7.30-7.39 (m, 3H), 7.13 (dd, J = 6.4, 2.4 Hz, 1H), 4.85 (sept, J = 6 Hz, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.09 (br, 2H), 1.84 (quin, J = 7.6 Hz, 2H), 1.56 (quin, J = 7.2 Hz, 2H), 1.48 (d, J = 6 Hz, 6H), 1.27-1.47 (br, 17H); MS. m/z 394.3,[M+Na]+。
12- (8-Isopropoxyquinolin-2-yl) dodecan-1-ol (E4)
YD: 34%. 1 H NMR (400 MHz, CDCl 3 ) δ8.05 (d, J = 7.6 Hz, 1H), 7.30-7.39 (m, 3H), 7.13 (dd, J = 6.4, 2.4 Hz, 1H), 4.85 (sept , J = 6 Hz, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.09 (br, 2H), 1.84 (quin, J = 7.6 Hz, 2H), 1.56 (quin, J = 7.2 Hz, 2H ), 1.48 (d, J = 6 Hz, 6H), 1.27-1.47 (br, 17H); MS. M / z 394.3, [M + Na] + .
13-(8-イソプロポキシキノリン-2-イル)トリデカン-1-オール(E5)
YD: 34%。 1H NMR (400 MHz, d4-MeOD) δ 8.11 (d, J = 8.4 Hz, 1H), 7.35-7.41 (m, 3H), 7.14 (d, J = 7.2 Hz, 1H), 4.81 (br, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 1.75 (quin, J = 7.2 Hz, 2H), 1.45-1.52 (m, 2H), 1.43 (d, J = 6.0 Hz, 6H), 1.25-1.42 (br, 19H); MS. m/z 408.0, [M+Na]+。
13- (8-Isopropoxyquinolin-2-yl) tridecan-1-ol (E5)
YD: 34%. 1 H NMR (400 MHz, d4-MeOD) δ 8.11 (d, J = 8.4 Hz, 1H), 7.35-7.41 (m, 3H), 7.14 (d, J = 7.2 Hz, 1H), 4.81 (br, 1H ), 3.52 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 1.75 (quin, J = 7.2 Hz, 2H), 1.45-1.52 (m, 2H), 1.43 (d , J = 6.0 Hz, 6H), 1.25-1.42 (br, 19H); MS. M / z 408.0, [M + Na] + .
14-(8-イソプロポキシキノリン-2-イル)テトラデカン-1-オール(E6)
YD: 36%。 1H NMR (400 MHz, d4-MeOD) δ8.13 (d, J = 8.8 Hz, 1H), 7.37-7.43 (m, 3H), 7.16 (dd, J = 7.2, 1.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.49-1.52 (m, 2H), 1.46 (d, J = 6.4 Hz, 6H), 1.26-1.41 (br, 21H); MS. m/z 422.3, [M+Na]+。
14- (8-Isopropoxyquinolin-2-yl) tetradecan-1-ol (E6)
YD: 36%. 1 H NMR (400 MHz, d4-MeOD) δ8.13 (d, J = 8.8 Hz, 1H), 7.37-7.43 (m, 3H), 7.16 (dd, J = 7.2, 1.6 Hz, 1H), 4.86 ( br, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.49-1.52 (m, 2H), 1.46 (d, J = 6.4 Hz, 6H), 1.26-1.41 (br, 21H); MS. M / z 422.3, [M + Na] + .
15-(8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール(E7)
YD: 36%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.4 Hz, 1H), 7.27-7.36 (m, 3H), 7.10-7.13 (m, 1H), 4.82 (sept, J = 4.1 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.52-1.55 (m, 2H), 1.48 (d, J = 2 Hz, 6H), 1.31-1.47 (br, 21H); MS. m/z 436.3, [M+Na]+。
15- (8-Isopropoxyquinolin-2-yl) pentadecan-1-ol (E7)
YD: 36%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.4 Hz, 1H), 7.27-7.36 (m, 3H), 7.10-7.13 (m, 1H), 4.82 (sept, J = 4.1 Hz , 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.52-1.55 (m, 2H), 1.48 (d, J = 2 Hz, 6H), 1.31-1.47 (br, 21H); MS. m / z 436.3, [M + Na] + .
11-(8-イソプロポキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール(E8)
YD: 48%。 1H NMR (400 MHz, CDCl3) δ8.09 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 4.75 (sept, J = 6 Hz, 1H), 3.55 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.51 (s, 3H), 1.81 (t, J = 7.2 Hz, 2H), 1.23-1.49 (br, 23H); MS. m/z 394.3, [M+Na]+。
11- (8-Isopropoxy-5-methylquinolin-2-yl) undecan-1-ol (E8)
YD: 48%. 1 H NMR (400 MHz, CDCl 3 ) δ8.09 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.97 ( t, J = 7.6 Hz, 1H), 4.75 (sept, J = 6 Hz, 1H), 3.55 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.51 (s, 3H), 1.81 (t, J = 7.2 Hz, 2H), 1.23-1.49 (br, 23H); MS. M / z 394.3, [M + Na] + .
11-(5-フルオロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール(E9)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ8.30 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 4.79 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 1.74 (quin, J =7.6 Hz, 2H), 1.45-1.51 (m, 2H), 1.42 (d, J = 6.4 Hz, 6H), 1.12-1.39 (br, 15H); MS. m/z 398.2, [M+Na]+。
11- (5-Fluoro-8-isopropoxyquinolin-2-yl) undecan-1-ol (E9)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ8.30 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 4.79 (m, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.45-1.51 (m, 2H) , 1.42 (d, J = 6.4 Hz, 6H), 1.12-1.39 (br, 15H); MS. M / z 398.2, [M + Na] + .
9-(5-クロロ-8-イソプロポキシキノリン-2-イル)ノナン-1-オール(E10)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ8.45 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.85 (m, 1H), 3.51 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.49 (quin, J = 6.4 Hz, 2H), 1.45 (d, J = 6.0 Hz, 6H), 1.30-1.42 (br, 11H); MS. m/z 364.2, [M+H]+。
9- (5-Chloro-8-isopropoxyquinolin-2-yl) nonan-1-ol (E10)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ8.45 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.85 (m, 1H), 3.51 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.6 Hz , 2H), 1.49 (quin, J = 6.4 Hz, 2H), 1.45 (d, J = 6.0 Hz, 6H), 1.30-1.42 (br, 11H); MS.m / z 364.2, [M + H] + .
11-(5-クロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール(E11)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ8.47 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.89 (m, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.41 (d, J = 5.6 Hz, 6H), 1.21 ~ 1.39 (br, 15H); MS. m/z 414.2, [M+Na]+。
11- (5-Chloro-8-isopropoxyquinolin-2-yl) undecan-1-ol (E11)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ8.47 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.89 (m, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 1.79 (quin, J = 7.6 Hz , 2H), 1.48 (quin, J = 6.8 Hz, 2H), 1.41 (d, J = 5.6 Hz, 6H), 1.21 to 1.39 (br, 15H); MS.m / z 414.2, [M + Na] + .
15-(5-クロロ-8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール(E12)
YD: 46%。 1H NMR (400 MHz, d4-MeOD +CDCl3) δ8.46 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.85 (m, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.25-1.39 (m, 23H); MS. m/z 448.3, [M+H]+。
15- (5-Chloro-8-isopropoxyquinolin-2-yl) pentadecan-1-ol (E12)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.46 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H ), 7.11 (d, J = 8.4 Hz, 1H), 4.85 (m, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.25-1.39 (m, 23H); MS.m / z 448.3, (M + H] + .
11-(5-ブロモ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール(E13)
YD: 40%。 1H NMR (400 MHz, d4-MeOD) δ8.43 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.2 Hz, 2H), 1.50-1.52 (m, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.28-1.41 (br, 15H); MS. m/z 458.2, [M+Na]+。
11- (5-Bromo-8-isopropoxyquinolin-2-yl) undecan-1-ol (E13)
YD: 40%. 1 H NMR (400 MHz, d4-MeOD) δ8.43 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.2 Hz , 2H), 1.50-1.52 (m, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.28-1.41 (br, 15H); MS. M / z 458.2, [M + Na] + .
11-(5,7-ジクロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール(E14)
YD: 37%。 1H NMR (400 MHz, CDCl3) δ8.36 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 5.13 (m, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.86 (quin, J = 6.8 Hz, 2H), 1.52-1.59 (m, 4H), 1.27-1.44 (br, 20H); MS. m/z 448.4, [M+Na]+。
11- (5,7-Dichloro-8-isopropoxyquinolin-2-yl) undecan-1-ol (E14)
YD: 37%. 1 H NMR (400 MHz, CDCl 3 ) δ8.36 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 5.13 ( m, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.86 (quin, J = 6.8 Hz, 2H), 1.52-1.59 (m, 4H), 1.27-1.44 (br, 20H); MS. M / z 448.4, [M + Na] + .
実施例4
(8-シクロプロピルメチレンオキシキノール(cyclopropylmethylenoxyquinol)-2-イル)アルキルアルコール誘導体の調製
Preparation of (8-cyclopropylmethylenoxyquinol-2-yl) alkyl alcohol derivatives
試薬及び条件:
(a) 臭化メチレンシクロプロピル(methylenecyclopropoyl)、K2CO3、DMF、60℃、13時間;(b) 1) LHMDS、THF、0℃、1時間;2) Br(CH2)n-1OH、室温、12から20時間。
Reagents and conditions:
(a) methylenecyclopropoyl bromide, K 2 CO 3 , DMF, 60 ° C, 13 hours; (b) 1) LHMDS, THF, 0 ° C, 1 hour; 2) Br (CH 2 ) n-1 OH, room temperature, 12 to 20 hours.
方法:
臭化メチレンシクロプロピル(1.0g、6.3mmol)を、13時間60℃で、25mlのDMF中の2-メチルキナルジン(1.0g、6.3mmol)及びK2CO3(2.5g、18.1mmol)の撹拌溶液に加えた。反応混合物を、H2O(200ml)によってクエンチして、EtOAc(30ml X 3)によって抽出した。有機層を、減圧蒸発によって濃縮し、残留物をHex/EA(8:1〜6:1)にてフラッシュカラムクロマトグラフィーによって精製して中間体である5-クロロ-8-(シクロプロピルメトキシ)-2-メチルキノリンを得た。LHMDS(2.2当量)を、THF溶液中の中間体(0.5g、2.3mmol)の撹拌溶液を用いて0℃で1時間処理した。対応するBr(CH2)n-1OH(1.1 - 1.2当量)を反応混合物に加えて、12時間以上から20時間、室温に戻した。溶媒を減圧下で除去した。茶色の油状残留物を、Hex/EA又はDCM/EAにてフラッシュカラムクロマトグラフィーによって精製し、Hex/EAにて再結晶化して化合物Fを得た。
Method:
Methylenecyclopropyl bromide (1.0 g, 6.3 mmol) was added 13 hours at 60 ° C. with 2-methylquinaldine (1.0 g, 6.3 mmol) and K 2 CO 3 (2.5 g, 18.1 mmol) in 25 ml DMF. To the stirring solution. The reaction mixture was quenched with H 2 O (200 ml) and extracted with EtOAc (30 ml × 3). The organic layer was concentrated by evaporation under reduced pressure and the residue was purified by flash column chromatography on Hex / EA (8: 1-6: 1) to provide the intermediate 5-chloro-8- (cyclopropylmethoxy). -2-Methylquinoline was obtained. LHMDS (2.2 eq) was treated with a stirred solution of the intermediate (0.5 g, 2.3 mmol) in THF solution at 0 ° C. for 1 h. The corresponding Br (CH 2 ) n-1 OH (1.1-1.2 eq) was added to the reaction mixture and allowed to warm to room temperature over 12 to 20 hours. The solvent was removed under reduced pressure. The brown oily residue was purified by flash column chromatography with Hex / EA or DCM / EA and recrystallized with Hex / EA to give compound F.
9-(8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール(F1)
YD: 49%。 1H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.38-7.43 (m, 3H), 7.14 (dd, J = 5.6, 3.2 Hz, 1H), 4.06 (d, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H),1.48-1.52 (m, 3H), 1.32-1.47 (m, 11H), 0.65-0.70 (m, 2H), 0.34-0.45 (m, 2H); MS. m/z 342.2, [M+H]+。
9- (8- (Cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol (F1)
YD: 49%. 1 H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.4 Hz, 1H), 7.38-7.43 (m, 3H), 7.14 (dd, J = 5.6, 3.2 Hz, 1H), 4.06 ( d, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.48-1.52 ( m, 3H), 1.32-1.47 (m, 11H), 0.65-0.70 (m, 2H), 0.34-0.45 (m, 2H); MS. m / z 342.2, [M + H] + .
10-(8-(シクロプロピルメトキシ)キノリン-2-イル)デカン-1-オール(F2)
YD: 43%。 1H NMR (400 MHz, d4-MeOD) δ8.16 (d, J = 8.4 Hz, 1H), 7.40 ~ 7.43 (m, 3H), 7.15 (dd, J = 5.6, 3.2 Hz, 1H), 4.07 (d, J = 7.2 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H),1.47-1.53 (m, 3H), 1.31-1.44 (m, 13H), 0.67-0.69 (m, 2H), 0.44-0.46 (m, 2H); MS. m/z 356.2, [M+H]+。
10- (8- (Cyclopropylmethoxy) quinolin-2-yl) decan-1-ol (F2)
YD: 43%. 1 H NMR (400 MHz, d4-MeOD) δ8.16 (d, J = 8.4 Hz, 1H), 7.40 to 7.43 (m, 3H), 7.15 (dd, J = 5.6, 3.2 Hz, 1H), 4.07 ( d, J = 7.2 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.47-1.53 ( m, 3H), 1.31-1.44 (m, 13H), 0.67-0.69 (m, 2H), 0.44-0.46 (m, 2H); MS. m / z 356.2, [M + H] + .
