JP7384179B2 - Pharmaceutical composition containing benzene derivative - Google Patents
Pharmaceutical composition containing benzene derivative Download PDFInfo
- Publication number
- JP7384179B2 JP7384179B2 JP2021012154A JP2021012154A JP7384179B2 JP 7384179 B2 JP7384179 B2 JP 7384179B2 JP 2021012154 A JP2021012154 A JP 2021012154A JP 2021012154 A JP2021012154 A JP 2021012154A JP 7384179 B2 JP7384179 B2 JP 7384179B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- propanoic acid
- benzenesulfonamido
- enoxy
- compound
- 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.)
- Active
Links
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 416
- -1 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid Chemical compound 0.000 claims description 289
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- 125000002947 alkylene group Chemical group 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 33
- MRQCTVFREAWOSE-XCVCLJGOSA-N 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(/C=C/CCCOC2=C(CCC(=O)O)C=CC=C2)=C1 MRQCTVFREAWOSE-XCVCLJGOSA-N 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 27
- 230000008439 repair process Effects 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 25
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 23
- ZFEBYVQURYDCOL-JLQMKUNGSA-N 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)/C=C/[C@@H](CCOC3=CC=CC=C3CCC(=O)O)O ZFEBYVQURYDCOL-JLQMKUNGSA-N 0.000 claims description 23
- HXTMCTJSQGOWAG-UHFFFAOYSA-N 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid Chemical compound C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(CCCCCOC2=CC=CC=C2CCC(=O)O)=C1 HXTMCTJSQGOWAG-UHFFFAOYSA-N 0.000 claims description 23
- 210000004116 schwann cell Anatomy 0.000 claims description 21
- 208000012902 Nervous system disease Diseases 0.000 claims description 20
- 230000004112 neuroprotection Effects 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 201000001119 neuropathy Diseases 0.000 claims description 18
- 230000007823 neuropathy Effects 0.000 claims description 18
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 17
- LJPBUSOGJOVISS-QQDPUAARSA-N 3-[2-[(E,4R)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)/C=C/[C@@H](CCCC3=CC=CC=C3CCC(=O)O)O LJPBUSOGJOVISS-QQDPUAARSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 230000000324 neuroprotective effect Effects 0.000 claims description 16
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 101100273648 Mus musculus Ccna2 gene Proteins 0.000 claims description 14
- 208000025966 Neurological disease Diseases 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- RGKMEAOZQNYECW-FYWRMAATSA-N 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Chemical compound C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(/C=C/C(O)COC2=CC=CC=C2CCC(=O)O)=C1 RGKMEAOZQNYECW-FYWRMAATSA-N 0.000 claims description 13
- 101100059444 Mus musculus Ccnb1 gene Proteins 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- QBVVZNZVUKOJSI-UHFFFAOYSA-N 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)CCOCCOC3=CC=CC=C3CCC(=O)O QBVVZNZVUKOJSI-UHFFFAOYSA-N 0.000 claims description 12
- 235000019260 propionic acid Nutrition 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 11
- YRFIKVOPMOJXRV-QHCPKHFHSA-N 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)CC[C@@H](CCOC3=CC=CC=C3CCC(=O)O)O YRFIKVOPMOJXRV-QHCPKHFHSA-N 0.000 claims description 10
- 230000024245 cell differentiation Effects 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 210000004498 neuroglial cell Anatomy 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- YRFIKVOPMOJXRV-HSZRJFAPSA-N 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)CC[C@H](CCOC3=CC=CC=C3CCC(=O)O)O YRFIKVOPMOJXRV-HSZRJFAPSA-N 0.000 claims description 8
- LJPBUSOGJOVISS-LEJURUINSA-N 3-[2-[(E,4S)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)/C=C/[C@H](CCCC3=CC=CC=C3CCC(=O)O)O LJPBUSOGJOVISS-LEJURUINSA-N 0.000 claims description 8
- 230000001404 mediated effect Effects 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000003449 preventive effect Effects 0.000 claims description 8
- 230000001737 promoting effect Effects 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- VZDRPYJFWOAANS-DTPJYZGHSA-N 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=C(C=C2)/C=C/[C@@H](CCOC3=CC=CC=C3CCC(=O)O)O VZDRPYJFWOAANS-DTPJYZGHSA-N 0.000 claims description 7
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 7
- LAZNIUILWXDFHF-VKXNWWILSA-N 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(CCCC1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O LAZNIUILWXDFHF-VKXNWWILSA-N 0.000 claims description 6
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 6
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 6
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 claims description 6
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 6
- 229940044683 chemotherapy drug Drugs 0.000 claims description 6
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 claims description 6
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- VNGLMXQSSKUFJY-INJZMFEXSA-N 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(/C=C/[C@@H](CCOC2=C(CCC(=O)O)C=CC=C2)O)=C1C VNGLMXQSSKUFJY-INJZMFEXSA-N 0.000 claims description 5
- 206010003497 Asphyxia Diseases 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 208000015114 central nervous system disease Diseases 0.000 claims description 5
- 238000001647 drug administration Methods 0.000 claims description 5
- 230000023105 myelination Effects 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- WJIJCKFLRPPSLM-IZZNHLLZSA-N 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)CCC1=CC(=CC=C1)[C@@H](CC1=CC=CC=C1)O WJIJCKFLRPPSLM-IZZNHLLZSA-N 0.000 claims description 4
- WJIJCKFLRPPSLM-UIOOFZCWSA-N 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)CCC1=CC(=CC=C1)[C@H](CC1=CC=CC=C1)O WJIJCKFLRPPSLM-UIOOFZCWSA-N 0.000 claims description 4
- BQNLJVKDXHXYTD-JOPBRCQMSA-N 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid Chemical compound C1=CC(S(=O)(=O)NC2=CC=CC(/C=C/[C@@H](CCOC3=C(CCCC(=O)O)C=CC=C3)O)=C2)=CC=C1 BQNLJVKDXHXYTD-JOPBRCQMSA-N 0.000 claims description 4
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 231100000331 toxic Toxicity 0.000 claims description 4
- 230000002588 toxic effect Effects 0.000 claims description 4
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- YYLIZVGGSGZJSZ-UHFFFAOYSA-N 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)CCC(=O)CCCC3=CC=CC=C3CCC(=O)O YYLIZVGGSGZJSZ-UHFFFAOYSA-N 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 3
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 3
- 229910001385 heavy metal Inorganic materials 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 206010065579 multifocal motor neuropathy Diseases 0.000 claims description 3
- 231100000614 poison Toxicity 0.000 claims description 3
- 230000000069 prophylactic effect Effects 0.000 claims description 3
- 239000000932 sedative agent Substances 0.000 claims description 3
- 229940125723 sedative agent Drugs 0.000 claims description 3
- 239000003440 toxic substance Substances 0.000 claims description 3
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 229940125681 anticonvulsant agent Drugs 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 603
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 363
- 239000000243 solution Substances 0.000 description 249
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 230
- 238000005481 NMR spectroscopy Methods 0.000 description 193
- 230000014759 maintenance of location Effects 0.000 description 186
- 238000004128 high performance liquid chromatography Methods 0.000 description 184
- 239000000203 mixture Substances 0.000 description 154
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 150
- 230000000704 physical effect Effects 0.000 description 149
- 238000006243 chemical reaction Methods 0.000 description 118
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 230000002829 reductive effect Effects 0.000 description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 78
- 239000012044 organic layer Substances 0.000 description 77
- 238000010898 silica gel chromatography Methods 0.000 description 76
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 73
- 229910052938 sodium sulfate Inorganic materials 0.000 description 73
- 235000011152 sodium sulphate Nutrition 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 67
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 238000004809 thin layer chromatography Methods 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000000034 method Methods 0.000 description 31
- 229920006395 saturated elastomer Polymers 0.000 description 31
- 238000001816 cooling Methods 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 239000012071 phase Substances 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 210000005036 nerve Anatomy 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 235000011054 acetic acid Nutrition 0.000 description 18
- PNTFBASRFYOFKZ-UHFFFAOYSA-N n-(3-bromophenyl)benzenesulfonamide Chemical compound BrC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 PNTFBASRFYOFKZ-UHFFFAOYSA-N 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 238000010511 deprotection reaction Methods 0.000 description 15
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 13
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- YMXREWKKROWOSO-VOTSOKGWSA-N methyl (e)-3-(2-hydroxyphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC=C1O YMXREWKKROWOSO-VOTSOKGWSA-N 0.000 description 11
- 125000002950 monocyclic group Chemical group 0.000 description 11
- 230000001953 sensory effect Effects 0.000 description 11
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 11
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000003040 nociceptive effect Effects 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 230000032050 esterification Effects 0.000 description 9
- 238000005886 esterification reaction Methods 0.000 description 9
- 239000003889 eye drop Substances 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 9
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 8
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 230000004069 differentiation Effects 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 229930192474 thiophene Natural products 0.000 description 7
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 6
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 6
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- 210000004126 nerve fiber Anatomy 0.000 description 6
- 210000000653 nervous system Anatomy 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 5
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 description 5
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 5
- 125000004450 alkenylene group Chemical group 0.000 description 5
- 125000004419 alkynylene group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 5
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229960001052 streptozocin Drugs 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000003536 tetrazoles Chemical class 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- UUZJJNBYJDFQHL-UHFFFAOYSA-N 1,2,3-triazolidine Chemical compound C1CNNN1 UUZJJNBYJDFQHL-UHFFFAOYSA-N 0.000 description 4
- AGSHYIAAUGKFEA-UHFFFAOYSA-N 1,2,5-oxadiazolidine Chemical compound C1CNON1 AGSHYIAAUGKFEA-UHFFFAOYSA-N 0.000 description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 4
- YTGJKIFAZROQBQ-UHFFFAOYSA-N 1-(3-bromophenyl)-2-phenylethanone Chemical compound BrC1=CC=CC(C(=O)CC=2C=CC=CC=2)=C1 YTGJKIFAZROQBQ-UHFFFAOYSA-N 0.000 description 4
- UAWVMPOAIVZWFQ-UHFFFAOYSA-N 1-(chloromethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CCl UAWVMPOAIVZWFQ-UHFFFAOYSA-N 0.000 description 4
- VMKAFJQFKBASMU-UHFFFAOYSA-N 1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C12CCCN2B(C)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-UHFFFAOYSA-N 0.000 description 4
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 4
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 210000003855 cell nucleus Anatomy 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 description 4
- 150000002244 furazanes Chemical class 0.000 description 4
- 229960003180 glutathione Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- DTHHUAXKOMWYBI-UHFFFAOYSA-N oxadiazolidine Chemical compound C1CONN1 DTHHUAXKOMWYBI-UHFFFAOYSA-N 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 210000000278 spinal cord Anatomy 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 4
- TVQOEGVBMRCMFR-UHFFFAOYSA-N thiadiazinane Chemical compound C1CNNSC1 TVQOEGVBMRCMFR-UHFFFAOYSA-N 0.000 description 4
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 4
- AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 4
- 235000019798 tripotassium phosphate Nutrition 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 3
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 description 3
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 3
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 3
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 3
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 3
- BKWQKVJYXODDAC-UHFFFAOYSA-N 1,2-dihydropyridazine Chemical compound N1NC=CC=C1 BKWQKVJYXODDAC-UHFFFAOYSA-N 0.000 description 3
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 3
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 3
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 3
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 3
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 3
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical compound C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 3
- OYJGEOAXBALSMM-UHFFFAOYSA-N 2,3-dihydro-1,3-thiazole Chemical compound C1NC=CS1 OYJGEOAXBALSMM-UHFFFAOYSA-N 0.000 description 3
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 3
- PZJFUNZDCRKXPZ-UHFFFAOYSA-N 2,5-dihydro-1h-tetrazole Chemical compound C1NNN=N1 PZJFUNZDCRKXPZ-UHFFFAOYSA-N 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 3
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 3
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical compound N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 3
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 3
- NWWJFMCCTZLKNT-UHFFFAOYSA-N 3,4-dihydro-2h-thiazine Chemical compound C1CC=CSN1 NWWJFMCCTZLKNT-UHFFFAOYSA-N 0.000 description 3
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2h-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- YDIYEOMDOWUDTJ-UHFFFAOYSA-N 4-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=C(C(O)=O)C=C1 YDIYEOMDOWUDTJ-UHFFFAOYSA-N 0.000 description 3
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 3
- UXFIKVWAAMKFQE-UHFFFAOYSA-N 5-chloropent-1-yne Chemical compound ClCCCC#C UXFIKVWAAMKFQE-UHFFFAOYSA-N 0.000 description 3
- DGBMOFXIJPHQAW-UHFFFAOYSA-N 5-fluoro-2-phenylmethoxybenzaldehyde Chemical compound O=CC1=CC(F)=CC=C1OCC1=CC=CC=C1 DGBMOFXIJPHQAW-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- BVBSGGBDFJUSIH-UHFFFAOYSA-N Methyl (2-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1O BVBSGGBDFJUSIH-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 125000000815 N-oxide group Chemical group 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 3
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 3
- 239000001361 adipic acid Substances 0.000 description 3
- 235000011037 adipic acid Nutrition 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 210000001130 astrocyte Anatomy 0.000 description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 210000000274 microglia Anatomy 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- 210000004248 oligodendroglia Anatomy 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 3
- ZFZSSYBIQDLZJX-UHFFFAOYSA-N pent-1-en-3-yl benzoate Chemical compound CCC(C=C)OC(=O)C1=CC=CC=C1 ZFZSSYBIQDLZJX-UHFFFAOYSA-N 0.000 description 3
- 210000000578 peripheral nerve Anatomy 0.000 description 3
- 210000001428 peripheral nervous system Anatomy 0.000 description 3
- 208000027232 peripheral nervous system disease Diseases 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 3
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 210000001057 smooth muscle myoblast Anatomy 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 230000000392 somatic effect Effects 0.000 description 3
- 210000001032 spinal nerve Anatomy 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 3
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 2
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 2
- JYLIIPKJJWWRMG-UHFFFAOYSA-N 1-(4-bromophenyl)-2-phenylethanol Chemical compound C=1C=C(Br)C=CC=1C(O)CC1=CC=CC=C1 JYLIIPKJJWWRMG-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- RUTOZYXOYXWKPS-UHFFFAOYSA-N 2-(3-bromophenyl)-1-phenylethanone Chemical compound BrC1=CC=CC(CC(=O)C=2C=CC=CC=2)=C1 RUTOZYXOYXWKPS-UHFFFAOYSA-N 0.000 description 2
- WKAVKKUXZAWHDM-UHFFFAOYSA-N 2-acetamidopentanedioic acid;2-(dimethylamino)ethanol Chemical compound CN(C)CCO.CC(=O)NC(C(O)=O)CCC(O)=O WKAVKKUXZAWHDM-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- VMUXSMXIQBNMGZ-UHFFFAOYSA-N 3,4-dihydrocoumarin Chemical compound C1=CC=C2OC(=O)CCC2=C1 VMUXSMXIQBNMGZ-UHFFFAOYSA-N 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 2
- AYUAEJPYEJEHJN-UHFFFAOYSA-N 4-bromo-1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC(Br)=CS1 AYUAEJPYEJEHJN-UHFFFAOYSA-N 0.000 description 2
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- AITOXQJIQADAHR-FVNWOWOISA-N C(C1=CC=CC=C1)(=O)O[C@@H](/C=C/C1=CC(=CC=C1)[N+](=O)[O-])CCO Chemical compound C(C1=CC=CC=C1)(=O)O[C@@H](/C=C/C1=CC(=CC=C1)[N+](=O)[O-])CCO AITOXQJIQADAHR-FVNWOWOISA-N 0.000 description 2
- AITOXQJIQADAHR-OAGJVSPASA-N C(C1=CC=CC=C1)(=O)O[C@H](/C=C/C1=CC(=CC=C1)[N+](=O)[O-])CCO Chemical compound C(C1=CC=CC=C1)(=O)O[C@H](/C=C/C1=CC(=CC=C1)[N+](=O)[O-])CCO AITOXQJIQADAHR-OAGJVSPASA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 229920001091 Poly(octyl cyanoacrylate) Polymers 0.000 description 2
- 208000035217 Ring chromosome 1 syndrome Diseases 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical compound CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 2
- 239000012391 XPhos Pd G2 Substances 0.000 description 2
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000012378 ammonium molybdate tetrahydrate Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- FIXLYHHVMHXSCP-UHFFFAOYSA-H azane;dihydroxy(dioxo)molybdenum;trioxomolybdenum;tetrahydrate Chemical compound N.N.N.N.N.N.O.O.O.O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O FIXLYHHVMHXSCP-UHFFFAOYSA-H 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 210000000860 cochlear nerve Anatomy 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 210000003792 cranial nerve Anatomy 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 2
- 229960002887 deanol Drugs 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- DMSHWWDRAYHEBS-UHFFFAOYSA-N dihydrocoumarin Natural products C1CC(=O)OC2=C1C=C(OC)C(OC)=C2 DMSHWWDRAYHEBS-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 210000000256 facial nerve Anatomy 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 210000001932 glossopharyngeal nerve Anatomy 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- IMOQCGSCOCUDGV-UHFFFAOYSA-N methyl 2-(acetyloxymethyl)prop-2-enoate Chemical compound COC(=O)C(=C)COC(C)=O IMOQCGSCOCUDGV-UHFFFAOYSA-N 0.000 description 2
- IIFOKIAATXLZIB-UHFFFAOYSA-N methyl 3-(3-hydroxyphenyl)propanoate Chemical compound COC(=O)CCC1=CC=CC(O)=C1 IIFOKIAATXLZIB-UHFFFAOYSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- XYNPRCCUVAUTHD-UHFFFAOYSA-N n-(3-formylphenyl)benzenesulfonamide Chemical compound O=CC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 XYNPRCCUVAUTHD-UHFFFAOYSA-N 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 231100000862 numbness Toxicity 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000196 olfactory nerve Anatomy 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- PQZJTHGEFIQMCO-UHFFFAOYSA-N oxetan-2-ylmethanol Chemical compound OCC1CCO1 PQZJTHGEFIQMCO-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- 208000035824 paresthesia Diseases 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- IQBWGLVQMBGFBF-UHFFFAOYSA-N propan-2-yl 3-(2-hydroxyphenyl)propanoate Chemical compound CC(C)OC(=O)CCC1=CC=CC=C1O IQBWGLVQMBGFBF-UHFFFAOYSA-N 0.000 description 2
- UGCOXQUITWUNHN-UHFFFAOYSA-N propan-2-yl 3-(2-pent-4-ynoxyphenyl)propanoate Chemical compound C(CCC#C)OC1=C(C=CC=C1)CCC(=O)OC(C)C UGCOXQUITWUNHN-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000011251 protective drug Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 2
- 210000002265 sensory receptor cell Anatomy 0.000 description 2
- 102000027509 sensory receptors Human genes 0.000 description 2
- 108091008691 sensory receptors Proteins 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 210000000273 spinal nerve root Anatomy 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- PMOWTIHVNWZYFI-AATRIKPKSA-N trans-2-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1O PMOWTIHVNWZYFI-AATRIKPKSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 210000003901 trigeminal nerve Anatomy 0.000 description 2
- 125000004953 trihalomethyl group Chemical group 0.000 description 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 210000001186 vagus nerve Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- JQADIGSVVKPZJZ-PFEQFJNWSA-N (1R)-1-(3-bromophenyl)-2-phenylethanol 1-(3-bromophenyl)-2-phenylethanone Chemical compound C1=CC=C(C=C1)C[C@H](C2=CC(=CC=C2)Br)O.C1=CC=C(C=C1)CC(=O)C2=CC(=CC=C2)Br JQADIGSVVKPZJZ-PFEQFJNWSA-N 0.000 description 1
- MKKIMGNHQCQWRN-AWEZNQCLSA-N (1S)-1-(3-bromophenyl)-2-phenylethanol Chemical compound BrC=1C=C(C=CC=1)[C@H](CC1=CC=CC=C1)O MKKIMGNHQCQWRN-AWEZNQCLSA-N 0.000 description 1
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- OLVAYVFWOAODJK-MRXNPFEDSA-N (2R)-1-[tert-butyl(dimethyl)silyl]oxy-4-[(4-methoxyphenyl)methoxy]butan-2-ol Chemical compound [Si](C)(C)(C(C)(C)C)OC[C@@H](CCOCC1=CC=C(C=C1)OC)O OLVAYVFWOAODJK-MRXNPFEDSA-N 0.000 description 1
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OQJBFFCUFALWQL-BUHFOSPRSA-N (ne)-n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)\N=N\C(=O)N1CCCCC1 OQJBFFCUFALWQL-BUHFOSPRSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 1
- ODJQFZXHKPCJMD-UHFFFAOYSA-N 1,2,3,3a,4,5,6,7,8,8a-decahydroazulene Chemical compound C1CCCCC2CCCC21 ODJQFZXHKPCJMD-UHFFFAOYSA-N 0.000 description 1
- PIHAUZGWAXLKCA-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydro-1,8-naphthyridine Chemical compound N1CCCC2CCCNC21 PIHAUZGWAXLKCA-UHFFFAOYSA-N 0.000 description 1
- VKJHANNFFHMLBB-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydrocinnoline Chemical compound N1NCCC2CCCCC21 VKJHANNFFHMLBB-UHFFFAOYSA-N 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- AEBKORRYDYKJLT-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydrophthalazine Chemical compound C1NNCC2CCCCC21 AEBKORRYDYKJLT-UHFFFAOYSA-N 0.000 description 1
- HZNXIPDYYIWDNM-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinazoline Chemical compound N1CNCC2CCCCC21 HZNXIPDYYIWDNM-UHFFFAOYSA-N 0.000 description 1
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 1
- MDEXMBGPIZUUBI-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoxaline Chemical compound N1CCNC2CCCCC21 MDEXMBGPIZUUBI-UHFFFAOYSA-N 0.000 description 1
- ZCZVGQCBSJLDDS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine Chemical compound C1=CC=C2CCCNC2=N1 ZCZVGQCBSJLDDS-UHFFFAOYSA-N 0.000 description 1
- WXRSSOIHEAVYLL-UHFFFAOYSA-N 1,2,3,4-tetrahydrocinnoline Chemical compound C1=CC=C2NNCCC2=C1 WXRSSOIHEAVYLL-UHFFFAOYSA-N 0.000 description 1
- STIWEDICJHIFJT-UHFFFAOYSA-N 1,2,3,4-tetrahydrophthalazine Chemical compound C1=CC=C2CNNCC2=C1 STIWEDICJHIFJT-UHFFFAOYSA-N 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- DPHVWRMZSWGLLA-UHFFFAOYSA-N 1,2-benzodithiine Chemical compound C1=CC=C2C=CSSC2=C1 DPHVWRMZSWGLLA-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- XEYKWYIXHMEQGM-UHFFFAOYSA-N 1,2-dihydro-1,8-naphthyridine Chemical compound C1=CC=C2C=CCNC2=N1 XEYKWYIXHMEQGM-UHFFFAOYSA-N 0.000 description 1
- QRDNXAYNXUKMOO-UHFFFAOYSA-N 1,2-dihydrocinnoline Chemical compound C1=CC=C2C=CNNC2=C1 QRDNXAYNXUKMOO-UHFFFAOYSA-N 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- XXBQLHATYQHJQC-UHFFFAOYSA-N 1,2-dihydroquinoxaline Chemical compound C1=CC=C2N=CCNC2=C1 XXBQLHATYQHJQC-UHFFFAOYSA-N 0.000 description 1
- OURMWAURVCHQRC-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1.C1CNOC1 OURMWAURVCHQRC-UHFFFAOYSA-N 0.000 description 1
- HGQBCKVFVUCIML-UHFFFAOYSA-N 1,3,3a,4,5,6,7,7a-octahydro-2-benzofuran Chemical compound C1CCCC2COCC21 HGQBCKVFVUCIML-UHFFFAOYSA-N 0.000 description 1
- SJXUGVWKLLOJDR-UHFFFAOYSA-N 1,3,3a,4,5,6,7,7a-octahydro-2-benzothiophene Chemical compound C1CCCC2CSCC21 SJXUGVWKLLOJDR-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical compound C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- IFPDXYZJIIRYRN-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1.C1CSCN1 IFPDXYZJIIRYRN-UHFFFAOYSA-N 0.000 description 1
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- XLXRVSWQLLWGJN-UHFFFAOYSA-N 1-(3-bromophenyl)-2-methyl-2-phenylpropan-1-ol 1-(3-bromophenyl)-2-phenylethanone Chemical compound CC(C)(C1=CC=CC=C1)C(C2=CC(=CC=C2)Br)O.C1=CC=C(C=C1)CC(=O)C2=CC(=CC=C2)Br XLXRVSWQLLWGJN-UHFFFAOYSA-N 0.000 description 1
- MOVKRUUKWKZHRW-UHFFFAOYSA-N 1-(3-bromophenyl)-3-phenylpropan-1-ol Chemical compound C=1C=CC(Br)=CC=1C(O)CCC1=CC=CC=C1 MOVKRUUKWKZHRW-UHFFFAOYSA-N 0.000 description 1
- GCLUXQIYHGEHMX-UHFFFAOYSA-N 1-(4-bromo-1,3-thiazol-2-yl)-2-phenylethanone Chemical compound Brc1csc(n1)C(=O)Cc1ccccc1 GCLUXQIYHGEHMX-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- FWIROFMBWVMWLB-UHFFFAOYSA-N 1-bromo-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1 FWIROFMBWVMWLB-UHFFFAOYSA-N 0.000 description 1
- OEPRBXUJOQLYID-UHFFFAOYSA-N 1-fluoropentane Chemical compound CCCCCF OEPRBXUJOQLYID-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical group ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- OGHHATWOTABYKY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzothiazole Chemical compound C1CCCC2SCNC21 OGHHATWOTABYKY-UHFFFAOYSA-N 0.000 description 1
- XLRZZUUFKAXBGZ-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzoxazole Chemical compound C1CCCC2OCNC21 XLRZZUUFKAXBGZ-UHFFFAOYSA-N 0.000 description 1
- DNZWAKVIOXCEHH-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1-benzofuran Chemical compound C1CCCC2OCCC21 DNZWAKVIOXCEHH-UHFFFAOYSA-N 0.000 description 1