11-(8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール(F3)
YD: 45%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.4 Hz, 1H), 7.30 ~ 7.38 (m, 2H), 7.05 (dd, J = 6.4, 2.4 Hz, 1H), 4.11 (d, J = 6.8 Hz, 1H), 3.63 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 8.0 Hz, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.48-1.59 (m, 3H), 1.26-1.46 (br, 15H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.44 (dd, J = 13.2, 5.6 Hz, 2H); MS. m/z 392.2, [M+Na]+。
11- (8- (Cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol (F3)
YD: 45%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.4 Hz, 1H), 7.30 to 7.38 (m, 2H), 7.05 (dd, J = 6.4, 2.4 Hz, 1H), 4.11 (d , J = 6.8 Hz, 1H), 3.63 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 8.0 Hz, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.48-1.59 (m , 3H), 1.26-1.46 (br, 15H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.44 (dd, J = 13.2, 5.6 Hz, 2H); MS.m / z 392.2, (M + Na] + .
12-(8-(シクロプロピルメトキシ)キノリン-2-イル)ドデカン-1-オール(F4)
YD: 36%。 1H NMR (400 MHz, CDCl3) δ8.01 (d, J = 8.4 Hz, 1H), 7.29-7.38 (m, 3H), 7.06 (dd, J = 6.0, 2.4 Hz, 1H), 4.11 (d, J = 6.8 Hz, 1H), 3.63 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 7.2 Hz, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.48-1.59 (m, 3H), 1.27-1.47 (br, 17H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.42-0.48 (m, 2H); MS. m/z 384.3, [M+H]+。
12- (8- (Cyclopropylmethoxy) quinolin-2-yl) dodecan-1-ol (F4)
YD: 36%. 1 H NMR (400 MHz, CDCl 3 ) δ8.01 (d, J = 8.4 Hz, 1H), 7.29-7.38 (m, 3H), 7.06 (dd, J = 6.0, 2.4 Hz, 1H), 4.11 (d , J = 6.8 Hz, 1H), 3.63 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 7.2 Hz, 2H), 1.83 (quin, J = 7.6 Hz, 2H), 1.48-1.59 (m , 3H), 1.27-1.47 (br, 17H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.42-0.48 (m, 2H); MS. M / z 384.3, [M + H] + .
13-(8-(シクロプロピルメトキシ)キノリン-2-イル)トリデカン-1-オール(F5)
YD: 42%。 1H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.38 ~ 7.41 (m, 3H), 7.05 (dd, J = 5.6, 3.2 Hz, 1H), 4.05 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H),1.44-1.52 (m, 3H), 1.26-1.40 (m, 19H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.40-0.47 (m, 2H); MS. m/z 420.0, [M+Na]+。
13- (8- (Cyclopropylmethoxy) quinolin-2-yl) tridecan-1-ol (F5)
YD: 42%. 1 H NMR (400 MHz, d4-MeOD) δ8.14 (d, J = 8.4 Hz, 1H), 7.38 to 7.41 (m, 3H), 7.05 (dd, J = 5.6, 3.2 Hz, 1H), 4.05 ( d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.44-1.52 ( m, 3H), 1.26-1.40 (m, 19H), 0.67 (dd, J = 13.2, 5.6 Hz, 2H), 0.40-0.47 (m, 2H); MS.m / z 420.0, [M + Na] + .
14-(8-(シクロプロピルメトキシ)キノリン-2-イル)テトラデカン-1-オール(F6)
YD: 37%。 1H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.8 Hz, 1H), 7.39 ~ 7.42 (m, 3H), 7.13 (dd, J = 5.6, 3.2 Hz, 1H), 4.05 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H),1.44-1.52 (m, 3H), 1.26-1.43 (m, 21H), 0.65-0.69 (m, 2H), 0.42 (dd, J = 10.0, 4.8 Hz, 2H); MS. m/z 434.3, [M+Na]+。
14- (8- (Cyclopropylmethoxy) quinolin-2-yl) tetradecan-1-ol (F6)
YD: 37%. 1 H NMR (400 MHz, d4-MeOD) δ8.15 (d, J = 8.8 Hz, 1H), 7.39 to 7.42 (m, 3H), 7.13 (dd, J = 5.6, 3.2 Hz, 1H), 4.05 ( d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.6 Hz, 2H), 1.44-1.52 ( m, 3H), 1.26-1.43 (m, 21H), 0.65-0.69 (m, 2H), 0.42 (dd, J = 10.0, 4.8 Hz, 2H); MS.m / z 434.3, [M + Na] + .
15-(8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール(F7)
YD: 69%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (br, 3H), 7.11 (d, J = 2.4 Hz, 1H), 4.05 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H),1.46-1.52 (m, 3H), 1.25-1.44 (m, 23H), 0.63-0.69 (m, 2H), 0.40-0.46 (m, 2H); MS. m/z 426.4, [M+H]+。
15- (8- (Cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol (F7)
YD: 69%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (br, 3H), 7.11 (d, J = 2.4 Hz, 1H), 4.05 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.78 (quin, J = 7.2 Hz, 2H), 1.46-1.52 (m, 3H), 1.25-1.44 (m, 23H), 0.63-0.69 (m, 2H), 0.40-0.46 (m, 2H); MS. m / z 426.4, [M + H] + .
11-(8-(シクロプロピルメトキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール(F8)
YD: 45%。 1H NMR (400 MHz, d4-MeOD) δ8.31 (d, J = 8.8 Hz, 1H), δ 7.44 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.57 (s, 3H), 1.79 (quin, J = 7.2 Hz, 2H), 1.29-1.52 (m, 18H), 0.65 -0.68 (m, 2H), 0.40-0.43 (m, 2H); MS. m/z 406.3, [M+Na]+。
11- (8- (Cyclopropylmethoxy) -5-methylquinolin-2-yl) undecan-1-ol (F8)
YD: 45%. 1 H NMR (400 MHz, d4-MeOD) δ8.31 (d, J = 8.8 Hz, 1H), δ 7.44 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.57 ( s, 3H), 1.79 (quin, J = 7.2 Hz, 2H), 1.29-1.52 (m, 18H), 0.65 -0.68 (m, 2H), 0.40-0.43 (m, 2H); MS.m / z 406.3 , [M + Na] + .
11-(8-(シクロプロピルメトキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール(F9)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ8.36 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.07-7.15 (m, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H),1.42-1.49 (m, 3H), 1.22-1.40 (m, 15H), 0.65-0.69 (m, 2H), 0.42 (dd, J = 10.4, 4.8 Hz, 2H); MS. m/z 410.2, [M+Na]+。
11- (8- (Cyclopropylmethoxy) -5-fluoroquinolin-2-yl) undecan-1-ol (F9)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ8.36 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.07-7.15 (m, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.42-1.49 (m, 3H), 1.22-1.40 (m, 15H), 0.65-0.69 (m, 2H), 0.42 (dd, J = 10.4, 4.8 Hz, 2H); MS. M / z 410.2, [M + Na] + .
9-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール(F10)
YD: 33%。 1H NMR (400 MHz, d4-MeOD) δ8.48 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 1.83 (t, J = 7.6 Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS. m/z 376.2, [M+H]+。
9- (5-Chloro-8- (cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol (F10)
YD: 33%. 1 H NMR (400 MHz, d4-MeOD) δ8.48 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.11 ( d, J = 8.4 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 1.83 (t, J = 7.6 Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS.m / z 376.2 , [M + H] + .
11-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール(F11)
YD: 34%。 1H NMR (400 MHz, CDCl3) δ8.41 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.4Hz 1H), 7.41 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H), 1.83 (t, J = 7.6 Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m, 2H), 0.43 -0.46 (m, 2H) ; MS. m/z 426.2, [M+Na]+。
11- (5-Chloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol (F11)
YD: 34%. 1 H NMR (400 MHz, CDCl 3 ) δ8.41 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.4Hz 1H), 7.41 (d, J = 2.4 Hz, 1H), 6.97 (d , J = 8.4 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H), 1.83 (t, J = 7.6 Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m, 2H), 0.43 -0.46 (m, 2H); MS.m / z 426.2, [M + Na] + .
15-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール(F12)
YD: 28%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.47 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.46-1.52 (m, 2H), 1.25-1.44 (br, 24H), 0.65-0.69 (m, 2H), 0.41-0.43 (m, 2H); MS. m/z 460.3, [M+Na]+。
15- (5-Chloro-8- (cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol (F12)
YD: 28%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.47 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H ), 7.10 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (quin, J = 7.6 Hz, 2H), 1.46-1.52 (m, 2H), 1.25-1.44 (br, 24H), 0.65-0.69 (m, 2H), 0.41-0.43 (m, 2H); MS. m / z 460.3, [M + Na] + .
11-(5-ブロモ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール(F13)
YD: 35%。 1H NMR (400 MHz, d4-MeOD) δ8.42 (d, J = 8.8 Hz, 1H), δ 7.67 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 7.2 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.46-1.52 (m, 3H), 1.28-1.44 (m, 15H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS. m/z 470.2, [M+Na]+。
11- (5-Bromo-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol (F13)
YD: 35%. 1 H NMR (400 MHz, d4-MeOD) δ8.42 (d, J = 8.8 Hz, 1H), δ 7.67 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 7.2 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 1.77 ( quin, J = 7.6 Hz, 2H), 1.46-1.52 (m, 3H), 1.28-1.44 (m, 15H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS.m / z 470.2, [M + Na] + .
11-(5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール(F14)
YD: 53%。 1H NMR (400 MHz, d4-MeOD) δ8.47 (d, J = 8.8 Hz, 1H), δ 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.86 (quin, J = 7.2 Hz, 2H), 1.48-1.53 (m, 2H), 1.29-1.38 (m, 16H), 0.62 (dd, J = 12.8, 5.2 Hz, 2H), 0.31 (dd, J = 10.8, 5.2 Hz, 2H); MS. m/z 460.2, [M+Na]+。
11- (5,7-Dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol (F14)
YD: 53%. 1 H NMR (400 MHz, d4-MeOD) δ 8.47 (d, J = 8.8 Hz, 1H), δ 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.86 (quin, J = 7.2 Hz, 2H), 1.48-1.53 (m, 2H), 1.29-1.38 (m, 16H), 0.62 (dd, J = 12.8, 5.2 Hz, 2H), 0.31 (dd, J = 10.8, 5.2 Hz, 2H) MS. M / z 460.2, [M + Na] + .
実施例5
(5,7-ジクロロ-8-ヒドロキシキノール-2-イル)アルキルアルコールの調製
Preparation of (5,7-dichloro-8-hydroxyquinol-2-yl) alkyl alcohol
試薬及び条件:
(a) NCS、CHCl3、室温、48時間。
Reagents and conditions:
(a) NCS, CHCl 3 , room temperature, 48 hours.
方法:
N-クロロスクシンイミド(0.3g、2.25mmol)を、48時間、CHCl3(20ml)中の化合物Bの撹拌溶液に加えた。反応混合物を、クラッシュアイスに注いで、CH2Cl2(20ml X 2)によって抽出した。抽出物を、Hex/EA(3:1)にてカラムクロマトグラフィーによって精製し、再結晶化して化合物(0.18g、49%)を得た。
Method:
N-chlorosuccinimide (0.3 g, 2.25 mmol) was added to a stirred solution of compound B in CHCl 3 (20 ml) for 48 hours. The reaction mixture was poured onto crushed ice and extracted with CH 2 Cl 2 (20 ml X 2). The extract was purified by column chromatography with Hex / EA (3: 1) and recrystallized to give the compound (0.18 g, 49%).
5,7-ジクロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール(G1)
YD: 49%。 1H NMR (400 MHz, CDCl3) δ8.38 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.56 (quin, J = 7.6 Hz , 2H), 1.27-1.38 (br, 15H); MS. m/z 382.0, [M-H]+。
5,7-Dichloro-2- (11-hydroxyundecyl) quinolin-8-ol (G1)
YD: 49%. 1 H NMR (400 MHz, CDCl 3 ) δ8.38 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.56 (quin, J = 7.6 Hz, 2H), 1.27-1.38 (br, 15H); MS. M / z 382.0, [MH] + .
実施例6
(5-クロロ-8-メトキシキノール-2-イル)アルキルアルコール又はアルキルアセテートの調製
Preparation of (5-chloro-8-methoxyquinol-2-yl) alkyl alcohol or alkyl acetate
試薬及び条件:
(a) HCl、ICl3、氷HOAc、H2O、6時間、室温。
Reagents and conditions:
(a) HCl, ICl 3 , ice HOAc, H 2 O, 6 hours, room temperature.
方法:
様々な長鎖置換(8-メトキシキノリン-2-イル)-オール(1.0当量)を、室温で、濃塩酸(0.5mL/mmol)に加え、赤みがかった黄色の混合物を5分間撹拌した。この混合物に、濃塩酸(2mL)中のICl3(1.5当量)溶液を滴状に加えた。黄色のゴム状混合物を、6時間室温で撹拌した。水をそれに加えて、EAで割った。有機層を塩水によって洗浄し、無水MgSO4にて乾燥させ、溶媒除去によってろ過して、得られた油状残留物を、CHCl3を使用してフラッシュカラムクロマトグラフィーにて精製し、H1からH5を得た。
Method:
Various long chain substituted (8-methoxyquinolin-2-yl) -ols (1.0 eq) were added to concentrated hydrochloric acid (0.5 mL / mmol) at room temperature and the reddish yellow mixture was stirred for 5 min. To this mixture was added dropwise a solution of ICl 3 (1.5 eq) in concentrated hydrochloric acid (2 mL). The yellow gum mixture was stirred for 6 hours at room temperature. Water was added to it and divided by EA. The organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered by removal of solvent, and the resulting oily residue was purified by flash column chromatography using CHCl 3 to remove H1 to H5. Obtained.
10-(5-クロロ-8-メトキシキノリン-2-イル)デカン-1-オール(H1a)及び酢酸(5-クロロ-8-メトキシキノリン-2-イル) 10-デシルエステル(H1b)
YD: 61%及び10%。 H1a: 1H NMR (200 MHz, CDCl3) δ8.41 (d, J = 8.68 Hz, 1H), 7.42 (dd, J = 8 Hz , J = 2 Hz , 2H), 6.91 (d, J = 8 Hz , 1H), 4.03 (s, 3H), 3.59 (t, J = 6 Hz , 2H), 3.59 (t, J = 4 Hz , 2H), 1.73 (m, 2H), 1.48 (m, 2H), 1.25 (br, 12H); HRMS (EI): Calcd for C20H28ClNO2:349.1803, Found:349.1781。 H1b: 1H NMR (400 MHz, CDCl3) δ8.41 (d, J = 8 Hz, 1H), 7.42 (dd, J = 8 Hz , J = 4Hz , 2H), 6.92 (d, J = 8 Hz , 1H), 4.06 (t, J = 8 Hz , 2H), 4.02 (s, 3H), 3.03 (t, J = 8 Hz, 2H), 2.02 (s, 3H), 1.79 (m, 2H), 1.59 (m, 2H), 1.40 (m, 2H), 1.23 (br, 12H); HRMS (FAB, M + H): Calcd for C22H31ClNO3 392.1992, Found 392.1983。
10- (5-Chloro-8-methoxyquinolin-2-yl) decan-1-ol (H1a) and acetic acid (5-chloro-8-methoxyquinolin-2-yl) 10-decyl ester (H1b)
YD: 61% and 10%. H1a: 1 H NMR (200 MHz, CDCl 3 ) δ8.41 (d, J = 8.68 Hz, 1H), 7.42 (dd, J = 8 Hz, J = 2 Hz, 2H), 6.91 (d, J = 8 Hz, 1H), 4.03 (s, 3H), 3.59 (t, J = 6 Hz, 2H), 3.59 (t, J = 4 Hz, 2H), 1.73 (m, 2H), 1.48 (m, 2H), 1.25 (br, 12H); HRMS (EI): Calcd for C 20 H 28 ClNO 2 : 349.1803, Found: 349.1781. H1b: 1 H NMR (400 MHz, CDCl 3 ) δ8.41 (d, J = 8 Hz, 1H), 7.42 (dd, J = 8 Hz, J = 4 Hz, 2H), 6.92 (d, J = 8 Hz , 1H), 4.06 (t, J = 8 Hz, 2H), 4.02 (s, 3H), 3.03 (t, J = 8 Hz, 2H), 2.02 (s, 3H), 1.79 (m, 2H), 1.59 (m, 2H), 1.40 ( m, 2H), 1.23 (br, 12H); HRMS (FAB, M + H): Calcd for C 22 H 31 ClNO 3 392.1992, Found 392.1983.
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール(H2a)及び酢酸(5-クロロ-8-メトキシキノリン-2-イル) 11-ウンデシルエステル(H2b)
YD: 60%及び12%。 H2a: 1H NMR (400 MHz, CDCl3) δ8.43 (d, J = 8.72 Hz, 1H), 7.44 (dd, J = 13.5 Hz , J = 5.3 Hz , 2H), 6.94 (d, J = 8.3 Hz , 1H), 4.05 (s, 3H), 3.62 (t, J = 6.6 Hz,2H), 3.07 (t, J = 5.2 Hz , 2H), 1.80 (m, 2H), 1.54 (m, 2H), 1.39 (m, 2H), 1.26 (br, 12H); HRMS (EI): Calcd for C21H30ClNO2 363.1960, Found 363.1941。 H2b: 1H NMR (400 MHz, CDCl3) δ8.41 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.3 Hz, J = 3.8 Hz, 2H), 6.91(d, J = 8.4 Hz, 1H), 4.06 (t, J = 7.8 Hz, 2H), 4.02 (s, 3H), 3.02 (t, J = 7.8 Hz, 2H), 2.01 (s, 3H), 1.78 (m, 2H), 1.58 (m, 2H), 1.39 (m, 2H), 1.22 (br, 12H); HRMS (EI): Calcd for C23H32ClNO3 405.2065, Found 405.2044。
11- (5-Chloro-8-methoxyquinolin-2-yl) undecan-1-ol (H2a) and acetic acid (5-chloro-8-methoxyquinolin-2-yl) 11-undecyl ester (H2b)
YD: 60% and 12%. H2a: 1 H NMR (400 MHz, CDCl 3 ) δ8.43 (d, J = 8.72 Hz, 1H), 7.44 (dd, J = 13.5 Hz, J = 5.3 Hz, 2H), 6.94 (d, J = 8.3 Hz, 1H), 4.05 (s, 3H), 3.62 (t, J = 6.6 Hz, 2H), 3.07 (t, J = 5.2 Hz, 2H), 1.80 (m, 2H), 1.54 (m, 2H), 1.39 (m, 2H), 1.26 (br, 12H); HRMS (EI): Calcd for C 21 H 30 ClNO 2 363.1960, Found 363.1941. H2b: 1 H NMR (400 MHz, CDCl 3 ) δ8.41 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.3 Hz, J = 3.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.06 (t, J = 7.8 Hz, 2H), 4.02 (s, 3H), 3.02 (t, J = 7.8 Hz, 2H), 2.01 (s, 3H), 1.78 (m, 2H), 1.58 (m, 2H), 1.39 (m, 2H), 1.22 (br, 12H); HRMS (EI): Calcd for C 23 H 32 ClNO 3 405.2065, Found 405.2044.
12-(5-クロロ-8-メトキシキノリン-2-イル)ドデカン-1-オール(H3a)及び酢酸(5-クロロ-8-メトキシキノリン-2-イル) 12-ドデシルエステル(H3b)
YD: 57%及び27%。 H3a: 1H NMR (400 MHz, CDCl3) δ8.46 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94(d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H), 1.23 (br, 14H); HRMS (EI): Calcd for C22H32ClNO2 377.2116, Found 377.2106。 H3b: 1H NMR (200 MHz, CDCl3) δ8.38 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.8 Hz, 2H), 4.01 (s, 3H), 3.02 (t, J = 7.8 Hz, 2H), 1.99 (s, 3H), 1.76 (m, 2H), 1.59 (m, 2H), 1.20 (br, 16H); HRMS (FAB, M+H): Calcd for C24H35ClNO3 420.2305, Found 420.2310。
12- (5-Chloro-8-methoxyquinolin-2-yl) dodecan-1-ol (H3a) and acetic acid (5-chloro-8-methoxyquinolin-2-yl) 12-dodecyl ester (H3b)
YD: 57% and 27%. H3a: 1 H NMR (400 MHz, CDCl 3 ) δ8.46 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H), 1.23 (br, 14H); HRMS (EI): Calcd for C 22 H 32 ClNO 2 377.2116, Found 377.2106. H3b: 1 H NMR (200 MHz, CDCl 3 ) δ8.38 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.8 Hz, 2H), 4.01 (s, 3H), 3.02 (t, J = 7.8 Hz, 2H), 1.99 (s, 3H), 1.76 (m, 2H), 1.59 (m, 2H ), 1.20 (br, 16H); HRMS (FAB, M + H): Calcd for C 24 H 35 ClNO 3 420.2305, Found 420.2310.
13-(5-クロロ-8-メトキシキノリン-2-イル)トリデカン-1-オール(H4a)及び酢酸(5-クロロ-8-メトキシキノリン-2-イル) 13-トリデシルエステル(H4b)
YD: 64%及び14%。 H4a: 1H NMR (400 MHz, CDCl3) δ8.46 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94(d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50(m, 2H), 1.40 (m, 2H), 1.23 (br, 16H); HRMS (EI): Calcd for C23H34ClNO2 391.2273, Found 391.2249。H4b: 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 8.5 Hz, J = 5.8 Hz, 2H), 6.89(d, J = 8.4 Hz, 1H), 4.01(t, J = 9.6 Hz, 2H), 4.00 (s, 3H), 3.00 (t, J = 7.9 Hz, 2H), 1.99 (s, 3H), 1.75 (m, 2H), 1.58 (m, 2H), 1.38 (m, 2H), 1.22 (br, 16H); HRMS (FAB, M + H): Calcd for C25H37ClNO3 434.2462, Found 434.2459。
13- (5-Chloro-8-methoxyquinolin-2-yl) tridecan-1-ol (H4a) and acetic acid (5-chloro-8-methoxyquinolin-2-yl) 13-tridecyl ester (H4b)
YD: 64% and 14%. H4a: 1 H NMR (400 MHz, CDCl 3 ) δ8.46 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H), 1.23 (br, 16H); HRMS (EI): Calcd for C 23 H 34 ClNO 2 391.2273, Found 391.2249. H4b: 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 8.5 Hz, J = 5.8 Hz, 2H), 6.89 (d, J = 8.4 Hz , 1H), 4.01 (t, J = 9.6 Hz, 2H), 4.00 (s, 3H), 3.00 (t, J = 7.9 Hz, 2H), 1.99 (s, 3H), 1.75 (m, 2H), 1.58 (m, 2H), 1.38 ( m, 2H), 1.22 (br, 16H); HRMS (FAB, M + H): Calcd for C 25 H 37 ClNO 3 434.2462, Found 434.2459.
実施例7
(8-ヒドロキシキノール-4-イル)又は(8-アルコキシキノール-4-イル)アルキルアルコールの調製
Preparation of (8-hydroxyquinol-4-yl) or (8-alkoxyquinol-4-yl) alkyl alcohol
試薬及び条件:
(a) メチルビニルケトン、HCl、還流。(b) MeI、K2CO3、アセトン、室温、8時間;EtI又は2-ブロモプロパン又は臭化メチレンシクロプロピル、K2CO3、DMF、60℃、(c) 1) LHMDS、THF、0℃、1時間;2) Br(CH2)n-1OH、室温、(d) BnBr、KOH、EtOH、還流。(e) H2、Pd/C、MeOH、室温、24時間。
Reagents and conditions:
(a) Methyl vinyl ketone, HCl, reflux. (b) MeI, K 2 CO 3 , acetone, room temperature, 8 hours; EtI or 2-bromopropane or methylenecyclopropyl bromide, K 2 CO 3 , DMF, 60 ° C., (c) 1) LHMDS, THF, 0 ° C, 1 hour; 2) Br (CH 2 ) n-1 OH, room temperature, (d) BnBr, KOH, EtOH, reflux. (e) H 2, Pd / C, MeOH, rt, 24 hr.
方法:
中間体であるINT 1を、メチルビニルケトンと反応させた2-アミノフェノールからの閉環を通じて合成した。INT 1を、様々なハロゲン化アルキルと反応させて中間体として8-アルコキシ-4メチルキノール誘導体を得た。対応するBr(CH2)n-1OHを中間体と反応させて、一連の化合物J及びIを合成した。保護基Jを、水素化(実施例1に示す方法)によって除去して化合物Kを得た。
Method:
The intermediate INT 1 was synthesized through ring closure from 2-aminophenol reacted with methyl vinyl ketone. INT 1 was reacted with various alkyl halides to give 8-alkoxy-4methylquinol derivatives as intermediates. The corresponding Br (CH 2 ) n-1 OH was reacted with the intermediate to synthesize a series of compounds J and I. The protecting group J was removed by hydrogenation (method shown in Example 1) to give compound K.
11-(8-メトキシキノリン-4-イル)ウンデカン-1-オール(I1)
YD: 34%。 1H NMR (400 MHz, CDCl3) δ8.80 (dd, J = 4.4, 0.6 Hz, 1H), 7.59 (dd, J = 8.4, 0.8 Hz, 1H), 7.44-7.49 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz, 2H), 1.55 (quin, J = 7.2 Hz, 2H), 1.23-1.45 (br, 15H); MS. m/z 329.9, [M+H]+。
11- (8-methoxyquinolin-4-yl) undecan-1-ol (I1)
YD: 34%. 1 H NMR (400 MHz, CDCl 3 ) δ8.80 (dd, J = 4.4, 0.6 Hz, 1H), 7.59 (dd, J = 8.4, 0.8 Hz, 1H), 7.44-7.49 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.6 Hz , 2H), 1.55 (quin, J = 7.2 Hz, 2H), 1.23-1.45 (br, 15H); MS. M / z 329.9, [M + H] + .
11-(8-エトキシキノリン-4-イル)ウンデカン-1-オール(I2)
YD: 42%。 H NMR (400 MHz, d4-MeOD) δ8.66 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 4.27 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.08 (d, J = 7.6 Hz, 2H), 1.75 (quin, J = 7.6 Hz, 2H), 1.50-1.57 (m, 5H), 1.21-1.49 (br, 15H); MS. m/z 366.2, [M+Na]+。
11- (8-Ethoxyquinolin-4-yl) undecan-1-ol (I2)
YD: 42%. H NMR (400 MHz, d4-MeOD) δ8.66 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.37 ( d, J = 8.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 4.27 (q, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.08 (d, J = 7.6 Hz, 2H), 1.75 (quin, J = 7.6 Hz, 2H), 1.50-1.57 (m, 5H), 1.21-1.49 (br, 15H); MS.m / z 366.2, [M + Na] + .