- NZOBCFVNZQYCCZ-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1-benzothiophene Chemical compound C1CCCC2SCCC21 NZOBCFVNZQYCCZ-UHFFFAOYSA-N 0.000 description 1
- MDNGXAFGRWQHNZ-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-benzimidazole Chemical compound C1CCCC2NCNC21 MDNGXAFGRWQHNZ-UHFFFAOYSA-N 0.000 description 1
- LVJPACZOEKXFAY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indazole Chemical compound C1CCCC2CNNC21 LVJPACZOEKXFAY-UHFFFAOYSA-N 0.000 description 1
- SCEIUGQQBYRBPP-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-azepine Chemical compound C1CCC=CNC1 SCEIUGQQBYRBPP-UHFFFAOYSA-N 0.000 description 1
- YYVKQFQZKSLYFN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-diazepine Chemical compound C1CNNC=CC1 YYVKQFQZKSLYFN-UHFFFAOYSA-N 0.000 description 1
- WHUAPUGLAGYTQS-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiadiazepine Chemical compound C1CC=CSNN1 WHUAPUGLAGYTQS-UHFFFAOYSA-N 0.000 description 1
- IFPKIMVCYSSDDJ-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiazepine Chemical compound C1CNSC=CC1 IFPKIMVCYSSDDJ-UHFFFAOYSA-N 0.000 description 1
- VRKPANGTGANDRQ-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiepine Chemical compound C1CCC=CSC1 VRKPANGTGANDRQ-UHFFFAOYSA-N 0.000 description 1
- HRCMXYXVAWHBTH-UHFFFAOYSA-N 2,3-dihydro-1,3-benzoxazole Chemical compound C1=CC=C2OCNC2=C1 HRCMXYXVAWHBTH-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- BEWVAZNECYSPMT-UHFFFAOYSA-N 2,3-dihydro-1h-azepine Chemical compound C1CC=CC=CN1 BEWVAZNECYSPMT-UHFFFAOYSA-N 0.000 description 1
- QHYXWSXPPUTDRA-UHFFFAOYSA-N 2,3-dihydro-1h-diazepine Chemical compound C1NNC=CC=C1 QHYXWSXPPUTDRA-UHFFFAOYSA-N 0.000 description 1
- QDKGOMZIPXGDDJ-UHFFFAOYSA-N 2,3-dihydro-1h-indazole Chemical compound C1=CC=C2CNNC2=C1 QDKGOMZIPXGDDJ-UHFFFAOYSA-N 0.000 description 1
- IZEOXCXHDBQQAP-UHFFFAOYSA-N 2,3-dihydrothiazepine Chemical compound C1NSC=CC=C1 IZEOXCXHDBQQAP-UHFFFAOYSA-N 0.000 description 1
- WMDHQEHPOVOEOG-UHFFFAOYSA-N 2-(2-bromoethyl)-1,3-dioxane Chemical compound BrCCC1OCCCO1 WMDHQEHPOVOEOG-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- UEWHUAOGMPCPHE-UHFFFAOYSA-N 2-(3-bromopropyl)-1,3-dioxane Chemical compound BrCCCC1OCCCO1 UEWHUAOGMPCPHE-UHFFFAOYSA-N 0.000 description 1
- QNYBOILAKBSWFG-UHFFFAOYSA-N 2-(phenylmethoxymethyl)oxirane Chemical compound C1OC1COCC1=CC=CC=C1 QNYBOILAKBSWFG-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NOBKDIKVPCRUMK-UHFFFAOYSA-N 2-[2-(3-nitrophenyl)ethoxy]ethanol Chemical compound [N+](=O)([O-])C=1C=C(CCOCCO)C=CC=1 NOBKDIKVPCRUMK-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- LYTMVABTDYMBQK-UHFFFAOYSA-N 2-benzothiophene Chemical compound C1=CC=CC2=CSC=C21 LYTMVABTDYMBQK-UHFFFAOYSA-N 0.000 description 1
- BEGREHRAUWCAHV-UHFFFAOYSA-N 2-bromo-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC(Br)=N1 BEGREHRAUWCAHV-UHFFFAOYSA-N 0.000 description 1
- GLCIPJOIEVLTPR-UHFFFAOYSA-N 2-chlorohexane Chemical compound CCCCC(C)Cl GLCIPJOIEVLTPR-UHFFFAOYSA-N 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- WGTASENVNYJZBK-UHFFFAOYSA-N 3,4,5-trimethoxyamphetamine Chemical compound COC1=CC(CC(C)N)=CC(OC)=C1OC WGTASENVNYJZBK-UHFFFAOYSA-N 0.000 description 1
- FSUYMKXZLQOFQY-UHFFFAOYSA-N 3,4-dihydro-1,2-benzodithiine Chemical compound C1=CC=C2SSCCC2=C1 FSUYMKXZLQOFQY-UHFFFAOYSA-N 0.000 description 1
- NTOIMCSZPGZTND-UHFFFAOYSA-N 3,4-dihydro-1,2-benzoxathiine Chemical compound C1=CC=C2OSCCC2=C1 NTOIMCSZPGZTND-UHFFFAOYSA-N 0.000 description 1
- IDUSJBBWEKNWAK-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzothiazine Chemical compound C1=CC=C2SNCCC2=C1 IDUSJBBWEKNWAK-UHFFFAOYSA-N 0.000 description 1
- BGDOLELXXPTPFX-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzoxazine Chemical compound C1=CC=C2ONCCC2=C1 BGDOLELXXPTPFX-UHFFFAOYSA-N 0.000 description 1
- NDTSIDOTKVWMRI-UHFFFAOYSA-N 3,4-dihydro-2h-pyrazino[2,3-b][1,4]oxazine Chemical compound C1=CN=C2NCCOC2=N1 NDTSIDOTKVWMRI-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- IVRBFGWMSGWWAL-QFIPXVFZSA-N 3-[2-[(3S)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid Chemical compound C1(CCCC1)S(=O)(=O)NC=1C=C(C=CC=1)CC[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O IVRBFGWMSGWWAL-QFIPXVFZSA-N 0.000 description 1
- GAPSARGWQARYOM-LFYBBSHMSA-N 3-[2-[(E)-5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-4-yl]pent-4-enoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C=1SC=C(N=1)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)O GAPSARGWQARYOM-LFYBBSHMSA-N 0.000 description 1
- ZMVYWNTWJSRMIE-NIAUNUSRSA-N 3-[2-[(E)-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CC1=CC=CC=C1)C=1C=C(C=CC=1)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)O ZMVYWNTWJSRMIE-NIAUNUSRSA-N 0.000 description 1
- ZMVYWNTWJSRMIE-CLVJJCCZSA-N 3-[2-[(E)-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@@H](CC1=CC=CC=C1)C=1C=C(C=CC=1)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)O ZMVYWNTWJSRMIE-CLVJJCCZSA-N 0.000 description 1
- KYRKSQJCKDLHBJ-WLRTZDKTSA-N 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pent-4-enoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C=1N=C(SC=1)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)O KYRKSQJCKDLHBJ-WLRTZDKTSA-N 0.000 description 1
- YTMMUZNXUCQNSB-WEVVVXLNSA-N 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C1=CC=C(C=C1)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)O YTMMUZNXUCQNSB-WEVVVXLNSA-N 0.000 description 1
- IKVIGLXFCNQSJZ-QZXKJJRQSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)C(CC1=CC=CC=C1)O IKVIGLXFCNQSJZ-QZXKJJRQSA-N 0.000 description 1
- ADMPMXJLELRYST-DHHHLDCZSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-3-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)C(CCC1=CC=CC=C1)O ADMPMXJLELRYST-DHHHLDCZSA-N 0.000 description 1
- UUWHVUNAUDHZPJ-UEBUVBOOSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(2-hydroxy-1-phenylpropan-2-yl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)C(CC1=CC=CC=C1)(C)O UUWHVUNAUDHZPJ-UEBUVBOOSA-N 0.000 description 1
- QENKGUGBCKMEDD-RCHCNPRSSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(oxan-4-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1CCOCC1 QENKGUGBCKMEDD-RCHCNPRSSA-N 0.000 description 1
- AVAFCCNNWHSFJD-RQOTYCFOSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylcarbamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)C(NC1=CC=CC=C1)=O AVAFCCNNWHSFJD-RQOTYCFOSA-N 0.000 description 1
- MAINPJGARPTHDB-JLQMKUNGSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylsulfamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)S(NC1=CC=CC=C1)(=O)=O MAINPJGARPTHDB-JLQMKUNGSA-N 0.000 description 1
- HKFSYBARPLARBP-SDNYCIMKSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(pyridin-2-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=NC=CC=C1 HKFSYBARPLARBP-SDNYCIMKSA-N 0.000 description 1
- BYRFNHCPEFPZHQ-DJGBTNNQSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-(thiophen-3-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=CSC=C1 BYRFNHCPEFPZHQ-DJGBTNNQSA-N 0.000 description 1
- YQFLZAPBEZWPOH-RQOTYCFOSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=C(C=CC=C1)C YQFLZAPBEZWPOH-RQOTYCFOSA-N 0.000 description 1
- BFGXQKFKZLJLJN-DSDNZOFKSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-propylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=C(C=CC=C1)CCC BFGXQKFKZLJLJN-DSDNZOFKSA-N 0.000 description 1
- ROGCTWPDMXVOQP-ZOBSEURRSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[(3-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=CC(=CC=C1)C ROGCTWPDMXVOQP-ZOBSEURRSA-N 0.000 description 1
- DLAZUTZQJRFWMW-CWSBKQHBSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[(4-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=CC=C(C=C1)C DLAZUTZQJRFWMW-CWSBKQHBSA-N 0.000 description 1
- KBEIZMORHSKDSX-VKXNWWILSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[[2-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=C(C=CC=C1)C(F)(F)F KBEIZMORHSKDSX-VKXNWWILSA-N 0.000 description 1
- HFJAVWZAAHVCLH-BWSGXRDBSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=CC(=CC=C1)C(F)(F)F HFJAVWZAAHVCLH-BWSGXRDBSA-N 0.000 description 1
- GSDNRNIUOJBEOE-UJVYDMDKSA-N 3-[2-[(E,3R)-3-hydroxy-5-[3-[[4-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)O)\C=C\C1=CC(=CC=C1)NS(=O)(=O)C1=CC=C(C=C1)C(F)(F)F GSDNRNIUOJBEOE-UJVYDMDKSA-N 0.000 description 1
- BSONBKHOESZBOF-INJZMFEXSA-N 3-[2-[(E,3R)-5-(2-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(C1=CC=CC=C1)(=O)NC1=C(C=CC=C1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O BSONBKHOESZBOF-INJZMFEXSA-N 0.000 description 1
- QDDJJLJRCAHQIA-RQOTYCFOSA-N 3-[2-[(E,3R)-5-(3-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(C1=CC=CC=C1)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O QDDJJLJRCAHQIA-RQOTYCFOSA-N 0.000 description 1
- TVBPTKPIVAPIEV-VXZGYFJVSA-N 3-[2-[(E,3R)-5-(4-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC=C(C=C1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O TVBPTKPIVAPIEV-VXZGYFJVSA-N 0.000 description 1
- SGWKWASJAOSTEP-JLQMKUNGSA-N 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CCC2=C(C=CC=C12)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O SGWKWASJAOSTEP-JLQMKUNGSA-N 0.000 description 1
- LHPOXJRCNZLRAF-PSVMIJIFSA-N 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-6-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CCC2=CC=C(C=C12)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O LHPOXJRCNZLRAF-PSVMIJIFSA-N 0.000 description 1
- XJZNEMSZKOVMPU-PCQKWUTHSA-N 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2-methylindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1C(=CC2=C(C=CC=C12)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)C XJZNEMSZKOVMPU-PCQKWUTHSA-N 0.000 description 1
- WQGUMQSZIYTXOX-BRGVFWSASA-N 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-5-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CCCC2=C(C=CC=C12)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O WQGUMQSZIYTXOX-BRGVFWSASA-N 0.000 description 1
- MUYGRDBLKRREPV-BEWKRWDNSA-N 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-7-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CCCC2=CC=C(C=C12)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O MUYGRDBLKRREPV-BEWKRWDNSA-N 0.000 description 1
- WWIUNEXPQYCRJG-MYILAFDMSA-N 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-1,3-dihydroisoindol-5-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CC2=CC=C(C=C2C1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O WWIUNEXPQYCRJG-MYILAFDMSA-N 0.000 description 1
- SPQSAGAEGVDPBL-XZXPPUMWSA-N 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinolin-7-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1CC2=CC(=CC=C2CC1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O SPQSAGAEGVDPBL-XZXPPUMWSA-N 0.000 description 1
- STLBALIBDGEPCQ-SRLUVNLFSA-N 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-bromophenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)/C=C/[C@@H](CCOC3=C(C=C(C=C3)Br)CCC(=O)O)O STLBALIBDGEPCQ-SRLUVNLFSA-N 0.000 description 1
- DJZCKTVCTKMEGE-CDIAOGBUSA-N 3-[2-[(E,3R)-5-[3-(benzylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(C1=CC=CC=C1)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O DJZCKTVCTKMEGE-CDIAOGBUSA-N 0.000 description 1
- DWNYSEHDFRDHBK-CDIAOGBUSA-N 3-[2-[(E,3R)-5-[3-(benzylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(C1=CC=CC=C1)S(=O)(=O)NC=1C=C(C=CC1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O DWNYSEHDFRDHBK-CDIAOGBUSA-N 0.000 description 1
- GQOKLZRRLDLPOL-VKXNWWILSA-N 3-[2-[(E,3R)-5-[3-[(2-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O GQOKLZRRLDLPOL-VKXNWWILSA-N 0.000 description 1
- GYDFSVBELDNCRT-VKXNWWILSA-N 3-[2-[(E,3R)-5-[3-[(2-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound FC1=C(C=CC=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O GYDFSVBELDNCRT-VKXNWWILSA-N 0.000 description 1
- QCHMZDQEQKYVLH-ULJHPHNHSA-N 3-[2-[(E,3R)-5-[3-[(3-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(CCC)C=1C=C(C=CC=1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O QCHMZDQEQKYVLH-ULJHPHNHSA-N 0.000 description 1
- KYGWKVGQFQWLOK-BWSGXRDBSA-N 3-[2-[(E,3R)-5-[3-[(3-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound ClC=1C=C(C=CC=1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O KYGWKVGQFQWLOK-BWSGXRDBSA-N 0.000 description 1
- PPUBVXIFABUNHI-BWSGXRDBSA-N 3-[2-[(E,3R)-5-[3-[(3-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O PPUBVXIFABUNHI-BWSGXRDBSA-N 0.000 description 1
- NJWCDTWQPHPZLD-PUHSMXRQSA-N 3-[2-[(E,3R)-5-[3-[(4-butoxyphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(CCC)OC1=CC=C(C=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O NJWCDTWQPHPZLD-PUHSMXRQSA-N 0.000 description 1
- LJLRLEOEGOJKNY-FCVQMFHESA-N 3-[2-[(E,3R)-5-[3-[(4-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C(CCC)C1=CC=C(C=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O LJLRLEOEGOJKNY-FCVQMFHESA-N 0.000 description 1
- YHMMORSQIOKXNE-UJVYDMDKSA-N 3-[2-[(E,3R)-5-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O YHMMORSQIOKXNE-UJVYDMDKSA-N 0.000 description 1
- ZKNDAUBHQGUIKN-UJVYDMDKSA-N 3-[2-[(E,3R)-5-[3-[(4-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound FC1=CC=C(C=C1)S(=O)(=O)NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O ZKNDAUBHQGUIKN-UJVYDMDKSA-N 0.000 description 1
- GWKZAQUIBKLQDL-RQOTYCFOSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2,2,2-trifluoroethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC(F)(F)F GWKZAQUIBKLQDL-RQOTYCFOSA-N 0.000 description 1
- ZFRNQSNJNJVXAB-KDKZVTFGSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(benzyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1=CC=CC=C1 ZFRNQSNJNJVXAB-KDKZVTFGSA-N 0.000 description 1
- WJJPUVVYFQUOBN-ULJHPHNHSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(cyclopropylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1CC1 WJJPUVVYFQUOBN-ULJHPHNHSA-N 0.000 description 1
- LVFZTPSGMGEKCI-AZBDZEDCSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(ethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC LVFZTPSGMGEKCI-AZBDZEDCSA-N 0.000 description 1
- RJGMZBLOOLUXCT-PCQKWUTHSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(methyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)C RJGMZBLOOLUXCT-PCQKWUTHSA-N 0.000 description 1
- XCHXCSIZINALEN-WJZHDFLTSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1OCCCC1 XCHXCSIZINALEN-WJZHDFLTSA-N 0.000 description 1
- UKGFTSFAGIJVMY-BIQOMCPKSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1OCC1 UKGFTSFAGIJVMY-BIQOMCPKSA-N 0.000 description 1
- LMIIIAHHYXWYTE-RFYAYMHSSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1COC1 LMIIIAHHYXWYTE-RFYAYMHSSA-N 0.000 description 1
- PMCUPKQCUHDYKW-TWJUCPNASA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1OCCC1 PMCUPKQCUHDYKW-TWJUCPNASA-N 0.000 description 1
- JUWZXQUAPJHLQM-ORXPQNRKSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC1COCC1 JUWZXQUAPJHLQM-ORXPQNRKSA-N 0.000 description 1
- HZJZXGKLKZDMDG-DSDNZOFKSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(propan-2-yl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)C(C)C HZJZXGKLKZDMDG-DSDNZOFKSA-N 0.000 description 1
- PUBUKFOMNGGAMF-DSDNZOFKSA-N 3-[2-[(E,3R)-5-[3-[benzenesulfonyl-(2-hydroxy-2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Chemical compound C1(=CC=CC=C1)S(=O)(=O)N(C=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)O)O)CC(C)(C)O PUBUKFOMNGGAMF-DSDNZOFKSA-N 0.000 description 1
- KZRZUPDKATXZHN-RUZDIDTESA-N 3-[2-[2-[2-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid Chemical compound O[C@H](CC1=CC=CC=C1)C=1C=C(C=CC=1)CCOCCOC1=C(C=CC=C1)CCC(=O)O KZRZUPDKATXZHN-RUZDIDTESA-N 0.000 description 1
- GCUPRCMCMJIOFY-UQIIZPHYSA-N 3-[2-[2-[2-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid propane Chemical compound CCC.C1=CC=C(C=C1)C[C@@H](C2=CC=CC(=C2)CCOCCOC3=CC=CC=C3CCC(=O)O)O GCUPRCMCMJIOFY-UQIIZPHYSA-N 0.000 description 1
- AFRNLESJCLWRAY-UHFFFAOYSA-N 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]-3-oxopentoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C=1C=C(C=CC=1)CCC(CCOC1=C(C=CC=C1)CCC(=O)O)=O AFRNLESJCLWRAY-UHFFFAOYSA-N 0.000 description 1
- OQUJTLLDQRMDTO-UHFFFAOYSA-N 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C=1C=C(C=CC=1)CCCCCOC1=C(C=CC=C1)CCC(=O)O OQUJTLLDQRMDTO-UHFFFAOYSA-N 0.000 description 1
- FYIKRBFGYOJJTL-UHFFFAOYSA-N 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid Chemical compound C1=CC=C(C=C1)S(=O)(=O)NC2=CC=CC(=C2)CCC(CCOC3=CC=CC=C3CCC(=O)O)(F)F FYIKRBFGYOJJTL-UHFFFAOYSA-N 0.000 description 1
- OQUJTLLDQRMDTO-AREMUKBSSA-N 3-[2-[5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid Chemical compound O[C@H](CC1=CC=CC=C1)C=1C=C(C=CC=1)CCCCCOC1=C(C=CC=C1)CCC(=O)O OQUJTLLDQRMDTO-AREMUKBSSA-N 0.000 description 1
- OQUJTLLDQRMDTO-SANMLTNESA-N 3-[2-[5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid Chemical compound O[C@@H](CC1=CC=CC=C1)C=1C=C(C=CC=1)CCCCCOC1=C(C=CC=C1)CCC(=O)O OQUJTLLDQRMDTO-SANMLTNESA-N 0.000 description 1
- UHFYIVQLNDCWBD-UHFFFAOYSA-N 3-[2-[5-[4-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid Chemical compound OC(CC1=CC=CC=C1)C1=CC=C(C=C1)CCCCCOC1=C(C=CC=C1)CCC(=O)O UHFYIVQLNDCWBD-UHFFFAOYSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical compound C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 description 1
- MMSGORBBOBYKPZ-UHFFFAOYSA-N 4-bromo-N-methoxy-N-methyl-1,3-thiazole-2-carboxamide Chemical compound CON(C)C(=O)c1nc(Br)cs1 MMSGORBBOBYKPZ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- CSDCTSHDYMZUAZ-UHFFFAOYSA-N 5-[(3-nitrophenyl)methylsulfanyl]-1-phenyltetrazole 5-[(3-nitrophenyl)methylsulfonyl]-1-phenyltetrazole Chemical compound C1=CC=C(C=C1)N2C(=NN=N2)SCC3=CC(=CC=C3)[N+](=O)[O-].C1=CC=C(C=C1)N2C(=NN=N2)S(=O)(=O)CC3=CC(=CC=C3)[N+](=O)[O-] CSDCTSHDYMZUAZ-UHFFFAOYSA-N 0.000 description 1
- QWCYCKWRMDPVED-LBPRGKRZSA-N 5-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethylsulfanyl]-1-phenyltetrazole Chemical compound CC1(OC[C@@H](O1)CCSC1=NN=NN1C1=CC=CC=C1)C QWCYCKWRMDPVED-LBPRGKRZSA-N 0.000 description 1
- HTYRTGGIOAMLRR-UHFFFAOYSA-N 5-amino-4-hydroxybenzene-1,3-disulfonic acid Chemical compound NC1=CC(S(O)(=O)=O)=CC(S(O)(=O)=O)=C1O HTYRTGGIOAMLRR-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005964 Acibenzolar-S-methyl Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- FRYRJNHMRVINIZ-UHFFFAOYSA-N B1CCOO1 Chemical compound B1CCOO1 FRYRJNHMRVINIZ-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 208000003508 Botulism Diseases 0.000 description 1
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- PHRIDXVBLOLROF-XCYQKHKUSA-N C(C)(C)(C)OC(=O)N[C@@H]1CC[C@H](CC1)CC/C=C/C(=O)OCC Chemical compound C(C)(C)(C)OC(=O)N[C@@H]1CC[C@H](CC1)CC/C=C/C(=O)OCC PHRIDXVBLOLROF-XCYQKHKUSA-N 0.000 description 1
- TZRGEMAFYUEXPM-SHTZXODSSA-N C(C)(C)(C)OC(=O)N[C@@H]1CC[C@H](CC1)CCCCC(=O)OCC Chemical compound C(C)(C)(C)OC(=O)N[C@@H]1CC[C@H](CC1)CCCCC(=O)OCC TZRGEMAFYUEXPM-SHTZXODSSA-N 0.000 description 1
- CIQQBGMTQRLGGL-HAQNSBGRSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC=O)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC=O)CC1 CIQQBGMTQRLGGL-HAQNSBGRSA-N 0.000 description 1
- XAWWUCMXDAXZAH-XOTMGTSJSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)C(C(C)(C)C3=CC=CC=C3)O)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)C(C(C)(C)C3=CC=CC=C3)O)O XAWWUCMXDAXZAH-XOTMGTSJSA-N 0.000 description 1
- CIIZUCRSLGEOBM-YZHQAQFHSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)N(CC(C)C)S(=O)(=O)C3=CC=CC=C3)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)N(CC(C)C)S(=O)(=O)C3=CC=CC=C3)O CIIZUCRSLGEOBM-YZHQAQFHSA-N 0.000 description 1
- NGXTURGDWWKLPS-BNEOJTTJSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)N(CCC3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)N(CCC3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4)O NGXTURGDWWKLPS-BNEOJTTJSA-N 0.000 description 1
- HZSFWAXFSRYKPZ-QDEBQFNMSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)NS(=O)(=O)C3=COC4=CC=CC=C43)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)NS(=O)(=O)C3=COC4=CC=CC=C43)O HZSFWAXFSRYKPZ-QDEBQFNMSA-N 0.000 description 1
- QSDNWTWLBCFFLN-WKKBHVDPSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)[C@@H](CC3=CC=CC=C3)O)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)[C@@H](CC3=CC=CC=C3)O)O QSDNWTWLBCFFLN-WKKBHVDPSA-N 0.000 description 1
- QSDNWTWLBCFFLN-KLULWGETSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)[C@H](CC3=CC=CC=C3)O)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC(=CC=C2)[C@H](CC3=CC=CC=C3)O)O QSDNWTWLBCFFLN-KLULWGETSA-N 0.000 description 1
- QRJZKVKQZPWSCK-KLULWGETSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC=CC(=C2)C[C@@H](C3=CC=CC=C3)O)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC=CC(=C2)C[C@@H](C3=CC=CC=C3)O)O QRJZKVKQZPWSCK-KLULWGETSA-N 0.000 description 1
- QRJZKVKQZPWSCK-WKKBHVDPSA-N CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC=CC(=C2)C[C@H](C3=CC=CC=C3)O)O Chemical compound CCCC1=CC=CC=C1OCC[C@H](/C=C/C2=CC=CC(=C2)C[C@H](C3=CC=CC=C3)O)O QRJZKVKQZPWSCK-WKKBHVDPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010252 Concentric sclerosis Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 208000009347 Cubital Tunnel Syndrome Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 239000001293 FEMA 3089 Substances 0.000 description 1
- 208000024720 Fabry Disease Diseases 0.000 description 1
- 206010016326 Feeling cold Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010016952 Food poisoning Diseases 0.000 description 1
- 208000019331 Foodborne disease Diseases 0.000 description 1
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000033830 Hot Flashes Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010070511 Hypoxic-ischaemic encephalopathy Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 208000027747 Kennedy disease Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- SYVFKBCMAJNZPT-UHFFFAOYSA-N N-(3-bromophenyl)-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide Chemical compound BrC=1C=C(C=CC=1)N(S(=O)(=O)C1=CC=CC=C1)CC(C)(C)O SYVFKBCMAJNZPT-UHFFFAOYSA-N 0.000 description 1
- QZQRQCJUNVUXQD-UHFFFAOYSA-N N-(3-bromophenyl)-N-(2-oxopropyl)benzenesulfonamide Chemical compound BrC=1C=C(C=CC=1)N(S(=O)(=O)C1=CC=CC=C1)CC(C)=O QZQRQCJUNVUXQD-UHFFFAOYSA-N 0.000 description 1
- FNXHRBHTDCXALN-UHFFFAOYSA-N N-(3-bromophenyl)-N-(oxetan-2-ylmethyl)benzenesulfonamide Chemical compound BrC=1C=C(C=CC=1)N(S(=O)(=O)C1=CC=CC=C1)CC1OCC1 FNXHRBHTDCXALN-UHFFFAOYSA-N 0.000 description 1
- GRWVJEIGLDNZEN-UHFFFAOYSA-N N-(benzenesulfonyl)-N-(3-bromophenyl)benzenesulfonamide Chemical compound BrC=1C=C(C=CC=1)N(S(=O)(=O)C1=CC=CC=C1)S(=O)(=O)C1=CC=CC=C1 GRWVJEIGLDNZEN-UHFFFAOYSA-N 0.000 description 1
- YETPFBRUCHJCCJ-UHFFFAOYSA-N N-(benzenesulfonyl)-N-[3-(4-hydroxybut-1-ynyl)phenyl]benzenesulfonamide Chemical compound OCCC#CC=1C=C(C=CC1)N(S(=O)(=O)C1=CC=CC=C1)S(=O)(=O)C1=CC=CC=C1 YETPFBRUCHJCCJ-UHFFFAOYSA-N 0.000 description 1
- HJDVHPJVUWZPIR-UHFFFAOYSA-N N-(benzenesulfonyl)-N-[3-(4-hydroxybutyl)phenyl]benzenesulfonamide Chemical compound OCCCCC=1C=C(C=CC=1)N(S(=O)(=O)C1=CC=CC=C1)S(=O)(=O)C1=CC=CC=C1 HJDVHPJVUWZPIR-UHFFFAOYSA-N 0.000 description 1
- YKFGOWJGLZUPFU-XCVCLJGOSA-N N-[3-[(E)-5-[2-[2-(1H-1,2,4-triazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl]benzenesulfonamide Chemical compound N1N=CN=C1CCC1=C(OCCC/C=C/C=2C=C(C=CC=2)NS(=O)(=O)C2=CC=CC=C2)C=CC=C1 YKFGOWJGLZUPFU-XCVCLJGOSA-N 0.000 description 1
- ALZOLWPWEMUKLD-RFYAYMHSSA-N N-[3-[(E,3R)-3-hydroxy-5-[2-(3-morpholin-4-yl-3-oxopropyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide Chemical compound O[C@@H](/C=C/C=1C=C(C=CC=1)NS(=O)(=O)C1=CC=CC=C1)CCOC1=C(C=CC=C1)CCC(=O)N1CCOCC1 ALZOLWPWEMUKLD-RFYAYMHSSA-N 0.000 description 1
- NKDRBXVTZQPWBS-YERXGYGTSA-N N-[3-[(E,4S)-4,5-dihydroxypent-1-enyl]phenyl]benzenesulfonamide Chemical compound O[C@@H](C/C=C/C=1C=C(C=CC=1)NS(=O)(=O)C1=CC=CC=C1)CO NKDRBXVTZQPWBS-YERXGYGTSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241000772415 Neovison vison Species 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- DCEBDQXTGFQJEK-HDJSIYSDSA-N OCCCCC[C@@H]1CC[C@H](CC1)NC(OC(C)(C)C)=O Chemical compound OCCCCC[C@@H]1CC[C@H](CC1)NC(OC(C)(C)C)=O DCEBDQXTGFQJEK-HDJSIYSDSA-N 0.000 description 1
- 101100112680 Ostreococcus tauri CycD gene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010056332 Panencephalitis Diseases 0.000 description 1
- 206010033892 Paraplegia Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 208000008713 Piriformis Muscle Syndrome Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241000097929 Porphyria Species 0.000 description 1
- 208000010642 Porphyrias Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000032319 Primary lateral sclerosis Diseases 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 208000005587 Refsum Disease Diseases 0.000 description 1
- 101001110844 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L5 Proteins 0.000 description 1
- 229920002536 Scavenger resin Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000032930 Spastic paraplegia Diseases 0.000 description 1
- 208000010112 Spinocerebellar Degenerations Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042928 Syringomyelia Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 206010043121 Tarsal tunnel syndrome Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 206010046298 Upper motor neurone lesion Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010063661 Vascular encephalopathy Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000007642 Vitamin B Deficiency Diseases 0.000 description 1
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 description 1
- LNFQUQGHBDRNLI-GOSISDBHSA-N [(2R)-1-hydroxy-4-[(4-methoxyphenyl)methoxy]butan-2-yl] benzoate Chemical compound C(C1=CC=CC=C1)(=O)O[C@@H](CO)CCOCC1=CC=C(C=C1)OC LNFQUQGHBDRNLI-GOSISDBHSA-N 0.000 description 1
- SXXXAJMYIZUVBA-GOSISDBHSA-N [(2R)-4-[(4-methoxyphenyl)methoxy]-1-oxobutan-2-yl] benzoate Chemical compound C(C1=CC=CC=C1)(=O)O[C@@H](C=O)CCOCC1=CC=C(C=C1)OC SXXXAJMYIZUVBA-GOSISDBHSA-N 0.000 description 1
- CJGYSWNGNKCJSB-YVLZZHOMSA-M [(4ar,6r,7r,7ar)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl] butanoate Chemical compound C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 CJGYSWNGNKCJSB-YVLZZHOMSA-M 0.000 description 1
- GTXOQABPRULCSL-RATVVNGRSA-N [(E,3R)-1-(3-aminophenyl)-5-[2-[(E)-3-methoxy-3-oxoprop-1-enyl]phenoxy]pent-1-en-3-yl] benzoate Chemical compound C(C1=CC=CC=C1)(=O)O[C@@H](/C=C/C1=CC(=CC=C1)N)CCOC1=C(C=CC=C1)\C=C\C(=O)OC GTXOQABPRULCSL-RATVVNGRSA-N 0.000 description 1