11-(8-イソプロポキシキノリン-4-イル)ウンデカン-1-オール(I3)
YD: 48%。 1H NMR (400 MHz, d4-MeOD) δ 8.65 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.84 (br, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.07 (d, J = 7.6 Hz, 2H), 1.74 (br, 2H), 1.43-1.50 (br, 9H), 1.29-1.34 (br, 14H); MS. m/z 380.3, [M+Na]+。
11- (8-Isopropoxyquinolin-4-yl) undecan-1-ol (I3)
YD: 48%. 1 H NMR (400 MHz, d4-MeOD) δ 8.65 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 ( d, J = 4.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.84 (br, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.07 (d, J = 7.6 Hz, 2H), 1.74 (br, 2H), 1.43-1.50 (br, 9H), 1.29-1.34 (br, 14H); MS. M / z 380.3, [M + Na] + .
11-(8-(シクロプロピルメトキシ)キノリン-4-イル)ウンデカン-1-オール(I4)
YD: 53%。 1H NMR (400 MHz, d4-MeOD) δ8.66 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.03 (d, J = 6.8 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.06 (d, J = 7.6 Hz, 2H), 1.69-1.75 (m, 2H), 1.28-1.52 (br, 18H), 0.65-0.68 (m, 2H), 0.42-0.43 (m, 2H); MS. m/z 392.2 [M+Na]+。
11- (8- (Cyclopropylmethoxy) quinolin-4-yl) undecan-1-ol (I4)
YD: 53%. 1 H NMR (400 MHz, d4-MeOD) δ8.66 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.03 (d, J = 6.8 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.06 (d , J = 7.6 Hz, 2H), 1.69-1.75 (m, 2H), 1.28-1.52 (br, 18H), 0.65-0.68 (m, 2H), 0.42-0.43 (m, 2H); MS.m / z 392.2 [M + Na] + .
11-(8-(ベンジルオキシ)キノリン-4-イル)ウンデカン-1-オール(J1)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ 8.66 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.30-7.38 (m, 3H), 7.26-7.28 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.06 (t, J = 8 Hz, 2H), 1.73 (q, J = 7.6 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.28-1.48 (m, 15H); MS. m/z 428.3, [M+Na]+。
11- (8- (Benzyloxy) quinolin-4-yl) undecan-1-ol (J1)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ 8.66 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.45 ( t, J = 8.0 Hz, 1H), 7.30-7.38 (m, 3H), 7.26-7.28 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H), 3.52 (t , J = 6.4 Hz, 2H), 3.06 (t, J = 8 Hz, 2H), 1.73 (q, J = 7.6 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.28-1.48 (m , 15H); MS. M / z 428.3, [M + Na] + .
12-(8-(ベンジルオキシ)キノリン-4-イル)ドデカン-1-オール(J2)
YD: 46%。 1H NMR (400 MHz, d4-MeOD) δ 8.67 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.30-7.39 (m, 3H), 7.27-7.30 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 1.74 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.2 Hz, 2H), 1.23-1.45 (m, 17H); MS. m/z 442.3, [M+Na]+。
12- (8- (Benzyloxy) quinolin-4-yl) dodecan-1-ol (J2)
YD: 46%. 1 H NMR (400 MHz, d4-MeOD) δ 8.67 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.45 ( t, J = 8.0 Hz, 1H), 7.30-7.39 (m, 3H), 7.27-7.30 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 3.52 (t , J = 6.4 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 1.74 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.2 Hz, 2H), 1.23-1.45 (m , 17H); MS. M / z 442.3, [M + Na] + .
4-(11-ヒドロキシウンデシル)キノリン-8-オール(K1)
YD: 84%。 1H NMR (400 MHz, d4-MeOD) δ 8.63 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 3.51 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 1.71 (t, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.12-1.31 (br, 15H); MS. m/z 316.2, [M+H]+。
4- (11-Hydroxyundecyl) quinolin-8-ol (K1)
YD: 84%. 1 H NMR (400 MHz, d4-MeOD) δ 8.63 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 ( d, J = 4.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 3.51 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 1.71 (t, J = 7.6 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.12-1.31 (br, 15H); MS. M / z 316.2, [M + H] + .
4-(12-ヒドロキシウンデシル)キノリン-8-オール(K2)
YD: 86%。 1H NMR (400 MHz, CDCl3) δ8.52 (d, J = 4.4 Hz, 1H), 7.36 (dd, J = 8.4, 0.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 4.4 Hz, 1H), 6.99 (dd, J = 7.6, 1.2 Hz, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.61 (quin, J = 7.6 Hz, 2H), 1.40 (quin, J = 6.8 Hz, 2H), 1.12-1.31 (br, 17H); MS. m/z 352.2, [M+Na]+。
4- (12-Hydroxyundecyl) quinolin-8-ol (K2)
YD: 86%. 1 H NMR (400 MHz, CDCl 3 ) δ8.52 (d, J = 4.4 Hz, 1H), 7.36 (dd, J = 8.4, 0.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 4.4 Hz, 1H), 6.99 (dd, J = 7.6, 1.2 Hz, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.61 (quin, J = 7.6 Hz, 2H), 1.40 (quin, J = 6.8 Hz, 2H), 1.12-1.31 (br, 17H); MS. M / z 352.2, [M + Na] + .
実施例8
(8-トリフルオロメトキシキノール-2-イル)アルキルアルコールの調製。
Preparation of (8-trifluoromethoxyquinol-2-yl) alkyl alcohol.
方法:
中間体を、クロトンアルデヒドと反応させた2-トリフルオロメトキシアニリンからの閉環を通じて合成した。中間体を、(上にて示す通り)対応するBr(CH2)n-1OHと反応させて一連の化合物Lを合成した。
Method:
The intermediate was synthesized through ring closure from 2-trifluoromethoxyaniline reacted with crotonaldehyde. The intermediate was reacted with the corresponding Br (CH 2 ) n-1 OH (as shown above) to synthesize a series of compounds L.
9-(8-(トリフルオロメトキシ)キノリン-2-イル)ノナ-1-オール(L1)
YD: 41%。 1H NMR (400 MHz, CDCl3) δ8.06 (dd, J = 8.4, 1.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 1.81-1.85 (br, 2H), 1.53-1.56 (br, 2H), 1.21-1.35 (m, 15H); MS. m/z 355.9, [M+H]+。
9- (8- (Trifluoromethoxy) quinolin-2-yl) non-1-ol (L1)
YD: 41%. 1 H NMR (400 MHz, CDCl 3 ) δ8.06 (dd, J = 8.4, 1.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 1.81-1.85 (br, 2H), 1.53-1.56 (br, 2H), 1.21-1.35 (m, 15H); MS. M / z 355.9, [M + H] + .
11-(8-(トリフルオロメトキシ)キノリン-2-イル)ウンデカン-1-オール(L2)
YD: 41%。 1H NMR (400 MHz, d4-MeOD) δ8.26 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.47-7.56 (m, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.21-1.35 (m, 15H); MS. m/z 406.2, [M+Na]+。
11- (8- (trifluoromethoxy) quinolin-2-yl) undecan-1-ol (L2)
YD: 41%. 1 H NMR (400 MHz, d4-MeOD) δ8.26 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.47 -7.56 (m, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.79 (quin, J = 6.8 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.21-1.35 (m, 15H); MS. M / z 406.2, [M + Na] + .
14-(8-(トリフルオロメトキシ)キノリン-2-イル)テトラデカン-1-オール(L3)
YD: 37%。 1H NMR (400 MHz, d4-MeOD) δ 8.27 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.49-7.56 (m, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.27-1.37 (m, 21H); MS. m/z 448.2, [M+Na]+。
14- (8- (Trifluoromethoxy) quinolin-2-yl) tetradecan-1-ol (L3)
YD: 37%. 1 H NMR (400 MHz, d4-MeOD) δ 8.27 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.49- 7.56 (m, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.82 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.27-1.37 (m, 21H); MS. M / z 448.2, [M + Na] + .
15-(8-(トリフルオロメトキシ)キノリン-2-イル)ペンタデカン-1-オール(L4)
YD: 32%。 1H NMR (400 MHz, d4-MeOD+CDCl3) δ8.21 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 7.2 Hz, 2H), 1.15-1.41 (br, 23H); MS. m/z 462.2, [M+Na]+。
15- (8- (Trifluoromethoxy) quinolin-2-yl) pentadecan-1-ol (L4)
YD: 32%. 1 H NMR (400 MHz, d4-MeOD + CDCl 3 ) δ8.21 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H ), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.50 (quin, J = 7.2 Hz, 2H), 1.15-1.41 (br, 23H); MS. M / z 462.2, [M + Na] + .
実施例9
2-N-置換アルコール-8-ヒドロキシキノリンの調製
Preparation of 2-N-substituted alcohol-8-hydroxyquinoline
試薬及び条件:
(a) SeO2、ジオキサン、50から80℃;(b) N-メチルプロパルギルアミン(methylpropagylamine)又は2-(ピペラジン(piperazin)-1-イル)エタノール又はNH2(CH2)n-1OH、NaBH(OAc)3、1,2-ジクロロエタン、室温。
Reagents and conditions:
(a) SeO 2, dioxane, 50 from 80 ° C.; (b) N-methyl-propargylamine (Methylpropagylamine) or 2- (piperazine (Piperazin)-1-yl) ethanol or NH 2 (CH 2) n- 1 OH, NaBH (OAc) 3 , 1,2-dichloroethane, room temperature.
方法:
ジオキサン(15ml)中の8-ヒドロキシ-2-メチルキノール(6.0g、37.7mmol)の溶液を、50℃で、ジオキサン(80ml)中のSeO2(6.3g、56.8mmol)の撹拌溶液に滴状に加え、混合物を、20時間以上80℃に加熱した。得られた混合物をろ過した。ろ液を濃縮して残留物を、Hex/EA =(15:1〜10:1)にてカラムクロマトグラフィーによって精製し、中間体として8-ヒドロキシキノリン-2-カルボキサルデヒド誘導体(2.45g、38%)を得た。中間体を、アミノアルコール、アミノアルキン又は他のヘテロ環を用いた還元的アミノ化によってN-置換化合物に変換して一連の化合物を得た。8-アルコキシ-2-メチルキノリンを酸化して8-アルコキシキノリン-2-カルボキサルデヒド誘導体を得て、次に同じ方法によって化合物MからOを得た。
Method:
A solution of 8-hydroxy-2-methylquinol (6.0 g, 37.7 mmol) in dioxane (15 ml) was added dropwise at 50 ° C. to a stirred solution of SeO 2 (6.3 g, 56.8 mmol) in dioxane (80 ml). In addition, the mixture was heated to 80 ° C. for more than 20 hours. The resulting mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography with Hex / EA = (15: 1 to 10: 1), and 8-hydroxyquinoline-2-carboxaldehyde derivative (2.45 g, 38%). Intermediates were converted to N-substituted compounds by reductive amination using aminoalcohols, aminoalkynes or other heterocycles to give a series of compounds. 8-Alkoxy-2-methylquinoline was oxidized to give 8-alkoxyquinoline-2-carboxaldehyde derivative, and then O was obtained from compound M by the same method.
2-((4-(2-ヒドロキシエチル)ピペラジン(piperazin)-1-イル)メチル)キノリン-8-オール(M1)
YD: 76%。 1H NMR (400 MHz, CDCl3) δ8.02 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 6.8 Hz, 1H), 3.73 (s, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 5.6 Hz, 10H); HRMS (ESI): Calcd for [M+Na]+: 310.1526, Found: 310.1527。
2-((4- (2-hydroxyethyl) piperazin-1-yl) methyl) quinolin-8-ol (M1)
YD: 76%. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.22 ( d, J = 7.6 Hz, 1H), 7.10 (d, J = 6.8 Hz, 1H), 3.73 (s, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 5.6 Hz, HRMS (ESI): Calcd for [M + Na] + : 310.1526, Found: 310.1527.
2-(4-((5-クロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール(M2)
YD: 76%。 1H NMR (400 MHz, CDCl3) δ8.23 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 2H), 3.44 (t, J = 4.8 Hz, 2H), 2.35-2.38 (m, 10H); MS. m/z 336.1, [M+H]+。
2- (4-((5-Chloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol (M2)
YD: 76%. 1 H NMR (400 MHz, CDCl 3 ) δ8.23 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.68 ( d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 2H), 3.44 (t, J = 4.8 Hz, 2H), 2.35-2.38 (m, 10H); MS.m / z 336.1, [M + H] + .
2-(4-((5-クロロ-8-エトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール(M3)
YD: 53%。 1H NMR (400 MHz, CDCl3) δ8.36 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.18 (q, J = 6.8 Hz, 3H), 3.84 (s, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.45-2.50 (br, 10H), 1.49 (t, J = 6.8 Hz, 3H); MS. m/z 350.1, [M+H]+。
2- (4-((5-Chloro-8-ethoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol (M3)
YD: 53%. 1 H NMR (400 MHz, CDCl 3 ) δ8.36 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.83 ( d, J = 8.4 Hz, 1H), 4.18 (q, J = 6.8 Hz, 3H), 3.84 (s, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.45-2.50 (br, 10H), 1.49 (t, J = 6.8 Hz, 3H); MS. M / z 350.1, [M + H] + .
2-(4-((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール(M4)
YD: 61%。 1H NMR (400 MHz, d4-MeOD) δ8.52 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.87 (m, 1H), 3.89 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.54-2.62 (br, 10H), 1.45 (t, J = 6.0 Hz, 6H); MS. m/z 364.1, [M+H]+。
2- (4-((5-Chloro-8-isopropoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol (M4)
YD: 61%. 1 H NMR (400 MHz, d4-MeOD) δ8.52 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.87 (m, 1H), 3.89 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.54-2.62 (br, 10H), 1.45 (t, J = 6.0 Hz, 6H); MS. M / z 364.1, [M + H] + .
2-(4-((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタン(M5)
YD: 76%。 1H NMR (400 MHz, d4-MeOD) δ8.40 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.84 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 4.8 Hz, 2H), 2.56 (br, 8H), 2.51 (t, J = 4.8 Hz, 2H), 1.37-1.43 (m, 1H), 0.62-0.66 (m, 2H), 0.37-0.40 (m, 2H); MS. m/z 376.2, [M+H]+。
2- (4-((5-Chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethane (M5)
YD: 76%. 1 H NMR (400 MHz, d4-MeOD) δ8.40 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.84 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 4.8 Hz , 2H), 2.56 (br, 8H), 2.51 (t, J = 4.8 Hz, 2H), 1.37-1.43 (m, 1H), 0.62-0.66 (m, 2H), 0.37-0.40 (m, 2H); MS. M / z 376.2, [M + H] + .
2-(4-((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール(M6)
YD: 39%。 1H NMR (400 MHz, d4-MeOD) δ 8.53 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 4.11 (s, 3H), 3.89 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.63 (br, 8H), 2.55 (t, J = 6.0 Hz, 2H), 1.93 (s, 1H); MS. m/z 370.1, [M+H]+。
2- (4-((5,7-Dichloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol (M6)
YD: 39%. 1 H NMR (400 MHz, d4-MeOD) δ 8.53 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 4.11 (s, 3H), 3.89 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.63 (br, 8H), 2.55 (t, J = 6.0 Hz, 2H), 1.93 (s, 1H); MS.m / z 370.1, [M + H] + .
2-(4-((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール(M7)
YD: 82%。 1H NMR (400 MHz, CDCl3) δ8.43 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 4.22 (d, J = 7.2 Hz, 2H), 3.88 (s, 2H) 3.61 (t, J = 6.4 Hz, 2H), 2.56 (t, J = 5.2 Hz, 10H), 1.41-1.44 (m, 1H), 0.57-0.62 (m, 2H), 0.33-0.37 (m, 2H); MS. m/z 410.1, [M+Na]+。
2- (4-((5,7-Dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethanol (M7)
YD: 82%. 1 H NMR (400 MHz, CDCl 3 ) δ8.43 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 4.22 (d, J = 7.2 Hz, 2H), 3.88 (s, 2H) 3.61 (t, J = 6.4 Hz, 2H), 2.56 (t, J = 5.2 Hz, 10H), 1.41-1.44 (m, 1H), 0.57-0.62 (m, 2H), 0.33-0.37 (m, 2H); MS. M / z 410.1, [M + Na] + .
2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール(N1)
YD: 49%。 1H NMR (400 MHz, CDCl3) δ8.08 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 3.90 (s, 2H), 3.41 (d, J = 2.0 Hz, 2H), 2.39 (s, 3H), 2.31 (d, J = 2.0 Hz, 1H); MS. m/z 249.1, [M+H]+。
2-((Methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol (N1)
YD: 49%. 1 H NMR (400 MHz, CDCl 3 ) δ8.08 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 ( d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 3.90 (s, 2H), 3.41 (d, J = 2.0 Hz, 2H), 2.39 (s, 3H), 2.31 ( d, J = 2.0 Hz, 1H); MS. m / z 249.1, [M + H] + .
5-クロロ-2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール(N2)
YD: 38%。 1H NMR (400 MHz, CDCl3) δ8.47 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.93 (s, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.40 (s, 3H), 2.31 (t, J = 2.0 Hz, 1H); MS. m/z 261.0, [M+H]+。
5-Chloro-2-((methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol (N2)
YD: 38%. 1 H NMR (400 MHz, CDCl 3 ) δ8.47 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.08 ( d, J = 8.4 Hz, 1H), 3.93 (s, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.40 (s, 3H), 2.31 (t, J = 2.0 Hz, 1H); MS. m / z 261.0, [M + H] + .
N-((5-クロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N3)
YD: 52%。 1H NMR (400 MHz, CDCl3) δ8.48 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.37 (s, 3H), 2.27 (t, J = 2.0 Hz, 1H), MS. m/z 297.0, [M+Na]+。
N-((5-Chloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N3)
YD: 52%. 1 H NMR (400 MHz, CDCl 3 ) δ8.48 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.93 ( d, J = 8.4 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.37 (s, 3H), 2.27 (t, J = 2.0 Hz, 1H), MS. M / z 297.0, [M + Na] + .
N-((5-クロロ-8-エトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N4)
YD: 64%。 1H NMR (400 MHz, CDCl3) δ8.48 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J = 2.0 Hz, 1H), 1.59 (t, J = 6.8 Hz, 3H); MS. m/z 289.1, [M+H]+。
N-((5-Chloro-8-ethoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N4)
YD: 64%. 1 H NMR (400 MHz, CDCl 3 ) δ8.48 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.96 ( d, J = 8.4 Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 ( t, J = 2.0 Hz, 1H), 1.59 (t, J = 6.8 Hz, 3H); MS. m / z 289.1, [M + H] + .
N-((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N5)
YD: 76%。 1H NMR (400 MHz, CDCl3) δ8.47 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (m, 1H), 3.99 (s, 2H), 3.44 (d, J = 2.4 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J = 2.4 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H); MS. m/z 303.1, [M+H]+。
N-((5-chloro-8-isopropoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N5)
YD: 76%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.03 ( d, J = 8.4 Hz, 1H), 4.80 (m, 1H), 3.99 (s, 2H), 3.44 (d, J = 2.4 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J = 2.4 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H); MS. M / z 303.1, [M + H] + .
N-((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N6)
YD: 58%。 1H NMR (400 MHz, CDCl3) δ8.48 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J = 2.0 Hz, 1H), 1.42 ~ 1.50 (m, 1H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS. m/z 337.1, [M+Na]+。
N-((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N6)
YD: 58%. 1 H NMR (400 MHz, CDCl 3 ) δ8.48 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.98 ( d, J = 8.4 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 ( t, J = 2.0 Hz, 1H), 1.42 to 1.50 (m, 1H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS.m / z 337.1, [M + Na] + .
N-((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N7)
YD: 58%。 1H NMR (400 MHz, CDCl3) δ8.47 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 4.20 (s, 3H), 3.99 (s, 2H), 3.43 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.29 (t, J = 2.0 Hz, 1H); MS. m/z 309.0, [M+H]+。
N-((5,7-dichloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N7)
YD: 58%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 4.20 (s, 3H), 3.99 (s, 2H), 3.43 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.29 (t, J = 2.0 Hz, 1H); MS.m / z 309.0, [M + H] + .
N-((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン(N8)
YD: 76%。 1H NMR (400 MHz, CDCl3) δ8.45 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 4.25 (d, J = 7.6 Hz, 2H), 3.95 (s, 2H), 3.40 (d, J = 2.0 Hz, 2H), 2.40 (s, 3H), 2.28 (t, J = 2.0 Hz, 1H), 1.41-1.45 (m, 1H), 0.57-0.62 (m, 2H), 0.36 (dd, J = 10.0, 4.8 Hz, 2H); MS. m/z 371.0, [M+Na]+。
N-((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine (N8)
YD: 76%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 4.25 (d, J = 7.6 Hz, 2H), 3.95 (s, 2H), 3.40 (d, J = 2.0 Hz, 2H), 2.40 (s, 3H), 2.28 (t, J = 2.0 Hz, 1H), 1.41-1.45 (m, 1H ), 0.57-0.62 (m, 2H), 0.36 (dd, J = 10.0, 4.8 Hz, 2H); MS. M / z 371.0, [M + Na] + .
8-((5-クロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール(O1)
YD: 44%。 1H NMR (400 MHz, d4-MeOD) δ8.55 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.07 (s, 5H), 3.50 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.56 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.29-1.32 (br, 10H); MS. m/z 351.2, [M+H]+。
8-((5-Chloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol (O1)
YD: 44%. 1 H NMR (400 MHz, d4-MeOD) δ8.55 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.07 (s, 5H), 3.50 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.56 (quin, J = 7.2 Hz , 2H), 1.50 (quin, J = 6.8 Hz, 2H), 1.29-1.32 (br, 10H); MS. M / z 351.2, [M + H] + .
8-((5-クロロ-8-エトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール(O2)
YD: 41%。 1H NMR (400 MHz, d4-MeOD) δ8.51 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 4.07 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 1.47-1.58 (m, 7H), 1.31 (br, 9H); MS. m/z 365.2, [M+H]+。
8-((5-Chloro-8-ethoxyquinolin-2-yl) methylamino) octan-1-ol (O2)
YD: 41%. 1 H NMR (400 MHz, d4-MeOD) δ8.51 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 4.07 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 7.2 Hz , 2H), 1.47-1.58 (m, 7H), 1.31 (br, 9H); MS. M / z 365.2, [M + H] + .
8-((5-クロロ-8-イソプロポキシキノリン-2-イル)メチルアミノ)オクタン-1-オール(O3)
YD: 31%。 1H NMR (400 MHz, d4-MeOD) δ8.55 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.89 (m, 1H), 4.15 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 6.8 Hz, 2H) 1.46-1.50 (m, 8H), 1.33 (br, 9H); MS. m/z 379.2,[M+H]+。
8-((5-Chloro-8-isopropoxyquinolin-2-yl) methylamino) octan-1-ol (O3)
YD: 31%. 1 H NMR (400 MHz, d4-MeOD) δ8.55 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.89 (m, 1H), 4.15 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 6.8 Hz, 2H) 1.46-1.50 (m, 8H), 1.33 (br, 9H); MS. m / z 379.2, [M + H] + .
8-((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール(O4)
YD: 29%。 1H NMR (400 MHz, d4-MeOD) δ8.54 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.09 (s + d, J = 6.8 Hz, 4H), 3.51 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 7.2 Hz, 2H), 1.43-1.51 (m, 3H), 1.29-1.42 (br, 10H), 0.66-0.89 (m, 2H), 0.44 (dd, J = 10.4, 4.8 Hz, 2H); MS. m/z 391.2, [M+H]+。
8-((5-Chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol (O4)
YD: 29%. 1 H NMR (400 MHz, d4-MeOD) δ8.54 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.09 (s + d, J = 6.8 Hz, 4H), 3.51 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 7.2 Hz, 2H), 1.43-1.51 (m, 3H), 1.29-1.42 (br, 10H), 0.66-0.89 (m, 2H), 0.44 (dd, J = 10.4, 4.8 Hz, 2H ); MS. M / z 391.2, [M + H] + .
8-((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール(O5)
YD: 37%。 1H NMR (400 MHz, d4-MeOD) δ8.54 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 4.14 (s, 3H), 4.12 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.60 (quin, J = 6.8 Hz, 2H), 1.50 (m, 2H), 1.33 (br, 9H); MS. m/z 385.1, [M+H]+。
8-((5,7-Dichloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol (O5)
YD: 37%. 1 H NMR (400 MHz, d4-MeOD) δ8.54 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 4.14 (s, 3H) , 4.12 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.60 (quin, J = 6.8 Hz, 2H), 1.50 (m, 2H) , 1.33 (br, 9H); MS. M / z 385.1, [M + H] + .
8-((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール(O6)
YD: 56%。 1H NMR (400 MHz, d4-MeOD) δ8.51 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 4.22 (d, J = 7.2 Hz, 2H), 4.10 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.28-1.42 (br, 11H), 0.55-0.60 (m, 2H), 0.30-0.33 (m, 2H); MS. m/z 425.2, [M+H]+。
8-((5,7-Dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol (O6)
YD: 56%. 1 H NMR (400 MHz, d4-MeOD) δ8.51 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 4.22 (d, J = 7.2 Hz, 2H), 4.10 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.28-1.42 (br, 11H), 0.55-0.60 (m, 2H), 0.30-0.33 (m, 2H); MS. m / z 425.2, [M + H] + .
6-(ビス((8-メトキシキノリン-2-イル)メチル)アミノ)ヘキサン-1-オール(P1)
1H NMR (400 MHz, d4-MeOD) δ8.18 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 4.02 (s, 6H), 3.99 (s, 4H), 3.40 (t, J = 6.8 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 1.56 (quin, J = 6.8 Hz, 2H), 1.41 (quin, J = 6.8 Hz, 2H), 1.27 (quin, J = 7.6 Hz, 2H), 1.18 (quin, J = 6.8 Hz, 2H); MS. m/z 482.3, [M+Na]+。
6- (Bis ((8-methoxyquinolin-2-yl) methyl) amino) hexan-1-ol (P1)
1 H NMR (400 MHz, d4-MeOD) δ8.18 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 4.02 (s, 6H), 3.99 (s, 4H), 3.40 (t, J = 6.8 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 1.56 (quin, J = 6.8 Hz, 2H), 1.41 (quin, J = 6.8 Hz, 2H), 1.27 (quin, J = 7.6 Hz, 2H), 1.18 (quin , J = 6.8 Hz, 2H); MS. M / z 482.3, [M + Na] + .