- JFJZZFHRBKGKAE-UHFFFAOYSA-M [Br-].CC(C)(C)OC(=O)C[Zn+] Chemical compound [Br-].CC(C)(C)OC(=O)C[Zn+] JFJZZFHRBKGKAE-UHFFFAOYSA-M 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 210000003208 abducens nerve Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000002187 accessory nerve Anatomy 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 208000030597 adult Refsum disease Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002070 alkenylidene group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000010210 aluminium Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003926 auditory cortex Anatomy 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- GRHLMSBCOPRFNA-UHFFFAOYSA-M azanide 2-oxidoacetate platinum(4+) Chemical compound N[Pt]1(N)OCC(=O)O1 GRHLMSBCOPRFNA-UHFFFAOYSA-M 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- MXMZCLLIUQEKSN-UHFFFAOYSA-N benzimidazoline Chemical compound C1=CC=C2NCNC2=C1 MXMZCLLIUQEKSN-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- NRYLYCPVJWJADR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO.CCC(O)CO NRYLYCPVJWJADR-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CHRHZFQUDFAQEQ-UHFFFAOYSA-L calcium;2-hydroxyacetate Chemical compound [Ca+2].OCC([O-])=O.OCC([O-])=O CHRHZFQUDFAQEQ-UHFFFAOYSA-L 0.000 description 1
- SHZIWNPUGXLXDT-UHFFFAOYSA-N caproic acid ethyl ester Natural products CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 210000004889 cervical nerve Anatomy 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- GPTJTTCOVDDHER-UHFFFAOYSA-N cyclononane Chemical compound C1CCCCCCCC1 GPTJTTCOVDDHER-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- IMYJOYAAVSFZMM-UHFFFAOYSA-L cyclopenta-1,3-diene;titanium(2+);dichloride Chemical compound [Cl-].[Cl-].[Ti+2].C1C=CC=[C-]1.C1C=CC=[C-]1 IMYJOYAAVSFZMM-UHFFFAOYSA-L 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 description 1
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229950010170 epalrestat Drugs 0.000 description 1
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DNORZUSMZSZZKU-UHFFFAOYSA-N ethyl 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate Chemical compound C=1C=C(Cl)C=CC=1CCCCCC1(C(=O)OCC)CO1 DNORZUSMZSZZKU-UHFFFAOYSA-N 0.000 description 1
- KCIYXEXQJICHSN-UHFFFAOYSA-N ethyl 3-(5-fluoro-2-hydroxyphenyl)propanoate Chemical compound CCOC(=O)CCc1cc(F)ccc1O KCIYXEXQJICHSN-UHFFFAOYSA-N 0.000 description 1
- VGFQZTXRCNQSNX-UHFFFAOYSA-N ethyl 3-[2-[2-[tert-butyl(dimethyl)silyl]oxy-3-hydroxypropoxy]phenyl]propanoate Chemical compound [Si](C)(C)(C(C)(C)C)OC(COC1=C(C=CC=C1)CCC(=O)OCC)CO VGFQZTXRCNQSNX-UHFFFAOYSA-N 0.000 description 1
- GZTLFMPFEGMGKE-UHFFFAOYSA-N ethyl 3-[2-[2-[tert-butyl(dimethyl)silyl]oxy-3-oxopropoxy]phenyl]propanoate Chemical compound [Si](C)(C)(C(C)(C)C)OC(COC1=C(C=CC=C1)CCC(=O)OCC)C=O GZTLFMPFEGMGKE-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Natural products OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000001339 gustatory effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 101150000808 hand1 gene Proteins 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 210000001169 hypoglossal nerve Anatomy 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- QGEFGPVWRJCFQP-UHFFFAOYSA-M magnesium;methanidylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C1=CC=CC=C1 QGEFGPVWRJCFQP-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960005321 mecobalamin Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- VAAZHWDCSRHQEH-UHFFFAOYSA-N methyl 1-[(2-hydroxyphenyl)methyl]cyclopropane-1-carboxylate Chemical compound COC(=O)C1(CC1)CC1=C(C=CC=C1)O VAAZHWDCSRHQEH-UHFFFAOYSA-N 0.000 description 1
- JKTBQSSJXUXBFH-UHFFFAOYSA-N methyl 2-(2-hydroxyphenyl)-2-methylpropanoate Chemical compound COC(=O)C(C)(C)C1=CC=CC=C1O JKTBQSSJXUXBFH-UHFFFAOYSA-N 0.000 description 1
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 1
- 235000007672 methylcobalamin Nutrition 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 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
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 208000019382 nerve compression syndrome Diseases 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 210000002589 oculomotor nerve Anatomy 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- RYDICHIKLKVOEJ-UHFFFAOYSA-N oxadiazepine Chemical compound O1C=CC=CN=N1 RYDICHIKLKVOEJ-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 208000031232 peroneal neuropathy Diseases 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical compound C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 206010049433 piriformis syndrome Diseases 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- QMWGRJQLANOEFD-UHFFFAOYSA-N propan-2-yl 3-[2-(3-hydroxypent-4-ynoxy)phenyl]propanoate Chemical compound OC(CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)C#C QMWGRJQLANOEFD-UHFFFAOYSA-N 0.000 description 1
- BIMPPEMDGQWENM-UHFFFAOYSA-N propan-2-yl 3-[2-(3-oxopropoxy)phenyl]propanoate Chemical compound O=CCCOC1=C(C=CC=C1)CCC(=O)OC(C)C BIMPPEMDGQWENM-UHFFFAOYSA-N 0.000 description 1
- QMWGRJQLANOEFD-HNNXBMFYSA-N propan-2-yl 3-[2-[(3R)-3-hydroxypent-4-ynoxy]phenyl]propanoate Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)C#C QMWGRJQLANOEFD-HNNXBMFYSA-N 0.000 description 1
- IMQDVVMRXHFVPA-SFHVURJKSA-N propan-2-yl 3-[2-[(3R)-3-trimethylsilyloxypent-4-ynoxy]phenyl]propanoate Chemical compound C[Si](O[C@H](CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)C#C)(C)C IMQDVVMRXHFVPA-SFHVURJKSA-N 0.000 description 1
- UASWCZFHDKOIPG-URLMMPGGSA-N propan-2-yl 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoate Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)CCC1=CC(=CC=C1)[C@@H](CC1=CC=CC=C1)O UASWCZFHDKOIPG-URLMMPGGSA-N 0.000 description 1
- WPMXIURUQKJSKE-OUKQBFOZSA-N propan-2-yl 3-[2-[(E)-3,3-difluoro-5-(3-nitrophenyl)pent-4-enoxy]phenyl]propanoate Chemical compound FC(CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)(\C=C\C1=CC(=CC=C1)[N+](=O)[O-])F WPMXIURUQKJSKE-OUKQBFOZSA-N 0.000 description 1
- HOFLLIZPUHVGIP-ZRDIBKRKSA-N propan-2-yl 3-[2-[(E)-5-(3-nitrophenyl)-3-oxopent-4-enoxy]phenyl]propanoate Chemical compound [N+](=O)([O-])C=1C=C(C=CC=1)/C=C/C(CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)=O HOFLLIZPUHVGIP-ZRDIBKRKSA-N 0.000 description 1
- OEBVXUBVLMZLPV-MHWRWJLKSA-N propan-2-yl 3-[2-[(E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoxy]phenyl]propanoate Chemical compound CC1(OB(OC1(C)C)/C=C/CCCOC1=C(C=CC=C1)CCC(=O)OC(C)C)C OEBVXUBVLMZLPV-MHWRWJLKSA-N 0.000 description 1
- KVQYNVSIJRZMBC-JMMADQGHSA-N propan-2-yl 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoate Chemical compound O[C@H](CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)\C=C\C1=CC(=CC=C1)[C@@H](CC1=CC=CC=C1)O KVQYNVSIJRZMBC-JMMADQGHSA-N 0.000 description 1
- XMQHPJSUDMZKSJ-RQOTYCFOSA-N propan-2-yl 3-[2-[(E,3R)-5-(3-aminophenyl)-3-trimethylsilyloxypent-4-enoxy]phenyl]propanoate Chemical compound NC=1C=C(C=CC=1)/C=C/[C@@H](CCOC1=C(C=CC=C1)CCC(=O)OC(C)C)O[Si](C)(C)C XMQHPJSUDMZKSJ-RQOTYCFOSA-N 0.000 description 1
- VKAYMPQMKOWFLD-UHFFFAOYSA-N propan-2-yl 3-[2-[2-(1,3-dioxan-2-yl)ethoxy]phenyl]propanoate Chemical compound O1C(OCCC1)CCOC1=C(C=CC=C1)CCC(=O)OC(C)C VKAYMPQMKOWFLD-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000009023 proprioceptive sensation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium 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
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000003447 supported reagent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- DASUJKKKKGHFBF-UHFFFAOYSA-L thallium(i) carbonate Chemical compound [Tl+].[Tl+].[O-]C([O-])=O DASUJKKKKGHFBF-UHFFFAOYSA-L 0.000 description 1
- RWXZKKKYLRFREK-UHFFFAOYSA-N thiadiazepane Chemical compound C1CCSNNC1 RWXZKKKYLRFREK-UHFFFAOYSA-N 0.000 description 1
- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 description 1
- PGAZQSBUJDVGIX-UHFFFAOYSA-N thiazepane Chemical compound C1CCNSCC1 PGAZQSBUJDVGIX-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 210000003448 thoracic nerve Anatomy 0.000 description 1
- 206010048627 thoracic outlet syndrome Diseases 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- WIOADUFWOUUQCV-UHFFFAOYSA-N triphenylphosphanium dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 WIOADUFWOUUQCV-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000003076 trochlear nerve Anatomy 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000000857 visual cortex Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本開示は、以下の一般式(I) The present disclosure relates to the following general formula (I)
(式中、すべての記号は後記と同じ意味を表す。)
で示される化合物またはその塩(以下、本発明化合物と略記することがある。)を含有する医薬組成物等に関する。
(In the formula, all symbols have the same meanings as below.)
The present invention relates to a pharmaceutical composition containing the compound represented by the above or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention).
神経系は、中枢神経系と末梢神経系に大別され、なかでも末梢神経系は、脳および脊髄と身体末梢とを連絡し、神経伝達を担う。末梢神経系は、体性神経系(脳脊髄神経系)と自律神経系に分類できる。さらに、体性神経系は脳神経と脊髄神経に分けられる。また、体性神経系を機能的に分類すると、感覚受容器から生じた神経信号(興奮)を中枢神経に伝えるものは求心性、あるいは感覚性の神経線維に分類され、それに対して、脳・脊髄から筋や腺等の効果器に向かう神経信号を伝えるものは遠心性、あるいは運動性の神経線維に分類される。脳神経は脳から出る末梢神経で12対が知られ、あるものは感覚性、あるものは運動性、またはあるものは混合性の神経線維から成っている。第1~第12神経対は、それぞれ嗅神経、視神経、動眼神経、滑車神経、三叉神経、外転神経、顔面神経、内耳神経、舌咽神経、迷走神経、副神経、舌下神経と呼ばれる。これらのうち、感覚性または混合性の神経線維から成る神経は、嗅神経、視神経、三叉神経、顔面神経、内耳神経、舌咽神経、迷走神経が知られている。脊髄神経は脊髄から発する末梢神経で左右31対が知られ、8対の頚神経、12対の胸神経、5対の腰神経、5対の仙骨神経と1対の尾骨神経が知られている。脊髄神経はすべて混合性の神経線維から成り、皮膚等に行く感覚線維(後根)と骨格筋に行く運動線維(前根)とを含んでいる。 The nervous system is broadly divided into the central nervous system and the peripheral nervous system, with the peripheral nervous system being responsible for communicating nerve transmission between the brain and spinal cord and the periphery of the body. The peripheral nervous system can be classified into the somatic nervous system (cerebrospinal nervous system) and the autonomic nervous system. Furthermore, the somatic nervous system is divided into cranial nerves and spinal nerves. Furthermore, when the somatic nervous system is functionally classified, those that transmit nerve signals (excitation) generated from sensory receptors to the central nervous system are classified as afferent or sensory nerve fibers; Those that transmit nerve signals from the spinal cord to effect organs such as muscles and glands are classified as efferent or motile nerve fibers. Cranial nerves are peripheral nerves that exit from the brain and are known in 12 pairs, some consisting of sensory, some motor, and some mixed nerve fibers. The first to twelfth nerve pairs are called the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, cochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve, respectively. Among these, known nerves consisting of sensory or mixed nerve fibers include the olfactory nerve, optic nerve, trigeminal nerve, facial nerve, cochlear nerve, glossopharyngeal nerve, and vagus nerve. Spinal nerves are peripheral nerves that originate from the spinal cord, and 31 pairs are known on the left and right, including 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves, and 1 pair of coccygeal nerves. . All spinal nerves are composed of mixed nerve fibers, including sensory fibers (dorsal roots) that go to the skin and motor fibers (ventral roots) that go to skeletal muscles.
感覚性の神経線維、すなわち感覚神経は視覚器、聴覚器、嗅覚器、味覚器および皮膚等の感覚受容器が受け取った光、音、温度や接触等の刺激を中枢神経系に正確に伝える機能を担っている。中枢神経系に伝えられた神経信号は、最終的には大脳皮質の各感覚野、例えば、視覚野、聴覚野等に伝達され、正常に感覚が認識される。しかしながら、これらの感覚神経が、例えば、ウイルス感染、腫瘍、癌、糖尿病、虚血、外傷、圧迫、薬物や放射線療法等により、軸索、ミエリン鞘またはシュワン細胞等が侵され、細胞死や脱髄等の様々な神経障害が引き起こされることがある。その結果、障害が生じた感覚神経では正確な神経伝達が行われないため、例えば、難聴や神経障害性疼痛等の疾患が発症する。これら以外に、特定の感覚神経だけでなく、感覚神経を含む様々な末梢神経が、例えば、代謝疾患、自己免疫疾患等の疾患、外傷、薬物中毒等の原因によって同時に障害を受ける末梢神経障害がある。本症は、単一神経、別々の領域にある2つ以上の神経、または多数の神経が同時に障害を受けることがある。その症状は、末梢部の刺痛、しびれ、灼熱感、関節の固有覚低下、振動覚低下、疼痛(神経障害性疼痛も含む)、異常感覚、冷えまたはほてり等が挙げられ、非常に複雑で多岐に渡っている。 Sensory nerve fibers, or sensory nerves, have the function of accurately transmitting stimuli such as light, sound, temperature, and touch received by sensory receptors such as visual, auditory, olfactory, and gustatory organs, and the skin to the central nervous system. is in charge of The nerve signals transmitted to the central nervous system are ultimately transmitted to each sensory area of the cerebral cortex, such as the visual cortex and the auditory cortex, so that sensations are normally recognized. However, these sensory nerves can be affected by axons, myelin sheaths, or Schwann cells due to viral infections, tumors, cancer, diabetes, ischemia, trauma, compression, drugs, radiation therapy, etc., resulting in cell death or withdrawal. Various neurological disorders such as spinal cord may be caused. As a result, accurate nerve transmission is not carried out in the damaged sensory nerves, leading to the development of diseases such as hearing loss and neuropathic pain. In addition to these, there are peripheral neuropathies in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to causes such as metabolic diseases, autoimmune diseases, trauma, drug addiction, etc. be. The disease may affect a single nerve, two or more nerves in separate areas, or multiple nerves simultaneously. Symptoms are extremely complex and include tingling, numbness, burning in the periphery, decreased joint proprioception, decreased vibration sensation, pain (including neuropathic pain), paresthesia, coldness or hot flashes, etc. It's wide-ranging.
しかしながら、上記のような末梢神経系疾患はその発生機序が不明な疾患であったり、神経の物理的な損傷であったりするため、それらの治療に際しては、主として症状改善等を目的とした対症療法が行われており、障害を受けた神経系に直接作用する根本治療となるような臨床上有用な薬剤はほとんど知られていない。 However, since the mechanisms of peripheral nervous system diseases mentioned above are unknown or physical damage to the nerves occurs, their treatment mainly involves symptomatic treatment aimed at improving symptoms. There are currently few clinically useful drugs known that act directly on the affected nervous system to provide a fundamental treatment.
本発明の課題は、神経保護および/または修復作用を有する化合物を含有する医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition containing a compound having neuroprotective and/or repair action.
本発明者らは、前記課題を解決するため鋭意検討した結果、以下に示す一般式(I)で示される化合物またはその塩を含有する医薬組成物等が、強力な神経保護および/または修復作用を有することを見出した。
すなわち、本発明は、一態様において、
[1]一般式(I)
As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical composition containing a compound represented by the general formula (I) shown below or a salt thereof has a strong neuroprotective and/or restorative effect. It was found that
That is, in one aspect of the present invention,
[1] General formula (I)
[式中、R1は、(1)-R11-COOR12、(2)-R13-CONR14R15、(3)-R17-CN、(4)-R18-CONHS(O)2-R19、(5)-R20-CycD、または [Wherein, R 1 is (1) -R 11 -COOR 12 , (2) -R 13 -CONR 14 R 15 , (3) -R 17 -CN, (4) -R 18 -CONHS(O) 2 -R 19 , (5)-R 20 -CycD, or
(基中、ring1は3~6員の含窒素単環式飽和複素環を表し、R101は、(1)ハロゲン原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表し、nは0から3の整数を表し、nが2以上のとき複数のR101は同じでも異なっていてもよい。)を表し、
R11、R13、R16、R17、R18、およびR20は、それぞれ独立して、(1)1~3個のハロゲン原子で置換されていてもよいC1~6アルキレン基、(2)1~3個のハロゲン原子で置換されていてもよいC2~6アルケニレン基、または(3)1~3個のハロゲン原子で置換されていてもよいC2~6アルキニレン基を表し、基中、アルキレン基、アルケニレン基またはアルキニレン基が分枝鎖の場合、同一の炭素原子から分枝した2個のC1~2アルキル基は一緒になってC3~5の飽和炭素環を形成してもよく、
R12、R14、R15およびR19は、それぞれ独立して、(1)水素原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表し、
CycDは、トリアゾールまたはテトラゾールを表し、
R2は、(1)ハロゲン原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表し、pは0から3の整数を表し、pが2以上のとき複数のR2はそれぞれ同じでも異なっていてもよく、
Xは、(1)CH2、または(2)酸素原子を表し、
L1は、(1)1~4個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基、(2)1~4個のRL1aで置換されていてもよい直鎖のC3~7アルケニレン基、(3)1~4個のRL1aで置換されていてもよい直鎖のC3~7アルキニレン基、または(4)(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)を表し、
RL1aは、(1)ハロゲン原子、(2)水酸基、(3)オキソ基、または(4)C1~2アルキル基を表し、RL1aが2個以上のとき複数のRL1aは同じでも異なっていてもよく、さらに同一の炭素原子に結合する2個のRL1aがそれぞれC1~2アルキル基のとき、該C1~2アルキル基は結合する炭素原子と一緒になってC3~5の飽和炭素環を形成してもよく、
(In the group, ring1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, and R101 is (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group) , n represents an integer from 0 to 3, and when n is 2 or more, multiple R 101 may be the same or different.),
R 11 , R 13 , R 16 , R 17 , R 18 , and R 20 each independently represent (1) a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, (2 ) represents a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) represents a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms; When the alkylene group, alkenylene group or alkynylene group is a branched chain, two C1-2 alkyl groups branched from the same carbon atom may join together to form a C3-5 saturated carbocycle,
R 12 , R 14 , R 15 and R 19 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group,
CycD represents triazole or tetrazole;
R 2 represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, p represents an integer from 0 to 3, and when p is 2 or more, multiple R 2 may be the same or different,
X represents (1) CH 2 or (2) oxygen atom,
L 1 is (1) a linear C3-7 alkylene group optionally substituted with 1 to 4 R L1a , (2) a linear C3-7 alkylene group optionally substituted with 1 to 4 R L1a ; C3-7 alkenylene group, (3) a linear C3-7 alkynylene group optionally substituted with 1 to 4 R L1a , or (4) (even if substituted with 1 to 2 R L1a ) represents a good linear C1-3 alkylene group) -O- (a straight-chain C1-3 alkylene group optionally substituted with 1 to 2 R L1a ),
R L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group, and when R L1a is two or more, multiple R L1a may be the same or different. Furthermore, when two R L1a bonded to the same carbon atom are each a C1-2 alkyl group, the C1-2 alkyl group together with the bonded carbon atom forms a C3-5 saturated carbocyclic ring. may be formed,
は、単結合、二重結合または三重結合を表し、
R3は、(1)水素原子、(2)ハロゲン原子、(3)水酸基、(4)C1~2アルキル基、または(5)メチリデン基を表し、qは0から2の整数を表し、
represents a single, double or triple bond,
R 3 represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group, and q represents an integer from 0 to 2;
が単結合であってqが2の場合、複数のR3は同じでも異なっていてもよく、また少なくともひとつのR3がメチル基の場合、隣接するL1中の炭素原子と一緒になってシクロプロパンを形成してもよく、
CycAは、(1)C5~10単環式もしくは二環式炭素環、または(2)5~10員の単環式もしくは二環式複素環を表し、
R4は、(1)ハロゲン原子、(2)水酸基、(3)C1~4アルキル基、(4)C1~4ハロアルキル基、(5)C1~4アルコキシ基、(6)C1~4ハロアルコキシ基、(7)シアノ基、または(8)-SO2-C1~2アルキル基を表し、rは0から6の整数を表し、rが2以上のとき複数のR4はそれぞれ同じでも異なっていてもよく、
L2は、-R31-L3-R32-を表し、
L3は、(1)-NR201-S(O)-、(2)-NR202-S(O)2-、(3)-NR203-C(O)-、(4)-CR204(OH)-、(5)-NR205-、(6)-S(O)-、または(7)-S(O)2-を表し、
R201、R202、R203、R204、およびR205は、それぞれ独立して、(1)水素原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表し、基中、アルキル基またはハロアルキル基は、(1)水酸基、(2)オキソ基、(3)C3~6単環式炭素環、または(4)3~6員の単環式複素環で置換されていてもよく、
R31およびR32は、それぞれ独立して、(1)結合手、または(2)ハロゲン原子、水酸基およびオキソ基からなる群から選択される1~3個の置換基で置換されていてもよいC1~3アルキレン基を表し、
CycBは、(1)C5~10単環式もしくは二環式炭素環、または(2)5~10員の単環式もしくは二環式複素環を表し、
R5は、(1)ハロゲン原子、(2)C1~6アルキル基、(3)C2~6アルケニル基、(4)C2~6アルキニル基、(5)C1~6ハロアルキル基、(6)C2~6ハロアルケニル基、(7)C2~6ハロアルキニル基、(8)C1~6アルコキシ基、または(9)C1~6ハロアルコキシ基を表し、tは0から6の整数を表し、tが2以上のとき複数のR5はそれぞれ同じでも異なっていてもよい。]で示される化合物またはその塩を含有する医薬組成物、
[1-1]さらに薬学的に許容される担体を含有する、前記[1]記載の医薬組成物、
[2]一般式(I)中、
is a single bond and q is 2, multiple R 3 may be the same or different, and if at least one R 3 is a methyl group, together with the adjacent carbon atoms in L 1 May form cyclopropane,
CycA represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle,
R 4 is (1) halogen atom, (2) hydroxyl group, (3) C1-4 alkyl group, (4) C1-4 haloalkyl group, (5) C1-4 alkoxy group, (6) C1-4 haloalkoxy group, (7) cyano group, or (8) -SO 2 -C1-2 alkyl group, r represents an integer from 0 to 6, and when r is 2 or more, multiple R 4s are the same or different. It's okay,
L 2 represents -R 31 -L 3 -R 32 -,
L 3 is (1) -NR 201 -S(O)-, (2) -NR 202 -S(O) 2 -, (3) -NR 203 -C(O)-, (4) -CR 204 (OH)-, (5)-NR 205 -, (6)-S(O)-, or (7)-S(O) 2 -,
R 201 , R 202 , R 203 , R 204 , and R 205 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, and The alkyl group or haloalkyl group is substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3-6 monocyclic carbocycle, or (4) a 3-6 membered monocyclic heterocycle. It's okay,
R 31 and R 32 may each be independently substituted with (1) a bond, or (2) 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an oxo group. Represents a C1-3 alkylene group,
CycB represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle,
R 5 is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2 -6 haloalkenyl group, (7) C2-6 haloalkynyl group, (8) C1-6 alkoxy group, or (9) C1-6 haloalkoxy group, t represents an integer from 0 to 6, and t When the number is 2 or more, the plurality of R 5 's may be the same or different. ] A pharmaceutical composition containing a compound or a salt thereof,
[1-1] The pharmaceutical composition according to [1] above, further comprising a pharmaceutically acceptable carrier;
[2] In general formula (I),
が、(1)=CH-(1~2個のRL1aで置換されていてもよい直鎖のC2~6アルキレン基)-、(2)-(1~2個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基)-、または(3)-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)である((1)~(3)においてRL1aは前記[1]記載と同じ意味を表す)、前記[1]記載の医薬組成物、
[3]R1が-R11-COOR12である、前記[1]または[2]のいずれかに記載の医薬組成物、
[4]L2が、(1)-NR202-S(O)2-、または(2)-CR204(OH)-CH2-である前記[1]~[3]のいずれかに記載の医薬組成物、
[5]CycAがC5~6単環式炭素環である前記[1]~[4]のいずれかに記載の医薬組成物、
[6]CycBがC5~6単環式炭素環である前記[1]~[5]のいずれかに記載の医薬組成物、
[7]一般式(I)が、一般式(I-1)
is, (1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 2 R L1a )-, (2) -(substituted with 1 to 2 R L1a ) a linear C3-7 alkylene group which may be substituted with 1 to 2 R (In (1) to (3), R L1a has the same meaning as described in [1] above) , [1] The pharmaceutical composition described,
[3] The pharmaceutical composition according to any one of [1] or [2] above, wherein R 1 is -R 11 -COOR 12 ;
[4] Any one of the above [1] to [3], wherein L 2 is (1) -NR 202 -S(O) 2 - or (2) -CR 204 (OH) -CH 2 - a pharmaceutical composition of
[5] The pharmaceutical composition according to any one of [1] to [4] above, wherein CycA is a C5-6 monocyclic carbocycle;
[6] The pharmaceutical composition according to any one of [1] to [5] above, wherein CycB is a C5-6 monocyclic carbocycle;
[7] General formula (I) is general formula (I-1)
[式中、R11-1はC2~4アルキレン基を表し、L1-1は1~2個のRL1aで置換されていてもよい直鎖のC3~4アルキレン基を表し、CycA1およびCycB1は、それぞれ独立してC5~6単環式炭素環を表し、L2-1は、(1)-NH-S(O)2-、または(2)-CH(OH)-CH2-を表し、その他の記号は前記[1]と同じ意味を表す。]である、前記[1]~[6]のいずれかに記載の医薬組成物、
[8]Xが酸素原子である、前記[1]~[7]のいずれかに記載の医薬組成物、
[9]一般式(I)で示される化合物またはその塩が、
(1)3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(2)3-[2-[(3S)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸、
(3)3-[2-[(3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸、
(4)3-[2-[(E,3R)-5-[4-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(5)3-[2-[(E,3R)-5-[3-(シクロペンチルスルホニルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(6)3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-2-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(7)4-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]ブタン酸、
(8)3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシブタ-3-エノキシ]フェニル]プロパン酸、
(9)(R)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸、
(10)(S)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸、
(11)3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸、
(12)3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]ペントキシ]フェニル]プロパン酸、
(13)3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸、
(14)3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸、
(15)3-[2-[2-[2-[3-(ベンゼンスルホンアミド)フェニル]エトキシ]エトキシ]フェニル]プロパン酸、
(16)3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-オキソヘキシル]フェニル]プロパン酸、もしくは
(17)3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]-3,3-ジフルオロペントキシ]フェニル]プロパン酸またはその塩である、前記[1]記載の医薬組成物、
[10]神経保護および/または修復のための、前記[1]~[9]のいずれかに記載の医薬組成物、
[11]神経保護および/または修復が、グリア細胞(例えば、ミクログリア、アストロサイト、オリゴデンドロサイト、上衣細胞、シュワン細胞、衛星細胞など)を介した神経保護および/または修復である、前記[10]記載の医薬組成物、
[12]グリア細胞を介した神経保護および/または修復が、シュワン細胞のミエリン化促進による神経保護および/または修復である、前記[11]記載の医薬組成物、
[13]神経障害の予防および/または治療剤である、前記[1]~[12]のいずれかに記載の医薬組成物、
[14]神経障害が末梢神経障害である前記[13]記載の医薬組成物、
[15]末梢神経障害が、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、結節性動脈周囲炎、アレルギー性血管炎、糖尿病性末梢神経障害、絞扼性神経障害、化学療法薬投与に伴う末梢神経障害、またはシャルコー・マリー・トゥース病に伴う末梢神経障害である、前記[14]記載の医薬組成物、
[2-1]前記[1]記載の一般式(I)で示される化合物またはその塩を含有するシュワン細胞分化促進剤、
[2-1-1]3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸またはその塩を含有するシュワン細胞分化促進剤、
[2-2]前記[1]記載の一般式(I)で示される化合物またはその塩を含有する神経保護および/または修復剤、
[2-2-1]3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸またはその塩を含有する神経保護および/または修復剤、
[2-2-2]神経保護および/または修復が、グリア細胞(例えば、ミクログリア、アストロサイト、オリゴデンドロサイト、上衣細胞、シュワン細胞、衛星細胞など)を介した神経保護および/または修復である、前記[2-2]または[2-2-1]のいずれかに記載の剤、
[2-2-3]グリア細胞を介した神経保護および/または修復が、シュワン細胞のミエリン化促進による神経保護および/または修復である、前記[2-2-2]記載の剤、
[2-3]前記[1]記載の一般式(I)で示される化合物またはその塩を含有する神経障害の予防および/または治療剤、
[2-3-1]3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸またはその塩を含有する神経障害の予防および/または治療剤、
[2-3-2]神経障害が末梢神経障害である前記[2-3]または[2-3-1]のいずれかに記載の剤、
[2-3-3]末梢神経障害が、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、結節性動脈周囲炎、アレルギー性血管炎、糖尿病性末梢神経障害、絞扼性神経障害、化学療法薬投与に伴う末梢神経障害、またはシャルコー・マリー・トゥース病に伴う末梢神経障害である、前記[2-3-2]記載の剤、
等に関する。
[In the formula, R 11-1 represents a C2-4 alkylene group, L 1-1 represents a linear C3-4 alkylene group optionally substituted with 1 to 2 R L1a , CycA 1 and CycB 1 each independently represents a C5-6 monocyclic carbocycle, and L 2-1 is (1) -NH-S(O) 2 - or (2) -CH(OH)-CH 2 -, and other symbols have the same meanings as [1] above. ] The pharmaceutical composition according to any one of [1] to [6] above,
[8] The pharmaceutical composition according to any one of [1] to [7] above, wherein X is an oxygen atom;
[9] The compound represented by general formula (I) or a salt thereof is
(1) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(2) 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid,
(3) 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid,
(4) 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(5) 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(6) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(7) 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid,
(8) 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid,
(9) (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid,
(10) (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid,
(11) 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid,
(12) 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid,
(13) 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid,
(14) 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid,
(15) 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid,
(16) 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid, or (17) 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid The pharmaceutical composition according to [1] above, which is amido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof;
[10] The pharmaceutical composition according to any one of [1] to [9] above, for neuroprotection and/or repair;
[11] The above-mentioned [10], wherein the neuroprotection and/or repair is neuroprotection and/or repair mediated by glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.) ] The pharmaceutical composition described in
[12] The pharmaceutical composition according to [11] above, wherein the neuroprotection and/or repair mediated by glial cells is neuroprotection and/or repair by promoting myelination of Schwann cells.