図1Aは、コンゴーレッド染色の後に顕微鏡分析を用いて亜鉛イオンの存在又は非存在下においてC12がAβ凝集を阻害したことを示している。図1B及び図2は、予め形成されたAβ凝集体をC12が溶解したことを示している。図3A-Bは、化合物C12、CQ及びC12中間体がニューロン細胞を亜鉛誘導fAβから保護したことを示している。化合物C12だけは、亜鉛非存在凝集体に対して効果的であった(図3B)。図4は、未分化PC12細胞に対する化合物C12によって生じる神経突起伸長の誘導を示している。図5は、キノリン誘導体がGAP43の発現を増加させていることを示している。図6は、化合物C12及びB3がfAβ誘導記憶-障害マウスの学習能力を向上させたことを示している。C12及びB3(10mg/kg)は、ロータロッドテストにおいてfAβ病変マウスが乗っている時間を増加させた。図7A-Dは、化合物C12が、モーリス水迷路検査において記憶-障害fAβ病変マウスの学習を向上させたことを示している。隠れた台上に登る動作の合計時間(図7A)及び距離の合計長さ(図7B)に関してマウスを評価し、隠れた台周辺の区域に入る(泳いだ総時間と比較した)相対時間を示す目標区域への出現(図7C)も定量化し、平均遊泳速度(図7D)を評価して、向上した運動活性から向上した記憶を区別した。図8は、化合物C12によって記憶-障害fAβ病変マウスにおけるGAP43レベルの増加とfAβレベルの減少を示している。 FIG. 1A shows that C12 inhibited Aβ aggregation in the presence or absence of zinc ions using microscopic analysis after Congo red staining. FIG. 1B and FIG. 2 show that C12 dissolved a preformed Aβ aggregate. Figures 3A-B show that compounds C12, CQ and C12 intermediate protected neuronal cells from zinc-induced fAβ. Only compound C12 was effective against zinc-free aggregates (FIG. 3B). FIG. 4 shows the induction of neurite outgrowth caused by compound C12 on undifferentiated PC12 cells. FIG. 5 shows that the quinoline derivative increases the expression of GAP43. FIG. 6 shows that compounds C12 and B3 improved the learning ability of fAβ-induced memory-disordered mice. C12 and B3 (10 mg / kg) increased the time that fAβ lesioned mice were riding in the rotarod test. FIGS. 7A-D show that compound C12 improved learning of memory-impaired fAβ lesioned mice in the Morris water maze test. Evaluate the mouse for the total time of climbing on the hidden platform (Figure 7A) and the total length of distance (Figure 7B) and the relative time to enter the area around the hidden platform (compared to the total time spent swimming). Appearance in the indicated target area (FIG. 7C) was also quantified and average swimming speed (FIG. 7D) was evaluated to distinguish improved memory from improved locomotor activity. FIG. 8 shows an increase in GAP43 levels and a decrease in fAβ levels in memory-impaired fAβ lesioned mice with compound C12.
本発明の例示的な実施形態に関する前述の説明は、図示及び説明の目的のためだけに示しており、網羅的であったり開示される厳密な形態に本発明を制限したりすることを意図するものではない。上記説明の観点から多くの修正形態及び変更形態が可能である。 The foregoing descriptions of exemplary embodiments of the invention are presented for purposes of illustration and description only and are intended to be exhaustive or to limit the invention to the precise forms disclosed. It is not a thing. Many modifications and variations are possible in light of the above description.
実施形態及び実施例は、本発明及びそれらの実用的な応用の原理を説明する目的で選択し記載しており、他の当業者が本発明及び各種実施形態を、予想される特定の用途に適している各種変更形態を伴って利用することができるようにしている。代わり実施形態は、その趣旨及び範囲を逸脱しない範囲内で、関係する当業者にとって明らかになるだろう。従って、本発明の範囲は、ここで記載されている前述の記述及び例示的な実施形態よりは、むしろ添付の特許請求の範囲によって規定される。 The embodiments and examples have been selected and described for the purpose of illustrating the principles of the invention and their practical application, and others skilled in the art will find the invention and various embodiments suitable for the specific applications envisaged. It can be used with various suitable modifications. Alternate embodiments will be apparent to those skilled in the art without departing from the spirit and scope thereof. Accordingly, the scope of the invention is defined by the appended claims rather than the foregoing description and exemplary embodiments described herein.
特許、特許出願及び様々な刊行物を含み得るいくつかの参考文献は、本発明の記述に引用され論じられている参考文献の引用又は議論は、単に本発明の記述を明確にするためだけに提供されているものであり、かかる任意の参考文献が本願明細書に記載の本発明に対する「先行技術」であるという自認でない。この明細書中で引用され議論されている全ての文献は、それらの全体が本願明細書に引用によって組み込まれており、各文献が引用によって個々に組み込まれているのと同程度に組込まれている。 Some references, which may include patents, patent applications, and various publications, are cited or discussed in the description of the present invention only to clarify the description of the invention. It is provided that there is no admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety and are incorporated to the same extent as if each reference was individually incorporated by reference. Yes.
Claims (15)
R1は、水素、(C1-C8)アルキル、(C1-C8)アルキレン(C3-C8)シクロアルキル、(C1-C8)ハロアルキル又は(C1-C8)アルキレン(C6-C20)アリールであり;
R2は、水素又はハロゲンであり;
R3は水素、ハロゲン、(C1-C8)アルキル又は(C1-C8)アルコキシであり;
R4は、水素、ハロゲン、(C1-C8)アルキル、(C1-C8)アルコキシ又は(C1-C8)ハロアルキルであり;
R5は、水素又は(C1-C20)アルカノールであり;
R6は、水素であり;
R7は、水素、(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルカノール、(C1-C8)アルキレン(C3-C8)ヘテロサイクリル(C1-C20)アルキル、(C1-C8)アルキレン(C1-C6)アルキルアミノ(C1-C6)アルキニル、(C1-C8)アルキレンアミノ(C1-C20)アルカノール又は(C1-C8)アルキレンアミノ(C1-C20)アルカノール(C1-C8)アルキレン置換(C3-C20)ヘテロアリールである、化合物又はその医薬的に許容可能な塩、溶媒和物若しくは水和物、プロドラッグ若しくは代謝産物。 Chemical formula (I)
R 1 is hydrogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkylene (C 3 -C 8 ) cycloalkyl, (C 1 -C 8 ) haloalkyl or (C 1 -C 8 ) alkylene (C 6 -C 20 ) aryl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, (C 1 -C 8 ) alkyl or (C 1 -C 8 ) alkoxy;
R 4 is hydrogen, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy or (C 1 -C 8 ) haloalkyl;
R 5 is hydrogen or (C 1 -C 20 ) alkanol;
R 6 is hydrogen;
R 7 is hydrogen, (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkanol, (C 1 -C 8 ) alkylene (C 3 -C 8 ) heterocyclyl (C 1 -C 20 ) alkyl, (C 1 -C 8 ) alkylene (C 1 -C 6 ) alkylamino (C 1 -C 6 ) alkynyl, (C 1 -C 8) is alkyleneamino (C 1 -C 20) alkanols or (C 1 -C 8) alkylene amino (C 1 -C 20) alkanols (C 1 -C 8) alkylene-substituted (C 3 -C 20) heteroaryl , A compound or a pharmaceutically acceptable salt, solvate or hydrate, prodrug or metabolite thereof.
R2は、水素、F又はClであり;
R3は、水素、F、Cl、CH3又はOCH3であり;
R4は、水素、F、Cl、Br、CH3、OCH3又はCF3であり;
R5は、水素、(CH2)11OH又は(CH2)12OHであり;
R6は、水素であり;
R7は、水素、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)14OH、(CH2)15OH、CH2(N(CH2CH2)2N)CH2CH2OH、CH2(N(CH2CH2)2N)CH2CH3、CH2N(CH3)CH2C≡CH、CH2NH(CH2)8OH又はCH2N((CH2)6OH)CH2(8-メトキシキノリン-2-イル)である、請求項1に記載の化合物。 R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CF 3 or benzyl;
R 2 is hydrogen, F or Cl;
R 3 is hydrogen, F, Cl, CH 3 or OCH 3 ;
R 4 is hydrogen, F, Cl, Br, CH 3 , OCH 3 or CF 3 ;
R 5 is hydrogen, (CH 2 ) 11 OH or (CH 2 ) 12 OH;
R 6 is hydrogen;
R 7 is hydrogen, (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 14 OH, (CH 2 ) 15 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 2 OH, CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 3 , CH 2 N (CH 3 ) CH 2 C≡CH, a CH 2 NH (CH 2) 8 OH or CH 2 N ((CH 2) 6 OH) CH 2 (8- methoxy-2-yl) compound according to claim 1.
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)14OH、(CH2)15OH、CH2(N(CH2CH2)2N)CH2CH2OH又はCH2N(CH3)CH2C≡CHである、請求項2に記載の化合物。 R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 , CF 3 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 14 OH, (CH 2 ) 15 OH, CH 2 (N ( CH 2 CH 2) 2 N) CH 2 CH 2 OH or CH 2 N (CH 3) a CH 2 C≡CH, compound of claim 2.
R2、R3、R5及びR6は、他と関係なくそれぞれ水素であり;
R4は、CH3、F、Cl、Br、CF3又はOCH3であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OH、(CH2)10OCOCH3、(CH2)11OCOCH3、(CH2)12OCOCH3、(CH2)13OCOCH3、CH2NH(CH2)8OH、CH2(N(CH2CH2)2N)CH2CH2OH、CH2(N(CH2CH2)2N)CH2CH3又はCH2N(CH3)CH2C≡CHである、請求項2に記載の化合物。 R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 5 and R 6 are each independently hydrogen;
R 4 is CH 3 , F, Cl, Br, CF 3 or OCH 3 ;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, (CH 2 ) 10 OCOCH 3 , (CH 2 ) 11 OCOCH 3 , (CH 2 ) 12 OCOCH 3 , (CH 2 ) 13 OCOCH 3 , CH 2 NH (CH 2 ) 8 OH, CH 2 (N (CH 2 CH 2 ) 2 N ) CH 2 CH 2 OH, CH 2 (N (CH 2 CH 2) 2 N) CH 2 CH 3 or CH 2 N (CH 3) a CH 2 C≡CH, compound of claim 2.
R2、R4は、他と関係なくそれぞれClであり;
R3、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、(CH2)11OH、CH2NH(CH2)8OH又はCH2N(CH3)CH2C≡CHである、請求項2に記載の化合物。 R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH (CH 2 ) 2 or CH 2 CH (CH 2 ) 2 ;
R 2 and R 4 are each Cl independently of the others;
R 3 , R 5 and R 6 are each independently hydrogen,
The compound according to claim 2, wherein R 7 is (CH 2 ) 11 OH, CH 2 NH (CH 2 ) 8 OH, or CH 2 N (CH 3 ) CH 2 C≡CH.
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、請求項2に記載の化合物。 R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 , CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
The compound according to claim 2, wherein R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH.
R2、R5及びR6は、他と関係なくそれぞれ水素であり;
R3及びR4は、他と関係なくそれぞれOCH3又はClであり;
R7は、(CH2)11OHである、請求項2に記載の化合物。 R 1 is CH 3 ;
R 2 , R 5 and R 6 are each independently hydrogen;
R 3 and R 4 are each independently OCH 3 or Cl;
The compound according to claim 2 , wherein R 7 is (CH 2 ) 11 OH.
9-(8-(ベンジルオキシ)キノリン-2-イル)ノナン-1-オール、
10-(8-(ベンジルオキシ)キノリン-2-イル)デカン-1-オール、
11-(8-(ベンジルオキシ)キノリン-2-イル)ウンデカン-1-オール、
12-(8-(ベンジルオキシ)キノリン-2-イル)ドデカン-1-オール、
13-(8-(ベンジルオキシ)キノリン-2-イル)トリデカン-1-オール、
14-((8-(ベンジルオキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(ベンジルオキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(8-(ベンジルオキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-6-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)-5-クロロキノリン-2-イル)ウンデカン-1-オール、
2-(9-ヒドロキシノニル)キノリン-8-オール、
2-(10-ヒドロキシデシル)キノリン-8-オール、
2-(11-ヒドロキシウンデシル)キノリン-8-オール、
2-(12-ヒドロキシウンデシル)キノリン-8-オール、
2-(13-ヒドロキシトリデシル)キノリン-8-オール、
2-(14-(-ヒドロキシテトラデシル)キノリン-8-オール、
2-(15-ヒドロキシペンタデシル)キノリン-8-オール、
2-(11-ヒドロキシウンデシル)-5-メチルキノリン-8-オール、
2-(11-ヒドロキシウンデシル)-6-メチルキノリン-8-オール、
5-クロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール、
9-(8-メトキシキノリン-2-イル)ノナン-1-オール、
10-(8-メトキシキノリン-2-イル)デカン-1-オール、
11-(8-メトキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-メトキシキノリン-2-イル)ドデカン-1-オール、
13-(8-メトキシキノリン-2-イル)トリデカン-1-オール、
14-((8-メトキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-メトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-メトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(5-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
12-(5-フルオロ-8-メトキシキノリン-2-イル)ドデカン-1-オール、
9-(5-クロロ-8-メトキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-メトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(8-メトキシ-5-(トリフルオロメチル)キノリン-2-イル)ウンデカン-1-オール、
11-(5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(8-メトキシ-6-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(6-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(6-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(7-フルオロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(7-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5-クロロ-6,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(6-クロロ-5,8-ジメトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-エトキシキノリン-2-イル)ノナン-1-オール、
10-(8-エトキシキノリン-2-イル)デカン-1-オール、
11-(8-エトキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-エトキシキノリン-2-イル)ドデカン-1-オール、
13-(8-エトキシキノリン-2-イル)トリデカン-1-オール、
14-((8-エトキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-エトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-エトキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-エトキシ-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-エトキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-エトキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-エトキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-イソプロポキシキノリン-2-イル)ノナン-1-オール、
10-(8-イソプロポキシキノリン-2-イル)デカン-1-オール、
11-(8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
12-(8-イソプロポキシキノリン-2-イル)ドデカン-1-オール、
13-(8-イソプロポキシキノリン-2-イル)トリデカン-1-オール、
14-((8-イソプロポキシキノリン-2-イル)テトラデカン-1-オール、
15-(8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(8-イソプロポキシ-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(5-フルオロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-イソプロポキシキノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-イソプロポキシキノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-イソプロポキシキノリン-2-イル)ウンデカン-1-オール、
9-(8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール、
10-(8-(シクロプロピルメトキシ)キノリン-2-イル)デカン-1-オール、
11-(8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
12-(8-(シクロプロピルメトキシ)キノリン-2-イル)ドデカン-1-オール、
13-(8-(シクロプロピルメトキシ)キノリン-2-イル)トリデカン-1-オール、
14-((8-(シクロプロピルメトキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(8-(シクロプロピルメトキシ)-5-メチルキノリン-2-イル)ウンデカン-1-オール、
11-(8-(シクロプロピルメトキシ)-5-フルオロキノリン-2-イル)ウンデカン-1-オール、
9-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ノナン-1-オール、
11-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
15-(5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
11-(5-ブロモ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
11-(5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)ウンデカン-1-オール、
5,7-ジクロロ-2-(11-ヒドロキシウンデシル)キノリン-8-オール、
10-(5-クロロ-8-メトキシキノリン-2-イル)デカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 10-デシルエステル、
11-(5-クロロ-8-メトキシキノリン-2-イル)ウンデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 11-ウンデシルエステル、
12-(5-クロロ-8-メトキシキノリン-2-イル)ドデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 12-ドデシルエステル、
13-(5-クロロ-8-メトキシキノリン-2-イル)トリデカン-1-オール、
酢酸(5-クロロ-8-メトキシキノリン-2-イル) 13-トリデシルエステル、
11-(8-メトキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-エトキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-イソプロポキシキノリン-4-(-イル)ウンデカン-1-オール、
11-(8-(シクロプロピルメトキシ)キノリン-4-(-イル)ウンデカン-1-オール、
11-(8-(ベンジルオキシ)キノリン-4-(-イル)ウンデカン-1-オール、
12-(8-(ベンジルオキシ)キノリン-4-(-イル)ドデカン-1-オール、
4-((11-ヒドロキシウンデシル)キノリン-8-オール、
4-((12-ヒドロキシウンデシル)キノリン-8-オール、
9-(8-(トリフルオロメトキシ)キノリン-2-イル)ノナ-1-オール、
11-(8-(トリフルオロメトキシ)キノリン-2-イル)ウンデカン-1-オール、
14-((8-(トリフルオロメトキシ)キノリン-2-イル)テトラデカン-1-オール、
15-(8-(トリフルオロメトキシ)キノリン-2-イル)ペンタデカン-1-オール、
2-((4-((2-ヒドロキシエチル)ピペラジン(piperazin)-1-イル)メチル)キノリン-8-オール、
2-(4-(((5-クロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-エトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタン、
2-(4-(((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-(4-(((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)ピペラジン(piperazin)-1-イル)エタノール、
2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール、
5-クロロ-2-((メチル(プロプ-2-イニル)アミノ)メチル)キノリン-8-オール、
N((5-クロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-エトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-イソプロポキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
N((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチル)-N-メチルプロプ-2-イン-1-アミン、
8-((5-クロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-エトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-イソプロポキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5-クロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5,7-ジクロロ-8-メトキシキノリン-2-イル)メチルアミノ)オクタン-1-オール、
8-((5,7-ジクロロ-8-(シクロプロピルメトキシ)キノリン-2-イル)メチルアミノ)オクタン-1-オール、及び6-(ビス((8-メトキシキノリン-2-イル)メチル)アミノ)ヘキサン-1-オールからなる群より選択される、請求項2に記載の化合物。 The compound is
9- (8- (benzyloxy) quinolin-2-yl) nonan-1-ol,
10- (8- (benzyloxy) quinolin-2-yl) decan-1-ol,
11- (8- (benzyloxy) quinolin-2-yl) undecan-1-ol,
12- (8- (benzyloxy) quinolin-2-yl) dodecan-1-ol,
13- (8- (benzyloxy) quinolin-2-yl) tridecan-1-ol,
14-((8- (benzyloxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (benzyloxy) quinolin-2-yl) pentadecan-1-ol,
11- (8- (benzyloxy) -5-methylquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -6-methylquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -5-fluoroquinolin-2-yl) undecan-1-ol,
11- (8- (benzyloxy) -5-chloroquinolin-2-yl) undecan-1-ol,
2- (9-hydroxynonyl) quinolin-8-ol,
2- (10-hydroxydecyl) quinolin-8-ol,
2- (11-hydroxyundecyl) quinolin-8-ol,
2- (12-hydroxyundecyl) quinolin-8-ol,
2- (13-hydroxytridecyl) quinolin-8-ol,
2- (14-(-hydroxytetradecyl) quinolin-8-ol,
2- (15-hydroxypentadecyl) quinolin-8-ol,
2- (11-hydroxyundecyl) -5-methylquinolin-8-ol,
2- (11-hydroxyundecyl) -6-methylquinolin-8-ol,
5-chloro-2- (11-hydroxyundecyl) quinolin-8-ol,
9- (8-methoxyquinolin-2-yl) nonan-1-ol,
10- (8-methoxyquinolin-2-yl) decan-1-ol,
11- (8-methoxyquinolin-2-yl) undecan-1-ol,
12- (8-methoxyquinolin-2-yl) dodecan-1-ol,
13- (8-methoxyquinolin-2-yl) tridecan-1-ol,
14-((8-methoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-methoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-methoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (5-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
12- (5-fluoro-8-methoxyquinolin-2-yl) dodecan-1-ol,
9- (5-chloro-8-methoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-methoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (8-methoxy-5- (trifluoromethyl) quinolin-2-yl) undecan-1-ol,
11- (5,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (8-methoxy-6-methylquinolin-2-yl) undecan-1-ol,
11- (6-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (6-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (7-fluoro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (7-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
11- (5-chloro-6,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (6-chloro-5,8-dimethoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-methoxyquinolin-2-yl) undecan-1-ol,
9- (8-ethoxyquinolin-2-yl) nonan-1-ol,
10- (8-ethoxyquinolin-2-yl) decan-1-ol,
11- (8-ethoxyquinolin-2-yl) undecan-1-ol,
12- (8-ethoxyquinolin-2-yl) dodecan-1-ol,
13- (8-ethoxyquinolin-2-yl) tridecan-1-ol,
14-((8-ethoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-ethoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-ethoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (8-ethoxy-5-fluoroquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8-ethoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-ethoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-ethoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-ethoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-ethoxyquinolin-2-yl) undecan-1-ol,
9- (8-isopropoxyquinolin-2-yl) nonan-1-ol,
10- (8-isopropoxyquinolin-2-yl) decan-1-ol,
11- (8-isopropoxyquinolin-2-yl) undecan-1-ol,
12- (8-isopropoxyquinolin-2-yl) dodecan-1-ol,
13- (8-isopropoxyquinolin-2-yl) tridecan-1-ol,
14-((8-isopropoxyquinolin-2-yl) tetradecan-1-ol,
15- (8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (8-isopropoxy-5-methylquinolin-2-yl) undecan-1-ol,
11- (5-fluoro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8-isopropoxyquinolin-2-yl) nonan-1-ol,
11- (5-chloro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-isopropoxyquinolin-2-yl) undecan-1-ol,
15- (5-chloro-8-isopropoxyquinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8-isopropoxyquinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8-isopropoxyquinolin-2-yl) undecan-1-ol,
9- (8- (cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol,
10- (8- (cyclopropylmethoxy) quinolin-2-yl) decan-1-ol,
11- (8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
12- (8- (cyclopropylmethoxy) quinolin-2-yl) dodecan-1-ol,
13- (8- (cyclopropylmethoxy) quinolin-2-yl) tridecan-1-ol,
14-((8- (cyclopropylmethoxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol,
11- (8- (cyclopropylmethoxy) -5-methylquinolin-2-yl) undecan-1-ol,
11- (8- (cyclopropylmethoxy) -5-fluoroquinolin-2-yl) undecan-1-ol,
9- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) nonan-1-ol,
11- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
15- (5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) pentadecan-1-ol,
11- (5-bromo-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
11- (5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) undecan-1-ol,
5,7-dichloro-2- (11-hydroxyundecyl) quinolin-8-ol,
10- (5-chloro-8-methoxyquinolin-2-yl) decan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 10-decyl ester,
11- (5-chloro-8-methoxyquinolin-2-yl) undecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 11-undecyl ester,
12- (5-chloro-8-methoxyquinolin-2-yl) dodecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 12-dodecyl ester,
13- (5-chloro-8-methoxyquinolin-2-yl) tridecan-1-ol,
Acetic acid (5-chloro-8-methoxyquinolin-2-yl) 13-tridecyl ester,
11- (8-methoxyquinolin-4-(-yl) undecan-1-ol,
11- (8-ethoxyquinolin-4-(-yl) undecan-1-ol,
11- (8-isopropoxyquinolin-4-(-yl) undecan-1-ol,
11- (8- (cyclopropylmethoxy) quinolin-4-(-yl) undecan-1-ol,
11- (8- (benzyloxy) quinolin-4-(-yl) undecan-1-ol,
12- (8- (benzyloxy) quinolin-4-(-yl) dodecan-1-ol,
4-((11-hydroxyundecyl) quinolin-8-ol,
4-((12-hydroxyundecyl) quinolin-8-ol,
9- (8- (trifluoromethoxy) quinolin-2-yl) non-1-ol,
11- (8- (trifluoromethoxy) quinolin-2-yl) undecan-1-ol,
14-((8- (trifluoromethoxy) quinolin-2-yl) tetradecan-1-ol,
15- (8- (trifluoromethoxy) quinolin-2-yl) pentadecan-1-ol,
2-((4-((2-hydroxyethyl) piperazin-1-yl) methyl) quinolin-8-ol,
2- (4-(((5-chloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8-ethoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8-isopropoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethane,
2- (4-(((5,7-dichloro-8-methoxyquinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2- (4-(((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) piperazin-1-yl) ethanol,
2-((methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol,
5-chloro-2-((methyl (prop-2-ynyl) amino) methyl) quinolin-8-ol,
N ((5-chloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8-ethoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8-isopropoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5,7-dichloro-8-methoxyquinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
N ((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methyl) -N-methylprop-2-yn-1-amine,
8-((5-chloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8-ethoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8-isopropoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5-chloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol,
8-((5,7-dichloro-8-methoxyquinolin-2-yl) methylamino) octan-1-ol,
8-((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl) methylamino) octan-1-ol and 6- (bis ((8-methoxyquinolin-2-yl) methyl) 3. A compound according to claim 2 selected from the group consisting of amino) hexan-1-ol.