[13] The pharmaceutical composition according to any one of [1] to [12] above, which is a preventive and/or therapeutic agent for neuropathy;
[14] The pharmaceutical composition according to [13] above, wherein the neuropathy is peripheral neuropathy;
[15] Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, or chemotherapy drug administration. The pharmaceutical composition according to [14] above, which is peripheral neuropathy or peripheral neuropathy associated with Charcot-Marie-Tooth disease;
[2-1] A Schwann cell differentiation promoter containing the compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-1-1] Schwann cell differentiation promoter containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof ,
[2-2] A neuroprotective and/or restorative agent containing a compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-2-1] Neuroprotective and/or containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof repair agent,
[2-2-2] Neuroprotection and/or repair is neuroprotection and/or repair mediated by glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.) , the agent according to any one of [2-2] or [2-2-1] above,
[2-2-3] The agent according to [2-2-2] above, wherein the neuroprotection and/or repair via glial cells is neuroprotection and/or repair by promoting myelination of Schwann cells;
[2-3] A preventive and/or therapeutic agent for neurological disorders containing the compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-3-1] Prevention of neurological disorders containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or its salts and /or therapeutic agent,
[2-3-2] The agent according to any one of [2-3] or [2-3-1] above, wherein the neuropathy is peripheral neuropathy;
[2-3-3] Peripheral neuropathy is caused by chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, chemotherapy The agent according to [2-3-2] above, which is peripheral neuropathy associated with drug administration or peripheral neuropathy associated with Charcot-Marie-Tooth disease;
Regarding etc.
本発明化合物を含有する医薬組成物は、強力な神経保護および/または修復作用を有するため、神経障害、例えば末梢神経障害の治療に有用である。 Pharmaceutical compositions containing the compounds of the present invention have strong neuroprotective and/or restorative effects and are therefore useful for treating neuropathies, such as peripheral neuropathies.
以下、本発明を詳細に説明する。
本発明において、3~6員の含窒素単環式飽和複素環とは、少なくとも1個以上の窒素原子を含有する単環式飽和複素環をいい、例えば、アジリジン、アゼチジン、ピロリジン、イミダゾリジン、トリアゾリジン、テトラゾリジン、ピラゾリジン、ピペリジン、ピペラジン、パーヒドロピリミジン、パーヒドロピリダジン、テトラヒドロオキサゾール(オキサゾリジン)、テトラヒドロイソオキサゾール(イソオキサゾリジン)、テトラヒドロチアゾール(チアゾリジン)、テトラヒドロイソチアゾール(イソチアゾリジン)、テトラヒドロフラザン、テトラヒドロオキサジアゾール(オキサジアゾリジン)、テトラヒドロオキサジン、テトラヒドロオキサジアジン、テトラヒドロチアジアゾール(チアジアゾリジン)、テトラヒドロチアジン、テトラヒドロチアジアジン、モルホリン、チオモルホリンが挙げられる。
The present invention will be explained in detail below.
In the present invention, a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle refers to a monocyclic saturated heterocycle containing at least one nitrogen atom, such as aziridine, azetidine, pyrrolidine, imidazolidine, Triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydroxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydro Examples include oxadiazole (oxadiazolidine), tetrahydroxazine, tetrahydroxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, morpholine, and thiomorpholine.
本発明において、ハロゲン原子とは、フッ素、塩素、臭素、ヨウ素等を意味する。 In the present invention, the halogen atom means fluorine, chlorine, bromine, iodine, etc.
本発明において、C1~4アルキル基には、直鎖状または分枝鎖状のC1~4アルキル基が含まれ、例えば、メチル、エチル、プロピル、ブチル、イソプロピル、イソブチル、sec-ブチル、またはtert-ブチルが挙げられる。 In the present invention, the C1-4 alkyl group includes straight-chain or branched C1-4 alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert. -butyl.
本発明において、C1~4ハロアルキル基とは、直鎖状または分枝鎖状のC1~4アルキル基が1個以上のハロゲン原子によって置換された基をいい、例えば、フルオロメチル、クロロメチル、ブロモメチル、ヨードメチル、ジフルオロメチル、トリフルオロメチル、1-フルオロエチル、2-フルオロエチル、2-クロロエチル、ペンタフルオロエチル、1-フルオロプロピル、2-クロロプロピル、3-フルオロプロピル、3-クロロプロピル、4,4,4-トリフルオロブチル、または4-ブロモブチルが挙げられる。 In the present invention, the C1-4 haloalkyl group refers to a group in which a linear or branched C1-4 alkyl group is substituted with one or more halogen atoms, such as fluoromethyl, chloromethyl, bromomethyl , iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4, Examples include 4,4-trifluorobutyl and 4-bromobutyl.
本発明において、C1~6アルキレン基には、直鎖状または分枝鎖状のC1~6アルキレン基が含まれ、例えば、メチレン、エチレン、プロピレン、ブチレン、ペンチレン、ヘキサニレンまたはそれらの異性体が挙げられる。 In the present invention, the C1-6 alkylene group includes linear or branched C1-6 alkylene groups, such as methylene, ethylene, propylene, butylene, pentylene, hexanylene, or isomers thereof. It will be done.
本発明において、C2~6アルケニレン基には、直鎖状または分枝鎖状のC2~6アルケニレン基が含まれ、例えば、エテニレン、プロペニレン、ブテニレン、ペンテニレン、ヘキセニレン、またはそれらの異性体が挙げられる。 In the present invention, the C2-6 alkenylene group includes linear or branched C2-6 alkenylene groups, such as ethenylene, propenylene, butenylene, pentenylene, hexenylene, or isomers thereof. .
本発明において、C2~6アルキニレン基には、直鎖状または分枝鎖状のC2~6アルキニレン基が含まれ、例えば、エチニレン、プロピニレン、ブチニレン、ペンチニレン、ヘキシニレン、またはそれらの異性体が挙げられる。 In the present invention, the C2-6 alkynylene group includes linear or branched C2-6 alkynylene groups, such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, or isomers thereof. .
本発明において、直鎖のC3~7アルキレン基としては、例えばプロピレン、ブチレン、ペンチレン、ヘキサニレンまたはヘプタニレンが挙げられる。 In the present invention, examples of the linear C3-7 alkylene group include propylene, butylene, pentylene, hexanylene, and heptanylene.
本発明において、直鎖のC3~7アルケニレン基としては、例えばプロペニレン、ブテニレン、ペンテニレン、ヘキセニレン、ヘプテニレン、またはそれらの異性体が挙げられる。 In the present invention, the linear C3-7 alkenylene group includes, for example, propenylene, butenylene, pentenylene, hexenylene, heptenylene, or isomers thereof.
本発明において、直鎖のC3~7アルキニレン基としては、例えばプロピニレン、ブチニレン、ペンチニレン、ヘキシニレン、またはそれらの異性体が挙げられる。 In the present invention, the linear C3-7 alkynylene group includes, for example, propynylene, butynylene, pentynylene, hexynylene, or isomers thereof.
本発明において、C1~2アルキル基とは、メチルまたはエチルをいう。 In the present invention, the C1-2 alkyl group refers to methyl or ethyl.
本発明において、C3~5の飽和炭素環とは、例えば、シクロプロパン、シクロブタン、シクロペンタンが挙げられる。 In the present invention, examples of the C3-5 saturated carbon ring include cyclopropane, cyclobutane, and cyclopentane.
本発明において、C5~10単環式または二環式炭素環とは、例えば、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロオクテン、シクロペンタジエン、シクロヘキサジエン、シクロヘプタジエン、シクロオクタジエン、ベンゼン、ペンタレン、パーヒドロペンタレン、アズレン、パーヒドロアズレン、インデン、パーヒドロインデン、インダン、ナフタレン、ジヒドロナフタレン、テトラヒドロナフタレン、パーヒドロナフタレンが挙げられる。 In the present invention, C5-10 monocyclic or bicyclic carbocycles include, for example, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, and cyclohexadiene. , cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene.
本発明において、5~10員の単環式もしくは二環式複素環とは、酸素原子、窒素原子および硫黄原子から選択されるヘテロ原子を含む5~10員の単環式または二環式複素環をいい、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、アゼピン、ジアゼピン、フラン、ピラン、オキセピン、チオフェン、チオピラン、チエピン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、フラザン、オキサジアゾール、オキサジン、オキサジアジン、オキサゼピン、オキサジアゼピン、チアジアゾール、チアジン、チアジアジン、チアゼピン、チアジアゼピン、インドール、イソインドール、インドリジン、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、イソベンゾチオフェン、ジチアナフタレン、インダゾール、キノリン、イソキノリン、キノリジン、プリン、フタラジン、プテリジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、ベンゾオキサゾール、ベンゾチアゾール、ベンゾイミダゾール、クロメン、ベンゾフラザン、ベンゾチアジアゾール、ベンゾトリアゾール、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ジヒドロピリジン、テトラヒドロピリジン、ピペリジン、ジヒドロピラジン、テトラヒドロピラジン、ピペラジン、ジヒドロピリミジン、テトラヒドロピリミジン、パーヒドロピリミジン、ジヒドロピリダジン、テトラヒドロピリダジン、パーヒドロピリダジン、ジヒドロアゼピン、テトラヒドロアゼピン、パーヒドロアゼピン、ジヒドロジアゼピン、テトラヒドロジアゼピン、パーヒドロジアゼピン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロオキセピン、テトラヒドロオキセピン、パーヒドロオキセピン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチオピラン、テトラヒドロチオピラン、ジヒドロチエピン、テトラヒドロチエピン、パーヒドロチエピン、ジヒドロオキサゾール、テトラヒドロオキサゾール(オキサゾリジン)、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール(イソオキサゾリジン)、ジヒドロチアゾール、テトラヒドロチアゾール(チアゾリジン)、ジヒドロイソチアゾール、テトラヒドロイソチアゾール(イソチアゾリジン)、ジヒドロフラザン、テトラヒドロフラザン、ジヒドロオキサジアゾール、テトラヒドロオキサジアゾール(オキサジアゾリジン)、ジヒドロオキサジン、テトラヒドロオキサジン、ジヒドロオキサジアジン、テトラヒドロオキサジアジン、ジヒドロオキサゼピン、テトラヒドロオキサゼピン、パーヒドロオキサゼピン、ジヒドロオキサジアゼピン、テトラヒドロオキサジアゼピン、パーヒドロオキサジアゼピン、ジヒドロチアジアゾール、テトラヒドロチアジアゾール(チアジアゾリジン)、ジヒドロチアジン、テトラヒドロチアジン、ジヒドロチアジアジン、テトラヒドロチアジアジン、ジヒドロチアゼピン、テトラヒドロチアゼピン、パーヒドロチアゼピン、ジヒドロチアジアゼピン、テトラヒドロチアジアゼピン、パーヒドロチアジアゼピン、モルホリン、チオモルホリン、オキサチアン、インドリン、イソインドリン、ジヒドロベンゾフラン、パーヒドロベンゾフラン、ジヒドロイソベンゾフラン、パーヒドロイソベンゾフラン、ジヒドロベンゾチオフェン、パーヒドロベンゾチオフェン、ジヒドロイソベンゾチオフェン、パーヒドロイソベンゾチオフェン、ジヒドロインダゾール、パーヒドロインダゾール、ジヒドロキノリン、テトラヒドロキノリン、パーヒドロキノリン、ジヒドロイソキノリン、テトラヒドロイソキノリン、パーヒドロイソキノリン、ジヒドロフタラジン、テトラヒドロフタラジン、パーヒドロフタラジン、ジヒドロナフチリジン、テトラヒドロナフチリジン、パーヒドロナフチリジン、ジヒドロキノキサリン、テトラヒドロキノキサリン、パーヒドロキノキサリン、ジヒドロキナゾリン、テトラヒドロキナゾリン、パーヒドロキナゾリン、ジヒドロシンノリン、テトラヒドロシンノリン、パーヒドロシンノリン、ベンゾオキサチアン、ジヒドロベンゾオキサジン、ジヒドロベンゾチアジン、ピラジノモルホリン、ジヒドロベンゾオキサゾール、パーヒドロベンゾオキサゾール、ジヒドロベンゾチアゾール、パーヒドロベンゾチアゾール、ジヒドロベンゾイミダゾール、パーヒドロベンゾイミダゾール、ジオキソラン、ジオキサン、ジチオラン、ジチアン、ジオキサインダン、ベンゾジオキサン、クロマン、ベンゾジチオラン、ベンゾジチアンが挙げられる。 In the present invention, a 5- to 10-membered monocyclic or bicyclic heterocycle refers to a 5- to 10-membered monocyclic or bicyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Refers to a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole, Furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, Quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, Triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine , Perhydroazepine, Dihydrodiazepine, Tetrahydrodiazepine, Perhydrodiazepine, Dihydrofuran, Tetrahydrofuran, Dihydropyran, Tetrahydropyran, Dihydroxepin, Tetrahydroxepine, Perhydroxepine, Dihydrothiophene, Tetrahydrothiophene , dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine) ), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine Zine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydro Thiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, indoline , isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, Tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, Dihydroquinazoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydrocinnoline, Tetrahydrocinnoline, Perhydrocinnoline, Benzoxathian, Dihydrobenzoxazine, Dihydrobenzothiazine, Pyrazinomorpholine, Dihydrobenzoxazole, Perhydrobenzoxazole, Dihydro Examples include benzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxindane, benzodioxane, chroman, benzodithiolane, and benzodithiane.
本発明において、C1~4アルコキシ基には、直鎖状または分枝鎖状のC1~4アルコキシ基が含まれ、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、イソブトキシ、sec-ブトキシ、tert-ブトキシが挙げられる。 In the present invention, the C1-4 alkoxy group includes linear or branched C1-4 alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -butoxy and tert-butoxy.
本発明において、C1~4ハロアルコキシ基とは、直鎖状または分枝鎖状のC1~4アルコキシ基が1個以上のハロゲン原子によって置換された基をいい、例えば、トリフルオロメトキシ、トリクロロメトキシ、クロロメトキシ、ブロモメトキシ、フルオロメトキシ、ヨードメトキシ、ジフルオロメトキシ、ジブロモメトキシ、2-クロロエトキシ、2,2,2-トリフルオロエトキシ、2,2,2-トリクロロエトキシ、3-ブロモプロポキシ、3-クロロプロポキシ、2,3-ジクロロプロポキシ、1-フルオロブトキシ、4-フルオロブトキシ、1-クロロブトキシが挙げられる。 In the present invention, the C1-4 haloalkoxy group refers to a group in which a linear or branched C1-4 alkoxy group is substituted with one or more halogen atoms, such as trifluoromethoxy, trichloromethoxy , chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3- Examples include chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, and 1-chlorobutoxy.
本発明において、C3~6単環式炭素環とは、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロペンテン、シクロヘキセン、シクロペンタジエン、シクロヘキサジエン、ベンゼンが挙げられる。 In the present invention, examples of the C3-6 monocyclic carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.
本発明において、3~6員の単環式複素環とは、酸素原子、窒素原子および硫黄原子から選択されるヘテロ原子を含む3~6員の単環式複素環をいい、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、フラン、ピラン、チオフェン、チオピラン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、フラザン、オキサジアゾール、オキサジン、オキサジアジン、チアジアゾール、チアジン、チアジアジン、アジリジン、アゼチジン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ジヒドロピリジン、テトラヒドロピリジン、ピペリジン、ジヒドロピラジン、テトラヒドロピラジン、ピペラジン、ジヒドロピリミジン、テトラヒドロピリミジン、パーヒドロピリミジン、ジヒドロピリダジン、テトラヒドロピリダジン、パーヒドロピリダジン、オキシラン、オキセタン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、チイラン、チエタン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチオピラン、テトラヒドロチオピラン、ジヒドロオキサゾール、テトラヒドロオキサゾール(オキサゾリジン)、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール(イソオキサゾリジン)、ジヒドロチアゾール、テトラヒドロチアゾール(チアゾリジン)、ジヒドロイソチアゾール、テトラヒドロイソチアゾール(イソチアゾリジン)、ジヒドロフラザン、テトラヒドロフラザン、ジヒドロオキサジアゾール、テトラヒドロオキサジアゾール(オキサジアゾリジン)、ジヒドロオキサジン、テトラヒドロオキサジン、ジヒドロオキサジアジン、テトラヒドロオキサジアジン、ジヒドロチアジアゾール、テトラヒドロチアジアゾール(チアジアゾリジン)、ジヒドロチアジン、テトラヒドロチアジン、ジヒドロチアジアジン、テトラヒドロチアジアジン、モルホリン、チオモルホリン、オキサチアン、ジオキソラン、ジオキサン、ジチオラン、ジチアンが挙げられる。 In the present invention, a 3- to 6-membered monocyclic heterocycle refers to a 3- to 6-membered monocyclic heterocycle containing a hetero atom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, Aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, Dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine) ), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxazi Azole (Oxadiazolidine), Dihydroxazine, Tetrahydroxazine, Dihydroxadiazine, Tetrahydroxadiazine, Dihydrothiadiazole, Tetrahydrothiadiazole (Thiadiazolidine), Dihydrothiazine, Tetrahydrothiazine, Dihydrothiadiazine, Tetrahydrothiadiazine Examples include gin, morpholine, thiomorpholine, oxathian, dioxolane, dioxane, dithiolane, and dithiane.
本発明において、5~6員の単環式複素環とは、酸素原子、窒素原子および硫黄原子から選択されるヘテロ原子を含む5~6員の単環式複素環をいい、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、フラン、ピラン、チオフェン、チオピラン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、フラザン、オキサジアゾール、オキサジン、オキサジアジン、チアジアゾール、チアジン、チアジアジン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ジヒドロピリジン、テトラヒドロピリジン、ピペリジン、ジヒドロピラジン、テトラヒドロピラジン、ピペラジン、ジヒドロピリミジン、テトラヒドロピリミジン、パーヒドロピリミジン、ジヒドロピリダジン、テトラヒドロピリダジン、パーヒドロピリダジン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチオピラン、テトラヒドロチオピラン、ジヒドロオキサゾール、テトラヒドロオキサゾール(オキサゾリジン)、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール(イソオキサゾリジン)、ジヒドロチアゾール、テトラヒドロチアゾール(チアゾリジン)、ジヒドロイソチアゾール、テトラヒドロイソチアゾール(イソチアゾリジン)、ジヒドロフラザン、テトラヒドロフラザン、ジヒドロオキサジアゾール、テトラヒドロオキサジアゾール(オキサジアゾリジン)、ジヒドロオキサジン、テトラヒドロオキサジン、ジヒドロオキサジアジン、テトラヒドロオキサジアジン、ジヒドロチアジアゾール、テトラヒドロチアジアゾール(チアジアゾリジン)、ジヒドロチアジン、テトラヒドロチアジン、ジヒドロチアジアジン、テトラヒドロチアジアジン、モルホリン、チオモルホリン、オキサチアン、ジオキソラン、ジオキサン、ジチオラン、ジチアンが挙げられる。 In the present invention, a 5- to 6-membered monocyclic heterocycle refers to a 5- to 6-membered monocyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, Pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydro Pyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine) ), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine , dihydroxadiazine, tetrahydroxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathian, dioxolane, dioxane , dithiolane, and dithiane.
本発明において、5~6員の単環式芳香族複素環とは、酸素原子、窒素原子および硫黄原子から選択されるヘテロ原子を含む5~6員の単環式芳香族複素環をいい、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、フラン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、フラザン、オキサジアゾール、チアジアゾールが挙げられる。 In the present invention, a 5- to 6-membered monocyclic aromatic heterocycle refers to a 5- to 6-membered monocyclic aromatic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, and thiadiazole.
本発明において、C1~3アルキレン基には、直鎖状または分枝鎖状のC1~3アルキレン基が含まれ、例えば、メチレン、エチレン、プロピレン、またはそれらの異性体が挙げられる。 In the present invention, the C1-3 alkylene group includes linear or branched C1-3 alkylene groups, such as methylene, ethylene, propylene, or isomers thereof.
本発明において、C1~6アルキル基には、直鎖状または分枝鎖状のC1~6アルキル基が含まれ、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、ヘキシル、またはそれらの異性体が挙げられる。 In the present invention, the C1-6 alkyl group includes linear or branched C1-6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Mention may be made of butyl, tert-butyl, pentyl, hexyl, or isomers thereof.
本発明において、C2~6アルケニル基には、直鎖状または分枝鎖状のC2~6アルケニル基が含まれ、例えば、エテニル、プロペニル、ブテニル、ペンテニル、ヘキセニル、またはそれらの異性体が挙げられる。 In the present invention, the C2-6 alkenyl group includes linear or branched C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, or isomers thereof. .
本発明において、C2~6アルキニル基には、直鎖状または分枝鎖状のC2~6アルキニル基が含まれ、例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、またはそれらの異性体が挙げられる。 In the present invention, the C2-6 alkynyl group includes linear or branched C2-6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, or isomers thereof. .
本発明において、C1~6ハロアルキル基には、直鎖状または分枝鎖状のC1~6アルキル基が1個以上のハロゲン原子によって置換された基をいい、例えば、フルオロメチル、クロロメチル、ブロモメチル、ヨードメチル、ジフルオロメチル、トリフルオロメチル、1-フルオロエチル、2-フルオロエチル、2-クロロエチル、ペンタフルオロエチル、1-フルオロプロピル、2-クロロプロピル、3-フルオロプロピル、3-クロロプロピル、4,4,4-トリフルオロブチル、4-ブロモブチル、1-フルオロペンタン、2-クロロヘキサンが挙げられる。 In the present invention, the C1-6 haloalkyl group refers to a group in which a linear or branched C1-6 alkyl group is substituted with one or more halogen atoms, such as fluoromethyl, chloromethyl, bromomethyl , iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4, Examples include 4,4-trifluorobutyl, 4-bromobutyl, 1-fluoropentane, and 2-chlorohexane.
本発明において、C2~6ハロアルケニル基とは、直鎖状または分枝鎖状のC2~6アルケニル基が1個以上のハロゲン原子によって置換された基をいい、例えば、1-フルオロエテニル、2-フルオロエテニル、2-クロロエテニル、ペンタフルオロエテニル、1-フルオロプロペニル、2-クロロプロペニル、3-フルオロプロペニル、3-クロロプロペニル、4,4,4-トリフルオロブテニル、4-ブロモブテニル、1-フルオロペンテニル、2-クロロヘキセニルが挙げられる。 In the present invention, the C2-6 haloalkenyl group refers to a group in which a linear or branched C2-6 alkenyl group is substituted with one or more halogen atoms, such as 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, pentafluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, 1 -fluoropentenyl and 2-chlorohexenyl.