(1)
化学式(II)
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は、他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は、他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素である、化合物と、臭化ベンジル、ヨウ化メチル、ヨウ化エチル、2-ブロモプロパン又は臭化メチレンシクロプロピルとを塩基性溶液中において約室温から約80℃にて反応させて、化学式(III)
R1は、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2又はベンジルであり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素である、化合物を取得するステップと、(2)
化学式(III)の化合物とリチウムビス(トリメチルシリル)アミド及び臭化(C1-C20)アルカノールとをテトラヒドロフラン中において0℃にて反応させて化学式(I)
R1は、CH3、CH2CH3、CH(CH3)2、CH2CH(CH3)2又はベンジルであり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
又は
R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClである若しくはR3はClであり、R4はOCH3である;
又は
R2、R4はClであり、R3、R5、R6は他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OHである、化合物を取得するステップと、
(3)
化学式(I)の化合物であって、
R1はベンジルである、化合物と、加圧水素ガスとパラジウム炭素とをメタノール中において室温にて、又は、三塩化ホウ素とをジクロロメタン中において0℃にて反応させて化学式(I)
R1、R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素である;
又は
R1、R2、R4、R5及びR6は他と関係なくそれぞれ水素であり、R3はCH3である;
又は
R1、R2、R3、R5及びR6は他と関係なくそれぞれ水素であり、R4はCH3、F、Cl又はBrである;
R1、R2、R5、R6は他と関係なくそれぞれ水素であり、R3はOCH3であり、R4はClであり;R3はClであり、R4はOCH3である;
又は
R2、R4はClであり、R1、R3、R5、R6は他と関係なくそれぞれ水素であり;
R7は、(CH2)9OH、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OHである、化合物を取得するステップ
又は
(4)
化学式(I)の化合物であって、
R1、R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり、
R7は(CH2)11OHである、化合物と、N-クロロスクシンイミドとを塩化メチル中において室温にて反応させて、化学式(I)の化合物であって、
R1、R3、R5及びR6は、他と関係なくそれぞれ水素であり、
R2及びR4は、他と関係なくそれぞれ塩素であり、
R7は、(CH2)11OHである、化合物を得るステップ
又は
(5)
化学式(I)の化合物であって
R1は、メチルであり、
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり、
R7は、(CH2)11OH、(CH2)12OH又は(CH2)13OHである、化合物と、濃塩酸、ICl3及び氷酢酸とを反応させて、化学式(I)の化合物であって、
R1は、メチルであり、
R2、R3、R5及びR6は、他と関係なくそれぞれ水素であり、
R4は、Clであり、
R7は、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH、(CH2)15OH、(CH2)10OCOCH3、(CH2)11OCOCH3、(CH2)12OCOCH3、(CH2)13OCOCH3である、化合物を得るステップ
又は
(6)
2-アミノフェノールとメチルビニルケトンとを塩酸中において反応させて、化学式(INT-1)
(7)
化学式(INT-1)の化合物とヨウ化メチル、ヨウ化エチル、2-ブロモプロパン、臭化メチレンシクロプロピル又は臭化ベンジルとを塩基性溶液中において反応させて化学式(III)
R10は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルである、化合物を得るステップと、
(8)
化学式(III)の化合物であって、
R10は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルである、化合物と、リチウムビス(トリメチルシリル)アミド及び11-ブロモ-ウンデカノール又は12-ブロモドデカノールとをテトラヒドロフラン中において0℃にて反応させて、化学式(I)の化合物であって、
R1は、メチル、エチル、2-プロピル、メチレンシクロプロピル又はベンジルであり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物を取得するステップと、
(9)
化学式(I)の化合物であって、
R1は、ベンジルであり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物と、加圧水素ガスとパラジウム炭素とをメタノール中において室温にて反応させて、化学式(I)の化合物であって、
R1は、水素であり;
R2、R3、R4、R6及びR7は、他と関係なくそれぞれ水素であり;
R5は、(CH2)11OH又は(CH2)12OHである、化合物を取得するステップ
又は
(10)
2-トリフルオロメトキサナリン(trifluoromethoxyanaline)とクロトンアルデヒドとを反応させて2-メチル-8-トリフルオメトキシキノリン(trifluormethoxyquinoline)を取得し、リチウムビス(トリメチルシリル)アミド及び臭化(C1C20)アルカノールを用いてテトラヒドロフラン中において0℃にて処理して、化学式(I)の化合物であって
R1は、トリフルオロメチル(trifluoroemethyl)であり;
R2、R3、R4、R5及びR7は、他と関係なくそれぞれ水素であり;
R7は、(CH2)10OH、(CH2)11OH、(CH2)12OH、(CH2)13OH又は(CH2)15OHである、化合物を取得するステップ
又は
(11)
化学式(IV)
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物と二酸化セレンとをジオキサン中において高温にて反応させて、化学式(VI)
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物を得るステップと
(12)
化学式(VI)の化合物であって、
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物とN-メチルプロパルギルアミン(methylpropagylamine)とを反応させて、化学式(I)の化合物であって、
R1は水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり;
R2、R3、R4、R5及びR6は他と関係なくそれぞれ水素であり;
R7は、CH2N(CH3)CH2C≡CHである、化合物を取得するステップ
又は
(13)
化学式(VI)の化合物であって、
R1は、水素、メチル、エチル、2-プロピル又はメチレンシクロプロピルである、化合物と2(ピペラジン(piperazin)-1-イル)エタノールとを反応させて、化学式(I)の化合物であって、
R1は、水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、CH2(N(CH2CH2)2N)CH2CH2OHである、化合物を取得するステップ
又は
(14)
化学式(VI)の化合物とアミノ(C1-C20)アルカノールとを反応させて、化学式(I)の化合物であって、
R1は、水素、CH3、CH2CH3、CH2CH(CH3)2、CH2CH(CH2)2又はCH(CH3)2であり;
R2、R3、R4、R5及びR6は、他と関係なくそれぞれ水素であり;
R7は、CH2NH(CH2)8OH又はCH2N((CH2)6OH)CH2(8-メトキシキノリン-2-イル)である、化合物を取得するステップと、を有する方法。 A method of preparing the compound of claim 1, wherein the method comprises:
(1)
Chemical formula (II)
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 , R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl;
Or
R 2 , R 4 is Cl, and R 3 , R 5 , R 6 are each independently hydrogen, the compound, benzyl bromide, methyl iodide, ethyl iodide, 2-bromopropane or bromide Methylenecyclopropyl is reacted in a basic solution at about room temperature to about 80 ° C. to obtain a chemical formula (III)
R 1 is CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl;
Or
R 2 , R 4 is Cl, and R 3 , R 5 , R 6 are each independently hydrogen, obtaining a compound, (2)
A compound of formula (III) is reacted with lithium bis (trimethylsilyl) amide and bromide (C 1 -C 20 ) alkanol in tetrahydrofuran at 0 ° C. to give a compound of formula (I)
R 1 is CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 or benzyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen independently of the others;
Or
R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
Or
R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 , R 4 is Cl or R 3 is Cl and R 4 is OCH 3 ;
Or
R 2 , R 4 are Cl, and R 3 , R 5 , R 6 are each independently hydrogen;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, the compound A step to obtain,
(3)
A compound of formula (I) comprising:
R 1 is benzyl, the compound of formula (I) is reacted with pressurized hydrogen gas and palladium carbon in methanol at room temperature or boron trichloride at 0 ° C. in dichloromethane.
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
Or
R 1 , R 2 , R 4 , R 5 and R 6 are each independently hydrogen and R 3 is CH 3 ;
Or
R 1 , R 2 , R 3 , R 5 and R 6 are each independently hydrogen and R 4 is CH 3 , F, Cl or Br;
R 1 , R 2 , R 5 and R 6 are each independently hydrogen, R 3 is OCH 3 and R 4 is Cl; R 3 is Cl and R 4 is OCH 3 ;
Or
R 2 , R 4 are Cl, and R 1 , R 3 , R 5 , R 6 are each hydrogen independently of the others;
R 7 is (CH 2 ) 9 OH, (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, the compound Step to get or
(Four)
A compound of formula (I) comprising:
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
R 7 is (CH 2 ) 11 OH, a compound of formula (I) obtained by reacting a compound with N-chlorosuccinimide in methyl chloride at room temperature,
R 1 , R 3 , R 5 and R 6 are each independently hydrogen,
R 2 and R 4 are each independently chlorine,
R 7 is (CH 2 ) 11 OH
(Five)
A compound of formula (I)
R 1 is methyl;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen,
R 7 is (CH 2 ) 11 OH, (CH 2 ) 12 OH or (CH 2 ) 13 OH, a compound of the formula (I) obtained by reacting a compound with concentrated hydrochloric acid, ICl 3 and glacial acetic acid. Because
R 1 is methyl;
R 2 , R 3 , R 5 and R 6 are each independently hydrogen,
R 4 is Cl;
R 7 is (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH, (CH 2 ) 15 OH, (CH 2 ) 10 OCOCH 3 , (CH 2 ) 11 OCOCH 3 , (CH 2 ) 12 OCOCH 3 , (CH 2 ) 13 OCOCH 3
(6)
Reaction of 2-aminophenol and methyl vinyl ketone in hydrochloric acid gives the chemical formula (INT-1)
(7)
A compound of the formula (INT-1) is reacted with methyl iodide, ethyl iodide, 2-bromopropane, methylenecyclopropyl bromide or benzyl bromide in a basic solution to give a chemical formula (III)
Obtaining a compound wherein R 10 is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl;
(8)
A compound of formula (III),
R 10 is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl, a compound and lithium bis (trimethylsilyl) amide and 11-bromo-undecanol or 12-bromododecanol at 0 ° C. in tetrahydrofuran. Reacted with a compound of formula (I),
R 1 is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH to obtain a compound;
(9)
A compound of formula (I) comprising:
R 1 is benzyl;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH, a compound of the formula (I) obtained by reacting a compound, pressurized hydrogen gas and palladium carbon in methanol at room temperature. ,
R 1 is hydrogen;
R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen,
R 5 is (CH 2 ) 11 OH or (CH 2 ) 12 OH
(Ten)
2-Trifluoromethoxyquinoline is obtained by reacting trifluoromethoxyanaline with trifluoromethoxyanaline to obtain lithium bis (trimethylsilyl) amide and bromide (C 1 C 20 ) alkanol A compound of formula (I), treated at 0 ° C. in tetrahydrofuran with
R 1 is trifluoroemethyl;
R 2 , R 3 , R 4 , R 5 and R 7 are each independently hydrogen,
R 7 is (CH 2 ) 10 OH, (CH 2 ) 11 OH, (CH 2 ) 12 OH, (CH 2 ) 13 OH or (CH 2 ) 15 OH
(11)
Chemical formula (IV)
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl. The compound and selenium dioxide are reacted at high temperature in dioxane to obtain a compound of formula (VI)
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl to obtain the compound
(12)
A compound of formula (VI),
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl, a compound of formula (I) obtained by reacting a compound with N-methylpropagylamine,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is CH 2 N (CH 3 ) CH 2 C≡CH, or
(13)
A compound of formula (VI),
R 1 is hydrogen, methyl, ethyl, 2-propyl or methylenecyclopropyl, a compound of formula (I) by reacting a compound with 2 (piperazin-1-yl) ethanol,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is CH 2 (N (CH 2 CH 2 ) 2 N) CH 2 CH 2 OH
(14)
A compound of the formula (I) obtained by reacting a compound of the formula (VI) with an amino (C 1 -C 20 ) alkanol,
R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , CH 2 CH (CH 2 ) 2 or CH (CH 3 ) 2 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen;
R 7 is CH 2 NH (CH 2 ) 8 OH or CH 2 N ((CH 2 ) 6 OH) CH 2 (8-methoxyquinolin-2-yl) to obtain a compound. .
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PCT/US2013/034960 WO2014163622A1 (en) | 2013-04-02 | 2013-04-02 | Multifunctional quinoline derivatives as anti-neurodegenerative agents |
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JP (1) | JP6153179B2 (en) |
KR (1) | KR101802048B1 (en) |
CN (1) | CN105452224B (en) |
AU (1) | AU2013385618B2 (en) |
BR (1) | BR112015024472A2 (en) |
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KR101725326B1 (en) * | 2015-04-23 | 2017-04-12 | 대한민국 | A novel isolated midroorganism having antibiotic activity and a production method of pseudane using the same |
CN105949120B (en) * | 2016-05-27 | 2018-07-24 | 广东工业大学 | A kind of application of four teeth chelating type list quinoline and preparation method thereof and metal ion control agent as neurodegenerative disease |
KR102281647B1 (en) * | 2020-12-09 | 2021-07-30 | 메디케어제약 주식회사 | Method of producing a derivative-piperazine |
CN113527200B (en) * | 2021-05-27 | 2022-12-02 | 北京斯利安药业有限公司 | Preparation method of cloquinadol |
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WO2005035534A1 (en) * | 2003-10-08 | 2005-04-21 | Ono Pharmaceutical Co., Ltd. | Heterocyclic bicyclo ring and heterocyclic tricyclo ring compounds and drugs comprising the same |
JP2006504646A (en) * | 2002-07-16 | 2006-02-09 | プラナ バイオテクノロジー リミティッド | 8-hydroxyquinoline derivatives |
JP2007513944A (en) * | 2003-12-11 | 2007-05-31 | アボット・ラボラトリーズ | HIV protease inhibitor sulfonamides |
CN102526052A (en) * | 2012-01-19 | 2012-07-04 | 华南师范大学 | Application of 2-gylcosyl chinoline compound in preparing acetylcholine esterase resisting medicines |
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GB9127306D0 (en) * | 1991-12-23 | 1992-02-19 | Boots Co Plc | Therapeutic agents |
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KR100538152B1 (en) * | 1997-07-07 | 2005-12-21 | 코와 가부시키가이샤 | Diamine derivatives and pharmaceutical containing the same |
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2013
- 2013-04-02 KR KR1020157026392A patent/KR101802048B1/en active IP Right Grant
- 2013-04-02 EP EP13881032.0A patent/EP2981525A4/en not_active Withdrawn
- 2013-04-02 CN CN201380075030.2A patent/CN105452224B/en not_active Expired - Fee Related
- 2013-04-02 JP JP2016506301A patent/JP6153179B2/en not_active Expired - Fee Related
- 2013-04-02 WO PCT/US2013/034960 patent/WO2014163622A1/en active Application Filing
- 2013-04-02 BR BR112015024472A patent/BR112015024472A2/en not_active IP Right Cessation
- 2013-04-02 RU RU2015137621A patent/RU2642466C2/en not_active IP Right Cessation
- 2013-04-02 AU AU2013385618A patent/AU2013385618B2/en not_active Ceased
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RU2642466C2 (en) | 2018-01-25 |
KR101802048B1 (en) | 2017-12-28 |
CN105452224B (en) | 2017-12-26 |
BR112015024472A2 (en) | 2017-07-18 |
AU2013385618B2 (en) | 2017-01-05 |
WO2014163622A1 (en) | 2014-10-09 |
IL241295A0 (en) | 2015-11-30 |
EP2981525A4 (en) | 2016-12-21 |
EP2981525A1 (en) | 2016-02-10 |
RU2015137621A (en) | 2017-05-11 |
CN105452224A (en) | 2016-03-30 |
JP6153179B2 (en) | 2017-06-28 |
WO2014163622A8 (en) | 2014-11-13 |
KR20150136070A (en) | 2015-12-04 |
AU2013385618A1 (en) | 2015-09-24 |
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