本発明において、C2~6ハロアルキニル基とは、直鎖状または分枝鎖状のC2~6アルキニル基が1個以上のハロゲン原子によって置換された基をいい、例えば、1-フルオロエチニル、2-フルオロエチニル、2-クロロエチニル、ペンタフルオロエチニル、1-フルオロプロピニル、2-クロロプロピニル、3-フルオロプロピニル、3-クロロプロピニル、4,4,4-トリフルオロブチニル、4-ブロモブチニル、1-フルオロペンチニル、2-クロロヘキシニルが挙げられる。 In the present invention, the C2-6 haloalkynyl group refers to a group in which a linear or branched C2-6 alkynyl group is substituted with one or more halogen atoms, such as 1-fluoroethynyl, 2-fluoroethynyl, -Fluoroethynyl, 2-chloroethynyl, pentafluoroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, 1- Examples include fluoropentynyl and 2-chlorohexynyl.
本発明において、C1~6アルコキシ基には、直鎖状または分枝鎖状のC1~6アルコキシ基が含まれ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブチルオキシ、tert-ブトキシ、n-ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、n-ヘキシルオキシ、イソヘキシルオキシが挙げられる。 In the present invention, the C1-6 alkoxy group includes linear or branched C1-6 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, Examples include n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, and isohexyloxy.
本発明において、C1~6ハロアルコキシ基とは、直鎖状または分枝鎖状のC1~6アルコキシ基が1個以上のハロゲン原子によって置換された基をいい、例えば、トリフルオロメトキシ、トリクロロメトキシ、クロロメトキシ、ブロモメトキシ、フルオロメトキシ、ヨードメトキシ、ジフルオロメトキシ、ジブロモメトキシ、2-クロロエトキシ、2,2,2-トリフルオロエトキシ、2,2,2-トリクロロエトキシ、3-ブロモプロポキシ、3-クロロプロポキシ、2,3-ジクロロプロポキシ、1-フルオロブトキシ、4-フルオロブトキシ、1-クロロブトキシ、2-フルオロペントキシ、3-クロロヘキシルオキシが挙げられる。 In the present invention, the C1-6 haloalkoxy group refers to a group in which a linear or branched C1-6 alkoxy group is substituted with one or more halogen atoms, such as trifluoromethoxy, trichloromethoxy , chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3- Examples include chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, 1-chlorobutoxy, 2-fluoropentoxy, and 3-chlorohexyloxy.
本発明において、直鎖のC2~6アルキレン基としては、例えば、エチレン、プロピレン、ブチレン、ペンチレン、ヘキサニレンが挙げられる。
本発明において、直鎖のC3~7アルキレン基としては、例えば、プロピレン、ブチレン、ペンチレン、ヘキサニレン、ヘプタニレンが挙げられる。
本発明において、直鎖のC1~3アルキレン基としては、例えば、メチレン、エチレン、プロピレンが挙げられる。
In the present invention, examples of the linear C2-6 alkylene group include ethylene, propylene, butylene, pentylene, and hexanylene.
In the present invention, examples of the linear C3-7 alkylene group include propylene, butylene, pentylene, hexanylene, and heptanylene.
In the present invention, examples of the linear C1-3 alkylene group include methylene, ethylene, and propylene.
本発明において、C5~6単環式炭素環とは、例えば、シクロペンタン、シクロヘキサン、シクロペンテン、シクロヘキセン、シクロペンタジエン、シクロヘキサジエン、ベンゼンが挙げられる。 In the present invention, examples of the C5-6 monocyclic carbocycle include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.
本発明において、C2~4アルキレン基には、直鎖状または分枝鎖状のC2~4アルキレン基が含まれ、例えば、エチレン、プロピレン、ブチレンまたはそれらの異性体が挙げられる。
本発明において、C3~4アルキレン基には、直鎖状または分枝鎖状のC3~4アルキレン基が含まれ、例えば、プロピレン、ブチレンまたはそれらの異性体が挙げられる。
In the present invention, the C2-4 alkylene group includes linear or branched C2-4 alkylene groups, such as ethylene, propylene, butylene, or isomers thereof.
In the present invention, the C3-4 alkylene group includes a linear or branched C3-4 alkylene group, such as propylene, butylene or isomers thereof.
本発明において、 In the present invention,
は、単結合、二重結合または三重結合を意味し、二重結合の場合、シス体またはトランス体が含まれる。 means a single bond, double bond or triple bond, and in the case of a double bond, the cis or trans form is included.
本発明において、L3の結合の向きは限定されず、例えば、L3が-NR202-S(O)2-の場合、L2は、-R31-NR202-S(O)2-R32でも、-R31-S(O)2-NR202-R32でも良い。 In the present invention, the bond direction of L 3 is not limited. For example, when L 3 is -NR 202 -S(O) 2 -, L 2 is -R 31 -NR 202 -S(O) 2 - It may be R 32 or -R 31 -S(O) 2 -NR 202 -R 32 .
本発明において、アルキル、アルケニル、アルキニル、アルキレン、アルケニレン、アルキニレンおよびアルコキシ基には、特に言及されていない限り、直鎖または分枝鎖のものが含まれる。 In the present invention, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and alkoxy groups include straight or branched chains, unless otherwise stated.
本発明において、R3がメチリデン基をとるとき、一般式(I)中の部分構造である式 In the present invention, when R 3 takes a methylidene group, the formula which is a partial structure in general formula (I)
[式中、すべての記号は前記と同じ意味を表す。]は、下記構造 [In the formula, all symbols have the same meanings as above. ] has the following structure
を取ること意味する。 It means to take.
本発明化合物は、CycA-ベンゼン環間の原子数が5以上である、以下の一般式(I)において示される化合物またはその塩である。 The compound of the present invention is a compound represented by the following general formula (I) or a salt thereof, in which the number of atoms between the CycA and benzene rings is 5 or more.
本発明において、R1としては、-R11-COOR12が好ましく、-R11-COOHがより好ましい。また、R11としては、それぞれ1~3個のハロゲン原子で置換されていてもよいC1~6アルキレン基が好ましく、1~3個のハロゲン原子で置換されていてもよいC2~4アルキレン基がより好ましい。 In the present invention, R 1 is preferably -R 11 -COOR 12 , more preferably -R 11 -COOH. Furthermore, R 11 is preferably a C1-6 alkylene group which may be substituted with 1 to 3 halogen atoms, and a C2-4 alkylene group which may be substituted with 1 to 3 halogen atoms. More preferred.
本発明において、R1が In the present invention, R 1 is
であるとき、ring1としては、6員の含窒素単環式飽和複素環がより好ましく、モルホリンがさらに好ましい。 When this is the case, ring1 is more preferably a 6-membered nitrogen-containing monocyclic saturated heterocycle, and even more preferably morpholine.
本発明において、R101は水素原子が好ましい。 In the present invention, R 101 is preferably a hydrogen atom.
本発明において、R11、R13、R16、R17、R18およびR20としては、それぞれ1~3個のハロゲン原子で置換されていてもよいC1~6アルキレン基が好ましく、1~3個のハロゲン原子で置換されていてもよいC2~4アルキレン基がより好ましい。 In the present invention, R 11 , R 13 , R 16 , R 17 , R 18 and R 20 are each preferably a C1-6 alkylene group optionally substituted with 1-3 halogen atoms, and 1-3 A C2-4 alkylene group optionally substituted with halogen atoms is more preferred.
本発明において、R12、R14、R15およびR19としては、それぞれ水素原子が好ましい。 In the present invention, each of R 12 , R 14 , R 15 and R 19 is preferably a hydrogen atom.
本発明において、R2としては、ハロゲン原子またはC1~4アルキル基が好ましい。 In the present invention, R 2 is preferably a halogen atom or a C1-4 alkyl group.
本発明において、Xとしては、酸素原子が好ましい。 In the present invention, X is preferably an oxygen atom.
本発明において、L1としては、(1)1~4個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基、または(2)(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)が好ましく、1~4個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基がより好ましい。 In the present invention, L 1 is (1) a linear C3-7 alkylene group optionally substituted with 1 to 4 R L1a , or (2) (substituted with 1 to 2 R L1a) . -O- (straight chain C1-3 alkylene group optionally substituted with 1-2 R L1a ) is preferred, and 1-4 R L1a A straight chain C3-7 alkylene group which may be substituted with is more preferred.
本発明において、 In the present invention,
としては、単結合または二重結合が好ましい。 A single bond or a double bond is preferable.
本発明において、 In the present invention,
としては、
(1)=CH-(1~3個のRL1aで置換されていてもよい直鎖のC2~6アルキレン基)-、(2)-(1~3個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基)-、または(3)-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-((1)~(3)においてRL1aは前記と同じ意味を表す)が好ましく、
(1)=CH-(1~3個のRL1aで置換されていてもよい直鎖のC2~6アルキレン基)-、または(2)-(1~3個のRL1aで置換されていてもよい直鎖のC3~7アルキレン基)-((1)~(2)においてRL1aは前記と同じ意味を表す)がより好ましく、
(1)=CH-(1~3個のRL1aで置換されていてもよい直鎖のC3アルキレン基)-、または(2)-(1~3個のRL1aで置換されていてもよい直鎖のC4アルキレン基)-((1)~(2)においてRL1aは前記と同じ意味を表す)がさらに好ましい。
as,
(1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 3 R L1a )-, (2)-(even if substituted with 1 to 3 R L1a ) a straight chain C3-7 alkylene group)-, or (3)-(a straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a )-O-(1-2 A linear C1-3 alkylene group optionally substituted with R L1a ) - (R L1a in (1) to (3) represents the same meaning as above) is preferable,
(1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 3 R L1a )-, or (2)-(substituted with 1 to 3 R L1a ) A linear C3-7 alkylene group)-(in (1) to (2), R L1a has the same meaning as above) is more preferable,
(1)=CH-(linear C3 alkylene group optionally substituted with 1 to 3 R L1a )-, or (2)-(optionally substituted with 1 to 3 R L1a ) More preferred is a linear C4 alkylene group) (in (1) to (2), R L1a has the same meaning as above).
本発明において、RL1aとしては、水酸基、ハロゲン原子またはオキソ基が好ましく、水酸基がより好ましい。 In the present invention, R L1a is preferably a hydroxyl group, a halogen atom, or an oxo group, and more preferably a hydroxyl group.
本発明において、R3としては、水素原子が好ましい。 In the present invention, R 3 is preferably a hydrogen atom.
本発明において、CycAとしては、(1)C5~6単環式炭素環または(2)5~10員の単環式もしくは二環式複素環が好ましく、ベンゼンまたは5~6員の単環式芳香族複素環がさらに好ましい。 In the present invention, CycA is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-10 membered monocyclic or bicyclic heterocycle, such as benzene or a 5-6 membered monocyclic ring. More preferred are aromatic heterocycles.
本発明において、CycAとしては、ベンゼン、シクロヘキサン、ピリジン、チアゾール、イソインドリンまたはテトラヒドロキノリンが好ましく、ベンゼン、イソインドリンまたはテトラヒドロキノリンがより好ましく、ベンゼンがさらに好ましい。 In the present invention, CycA is preferably benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, more preferably benzene, isoindoline or tetrahydroquinoline, and even more preferably benzene.
本発明において、R4としては、ハロゲン原子、C1~4アルキル基またはC1~4ハロアルキル基が好ましく、ハロゲン原子、メチル基またはトリハロメチル基がより好ましい。 In the present invention, R 4 is preferably a halogen atom, a C1-4 alkyl group or a C1-4 haloalkyl group, and more preferably a halogen atom, a methyl group or a trihalomethyl group.
本発明において、L3としては、-NR201-S(O)2-または-CR204(OH)が好ましい。 In the present invention, L 3 is preferably -NR 201 -S(O) 2 - or -CR 204 (OH).
本発明において、L2としては、-NR201-S(O)2-または-CR204(OH)-CH2-が好ましい。 In the present invention, L 2 is preferably -NR 201 -S(O) 2 - or -CR 204 (OH)-CH 2 -.
本発明において、R201、R202、R203、R204、およびR205としては、それぞれ水素原子、C1~4アルキル基、水酸基で置換されたC1~4アルキル基、C3~6単環式炭素環で置換されたC1~4アルキル基、または3~6員の単環式複素環で置換されたC1~4アルキル基が好ましく、水素原子がより好ましい。このうち、C3~6単環式炭素環で置換されたC1~4アルキル基としては、シクロプロパンまたはベンゼンで置換されたC1~4アルキル基が好ましく、3~6員の単環式複素環で置換されたC1~4アルキル基としては、オキセタン、テトラヒドロフラン、またはテトラヒドロピランで置換されたC1~4アルキル基が好ましい。 In the present invention, R 201 , R 202 , R 203 , R 204 , and R 205 are each a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group substituted with a hydroxyl group, or a C3-6 monocyclic carbon A C1-4 alkyl group substituted with a ring or a C1-4 alkyl group substituted with a 3- to 6-membered monocyclic heterocycle is preferred, and a hydrogen atom is more preferred. Among these, the C1-4 alkyl group substituted with a C3-6 monocyclic carbocycle is preferably a C1-4 alkyl group substituted with cyclopropane or benzene; The substituted C1-4 alkyl group is preferably a C1-4 alkyl group substituted with oxetane, tetrahydrofuran, or tetrahydropyran.
本発明において、R31としては、結合手またはC1~3アルキレン基が好ましく、結合手がより好ましい。 In the present invention, R 31 is preferably a bond or a C1-3 alkylene group, and more preferably a bond.
本発明において、R32としては、結合手またはC1~3アルキレン基が好ましく、C1~3アルキレン基がより好ましい。 In the present invention, R 32 is preferably a bond or a C1-3 alkylene group, more preferably a C1-3 alkylene group.
本発明において、CycBとしては、(1)C5~6単環式炭素環または(2)5~6員の単環式複素環が好ましく、ベンゼンまたは5~6員の単環式芳香族複素環がさらに好ましい。 In the present invention, CycB is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-6 membered monocyclic heterocycle, such as benzene or a 5-6 membered monocyclic aromatic heterocycle. is even more preferable.
本発明において、CycBとしては、シクロペンタン、ベンゼン、シクロヘキサン、チオフェン、ピリジンまたはベンゾフランが好ましく、ベンゼンがより好ましい。 In the present invention, CycB is preferably cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran, and more preferably benzene.
本発明において、R5としては、ハロゲン原子、C1~4アルキル基、C1~4ハロアルキル基またはC1~4アルコキシ基が好ましく、ハロゲン原子、C1~4アルキル基、トリハロメチル基またはC1~4アルコキシ基がより好ましい。 In the present invention, R 5 is preferably a halogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group, or a C1-4 alkoxy group; a halogen atom, a C1-4 alkyl group, a trihalomethyl group, or a C1-4 alkoxy group. is more preferable.
本発明において、rおよびtとしては、それぞれ0~3の整数が好ましく、0~2の整数がさらに好ましい。 In the present invention, r and t are each preferably an integer of 0 to 3, more preferably an integer of 0 to 2.
本発明において、一般式(I)中の部分構造である In the present invention, a partial structure in general formula (I)
[式中、すべての記号は前記と同じ意味を表す。]の構造としては、 [In the formula, all symbols have the same meanings as above. ] The structure of
が好ましく、 is preferable,
がより好ましい。 is more preferable.
本発明において、一般式(I)中の部分構造である式 In the present invention, the formula which is a partial structure in general formula (I)
[式中、すべての記号は前記と同じ意味を表す。]としては、 [In the formula, all symbols have the same meanings as above. ]as,
[式中、すべての記号は前記と同じ意味を表す。]が好ましい。 [In the formula, all symbols have the same meanings as above. ] is preferred.
本発明において、一般式(I)中の部分構造である式 In the present invention, the formula which is a partial structure in general formula (I)
[式中、すべての記号は前記と同じ意味を表す。]としては、 [In the formula, all symbols have the same meanings as above. ]as,
[式中、すべての記号は前記と同じ意味を表す。]が好ましい。 [In the formula, all symbols have the same meanings as above. ] is preferred.
本発明において、一般式(I)のある態様としては、一般式(I-i) In the present invention, as a certain embodiment of general formula (I), general formula (I-i)
[式中、L1-iは、(1)1~3個のRL1aで置換されていてもよい直鎖のC2~4アルキレン基、または(2)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-を表し、その他の記号は前記と同じ意味を表す。]が挙げられる。 [In the formula, L 1-i is (1) a linear C2-4 alkylene group optionally substituted with 1 to 3 R L1a , or (2) -O-(1 to 2 R represents a linear C1-3 alkylene group optionally substituted with L1a , and the other symbols have the same meanings as above. ].
本発明において、一般式(I-i)のある態様としては、一般式(I-ii) In the present invention, as a certain embodiment of general formula (I-i), general formula (I-ii)
[式中、L1-iiは1~3個のRL1aで置換されていてもよい直鎖のC2~4アルキレン基を表し、その他の記号は前記と同じ意味を表す。]、 [In the formula, L 1-ii represents a linear C2-4 alkylene group which may be substituted with 1 to 3 R L1a , and the other symbols have the same meanings as above. ],
一般式(I-iii) General formula (I-iii)
[式中、L1-iiiは(1)1~3個のRL1aで置換されていてもよい直鎖のC2~4アルキレン基、または(2)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-を表し、その他の記号は前記と同じ意味を表す。]、または [In the formula, L 1-iii is (1) a linear C2-4 alkylene group optionally substituted with 1 to 3 R L1a , or (2) -O-(1 to 2 R L1a represents a straight-chain C1-3 alkylene group (optionally substituted with )-, and the other symbols have the same meanings as above. ],or
一般式(I-iv) General formula (I-iv)
[式中、L1-ivは1~3個のRL1aで置換されていてもよい直鎖のC2~4アルキレン基を表し、その他の記号は前記と同じ意味を表す。]が挙げられる。 [In the formula, L 1-iv represents a linear C2-4 alkylene group which may be substituted with 1 to 3 R L1a , and the other symbols have the same meanings as above. ].
一般式(I-i)、(I-ii)、(I-iii)または(I-iv)で示される化合物またはその塩のある態様としては、
(1)R11がC2~4アルキレン基、
(2)Xが酸素原子、
(3)RL1aが水酸基、
(4)CycAが(i)C5~6単環式炭素環、または5~10員の単環式もしくは二環式複素環、(ii)ベンゼンもしくは5~6員の単環式芳香族複素環、(iii)C5~6単環式炭素環、または(iv)ベンゼン、シクロヘキサン、ピリジン、チアゾール、イソインドリンもしくはテトラヒドロキノリン、
(5)CycBが(i)C5~6単環式炭素環、もしくは5~6員の単環式複素環、(ii)ベンゼンもしくは5~6員の単環式芳香族複素環、(iii)C5~6単環式炭素環、または(iv)シクロペンタン、ベンゼン、シクロヘキサン、チオフェン、ピリジンもしくはベンゾフラン、
(6)L2が-NR201-S(O)2-もしくは-CR204(OH)-CH2-、または
(7)R11、X、RL1a、CycA、CycBおよびL2以外の記号が前述の基(例えば、「好ましい」、「より好ましい」または「さらに好ましい」とした基)、
(8)上記(1)~(7)に記載の定義の二以上の組み合わせである化合物またはその塩が挙げられる。
Certain embodiments of the compound represented by general formula (I-i), (I-ii), (I-iii) or (I-iv) or a salt thereof include:
(1) R 11 is a C2-4 alkylene group,
(2) X is an oxygen atom,
(3) R L1a is a hydroxyl group,
(4) CycA is (i) a C5-6 monocyclic carbocycle, or a 5-10 membered monocyclic or bicyclic heterocycle, (ii) benzene or a 5-6 membered monocyclic aromatic heterocycle , (iii) C5-6 monocyclic carbocycle, or (iv) benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline,
(5) CycB is (i) a C5-6 monocyclic carbocycle or a 5-6 membered monocyclic heterocycle, (ii) benzene or a 5-6 membered monocyclic aromatic heterocycle, (iii) C5-6 monocyclic carbocycle, or (iv) cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran,
(6) L 2 is -NR 201 -S(O) 2 - or -CR 204 (OH)-CH 2 -, or (7) R 11 , X, R L1a , CycA, CycB and symbols other than L 2 are the aforementioned groups (e.g., groups marked as "preferred", "more preferred" or "even more preferred"),
(8) Examples include compounds or salts thereof that are a combination of two or more of the definitions described in (1) to (7) above.
本発明において、一般式(I-i)、(I-ii)、(I-iii)または(I-iv)で示される化合物またはその塩として、好ましくは、
(1)Xが酸素原子であり、L2が-NR201-S(O)2-または-CR204(OH)-CH2-である化合物またはその塩、
(2)Xが酸素原子であり、L2が-NR201-S(O)2-または-CR204(OH)-CH2-であり、CycAおよびCycBがC5~6単環式炭素環である化合物またはその塩、
(3)R11がC2~4アルキレン基であり、Xが酸素原子であり、L2が-NR201-S(O)2-または-CR204(OH)-CH2-であり、CycAおよびCycBがC5~6単環式炭素環である化合物またはその塩、または
(4)Xが酸素原子であり、RL1aが水酸基であり、L2が-NR201-S(O)2-または-CR204(OH)-CH2-であり、CycAおよびCycBがC5~6単環式炭素環である化合物またはその塩である。
In the present invention, the compound represented by general formula (I-i), (I-ii), (I-iii) or (I-iv) or a salt thereof is preferably:
(1) A compound or a salt thereof in which X is an oxygen atom and L 2 is -NR 201 -S(O) 2 - or -CR 204 (OH)-CH 2 -,
(2) X is an oxygen atom, L 2 is -NR 201 -S(O) 2 - or -CR 204 (OH) -CH 2 -, and CycA and CycB are C5-6 monocyclic carbocycles. a compound or its salt,
(3) R 11 is a C2-4 alkylene group, X is an oxygen atom, L 2 is -NR 201 -S(O) 2 - or -CR 204 (OH) -CH 2 -, and CycA and A compound or a salt thereof in which CycB is a C5-6 monocyclic carbocycle, or (4) X is an oxygen atom, R L1a is a hydroxyl group, and L 2 is -NR 201 -S(O) 2 - or - CR 204 (OH)-CH 2 -, and CycA and CycB are C5-6 monocyclic carbocycles, or salts thereof.
本発明において、一般式(I)の別の態様としては、一般式(I-1) In the present invention, as another embodiment of general formula (I), general formula (I-1)
[式中、すべての記号は前記と同じ意味を表す。]が挙げられる。
本発明において、一般式(I-1)としては、一般式(I-1-A)
[In the formula, all symbols have the same meanings as above. ].
In the present invention, general formula (I-1) is represented by general formula (I-1-A)
[式中、L1-2は直鎖のC2~3アルキレン基を表し、その他の記号は前記と同じ意味を表す。]、 [In the formula, L 1-2 represents a linear C2-3 alkylene group, and the other symbols have the same meanings as above. ],
一般式(I-1-B) General formula (I-1-B)
[式中、すべての記号は前記と同じ意味を表す。]、 [In the formula, all symbols have the same meanings as above. ],
一般式(I-1-C) General formula (I-1-C)
[式中、すべての記号は前記と同じ意味を表す。]、 [In the formula, all symbols have the same meanings as above. ],
または一般式(I-1-D) or general formula (I-1-D)
[式中、すべての記号は前記と同じ意味を表す。]が好ましい。 [In the formula, all symbols have the same meanings as above. ] is preferred.
一般式(I-1-A)、(I-1-B)、(I-1-C)または(I-1-D)で示される化合物またはその塩のある態様としては、
(1)Xが酸素原子、
(2)CycA1がベンゼン、シクロヘキサン、ピリジン、チアゾール、イソインドリンもしくはテトラヒドロキノリン、
(3)CycB1がシクロペンタン、ベンゼン、シクロヘキサン、チオフェン、ピリジンもしくはベンゾフラン、
(4)X、CycA1およびCycB1以外の記号が前述の基(例えば、「好ましい」、「より好ましい」または「さらに好ましい」とした基)、
(5)上記(1)~(4)に記載の定義の二以上の組み合わせ
である化合物またはその塩が挙げられる。
Certain embodiments of the compound represented by general formula (I-1-A), (I-1-B), (I-1-C) or (I-1-D) or a salt thereof include:
(1) X is an oxygen atom,
(2) CycA 1 is benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline,
(3) CycB 1 is cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran,
(4) a group in which symbols other than X, CycA 1 and CycB 1 are as described above (e.g., a group designated as “preferable”, “more preferable” or “even more preferable”),
(5) Compounds or salts thereof that are a combination of two or more of the definitions described in (1) to (4) above are included.
[異性体]
本発明においては、特に断わらない限り、当業者にとって明らかなように記号
[isomer]
In the present invention, unless otherwise specified, symbols will be used as is clear to those skilled in the art.
は紙面の向こう側(すなわちα配置)に結合していることを表わし、 represents that it is connected to the other side of the paper (i.e. α configuration),
は紙面の手前側(すなわちβ配置)に結合していることを表わし、 indicates that it is connected to the front side of the paper (i.e. β configuration),
は、α配置とβ配置の任意の比率の混合物であることを表わす。 represents a mixture of α configuration and β configuration at an arbitrary ratio.
本発明においては、特に指示しない限り異性体はこれをすべて包含する。例えば、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキレン、アルケニレン、アルキニレン、アルキリデン、アルケニリデンには直鎖のものおよび分枝鎖のものが含まれる。さらに、二重結合、環、縮合環における異性体(E、Z、シス、トランス体)、不斉炭素の存在等による異性体(R、S体、α、β配置、エナンチオマー、ジアステレオマー)、旋光性を有する光学活性体(D、L、d、l体)、クロマトグラフ分離による極性体(高極性体、低極性体)、平衡化合物、回転異性体、これらの任意の割合の混合物、ラセミ混合物は、すべて本発明に含まれる。 In the present invention, all isomers are included unless otherwise specified. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene include straight chain and branched chains. Furthermore, isomers in double bonds, rings, condensed rings (E, Z, cis, trans forms), isomers due to the presence of asymmetric carbon, etc. (R, S forms, α, β configurations, enantiomers, diastereomers) , optically active substances with optical rotation (D, L, d, l forms), polar forms (highly polar forms, low polar forms) obtained by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in arbitrary proportions, All racemic mixtures are included in the invention.
また、本発明における光学活性な化合物は、100%純粋なものだけでなく、50%未満のその他の光学異性体が含まれていてもよい。 Furthermore, the optically active compound in the present invention may not only be 100% pure but may also contain less than 50% of other optical isomers.
本発明において、本発明化合物に関する言及はすべて、一般式(I)で示される化合物、その塩、そのN-オキシド体、その溶媒和物、もしくはその共結晶、または一般式(I)で示される化合物の塩のN-オキシド体、その溶媒和物、もしくはその共結晶を包含する。 In the present invention, all references to the compound of the present invention refer to a compound represented by general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a co-crystal thereof, or a compound represented by general formula (I). It includes the N-oxide form of a salt of the compound, its solvate, or its co-crystal.
一般式(I)で示される化合物は、公知の方法で相当する塩に変換される。塩は、水溶性のものが好ましい。また、塩は薬学的に許容される塩が好ましい。そのような塩としては、アルカリ金属(リチウム、カリウム、ナトリウム等)の塩、アルカリ土類金属(カルシウム、マグネシウム等)の塩、その他金属(銀、亜鉛等)の塩、アンモニウム塩、薬学的に許容される有機アミン(テトラメチルアンモニウム、コリン、トリエチルアミン、メチルアミン、ジメチルアミン、エチルアミン、ジエチルアミン、シクロペンチルアミン、ベンジルアミン、フェネチルアミン、tert-ブチルアミン、エチレンジアミン、ピペリジン、ピペラジン、モノエタノールアミン、ジエタノールアミン、トリス(ヒドロキシメチル)アミノメタン、N-ベンジル-2-フェネチルアミン、デアノール、2-(ジエチルアミノ)エタノール、1-(2-ヒドロキシエチル)ピロリジン、リジン、アルギニン、N-メチル-D-グルカミン等)の塩、酸付加物塩(無機酸塩(塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩、硝酸塩等)、有機酸塩(酢酸塩、トリフルオロ酢酸塩、乳酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、安息香酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、イセチオン酸塩、ナパジシル酸塩、グルクロン酸塩、グルコン酸塩等)等)等が挙げられる。 The compound represented by general formula (I) is converted into the corresponding salt by a known method. The salt is preferably water-soluble. Further, the salt is preferably a pharmaceutically acceptable salt. Such salts include salts of alkali metals (lithium, potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts, and pharmaceutical salts. Acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris( hydroxymethyl)aminomethane, N-benzyl-2-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.) salts, acids Adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartaric acid) salt, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisylate, glucuronate, gluconate, etc.).
一般式(I)で示される化合物またはその薬学的に許容される塩は、溶媒和していない形態で存在してもよいし、水、エタノールなどの薬学的に許容できる溶媒と溶媒和した形態で存在してもよい。溶媒和物として低毒性かつ水溶性であることが好ましく、さらに好ましくは水和物である。一般式(I)で示される化合物およびその塩は、公知の方法で溶媒和物に変換することができる。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. may exist. It is preferable that the solvate has low toxicity and water solubility, and hydrates are more preferable. The compound represented by general formula (I) and its salt can be converted into a solvate by a known method.
一般式(I)で示される化合物のN-オキシド体とは、一般式(I)で示される化合物の窒素原子が、酸化されたものを表す。また、一般式(I)で示される化合物のN―オキシド体は、さらに上記のアルカリ(土類)金属塩、アンモニウム塩、有機アミン塩、酸付加物塩となっていてもよい。 The N-oxide form of the compound represented by the general formula (I) refers to a compound in which the nitrogen atom of the compound represented by the general formula (I) is oxidized. Further, the N-oxide form of the compound represented by the general formula (I) may further be the above-mentioned alkali (earth) metal salt, ammonium salt, organic amine salt, or acid adduct salt.
一般式(I)で示される化合物またはその薬学的に許容される塩は、適切な共結晶形成剤と共結晶を形成した形態で存在してもよい。共結晶としては、薬学的に許容される共結晶形成剤と形成される、薬学的に許容されるものが好ましい。共結晶は、典型的に、2種類以上の異なる分子間相互作用で形成される結晶として定義される。また、共結晶は中性分子と塩の複合体であってもよい。共結晶は、公知の方法、例えば、融解結晶化によるか、溶媒からの再結晶によるか、または成分を一緒に物理的に粉砕することにより、調製することができる。適当な共結晶形成剤としては、有機酸(リンゴ酸、コハク酸、アジピン酸、グルコン酸、酒石酸、安息香酸、4-ヒドロキシ安息香酸、3-ヒドロキシ安息香酸、ニコチン酸、イソニコチン酸等)、有機アミン(イミダゾール、ジエタノールアミン、トリエタノールアミン、トリス(ヒドロキシメチル)アミノメタン、N-ベンジル--フェネチルアミン、デアノール、2-(ジエチルアミノ)エタノール、1-(2-ヒドロキシエチル)ピロリジン、4-(2-ヒドロキシエチル)モルホリン、N-メチル-D-グルカミン、グリシン、ヒスチジン、プロリン等)、その他有機化合物(カフェイン、サッカリン等)等が挙げられる。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof may exist in the form of a co-crystal with an appropriate co-crystal forming agent. The co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal forming agent. A co-crystal is typically defined as a crystal formed by interactions between two or more different molecules. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.); Organic amines (imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2- (hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, proline, etc.), and other organic compounds (caffeine, saccharin, etc.).
一般式(I)で示される化合物のプロドラッグは、生体内において酵素や胃酸等による反応により一般式(I)で示される化合物に変換する化合物をいう。一般式(I)で示される化合物のプロドラッグとしては、例えば、一般式(I)で示される化合物がアミノ基を有する場合、該アミノ基がアシル化、アルキル化、リン酸化された化合物(例えば、一般式(I)で示される化合物のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、アセトキシメチル化、tert-ブチル化された化合物等);一般式(I)で示される化合物が水酸基を有する場合、該水酸基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物(例えば、一般式(I)で示される化合物の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等);一般式(I)で示される化合物がカルボキシ基を有する場合、該カルボキシ基がエステル化、アミド化された化合物(例えば、一般式(I)で示される化合物のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等)等が挙げられる。これらの化合物は自体公知の方法によって製造することができる。また、一般式(I)で示される化合物のプロドラッグは溶媒和物であってもよい。また、一般式(I)で示される化合物のプロドラッグは、廣川書店1990年刊「医薬品の開発」第7巻「分子設計」163-198頁に記載されているような生理的条件で、一般式(I)で示される化合物に変化するものであってもよい。さらに、一般式(I)で示される化合物は同位元素(例えば、2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、35S、18F、36Cl、123I、125I等)等で標識されていてもよい。 A prodrug of a compound represented by general formula (I) refers to a compound that converts into a compound represented by general formula (I) by reaction with enzymes, gastric acid, etc. in vivo. As prodrugs of the compound represented by general formula (I), for example, when the compound represented by general formula (I) has an amino group, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g. , the amino group of the compound represented by general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranyl pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); When the compound represented by general formula (I) has a hydroxyl group, the hydroxyl group (For example, the hydroxyl group of the compound represented by general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonyl) When the compound represented by the general formula (I) has a carboxyl group, a compound in which the carboxyl group is esterified or amidated (for example, a carboxyl group of the compound represented by the general formula (I)); is ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidation compounds, etc.). These compounds can be produced by methods known per se. Further, the prodrug of the compound represented by general formula (I) may be a solvate. In addition, prodrugs of the compound represented by the general formula (I) can be prepared under physiological conditions as described in Hirokawa Shoten's 1990 "Pharmaceutical Development", Vol. It may be converted into a compound represented by (I). Furthermore, the compound represented by general formula (I) has isotopes (for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I, 125 I, etc.).
[本発明化合物の製造方法]
本発明化合物は、公知の方法、例えば、Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)に記載された方法、または実施例に示す方法等を適宜改良し、組み合わせて用いることで製造することができる。
[Method for producing the compound of the present invention]
The compound of the present invention can be prepared by a known method, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), or the method shown in Examples. It can be manufactured by appropriately improving and using them in combination.
一般式(I)で示される化合物のうち、一般式(I-A) Among the compounds represented by general formula (I), general formula (IA)
(式中、L1Mは、(1)1~4個のRL1aで置換されていてもよい直鎖のC2~6アルキレン基、(2)1~4個のRL1aで置換されていてもよい直鎖のC2~6アルケニレン基、(3)1~4個のRL1aで置換されていてもよい直鎖のC2~6アルキニレン基、または(4)(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)-O-(1~2個のRL1aで置換されていてもよい直鎖のC1~3アルキレン基)を表し、その他の記号は前記と同じ意味を表わす。)で示される化合物は、以下の反応工程式1に示される方法で製造することができる。 (In the formula, L 1M is (1) a linear C2-6 alkylene group optionally substituted with 1 to 4 R L1a , (2) optionally substituted with 1 to 4 R L1a a straight chain C2-6 alkynylene group, (3) a straight chain C2-6 alkynylene group optionally substituted with 1 to 4 R L1a , or (4) (substituted with 1 to 2 R L1a) -O- (straight chain C1-3 alkylene group optionally substituted with 1-2 R L1a ); other symbols are as above. ) can be produced by the method shown in Reaction Scheme 1 below.
(式中、Halはハロゲン原子を表し、その他の記号は前記と同じ意味を表す。)
反応工程式1中、反応1-1は、一般式(A-1)で示される化合物と、4,4,5,5-テトラメチル-1,3,2-ジオキサボロランを用いて、求核付加反応に付すことにより行うことができる。この求核付加反応は公知であり、例えば、有機溶媒(ヘキサン、ヘプタン、オクタン、ベンゼン、トルエン、テトラヒドロフラン(以下、THFと略記)、ジオキサン、ジメトキシエタン、ジエチルエーテルまたはそれらの2以上の混合溶媒等)中または無溶媒条件下で、0~120℃の温度で行われる。また、反応を促進させる目的で、触媒の存在下で行うこともできる。該触媒としては、例えば、ギ酸、酢酸、安息香酸、4-ジメチルアミノ安息香酸、シュワルツ試薬(CAS登録番号:37342-97-5)等が挙げられる。
(In the formula, Hal represents a halogen atom, and the other symbols have the same meanings as above.)
In reaction scheme 1, reaction 1-1 is a nucleophilic addition using a compound represented by general formula (A-1) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. This can be done by subjecting it to a reaction. This nucleophilic addition reaction is known, and examples include organic solvents (hexane, heptane, octane, benzene, toluene, tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethoxyethane, diethyl ether, or a mixed solvent of two or more thereof). ) or under solvent-free conditions at temperatures of 0 to 120°C. Moreover, for the purpose of promoting the reaction, it can also be carried out in the presence of a catalyst. Examples of the catalyst include formic acid, acetic acid, benzoic acid, 4-dimethylaminobenzoic acid, Schwartz's reagent (CAS registration number: 37342-97-5), and the like.
反応工程式1中、反応1-2は、一般式(A-2)で示される化合物と一般式(A-3)で示される化合物を用いて、鈴木カップリング反応に付すことにより行うことができる。この鈴木カップリング反応は公知であり、例えば、有機溶媒(トルエン、ベンゼン、N,N-ジメチルホルムアミド(以下、DMFと略記)、THF、メタノール、エタノール、アセトニトリル、ジメトキシエタン、アセトン、ジオキサン、ジメチルアセトアミド等)、または水、またはそれら2以上の混合溶媒等中、パラジウム触媒(テトラキス(トリフェニルホスフィン)パラジウム(Pd(PPh3)4)、ジクロロビス(トリフェニルホスフィン)パラジウム(Cl2Pd(PPh3)2)、酢酸パラジウム(Pd(OAc)2)、ビス(トリ-tert-ブチルホスフィン)パラジウム(0)(Pd(tBu3P)2)等)の存在下、塩基(水酸化ナトリウム、水酸化カリウム、トリエチルアミン、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム、炭酸タリウム、リン酸三カリウム、フッ化セシウム、水酸化バリウム、フッ化テトラブチルアンモニウム等)の存在下、室温~120℃で行うことができる。 In reaction scheme 1, reaction 1-2 can be carried out by subjecting a compound represented by general formula (A-2) and a compound represented by general formula (A-3) to a Suzuki coupling reaction. can. This Suzuki coupling reaction is known, and examples include organic solvents (toluene, benzene, N,N-dimethylformamide (hereinafter abbreviated as DMF), THF, methanol, ethanol, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide). etc.), or water, or a mixed solvent of two or more thereof, using a palladium catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), dichlorobis(triphenylphosphine)palladium (Cl 2 Pd(PPh 3 )). 2 ), palladium acetate (Pd(OAc) 2 ), bis(tri-tert-butylphosphine)palladium(0) (Pd(tBu3P)2), etc.) in the presence of bases (sodium hydroxide, potassium hydroxide, triethylamine). , sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) at room temperature to 120°C. .
さらに、一般式(I-A)で示される化合物を用いて還元反応に付すことにより、一般式(I-B) Furthermore, by subjecting to a reduction reaction using a compound represented by general formula (IA), general formula (IB) can be obtained.
(式中、全ての記号は前記と同じ意味を表す。)で示される化合物を製造することができる。この還元反応は公知であり、以下の方法で行うことができる。例えば、(1)金属を用いる還元反応、(2)ジイミド還元反応等が挙げられる。(1)金属を用いる還元反応は、例えば、有機溶媒(例えば、THF、ジオキサン、ジメトキシエタン、ジエチルエーテル、メタノール、エタノール、ベンゼン、トルエン、アセトン、メチルエチルケトン、アセトニトリル、DMF、酢酸エチル、酢酸、水、またはそれらの2以上の混合溶媒等)中、水素化触媒(パラジウム-炭素、パラジウム黒、パラジウム、水酸化パラジウム、二酸化白金、白金-炭素、ニッケル、ラネーニッケル、塩化ルテニウムなど)の存在下、酸(塩酸、硫酸、次亜塩素酸、ホウ酸、テトラフルオロホウ酸、酢酸、p-トルエンスルホン酸、シュウ酸、トリフルオロ酢酸(以下、TFAと略記)、ギ酸など)の存在下または非存在下、常圧または加圧下の水素雰囲気下、0~200℃で行なわれる。(2)ジイミド還元反応は、例えば、有機溶媒(トルエン、ベンゼン、DMF、THF、アセトニトリル、ジメトキシエタン、アセトン、ジオキサン、ジメチルアセトアミド、メタノール、エタノールまたはそれらの2以上の混合溶媒等)中、ヒドラジン化合物(ヒドラジン、ヒドラジン一水和物、トシルヒドラジン等)と塩基(水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム等)の存在下または非存在下、0~120℃で行うことができる。 A compound represented by the formula (in which all symbols have the same meanings as above) can be produced. This reduction reaction is known and can be carried out by the following method. Examples include (1) a reduction reaction using a metal, (2) a diimide reduction reaction, and the like. (1) The reduction reaction using a metal can be carried out using, for example, an organic solvent (such as THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid, water, or a mixed solvent of two or more thereof) in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.). In the presence or absence of hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid (hereinafter abbreviated as TFA), formic acid, etc.), It is carried out at 0 to 200° C. under a hydrogen atmosphere under normal pressure or pressurization. (2) The diimide reduction reaction is performed, for example, by using a hydrazine compound in an organic solvent (toluene, benzene, DMF, THF, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, methanol, ethanol, or a mixed solvent of two or more thereof). (hydrazine, hydrazine monohydrate, tosylhydrazine, etc.) and a base (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.) in the presence or absence of 0 to 120°C. It can be done with
一般式(I)で示される化合物のうち、一般式(I-C) Among the compounds represented by general formula (I), general formula (IC)
(式中の記号は前記と同じ意味を表す。)で示される化合物は、以下の反応工程式2に示される方法で製造することができる。
The compound represented by (the symbols in the formula have the same meanings as above) can be produced by the method shown in
(式中、すべての記号は前記と同じ意味を表わす。)
反応工程式2中、反応2-1は、一般式(A-1)で示される化合物と一般式(A-3)で示される化合物を薗頭反応に付すことにより行うことができる。この薗頭反応は公知であり、例えば、有機溶媒(酢酸エチル、酢酸イソプロピル、ベンゼン、トルエン、キシレン、ヘプタン、シクロヘキサン、THF、ジオキサン、ジメトキシエタン、エタノール、2-プロパノール、ポリエチレングリコール、ジメチルスルホキシド、DMF、N,N-ジメチルアセトアミド、N-メチル-2-ピロリジノン、塩化メチレン、クロロホルム、アセトン、アセトニトリル)、または水、またはそれらの2以上の混合溶媒等中、または無溶媒条件下、塩基(ジエチルアミン、トリエチルアミン、プロピルアミン、ジイソプロピルアミン、ジイソプロピルエチルアミン、ジブチルアミン、トリブチルアミン、ピロリジン、ピペリジン、N-メチルピペリジン、1,4-ジアザビシクロ[2.2.2]オクタン、ピリジン、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸ナトリウム、リン酸カリウム、フッ化カリウム等)存在下、触媒(パラジウム触媒(テトラキス(トリフェニルホスフィン)パラジウム(Pd(PPh3)4)、ジクロロビス(トリフェニルホスフィン)パラジウム(Cl2Pd(PPh3)2)、酢酸パラジウム(Pd(OAc)2)、ビス(トリ-tert-ブチルホスフィン)パラジウム(0)(Pd(tBu3P)2)等)、またはそれらと銅触媒(ヨウ化銅(I)等)との混合物等)存在下、相間移動触媒(例えば、塩化テトラブチルアンモニウム、臭化テトラブチルアンモニウム、ヨウ化テトラブチルアンモニウム、酢酸テトラブチルアンモニウム等)の存在下または非存在下、室温~120℃で反応させることにより行われる。
(In the formula, all symbols have the same meanings as above.)
In
反応工程式1および2中の一般式(A-3)で示される化合物のうち、一般式(A-3-1)
Among the compounds represented by general formula (A-3) in
(式中、すべての記号は前記と同じ意味を表す。)で示される化合物は、以下の反応工程式3に示される方法で製造することができる。 The compound represented by (wherein all symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 3 below.
(式中、すべての記号は前記と同じ意味を表す。) (In the formula, all symbols have the same meanings as above.)
反応工程式3中、反応3-1は、一般式(A-3-1a)で示される化合物と一般式(A-3-1b)で示される化合物をスルホンアミド化反応に付すことにより行うことができる。このスルホンアミド化反応は公知であり、例えば、有機溶媒(酢酸エチル、酢酸イソプロピル、ベンゼン、トルエン、キシレン、ヘプタン、シクロヘキサン、THF、ジオキサン、ジメトキシエタン、エタノール、2-プロパノール、ジメチルスルホキシド、DMF、N,N-ジメチルアセトアミド、N-メチル-2-ピロリジノン、塩化メチレン、クロロホルム、アセトン、アセトニトリル、またはそれらの2以上の混合溶媒等)中または無溶媒条件下で、塩基(ジイソプロピルエチルアミン、ピリジン、トリエチルアミン、ジメチルアニリン、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸ナトリウム、リン酸カリウム等)の存在下または非存在下、触媒(4-ジメチルアミノピリジン等)の存在下または非存在下、0~120℃で反応させることにより行われる。 In reaction scheme 3, reaction 3-1 is carried out by subjecting a compound represented by general formula (A-3-1a) and a compound represented by general formula (A-3-1b) to a sulfonamidation reaction. Can be done. This sulfonamidation reaction is known, and examples include organic solvents (ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane, cyclohexane, THF, dioxane, dimethoxyethane, ethanol, 2-propanol, dimethyl sulfoxide, DMF, N , N-dimethylacetamide, N-methyl-2-pyrrolidinone, methylene chloride, chloroform, acetone, acetonitrile, or a mixed solvent of two or more thereof) or under solvent-free conditions. dimethylaniline, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, etc.), in the presence or absence of a catalyst (4-dimethylaminopyridine, etc.), The reaction is carried out at 0 to 120°C.
反応工程式3中、反応3-2は、一般式(A-3-1c)で示される化合物と、一般式(A-3-1d)で示される化合物をアルキル化反応に付すか、一般式(A-3-1c)で示される化合物と、一般式(A-3-1e)で示される化合物を光延反応に付すことにより行うことができる。このアルキル化反応は公知であり、例えば、有機溶媒(DMF、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジエチルエーテル、THF、メチルt-ブチルエーテル、アセトニトリル、水、またはそれらの2以上の混合溶媒等)中、塩基(水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム、水酸化カルシウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、リチウムビス(トリメチルシリル)アミド、カリウムビス(トリメチルシリル)アミド、ナトリウムビス(トリメチルシリル)アミド等)の存在下、0~100℃で反応させることにより行われる。この光延反応は公知であり、例えば、有機溶媒(ジクロロメタン、ジエチルエーテル、THF、アセトニトリル、ベンゼン、トルエン等)中、アゾ化合物(アゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、1,1’-(アゾジカルボニル)ジピペリジン、1,1’-アゾビス(N,N-ジメチルホルムアミド)等)およびホスフィン化合物(トリフェニルホスフィン、トリブチルホスフィン、トリメチルホスフィン、ポリマーサポートトリフェニルホスフィン等)の存在下、0~80℃で反応させることにより行われる。 In reaction scheme 3, reaction 3-2 involves subjecting a compound represented by general formula (A-3-1c) and a compound represented by general formula (A-3-1d) to an alkylation reaction, or This can be carried out by subjecting a compound represented by (A-3-1c) and a compound represented by general formula (A-3-1e) to a Mitsunobu reaction. This alkylation reaction is known, and for example, a base is (sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl) amide, etc.) at 0 to 100°C. This Mitsunobu reaction is known, and for example, an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarboxylate), carbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) at 0 to 80 °C. This is done by reacting.
反応工程式1および2中の一般式(A-3)で示される化合物のうち、一般式(A-3-2)
Among the compounds represented by general formula (A-3) in
(式中、すべての記号は前記と同じ意味を表す。)で示される化合物は、以下の反応工程式4に示される方法で製造することができる。
The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in
(式中、すべての記号は前記と同じ意味を表す。) (In the formula, all symbols have the same meanings as above.)
反応工程式4中、反応4-1は、一般式(A-3-2a)で示される化合物を有機溶媒(例えば、THF、ジメトキシエタン、トルエン、ジクロロメタン、ジエチルエーテル、ジオキサン、メタノール等)中、塩化セリウムの存在下または非存在下、還元剤(例えば、水素化ホウ素ナトリウム、水素化ホウ素亜鉛等)を用いて、-20~50℃で反応させることにより行われる。また、一方の立体異性体のみを選択的に製造する場合には、不斉還元剤(例えば、クロロジイソピノカンフェニルボラン等)、または不斉補助剤と還元剤の組み合わせ((R)-2-メチル-CBS-オキサザボロリジンと水素化ホウ素・THF錯体またはボランジメチルスルフィド錯体、(S)-(-)-ビナフトールと水素化アルミニウムリチウム等)を用いて、-100~50℃の温度で行なわれる。
In
反応工程式1、反応工程式2、反応工程式3または反応工程式4中、各一般式で示される化合物に保護基が存在する場合、必要に応じて、脱保護反応を行うことができる。この保護基の脱保護反応は公知であり、以下の方法で行うことができる。例えば、(1)アルカリ加水分解による脱保護反応、(2)酸性条件下における脱保護反応、(3)加水素分解による脱保護反応、(4)シリル基の脱保護反応、(5)金属を用いる脱保護反応、(6)金属錯体を用いる脱保護反応等が挙げられる。
When a protecting group is present in the compound represented by each general formula in Reaction Scheme 1,
これらの方法を具体的に説明すると、
(1)アルカリ加水分解による脱保護反応は、例えば有機溶媒(例えば、メタノール、THF、ジオキサン等)中、アルカリ金属の水酸化物(例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等)、アルカリ土類金属の水酸化物(例えば、水酸化バリウム、水酸化カルシウム等)または炭酸塩(例えば、炭酸ナトリウム、炭酸カリウム等)あるいはその水溶液もしくはこれらの混合物を用いて、0~40℃で行なわれる。
(2)酸条件下での脱保護反応は、例えば有機溶媒(例えば、ジクロロメタン、クロロホルム、ジオキサン、酢酸エチル、メタノール、イソプロピルアルコール、THF、アニソール等)中、有機酸(例えば、酢酸、トリフルオロ酢酸、メタンスルホン酸、p-トシル酸等)、または無機酸(例えば、塩酸、硫酸等)もしくはこれらの混合物(例えば、臭化水素/酢酸等)中、2,2,2-トリフルオロエタノールの存在下または非存在下、0~100℃で行なわれる。
(3)加水素分解による脱保護反応は、例えば溶媒(例えば、エーテル系(例えば、THF、ジオキサン、ジメトキシエタン、ジエチルエーテル等)、アルコール系(例えば、メタノール、エタノール等)、ベンゼン系(例えば、ベンゼン、トルエン等)、ケトン系(例えば、アセトン、メチルエチルケトン等)、ニトリル系(例えば、アセトニトリル等)、アミド系(例えば、DMF等)、水、酢酸エチル、酢酸またはそれらの2以上の混合溶媒等)中、触媒(例えば、パラジウム-炭素、パラジウム黒、水酸化パラジウム-炭素、酸化白金、ラネーニッケル等)の存在下、常圧または加圧下の水素雰囲気下またはギ酸アンモニウム存在下、0~200℃で行なわれる。
(4)シリル基の脱保護反応は、例えば水と混和しうる有機溶媒(例えば、THF、アセトニトリル等)中、フッ化テトラブチルアンモニウムを用いて、0~40℃で行なわれる。また、例えば、有機酸(例えば、酢酸、トリフルオロ酢酸、メタンスルホン酸、p-トシル酸等)、または無機酸(例えば、塩酸、硫酸等)もしくはこれらの混合物(例えば、臭化水素/酢酸等)中、-10~100℃で行なわれる。
(5)金属を用いる脱保護反応は、例えば酸性溶媒(例えば、酢酸、pH4.2~7.2の緩衝液またはそれらの溶液とTHF等の有機溶媒との混合液)中、粉末亜鉛の存在下、必要であれば超音波をかけながら、0~40℃で行なわれる。
(6)金属錯体を用いる脱保護反応は、例えば有機溶媒(例えば、ジクロロメタン、DMF、THF、酢酸エチル、アセトニトリル、ジオキサン、エタノール等)、水またはそれらの混合溶媒中、トラップ試薬(例えば、水素化トリブチルスズ、トリエチルシラン、ジメドン、モルホリン、ジエチルアミン、ピロリジン等)、有機酸(例えば、酢酸、ギ酸、2-エチルヘキサン酸等)および/または有機酸塩(例えば、2-エチルヘキサン酸ナトリウム、2-エチルヘキサン酸カリウム等)の存在下、ホスフィン系試薬(例えば、トリフェニルホスフィン等)の存在下または非存在下、金属錯体(例えば、テトラキストリフェニルホスフィンパラジウム(0)、二塩化ビス(トリフェニルホスフィン)パラジウム(II)、酢酸パラジウム(II)、塩化トリス(トリフェニルホスフィン)ロジウム(I)等)を用いて、0~40℃で行なわれる。
To explain these methods specifically,
(1) Deprotection reaction by alkaline hydrolysis is performed using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (e.g., methanol, THF, dioxane, etc.), It is carried out at 0 to 40°C using alkaline earth metal hydroxides (e.g. barium hydroxide, calcium hydroxide, etc.) or carbonates (e.g. sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof. It will be done.
(2) The deprotection reaction under acidic conditions is carried out in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.) with an organic acid (e.g., acetic acid, trifluoroacetic acid, etc.). , methanesulfonic acid, p-tosylic acid, etc.) or inorganic acids (e.g. hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g. hydrogen bromide/acetic acid, etc.). The reaction is carried out at 0 to 100°C in the presence or absence of oxidation.
(3) The deprotection reaction by hydrolysis can be carried out using, for example, a solvent (e.g., ether type (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol type (e.g., methanol, ethanol, etc.), benzene type (e.g., benzene, toluene, etc.), ketone type (e.g., acetone, methyl ethyl ketone, etc.), nitrile type (e.g., acetonitrile, etc.), amide type (e.g., DMF, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc. ) in the presence of a catalyst (e.g. palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) at 0 to 200°C under a hydrogen atmosphere at normal or pressurized pressure or in the presence of ammonium formate. It is done.
(4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (eg, THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. Also, for example, organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g., hydrogen bromide/acetic acid, etc.). ) at -10 to 100°C.
(5) The deprotection reaction using a metal can be carried out in the presence of powdered zinc in an acidic solvent (for example, acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions and an organic solvent such as THF). The process is carried out at 0 to 40°C, with ultrasonication applied if necessary.
(6) The deprotection reaction using a metal complex can be carried out using a trap reagent (for example, hydrogenation tributyltin, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (e.g. acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (e.g. sodium 2-ethylhexanoate, 2-ethylhexanoate, etc.) metal complexes (e.g., tetrakistriphenylphosphine palladium(0), bis(triphenylphosphine) dichloride) in the presence or absence of phosphine-based reagents (e.g., triphenylphosphine, etc.); Palladium(II), palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.) is used at 0 to 40°C.
また、上記以外にも、例えばT. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999に記載された方法によって、脱保護反応を行なうことができる。
水酸基の保護基としては、例えば、メチル基、トリチル基、メトキシメチル(MOM)基、1-エトキシエチル(EE)基、メトキシエトキシメチル(MEM)基、2-テトラヒドロピラニル(THP)基、トリメチルシリル(TMS)基、トリエチルシリル(TES)基、t-ブチルジメチルシリル(TBDMS)基、t-ブチルジフェニルシリル(TBDPS)基、アセチル(Ac)基、ピバロイル基、ベンゾイル基、ベンジル(Bn)基、p-メトキシベンジル基、アリルオキシカルボニル(Alloc)基、2,2,2-トリクロロエトキシカルボニル(Troc)基等が挙げられる。
In addition to the above, deprotection reactions can also be carried out, for example, by the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
Examples of protecting groups for hydroxyl groups include methyl group, trityl group, methoxymethyl (MOM) group, 1-ethoxyethyl (EE) group, methoxyethoxymethyl (MEM) group, 2-tetrahydropyranyl (THP) group, and trimethylsilyl group. (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, Examples include p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, and 2,2,2-trichloroethoxycarbonyl (Troc) group.
アミノ基の保護基としては、例えばベンジルオキシカルボニル基、t-ブトキシカルボニル基、アリルオキシカルボニル(Alloc)基、1-メチル-1-(4-ビフェニル)エトキシカルボニル(Bpoc)基、トリフルオロアセチル基、9-フルオレニルメトキシカルボニル基、ベンジル(Bn)基、p-メトキシベンジル基、ベンジルオキシメチル(BOM)基、2-(トリメチルシリル)エトキシメチル(SEM)基等が挙げられる。
水酸基、アミノ基の保護基としては、上記した以外にも容易にかつ選択的に脱離できる基であれば特に限定されない。例えば、T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999に記載されたものが用いられる。
Examples of protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, and trifluoroacetyl group. , 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2-(trimethylsilyl)ethoxymethyl (SEM) group, and the like.
Protective groups for hydroxyl groups and amino groups are not particularly limited as long as they are groups that can be easily and selectively removed other than those mentioned above. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.
本明細書中の各反応において、出発原料として用いた化合物、例えば、一般式(A-1)、(A-3)、(A-3-1a)、(A-3-1b)で示される化合物は公知であるか、あるいは公知の方法により容易に製造することができる。 In each reaction in this specification, the compounds used as starting materials, for example, those represented by general formulas (A-1), (A-3), (A-3-1a), (A-3-1b) The compounds are known or can be easily prepared by known methods.
本明細書中の各反応において、加熱を伴う反応は、当業者にとって明らかなように、水浴、油浴、砂浴またはマイクロウェーブを用いて行なうことができる。 In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as will be apparent to those skilled in the art.
本明細書中の各反応において、適宜、高分子ポリマー(例えば、ポリスチレン、ポリアクリルアミド、ポリプロピレン、ポリエチレングリコール等)に担持させた固相担持試薬を用いてもよい。 In each reaction herein, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.
本明細書中の各反応において、反応生成物は通常の精製手段、例えば、常圧下または減圧下における蒸留、シリカゲルまたはケイ酸マグネシウムを用いた高速液体クロマトグラフィー、薄層クロマトグラフィー、イオン交換樹脂、スカベンジャー樹脂あるいはカラムクロマトグラフィーまたは洗浄、再結晶などの方法により精製することができる。精製は反応ごとに行なってもよいし、いくつかの反応終了後に行なってもよい。 In each reaction herein, the reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by methods such as scavenger resin or column chromatography, washing, and recrystallization. Purification may be performed for each reaction or after completion of several reactions.
[毒性]
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
[toxicity]
The toxicity of the compounds of the present invention is sufficiently low, and they can be safely used as pharmaceuticals.
[医薬品への適用]
本発明化合物は、神経保護および/または修復作用を有する。
本発明化合物は、一実施形態において、持続性に優れた神経保護および/または修復作用を有する。
そのため、本発明化合物は例えば、神経障害を伴う疾患の治療に有用である。
[Application to pharmaceuticals]
The compounds of the present invention have neuroprotective and/or repair effects.
In one embodiment, the compound of the present invention has a long-lasting neuroprotective and/or repair action.
Therefore, the compounds of the present invention are useful, for example, in the treatment of diseases accompanied by neurological disorders.
本発明において、神経保護および/または修復作用のある態様としては、グリア細胞(例えば、ミクログリア、アストロサイト、オリゴデンドロサイト、上衣細胞、シュワン細胞、衛星細胞など)を介した神経保護および/または修復作用が挙げられる。グリア細胞を介した神経保護および/または修復作用のある態様としては、シュワン細胞の分化促進作用(シュワン細胞のミエリン化促進作用を含む)が挙げられる。
本発明において、神経障害には、末梢神経障害や中枢神経障害が含まれる。末梢神経障害を伴う疾患としては、例えば、糖尿病性神経障害、尿毒症に伴う代謝性末梢神経障害、ビタミンB欠乏に伴う末梢神経障害、ジフテリア、ボツリヌス食中毒、ヘルペスウィルス(帯状疱疹)などの感染症に伴う末梢神経障害、抗けいれん薬のフェニトイン、抗菌薬(クロラムフェニコール、ニトロフラントイン、スルホンアミド系薬剤など)、化学療法薬(タキサン系:パクリタキセル、ドセタキセルなど、プラチナ製剤:オキサリプラチン、シスプラチン、カルボプラチン、ネダアプラチンなど、ビンカアルカロイド系:ビンブラスチン、ビンクリスチン、ビンデシンなど)、鎮静薬(バルビタールやヘキソバルビタールなど)の投与に伴う薬剤性末梢神経障害、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、絞扼性神経障害(例えば、手根管症候群、胸郭出口症候群、肘部管症候群、梨状筋症候群、足根管症候群、腓骨神経絞扼障害など)、多巣性運動ニューロパチーなどの免疫性末梢神経障害、結節性動脈周囲炎、アレルギー性血管炎、全身性エリテマトーデスなどのアレルギー疾患に伴う末梢神経障害、鉛、水銀、ヒ素、タリウムなどの重金属、シンナーなどの有機溶媒、有機リン系殺虫剤、リン酸トリオルソクレシル(TOCP)など毒性物質、アルコールの摂取に伴う中毒性末梢神経障害、がんが神経を圧迫することによる末梢神経障害、遺伝性疾患(例えば、甲状腺機能低下症、腎不全、シャルコー・マリー・トゥース病、レフサム病、ポルフィリン症、ファブリー病、遺伝性圧脆弱性ニューロパチーなど)に伴う末梢神経障害などが挙げられる。
In the present invention, embodiments having neuroprotective and/or repair effects include neuroprotection and/or repair via glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.). One example is the effect. Examples of the neuroprotective and/or repair action mediated by glial cells include the action of promoting Schwann cell differentiation (including the action of promoting myelination of Schwann cells).
In the present invention, neurological disorders include peripheral nerve disorders and central nervous disorders. Diseases associated with peripheral neuropathy include diabetic neuropathy, metabolic peripheral neuropathy associated with uremia, peripheral neuropathy associated with vitamin B deficiency, diphtheria, botulism food poisoning, and infectious diseases such as herpes virus (shingles). peripheral neuropathy associated with phenytoin, an anticonvulsant drug, antibiotics (chloramphenicol, nitrofurantoin, sulfonamides, etc.), chemotherapy drugs (taxanes: paclitaxel, docetaxel, etc., platinum drugs: oxaliplatin, cisplatin) , carboplatin, nedaplatin, vinca alkaloids: vinblastine, vincristine, vindesine, etc.), drug-induced peripheral neuropathy associated with administration of sedatives (barbital, hexobarbital, etc.), chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndromes, entrapment neuropathies (e.g., carpal tunnel syndrome, thoracic outlet syndrome, cubital tunnel syndrome, piriformis syndrome, tarsal tunnel syndrome, peroneal nerve entrapment disorder, etc.), and immune-related disorders such as multifocal motor neuropathies. Peripheral neuropathy, peripheral neuropathy associated with allergic diseases such as periarteritis nodosa, allergic vasculitis, and systemic lupus erythematosus, heavy metals such as lead, mercury, arsenic, and thallium, organic solvents such as thinner, and organophosphate pesticides. , toxic substances such as triorthocresyl phosphate (TOCP), toxic peripheral neuropathy associated with the intake of alcohol, peripheral neuropathy due to cancer compressing the nerves, genetic diseases (e.g. hypothyroidism, renal peripheral neuropathy associated with neuropathy, Charcot-Marie-Tooth disease, Refsum disease, porphyria, Fabry disease, hereditary pressure-fragile neuropathy, etc.).
中枢神経障害を伴う疾患としては、例えば、アルツハイマー病、パーキンソン病、レビー小体型認知症、前頭側頭葉変性症、進行性核上性麻痺、大脳皮質基底核変性症、ハンチントン病、ジストニア、プリオン病、多系統萎縮症、脊髄小脳変性症、筋萎縮性側索硬化症、原発性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、痙性対麻痺、脊髄空洞症、多発性硬化症、視神経脊髄炎、同心円硬化症、急性散在性脳脊髄炎、炎症性広汎性硬化症、亜急性硬化症全脳炎、進行性多巣性白質脳症などの感染性神経障害、低酸素脳症や橋中心髄鞘破壊症などの中毒・代謝性神経障害、Binswanger病などの血管性神経障害などが挙げられる。 Diseases associated with central nervous system disorders include, for example, Alzheimer's disease, Parkinson's disease, Lewy body dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, dystonia, and prion disease. disease, multiple system atrophy, spinocerebellar degeneration, amyotrophic lateral sclerosis, primary lateral sclerosis, spinobulbar muscular atrophy, spinal muscular atrophy, spastic paraplegia, syringomyelia, multiple Infectious neurological disorders such as sclerosis, neuromyelitis optica, concentric sclerosis, acute disseminated encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosis panencephalitis, progressive multifocal leukoencephalopathy, hypoxic encephalopathy, These include toxic and metabolic neuropathies such as central pontine myelinopathy, and vascular neuropathies such as Binswanger disease.
本発明において、神経障害のある態様としては、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、結節性動脈周囲炎、アレルギー性血管炎、糖尿病性末梢神経障害、絞扼性神経障害、化学療法薬(抗がん剤を含む)投与に伴う末梢神経障害、またはシャルコー・マリー・トゥース病に伴う末梢神経障害である。 In the present invention, aspects of neuropathy include chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and chemotherapy. Peripheral neuropathy associated with drug administration (including anticancer drugs) or peripheral neuropathy associated with Charcot-Marie-Tooth disease.
本発明において、末梢神経障害の予防および/または治療のある態様としては、末梢神経障害に伴う自覚症状(しびれ感、疼痛)または振動覚異常の予防および/または治療が挙げられ、別の態様としては末梢神経障害に伴う疼痛の予防および/または治療が挙げられる。 In the present invention, one embodiment of the prevention and/or treatment of peripheral neuropathy includes the prevention and/or treatment of subjective symptoms (numbness, pain) or vibration sensation abnormality associated with peripheral neuropathy; another embodiment is the prevention and/or treatment of peripheral neuropathy. Examples include the prevention and/or treatment of pain associated with peripheral neuropathy.
本発明化合物と他の薬物の併用薬は、1つの製剤中に両成分を配合した配合剤の形態で投与してもよく、また別々の製剤にして投与する形態をとってもよい。この別々の製剤にして投与する場合には、同時投与および時間差による投与が含まれる。また、時間差による投与は、本発明化合物を先に投与し、他の薬物を後に投与してもよいし、他の薬物を先に投与し、本発明化合物を後に投与してもよい。それぞれの投与方法は同じでも異なっていてもよい。 A combination drug containing the compound of the present invention and another drug may be administered in the form of a combination drug containing both components in one preparation, or may be administered in separate preparations. Administration in separate formulations includes simultaneous administration and staggered administration. In addition, in staggered administration, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. The respective administration methods may be the same or different.
上記併用薬により、予防および/または治療効果を奏する疾患は特に限定されず、本発明化合物の予防および/または治療効果を補完および/または増強する疾患であればよい。 The diseases for which the above-mentioned concomitant drugs have a preventive and/or therapeutic effect are not particularly limited, as long as they complement and/or enhance the preventive and/or therapeutic effects of the compound of the present invention.
本発明化合物の神経障害を伴う疾患に対する予防および/または治療効果の補完および/または増強のための他の薬物としては、例えば、アルドース還元酵素阻害薬、ビタミン剤、脳保護薬が挙げられる。アルドース還元酵素阻害薬としては、エパルレスタットが挙げられる。ビタミン剤としては、メコバラミンなどが挙げられる。脳保護薬としては、エダラボンが挙げられる。 Examples of other drugs for supplementing and/or enhancing the prophylactic and/or therapeutic effects of the compound of the present invention against diseases accompanied by neurological disorders include, for example, aldose reductase inhibitors, vitamins, and brain protective drugs. Examples of aldose reductase inhibitors include epalrestat. Examples of vitamins include mecobalamin. Brain protective drugs include edaravone.
また、本発明化合物と組み合わせる併用薬としては、現在までに見出されているものだけでなく今後見出されるものも含まれる。 Furthermore, concomitant drugs that can be combined with the compound of the present invention include not only those that have been discovered to date but also those that will be discovered in the future.
本発明化合物は、通常、薬学的に許容される担体とともに適当な医薬組成物として製剤化したうえで、全身的または局所的に、経口または非経口の形で投与される。経口剤としては、例えば、内服用液剤(例えば、エリキシル剤、シロップ剤、薬剤的に許容される水剤、懸濁剤、乳剤)、内服用固形剤(例えば、錠剤(舌下錠、口腔内崩壊錠を含む)、丸剤、カプセル剤(ハードカプセル、ソフトカプセル、ゼラチンカプセル、マイクロカプセルを含む)、散剤、顆粒剤、トローチ剤)等が挙げられる。非経口剤としては、例えば、液剤(例えば、注射剤(硝子体内注射剤、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤、点滴剤等)、点眼剤(例えば、水性点眼剤(水性点眼液、水性懸濁点眼液、粘性点眼液、可溶化点眼液等)、非水性点眼剤(非水性点眼液、非水性懸濁点眼液等))等)、外用剤(例えば、軟膏(眼軟膏等))、点耳剤等が挙げられる。これらの製剤は、速放性製剤、徐放性製剤などの放出制御剤であってもよい。これらの製剤は公知の方法、例えば、日本薬局方に記載の方法等により製造することができる。 The compound of the present invention is usually formulated as a suitable pharmaceutical composition with a pharmaceutically acceptable carrier, and then administered systemically or locally, orally or parenterally. Oral preparations include, for example, liquid preparations for internal use (e.g., elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for oral use (e.g., tablets (sublingual tablets, oral tablets), Examples include disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches). Parenteral preparations include, for example, liquid preparations (e.g., injections (intravitreal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drops, etc.), eye drops (e.g., aqueous Eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.)), external preparations (e.g. , ointment (eye ointment, etc.)), ear drops, etc. These formulations may be release controlled agents such as immediate release formulations and sustained release formulations. These preparations can be manufactured by known methods, for example, the method described in the Japanese Pharmacopoeia.
経口剤としての内服用液剤は、例えば、有効成分を一般的に用いられる希釈剤(例えば、精製水、エタノールまたはそれらの混液等)に溶解、懸濁または乳化されることにより製造される。さらにこの液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香剤、保存剤、緩衝剤等を含有していてもよい。 A liquid preparation for internal use as an oral preparation is produced, for example, by dissolving, suspending, or emulsifying the active ingredient in a commonly used diluent (eg, purified water, ethanol, or a mixture thereof). Furthermore, this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, and the like.
経口剤としての内服用固形剤は、例えば、有効成分を賦形剤(例えば、ラクトース、マンニトール、グルコース、微結晶セルロース、デンプン等)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等)、崩壊剤(例えば、繊維素グリコール酸カルシウム等)、滑沢剤(例えば、ステアリン酸マグネシウム等)、安定剤、溶解補助剤(グルタミン酸、アスパラギン酸等)等と混合し、常法に従って製剤化される。また、必要によりコーティング剤(例えば、白糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等)で被覆していてもよいし、また2以上の層で被覆していてもよい。 Solid preparations for internal use as oral preparations include, for example, active ingredients combined with excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.) and binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). (magnesium acid, etc.), disintegrants (e.g., calcium glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizing agents (e.g., glutamic acid, aspartic acid, etc.), and then It is formulated according to the following. Further, if necessary, it may be coated with a coating agent (for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), or may be coated with two or more layers.
非経口剤としての外用剤は公知の方法または通常使用されている処方により製造される。例えば、軟膏剤は有効成分を基剤に研和または溶融させて製造される。軟膏基剤は公知あるいは通常使用されているものから選ばれる。例えば、高級脂肪酸または高級脂肪酸エステル(例えば、アジピン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、アジピン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステル、オレイン酸エステル等)、ロウ類(例えば、ミツロウ、鯨ロウ、セレシン等)、界面活性剤(例えば、ポリオキシエチレンアルキルエーテルリン酸エステル等)、高級アルコール(例えば、セタノール、ステアリルアルコール、セトステアリルアルコール等)、シリコン油(例えば、ジメチルポリシロキサン等)、炭化水素類(例えば、親水ワセリン、白色ワセリン、精製ラノリン、流動パラフィン等)、グリコール類(例えば、エチレングリコール、ジエチレングリコール、プロピレングリコール、ポリエチレングリコール、マクロゴール等)、植物油(例えば、ヒマシ油、オリーブ油、ごま油、テレピン油等)、動物油(例えば、ミンク油、卵黄油、スクワラン、スクワレン等)、水、吸収促進剤、かぶれ防止剤から選ばれるもの単独または2種以上を混合して用いられる。さらに、保湿剤、保存剤、安定化剤、抗酸化剤、着香剤等を含んでいてもよい。 External preparations as parenteral preparations are manufactured by known methods or commonly used formulations. For example, ointments are prepared by blending or melting the active ingredient into a base. The ointment base is selected from those known or commonly used. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes. (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g. , castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (for example, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents, either alone or in combination of two or more. It is used as Furthermore, it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent, and the like.
非経口剤としての注射剤には溶液、懸濁液、乳濁液および用時溶剤に溶解または懸濁して用いる固形の注射剤を包含される。注射剤は、例えば有効成分を溶剤に溶解、懸濁または乳化させて用いられる。溶剤として、例えば注射用蒸留水、生理食塩水、植物油、プロピレングリコール、ポリエチレングリコール、エタノールのようなアルコール類等およびそれらの組み合わせが用いられる。さらにこの注射剤は、安定剤、溶解補助剤(例えば、グルタミン酸、アスパラギン酸、ポリソルベート80(登録商標)等)、懸濁化剤、乳化剤、無痛化剤、緩衝剤、保存剤等を含んでいてもよい。これらは最終工程において滅菌するか無菌操作法によって製造される。また無菌の固形剤、例えば凍結乾燥品を製造し、その使用前に無菌化または無菌の注射用蒸留水または他の溶剤に溶解して使用することもできる。 Parenteral injections include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injections are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Examples of the solvent used include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this injection contains stabilizers, solubilizing agents (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifying agents, soothing agents, buffers, preservatives, etc. Good too. These are sterilized in the final step or manufactured using aseptic procedures. It is also possible to prepare a sterile solid preparation, such as a lyophilized product, and dissolve it in sterilized or sterile injection-grade distilled water or other solvent before use.
本発明化合物または本発明化合物と他の薬剤の併用剤を上記の目的で用いるには、通常、全身的または局所的に、経口または非経口の形で投与される。投与量は、年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、通常、成人一人当たり、一回につき、1ngから1000mgの範囲で一日一回から数回経口投与されるかまたは成人一人当たり、一回につき、0.1ngから10mgの範囲で一日一回から数回非経口投与されるかまたは一日1時間から24時間の範囲で静脈内に持続投与される。もちろん前記したように、投与量は種々の条件により変動するので、上記投与量より少ない量で十分な場合もあるし、また範囲を越えて投与の必要な場合もある。 When using the compound of the present invention or a combination of the compound of the present invention and other drugs for the above-mentioned purposes, it is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually administered orally in the range of 1 ng to 1000 mg per adult, once to several times a day. Alternatively, the drug may be administered parenterally once to several times a day in the range of 0.1 ng to 10 mg per adult, or continuously administered intravenously for a period of 1 to 24 hours a day. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases in which a smaller amount than the above-mentioned dosage is sufficient, and there are also cases in which it is necessary to administer an amount that exceeds the above range.
以下、実施例によって本発明を詳述するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.
クロマトグラフィーによる分離の箇所およびTLCに示されている括弧内の溶媒は、使用した溶出溶媒または展開溶媒を示し、割合は体積比を表す。
以下の実施例におけるLC/MS分析で用いられた条件を以下に示す。
カラム:YMC Triart C18、2.0mm×30mm、1.9μm;流量:1.0mL/min;温度:30℃;移動相A:0.1%TFA水溶液;移動相B:0.1%TFAアセトニトリル溶液:グラジエント(移動相A:移動相Bの比率を記載):0~0.10分(95:5)、0.10~1.20分(95:5から5:95)、1.20分~1.50分(5:95)。
NMRの箇所に示されているカッコ内は測定に使用した溶媒を示す。
本明細書中に用いた化合物名は、一般的にIUPACの規則に準じて命名を行なうコンピュータプログラム、Advanced Chemistry Development社のACD/Name(登録商標)を用いるか、または、IUPAC命名法に準じて命名したものである。
The solvent in parentheses shown at the point of chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the proportions represent volume ratios.
The conditions used in the LC/MS analysis in the following examples are shown below.
Column: YMC Triart C18, 2.0 mm x 30 mm, 1.9 μm; flow rate: 1.0 mL/min; temperature: 30°C; mobile phase A: 0.1% TFA aqueous solution; mobile phase B: 0.1% TFA acetonitrile Solution: Gradient (state the ratio of mobile phase A: mobile phase B): 0 to 0.10 minutes (95:5), 0.10 to 1.20 minutes (95:5 to 5:95), 1.20 minutes to 1.50 minutes (5:95).
The number in parentheses shown in the NMR section indicates the solvent used in the measurement.
The compound names used in this specification are generally named using ACD/Name (registered trademark) of Advanced Chemistry Development, a computer program that names according to IUPAC rules, or according to IUPAC nomenclature. This is what we named it.
実施例1:イソプロピル 3-(2-ヒドロキシフェニル)プロパノエート
3,4-ジヒドロクマリン(50.0g)のイソプロピルアルコール(500mL)溶液に、硫酸(0.26mL)を加え、反応混合物を室温で2時間撹拌した。反応混合物を減圧濃縮し、得られた残さを酢酸エチルで希釈した。飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(73.2g)を得た。
1H-NMR(CDCl3):δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35。
Example 1: Isopropyl 3-(2-hydroxyphenyl)propanoate To a solution of 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL) was added sulfuric acid (0.26 mL), and the reaction mixture was heated at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (73.2 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.
実施例2:イソプロピル 3-(2-(2-(1,3-ジオキサン-2-イル)エトキシ)フェニル)プロパノエート
実施例1で製造した化合物(2.00g)および2-(2-ブロモエチル)-1,3-ジオキサン(2.43g)のDMF(4mL)溶液に、リン酸カリウム(2.85g)を加え、反応混合物を70℃で2時間撹拌した。反応混合物を1M塩酸に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→4:1)によって精製することにより、以下の物性値を有する標題化合物(2.73g)を得た。
TLC:Rf0.57(ヘキサン:酢酸エチル=2:1)。
Example 2: Isopropyl 3-(2-(2-(1,3-dioxan-2-yl)ethoxy)phenyl)propanoate The compound prepared in Example 1 (2.00 g) and 2-(2-bromoethyl)- Potassium phosphate (2.85 g) was added to a solution of 1,3-dioxane (2.43 g) in DMF (4 mL), and the reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5→4:1) to obtain the title compound (2.73 g) having the following physical properties.
TLC: Rf 0.57 (hexane: ethyl acetate = 2:1).
実施例3:イソプロピル 3-(2-(3-オキソプロポキシ)フェニル)プロパノエート
実施例2で製造した化合物(500mg)およびルチジン(0.40mL)のジクロロメタン(1.5mL)溶液を-15℃に冷却し、トリメチルシリルトリフルオロメタンスルホナート(0.42mL)を加えた。反応混合物を0℃で2時間撹拌した。反応溶液に氷(10g)を加え、0℃で15分間撹拌した。水と酢酸エチルを加え0℃で20時間撹拌し,反応混合物を1M塩酸と酢酸エチルに注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(443mg)を得た。
1H-NMR(CDCl3):δ 1.20, 2.50-2.55, 2.93-2.96, 4.33, 4.98, 6.85-6.92, 7.14-7.19, 9.90。
Example 3: Isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate A solution of the compound prepared in Example 2 (500 mg) and lutidine (0.40 mL) in dichloromethane (1.5 mL) was cooled to -15°C. and trimethylsilyltrifluoromethanesulfonate (0.42 mL) was added. The reaction mixture was stirred at 0°C for 2 hours. Ice (10 g) was added to the reaction solution, and the mixture was stirred at 0° C. for 15 minutes. Water and ethyl acetate were added, and the mixture was stirred at 0°C for 20 hours. The reaction mixture was poured into 1M hydrochloric acid and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (443 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.20, 2.50-2.55, 2.93-2.96, 4.33, 4.98, 6.85-6.92, 7.14-7.19, 9.90.
実施例4:イソプロピル 3-(2-((3-ヒドロキシ-5-(トリメチルシリル)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
トリメチルシリルアセチレン(5.0mL)のTHF(70mL)溶液を-70℃に冷却し、n-ブチルリチウム(1.6Mヘキサン溶液、20mL)を加え、反応混合物を-70℃で30分間撹拌した。実施例3で製造した化合物(7.15g)のTHF(10mL)溶液を滴下し、反応混合物を0℃で2時間撹拌した。反応混合物を飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→7:3)によって精製することにより、以下の物性値を有する標題化合物(1.8g)を得た。
1H-NMR(CDCl3):δ 0.17, 1.19, 2.22-2.33, 2.56, 2.87-2.98, 4.09-4.23, 4.70, 3.60-4.93-5.03, 6.86-6.91, 7.14-7.18。
Example 4: A solution of isopropyl 3-(2-((3-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)oxy)phenyl)propanoate trimethylsilylacetylene (5.0 mL) in THF (70 mL) After cooling to −70° C., n-butyllithium (1.6 M in hexane, 20 mL) was added, and the reaction mixture was stirred at −70° C. for 30 minutes. A solution of the compound prepared in Example 3 (7.15 g) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5→7:3) to obtain the title compound (1.8 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.17, 1.19, 2.22-2.33, 2.56, 2.87-2.98, 4.09-4.23, 4.70, 3.60-4.93-5.03, 6.86-6.91, 7.14-7.18.
実施例5:イソプロピル 3-(2-((3-ヒドロキシペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例4で製造した化合物(6.89g)のTHF(38mL)溶液を0℃に冷却し、フッ化テトラブチルアンモニウム(以下、TBAFと略記)(1.0M THF溶液、7.3mL)を加えた。反応混合物を0℃で10分間撹拌した。反応混合物を1M塩酸に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→1:1)によって精製することにより、以下の物性値を有する標題化合物(5.06g)を得た。
1H-NMR(CDCl3):δ 1.19, 2.20-2.26, 2.43, 2.50-2.59, 2.87-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21。
Example 5: Isopropyl 3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate A solution of the compound prepared in Example 4 (6.89 g) in THF (38 mL) was The mixture was cooled to 0.degree. C., and tetrabutylammonium fluoride (hereinafter abbreviated as TBAF) (1.0 M THF solution, 7.3 mL) was added. The reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5→1:1) to obtain the title compound (5.06 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.19, 2.20-2.26, 2.43, 2.50-2.59, 2.87-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.
実施例6:イソプロピル (R)-3-(2-((3-ヒドロキシペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例5で製造した化合物(1.2g)のヘプタン(24mL)溶液に,ビニルアセテート(4mL)を加えた。CHIRAZYME L-5 CA(商品名)(0.4g)を加え、反応混合物を45℃で9時間撹拌した。反応混合物をセライト(商品名)でろ過後、ろ液を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→1:1)によって精製することにより、以下の物性値を有する標題化合物(0.54g、>99%ee)を得た。得られた化合物を高速液体クロマトグラフィー(使用カラム:株式会社ダイセル CHIRALPAK-IB(4.6mm×250mm)、移動相:ヘキサン:2-プロパノール=95:5、流速:1mL/min、波長:254nm、カラム温度:40℃)で分析した結果、保持時間は10.6分であった。
1H-NMR(CDCl3):δ 1.19, 2.20-2.26, 2.41, 2.50-2.59, 2.90-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21。
Example 6: Isopropyl (R)-3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate The compound prepared in Example 5 (1.2 g) in heptane (24 mL) ) To the solution, vinyl acetate (4 mL) was added. CHIRAZYME L-5 CA (trade name) (0.4 g) was added, and the reaction mixture was stirred at 45° C. for 9 hours. After filtering the reaction mixture through Celite (trade name), the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 → 1:1) to obtain the title compound (0.54 g, >99% ee) having the following physical properties. . The obtained compound was subjected to high performance liquid chromatography (column used: Daicel Corporation CHIRALPAK-IB (4.6 mm x 250 mm), mobile phase: hexane:2-propanol = 95:5, flow rate: 1 mL/min, wavelength: 254 nm, As a result of analysis at a column temperature of 40° C., the retention time was 10.6 minutes.
1H -NMR ( CDCl3 ): δ 1.19, 2.20-2.26, 2.41, 2.50-2.59, 2.90-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.
実施例7:イソプロピル (R)-3-(2-((3-((トリメチルシリル)オキシ)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例6で製造した化合物(500mg)のDMF(3.4mL)溶液を0℃に冷却し、クロロトリメチルシラン(0.24mL)を加えた。反応混合物を室温で2時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→9:1)によって精製することにより、以下の物性値を有する標題化合物(600mg)を得た。
1H-NMR(CDCl3):δ 0.17, 1.21, 2.18, 2.43, 2.54-2.59, 2.90-2.95, 4.06-4.15, 4.67, 4.99, 6.83-6.89, 7.14-7.20。
Example 7: Isopropyl (R)-3-(2-((3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate of the compound prepared in Example 6 (500 mg) The DMF (3.4 mL) solution was cooled to 0° C. and chlorotrimethylsilane (0.24 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0→9:1) to obtain the title compound (600 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.17, 1.21, 2.18, 2.43, 2.54-2.59, 2.90-2.95, 4.06-4.15, 4.67, 4.99, 6.83-6.89, 7.14-7.20.
実施例8:イソプロピル (R,E)-3-(2-((5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-3-((トリメチルシリル)オキシ)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例7で製造した化合物(2.45g)のヘプタン(6mL)溶液に、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(2.09g)および4-ジメチルアミノ安息香酸(53.9mg)を加え、100℃で13時間撹拌した。反応溶液を室温まで冷却後、濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:1→3:1)によって精製することにより、以下の物性値を有する標題化合物(1.45g)を得た。
HPLC保持時間(分):1.14。
Example 8: Isopropyl (R,E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl) )oxy)pent-4-en-1-yl)oxy)phenyl)
HPLC retention time (min): 1.14.
実施例9:N-(3-ブロモフェニル)ベンゼンスルホンアミド
3-ブロモアニリン(1.02g)のジクロロメタン(20mL)溶液に、0℃でピリジン(0.95mL)、N,N-ジメチルアミノピリジン(以下、DMAPと略記)(72.4mg)および塩化ベンゼンスルホニル(1.10g)を加え、室温で2時間撹拌した。反応溶液を濃縮後、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(1.96g)を得た。
HPLC保持時間(分):0.98。
Example 9: N-(3-Bromophenyl)benzenesulfonamide To a solution of 3-bromoaniline (1.02 g) in dichloromethane (20 mL) was added pyridine (0.95 mL), N,N-dimethylaminopyridine ( (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9:1 → 2:1) to obtain the title compound (1.96 g) having the following physical properties. Ta.
HPLC retention time (min): 0.98.
実施例10:プロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエート
実施例8で製造した化合物(2.00g)のTHF(18mL)溶液に、実施例9で製造した化合物(1.18g)、クロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(CAS登録番号:1310584-14-5)(0.30g)および2Mリン酸三カリウム水溶液(5.7mL)を加え、60℃で2時間撹拌した。反応溶液を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さのTHF(6mL)に、TBAF(1.0M THF溶液、6.3mL)を加え、室温で1時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(1.41g)を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.21, 2.05-2.17, 2.21, 2.57-2.61, 2.91-2.95, 4.11-4.19, 4.62, 5.02, 6.25, 6.55, 6.72, 6.85-6.91, 6.99, 7.09-7.22, 7.41-7.45, 7.53, 7.75-7.78。
Example 10: Propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate in Example 8 The compound prepared in Example 9 (1.18 g) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1) were added to a solution of the prepared compound (2.00 g) in THF (18 mL). ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS registration number: 1310584-14-5) (0.30 g) and 2M aqueous tripotassium phosphate solution (5.7 mL) was added and stirred at 60°C for 2 hours. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. TBAF (1.0 M THF solution, 6.3 mL) was added to the resulting residue in THF (6 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→2:1) to obtain the title compound (1.41 g) having the following physical properties.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 1.21, 2.05-2.17, 2.21, 2.57-2.61, 2.91-2.95, 4.11-4.19, 4.62, 5.02, 6.25, 6.55, 6.72, 6.85-6.91, 6.99, 7.09-7.22, 7.41-7.45, 7.53, 7.75-7.78.
実施例11:3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸 Example 11: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid
実施例10で製造した化合物(680mg)のTHF(5mL)とメタノール(1mL)の溶液に、1M水酸化リチウム水溶液(5mL)を加え、30℃で18時間撹拌した。1M塩酸を加え酸性にし、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮することにより、以下の物性値を有する標題化合物(600mg)を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56, 7.75-7.78。
To a solution of the compound produced in Example 10 (680 mg) in THF (5 mL) and methanol (1 mL) was added 1M lithium hydroxide aqueous solution (5 mL), and the mixture was stirred at 30°C for 18 hours. The mixture was made acidic by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (600 mg) having the following physical properties.
HPLC retention time (min): 0.93;
1H -NMR (CD 3 OD): δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45- 7.50, 7.56 , 7.75-7.78.
実施例12(1)~(13)
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例10→実施例11と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
Example 12 (1) to (13)
By using a corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and subjecting it to the same operation as in Example 10 → Example 11, the following examples were prepared. The compound was obtained.
実施例12(1):3-[2-[(E,3R)-5-(3-ベンズアミドフェニル)-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 2.10-2.15, 2.59-2.63, 2.93-2.97, 4.13, 4.21, 4.60, 6.39, 6.67, 6.86, 6.95, 7.16, 7.24, 7.33, 7.52-7.63, 7.81, 7.95-7.97。
Example 12 (1): 3-[2-[(E,3R)-5-(3-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0. 95;
1H -NMR (CD 3 OD): δ 2.10-2.15, 2.59-2.63, 2.93-2.97, 4.13, 4.21, 4.60, 6.39, 6.67, 6.86, 6.95, 7.16, 7.24, 7.33, 7.52-7.63 , 7.81, 7.95 -7.97.
実施例12(2):3-[2-[(E,3R)-5-[4-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸 Example 12 (2): 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid
HPLC保持時間(分):0.92;
MS(ESI,Pos.):464(M+H-H2O)+。
HPLC retention time (min): 0.92;
MS (ESI, Pos.): 464 (M+H- H2O ) + .
実施例12(3):3-[2-[(E,3R)-5-(4-ベンズアミドフェニル)-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 2.10-2.14, 2.58-2.63, 2.93-2.97, 4.13, 4.20, 4.58, 6.32, 6.64, 6.86, 6.95, 7.15-7.20, 7.44-7.55, 7.60, 7.67-7.71, 7.93-7.97。
Example 12 (3): 3-[2-[(E,3R)-5-(4-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0. 95;
1H -NMR ( CD3OD ): δ 2.10-2.14, 2.58-2.63, 2.93-2.97, 4.13, 4.20, 4.58, 6.32, 6.64, 6.86, 6.95, 7.15-7.20, 7.44-7.55, 7.60, 7.67-7.71 , 7.93-7.97.
実施例12(4):3-[2-[(E,3R)-5-[2-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
MS(ESI,Pos.):464(M+H-H2O)+。
Example 12 (4): 3-[2-[(E,3R)-5-[2-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min ): 0.94;
MS (ESI, Pos.): 464 (M+H- H2O ) + .
実施例12(5):3-[2-[(E,3R)-5-(2-ベンズアミドフェニル)-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.89;
MS(ESI,Pos.):428(M+H-H2O)+。
Example 12 (5): 3-[2-[(E,3R)-5-(2-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0. 89;
MS (ESI, Pos.): 428 (M+H- H2O ) + .
実施例12(6):3-[2-[(E,3R)-5-[3-(ベンジルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.85;
1H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.92-2.95, 4.10, 4.17, 4.33, 4.52, 6.19, 6.49-6.56, 6.69-6.71, 6.85, 6.93, 7.04, 7.15-7.24, 7.29-7.33, 7.37-7.39。
Example 12 (6): 3-[2-[(E,3R)-5-[3-(benzylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :0.85;
1H -NMR (CD 3 OD): δ 2.05-2.10, 2.57-2.61, 2.92-2.95, 4.10, 4.17, 4.33, 4.52, 6.19, 6.49-6.56, 6.69-6.71, 6.85, 6.93, 7.04, 7.15-7.24 , 7.29-7.33, 7.37-7.39.
実施例12(7):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(フェニルスルファモイル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
MS(ESI,Pos.):464(M+H-H2O)+。
Example 12 (7): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylsulfamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.94;
MS (ESI, Pos.): 464 (M+H- H2O ) + .
実施例12(8):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(フェニルカルバモイル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.95;
MS(ESI,Pos.):428(M+H-H2O)+。
Example 12 (8): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylcarbamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :0.95;
MS (ESI, Pos.): 428 (M+H- H2O ) + .
実施例12(9):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
1H-NMR(CD3OD):δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.62, 6.86, 6.94, 7.10-7.31。
Example 12 (9): 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96;
1H -NMR ( CD3OD ): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.62, 6.86, 6.94, 7.10-7.31.
実施例12(10):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミドメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.93;
MS(ESI,Pos.):478(M+H-H2O)+。
Example 12 (10): 3-[2-[(E,3R)-5-[3-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.93;
MS (ESI, Pos.): 478 (M+H- H2O ) + .
実施例12(11):3-[2-[(E,3R)-5-[2-(ベンゼンスルホンアミドメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
1H-NMR(CDCl3):δ 1.99-2.07, 2.11-2.19, 2.68-2.72, 2.95-3.08, 4.12-4.26, 4.73-4.78, 6.12, 6.59, 6.86-6.92, 7.04-7.11, 7.16-7.23, 7.33-7.38, 7.44-7.48, 7.64-7.67。
Example 12 (11): 3-[2-[(E,3R)-5-[2-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.97;
1H -NMR ( CDCl3 ): δ 1.99-2.07, 2.11-2.19, 2.68-2.72, 2.95-3.08, 4.12-4.26, 4.73-4.78, 6.12, 6.59, 6.86-6.92, 7.04-7.11, 7.1 6-7.23, 7.33-7.38, 7.44-7.48, 7.64-7.67.
実施例12(12):3-[2-[(E,3R)-5-[1-(ベンゼンスルホニル)-2-メチルインドール-4-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
MS(ESI,Pos.):502(M+H-H2O)+。
Example 12 (12): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2-methylindol-4-yl]-3-hydroxypent-4-enoxy]phenyl] Propanoic acid HPLC retention time (min): 1.10;
MS (ESI, Pos.): 502 (M+H- H2O ) + .
実施例12(13):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(2-ヒドロキシ-1-フェニルプロパン-2-イル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 2.10-2.15, 2.65-2.68, 2.94-3.14, 4.12-4.22, 4.62, 6.28, 6.64, 6.86-6.91, 7.00-7.02, 7.15-7.28, 7.44。
Example 12 (13): 3-[2-[(E,3R)-3-hydroxy-5-[3-(2-hydroxy-1-phenylpropan-2-yl)phenyl]pent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 2.10-2.15, 2.65-2.68, 2.94-3.14, 4.12-4.22, 4.62, 6.28, 6.64, 6.86-6.91, 7.00-7.02, 7.15-7.28, 7.44.
実施例13(1)~(19)
実施例9で使用した3-ブロモアニリンの代わりに相当するアミン化合物を用いて、実施例9→実施例10→実施例11と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
Example 13 (1) to (19)
By using the corresponding amine compound instead of 3-bromoaniline used in Example 9 and subjecting it to the same operations as in Example 9 → Example 10 → Example 11, the following example compounds were obtained. Ta.
実施例13(1):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-2-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸 Example 13 (1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid
HPLC保持時間(分):0.94;
1H-NMR(CD3OD):δ 1.96, 2.07-2.12, 2.56-2.60, 2.90-2.94, 4.10, 4.18, 4.57, 6.12, 6.78, 6.84-6.93, 7.04, 7.15-7.20, 7.36, 7.47-7.51, 7.60, 7.65-7.67。
HPLC retention time (min): 0.94;
1H -NMR (CD 3 OD): δ 1.96, 2.07-2.12, 2.56-2.60, 2.90-2.94, 4.10, 4.18, 4.57, 6.12, 6.78, 6.84-6.93, 7.04, 7.15-7.20, 7.36, 7.47-7.51 , 7.60, 7.65-7.67.
実施例13(2):3-[2-[(E,3R)-5-[5-(ベンゼンスルホンアミド)-2-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 2.05-2.11, 2.19, 2.56-2.60, 2.91-2.95, 4.09, 4.19, 4.56, 6.01, 6.76, 6.84-6.94, 6.99, 7.12-7.20, 7.44-7.48, 7.56, 7.73-7.75。
Example 13 (2): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.95;
1H -NMR (CD 3 OD): δ 2.05-2.11, 2.19, 2.56-2.60, 2.91-2.95, 4.09, 4.19, 4.56, 6.01, 6.76, 6.84-6.94, 6.99, 7.12-7.20, 7.44- 7.48, 7.56 , 7.73-7.75.
実施例13(3):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-5-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
1H-NMR(CD3OD):δ 1.93-1.98, 2.12, 2.45-2.49, 2.79-2.83, 3.98, 4.05, 4.41, 6.09, 6.37, 6.69, 6.74, 6.80-6.83, 7.03-7.08, 7.34-7.38, 7.44, 7.63-7.66。
Example 13 (3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.96;
1H -NMR ( CD3OD ): δ 1.93-1.98, 2.12, 2.45-2.49, 2.79-2.83, 3.98, 4.05, 4.41, 6.09, 6.37, 6.69, 6.74, 6.80-6.83, 7.03-7.08, 7.34-7.38 , 7.44, 7.63-7.66.
実施例13(4):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-4-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
1H-NMR(CD3OD):δ 1.89-1.97, 1.91, 2.46-2.50, 2.81-2.84, 3.98, 4.06, 4.40, 5.98, 6.37, 6.75, 6.83, 6.90, 6.97, 7.04-7.09, 7.34-7.38, 7.46, 7.56-7.58。
Example 13 (4): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.94;
1H -NMR (CD 3 OD): δ 1.89-1.97, 1.91, 2.46-2.50, 2.81-2.84, 3.98, 4.06, 4.40, 5.98, 6.37, 6.75, 6.83, 6.90, 6.97, 7.04-7.09 , 7.34-7.38 , 7.46, 7.56-7.58.
実施例13(5):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-2-フルオロフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
1H-NMR(CD3OD):δ 2.03-2.09, 2.55-2.59, 2.89-2.93, 4.09, 4.16, 4.53, 6.36, 6.63, 6.86, 6.92, 7.06, 7.15-7.19, 7.30-7.37, 7.45-7.49, 7.57, 7.75-7.77。
Example 13 (5): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.94;
1H -NMR ( CD3OD ): δ 2.03-2.09, 2.55-2.59, 2.89-2.93, 4.09, 4.16, 4.53, 6.36, 6.63, 6.86, 6.92, 7.06, 7.15-7.19, 7.30-7.37, 7.45-7.49 , 7.57, 7.75-7.77.
実施例13(6):3-[2-[(E,3R)-5-[5-(ベンゼンスルホンアミド)-2-フルオロフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
1H-NMR(CD3OD):δ 1.90-2.01, 2.45-2.49, 2.79-2.83, 3.99, 4.07, 4.43, 6.17, 6.56, 6.75, 6.81-6.88, 7.03-7.09, 7.34-7.38, 7.45, 7.60-7.63。
Example 13 (6): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.94;
1H -NMR (CD 3 OD): δ 1.90-2.01, 2.45-2.49, 2.79-2.83, 3.99, 4.07, 4.43, 6.17, 6.56, 6.75, 6.81-6.88, 7.03-7.09, 7.34-7.38, 7.45, 7.60 -7.63.
実施例13(7):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-5-フルオロフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
1H-NMR(CD3OD):δ 1.92-1.98, 2.44-2.48, 2.78-2.82, 3.98, 4.06, 4.42, 6.17, 6.39, 6.68, 6.70-6.82, 7.03-7.08, 7.37-7.41, 7.47, 7.68-7.71。
Example 13 (7): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.96;
1H -NMR ( CD3OD ): δ 1.92-1.98, 2.44-2.48, 2.78-2.82, 3.98, 4.06, 4.42, 6.17, 6.39, 6.68, 6.70-6.82, 7.03-7.08, 7.37-7.41, 7.47, 7.68 -7.71.
実施例13(8):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-4-フルオロフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.92;
1H-NMR(CD3OD):δ 1.95-2.00, 2.45-2.49, 2.81-2.84, 4.00, 4.07, 4.44, 6.10, 6.45, 6.75, 6.81-6.86, 7.04-7.10, 7.34-7.39, 7.47, 7.64-7.66。
実施例13(9): 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミ
Example 13 (8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.92;
1H -NMR (CD 3 OD): δ 1.95-2.00, 2.45-2.49, 2.81-2.84, 4.00, 4.07, 4.44, 6.10, 6.45, 6.75, 6.81-6.86, 7.04-7.10, 7.34-7.39, 7.47, 7.64 -7.66.
Example 13 (9): 3-[2-[(E,3R)-5-[3-(benzenesulfonamide
ド)-2-(トリフルオロメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 1.94-2.00, 2.43-2.47, 2.78-2.82, 3.99, 4.06, 4.45, 6.08, 6.74, 6.79-6.85, 7.03-7.10, 7.32-7.43, 7.50, 7.58-7.60。
do)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95;
1H -NMR ( CD3OD ): δ 1.94-2.00, 2.43-2.47, 2.78-2.82, 3.99, 4.06, 4.45, 6.08, 6.74, 6.79-6.85, 7.03-7.10, 7.32-7.43, 7.50, 7.58-7.60 .
実施例13(10):3-[2-[(E,3R)-5-[5-(ベンゼンスルホンアミド)-2-(トリフルオロメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CD3OD):δ 1.94-2.00, 2.43-2.47, 2.79-2.83, 3.99, 4.07, 4.47, 6.09, 6.73-6.82, 7.04-7.08, 7.27, 7.38-7.42, 7.48, 7.73-7.76。
Example 13 (10): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl ] Propanoic acid HPLC retention time (min): 0.99;
1H -NMR (CD 3 OD): δ 1.94-2.00, 2.43-2.47, 2.79-2.83, 3.99, 4.07, 4.47, 6.09, 6.73-6.82, 7.04-7.08, 7.27, 7.38-7.42, 7.48, 7.73-7.76 .
実施例13(11):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-5-(トリフルオロメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CD3OD):δ 1.91-2.03, 2.42-2.46, 2.79-2.83, 3.99, 4.07, 4.46, 6.25,6.49, 6.74, 6.81, 7.03-7.07, 7.16, 7.22-7.26, 7.37-7.41, 7.47, 7.67-7.70。
Example 13 (11): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl ] Propanoic acid HPLC retention time (min): 0.99;
1H -NMR (CD 3 OD): δ 1.91-2.03, 2.42-2.46, 2.79-2.83, 3.99, 4.07, 4.46, 6.25, 6.49, 6.74, 6.81, 7.03-7.07, 7.16, 7.22-7.26, 7.37-7.41 , 7.47, 7.67-7.70.
実施例13(12):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-4-(トリフルオロメチル)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 1.94-2.00, 2.46-2.50, 2.80-2.84, 4.00, 4.08, 4.46, 6.19, 6.49, 6.76, 6.84, 7.05-7.10, 7.24, 7.28, 7.39-7.52, 7.67-7.70。
Example 13 (12): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl ] Propanoic acid HPLC retention time (min): 0.97;
1H -NMR (CD 3 OD): δ 1.94-2.00, 2.46-2.50, 2.80-2.84, 4.00, 4.08, 4.46, 6.19, 6.49, 6.76, 6.84, 7.05-7.10, 7.24, 7.28, 7.39 -7.52, 7.67 -7.70.
実施例13(13):3-[2-[(E,3R)-5-[6-(ベンゼンスルホンアミド)ピリジン-2-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.85;
1H-NMR(CD3OD):δ 1.92-2.00, 2.45-2.49, 2.79-2.83, 3.96-4.10, 4.47, 6.42, 6.64, 6.75, 6.79-6.83, 6.88, 7.03-7.08, 7.36-7.49, 7.85-7.88。
Example 13 (13): 3-[2-[(E,3R)-5-[6-(benzenesulfonamido)pyridin-2-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.85;
1H -NMR (CD 3 OD): δ 1.92-2.00, 2.45-2.49, 2.79-2.83, 3.96-4.10, 4.47, 6.42, 6.64, 6.75, 6.79-6.83, 6.88, 7.03-7.08, 7.36-7 .49, 7.85 -7.88.
実施例13(14):3-[2-[(E,3R)-5-[1-(ベンゼンスルホニル)-2,3-ジヒドロインドール-6-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.11-2.16, 2.59-2.63, 2.82-2.86, 2.94-2.98, 3.94-3.98, 4.14, 4.22, 4.60, 6.34, 6.66, 6.87, 6.96, 7.05-7.09, 7.16-7.21, 7.48-7.52, 7.63, 7.66, 7.78-7.81。
Example 13 (14): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-6-yl]-3-hydroxypent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 2.11-2.16, 2.59-2.63, 2.82-2.86, 2.94-2.98, 3.94-3.98, 4.14, 4.22, 4.60, 6.34, 6.66, 6.87, 6.96, 7.05- 7.09, 7.16 -7.21, 7.48-7.52, 7.63, 7.66, 7.78-7.81.
実施例13(15):3-[2-[(E,3R)-5-[1-(ベンゼンスルホニル)-2,3-ジヒドロインドール-4-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.04-2.09, 2.51-2.55, 2.70-2.89, 3.89-3.96, 4.08, 4.14, 4.53, 6.23, 6.50, 6.83, 6.90, 7.08-7.19, 7.48-7.53, 7.63, 7.78-7.81。
Example 13 (15): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-4-yl]-3-hydroxypent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR (CD 3 OD): δ 2.04-2.09, 2.51-2.55, 2.70-2.89, 3.89-3.96, 4.08, 4.14, 4.53, 6.23, 6.50, 6.83, 6.90, 7.08-7.19, 7.48- 7.53, 7.63 , 7.78-7.81.
実施例13(16):3-[2-[(E,3R)-5-[2-(ベンゼンスルホニル)-1,3-ジヒドロイソインドール-5-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.06-2.10, 2.55-2.59, 2.89-2.93, 4.10, 4.17, 4.54, 4.60, 6.31, 6.60, 6.85, 6.92, 7.13-7.18, 7.28-7.30, 7.58-7.68, 7.90-7.93。
Example 13 (16): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-1,3-dihydroisoindol-5-yl]-3-hydroxypent-4-enoxy ]Phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 2.06-2.10, 2.55-2.59, 2.89-2.93, 4.10, 4.17, 4.54, 4.60, 6.31, 6.60, 6.85, 6.92, 7.13-7.18, 7.28-7.30, 7.58-7.68 , 7.90-7.93.
実施例13(17):3-[2-[(E,3R)-5-[1-(ベンゼンスルホニル)-3,4-ジヒドロ-2H-キノリン-7-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.59-1.66, 2.10-2.15, 2.40-2.43, 2.59-2.63, 2.93-2.97, 3.82-3.85, 4.14, 4.21, 4.59, 6.31, 6.62, 6.86, 6.94-7.01, 7.16-7.21, 7.45-7.49, 7.59-7.63, 7.79。
Example 13 (17): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-7-yl]-3-hydroxypent-4 -enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR (CD 3 OD): δ 1.59-1.66, 2.10-2.15, 2.40-2.43, 2.59-2.63, 2.93-2.97, 3.82-3.85, 4.14, 4.21, 4.59, 6.31, 6.62, 6.86, 6.94-7.01 , 7.16-7.21, 7.45-7.49, 7.59-7.63, 7.79.
実施例13(18):3-[2-[(E,3R)-5-[1-(ベンゼンスルホニル)-3,4-ジヒドロ-2H-キノリン-5-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.50-1.57, 2.01-2.15, 2.19-2.37, 2.53-2.57, 2.88-2.92, 3.75-3.78, 4.07, 4.16, 4.56, 6.12, 6.67, 6.84, 6.90, 7.13-7.21, 7.32, 7.45-7.49, 7.56-7.65。
Example 13 (18): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-5-yl]-3-hydroxypent-4 -enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 1.50-1.57, 2.01-2.15, 2.19-2.37, 2.53-2.57, 2.88-2.92, 3.75-3.78, 4.07, 4.16, 4.56, 6.12, 6.67, 6.84, 6.90, 7.13 -7.21, 7.32, 7.45-7.49, 7.56-7.65.
実施例13(19):3-[2-[(E,3R)-5-[2-(ベンゼンスルホニル)-3,4-ジヒドロ-1H-イソキノリン-7-イル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.07-2.12, 2.57-2.61, 2.87-2.95, 3.36-3.39, 4.11, 4.18, 4.25, 4.55, 6.29, 6.57, 6.85, 6.93, 7.05, 7.14-7.19, 7.23, 7.59-7.70, 7.87-7.89。
Example 13 (19): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinolin-7-yl]-3-hydroxypent-4 -enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 2.07-2.12, 2.57-2.61, 2.87-2.95, 3.36-3.39, 4.11, 4.18, 4.25, 4.55, 6.29, 6.57, 6.85, 6.93, 7.05, 7.14 -7.19, 7.23 , 7.59-7.70, 7.87-7.89.
実施例14:N-(3-ブロモフェニル)-N-(オキセタン-2-イルメチル)ベンゼンスルホンアミド
実施例9で製造した化合物(313mg)のTHF(2mL)溶液に、オキセタン-2-イルメタノール(132mg)、トリフェニルホスフィン(394mg)、アゾジカルボン酸ジエチル(40%トルエン溶液、0.68mL)を加え、室温で2時間撹拌した.反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1→1:1)によって精製することにより、以下の物性値を有する標題化合物(381mg)を得た。
TLC:Rf 0.34(ヘキサン:酢酸エチル=2:1)
Example 14: N-(3-Bromophenyl)-N-(oxetan-2-ylmethyl)benzenesulfonamide To a solution of the compound prepared in Example 9 (313 mg) in THF (2 mL) was added oxetan-2-ylmethanol ( 132 mg), triphenylphosphine (394 mg), and diethyl azodicarboxylate (40% toluene solution, 0.68 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1→1:1) to obtain the title compound (381 mg) having the following physical properties.
TLC: Rf 0.34 (hexane: ethyl acetate = 2:1)
実施例15:3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(オキセタン-2-イルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに実施例14で製造した化合物を用いて、実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 2.06-2.10, 2.48-2.69, 2.91-2.95, 3.80, 4.00, 4.10, 4.18, 4.47-4.64, 4.83, 6.21, 6.55, 6.87, 6.94-6.96, 7.03, 7.17-7.21, 7.27, 7.38, 7.50-7.54, 7.60-7.65。
Example 15: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Practice By using the compound prepared in Example 14 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and performing the same operations as in Example 10→Example 11, the following results were obtained. The title compound having physical properties was obtained.
HPLC retention time (min): 0.95;
1H -NMR ( CD3OD ): δ 2.06-2.10, 2.48-2.69, 2.91-2.95, 3.80, 4.00, 4.10, 4.18, 4.47-4.64, 4.83, 6.21, 6.55, 6.87, 6.94-6.96, 7.03, 7.17 -7.21, 7.27, 7.38, 7.50-7.54, 7.60-7.65.
実施例16(1)~(8)
実施例14で使用したオキセタン-2-イルメタノールの代わりに相当するアルコール化合物を、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例14→実施例10→実施例11と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 16 (1) to (8)
The experiment was carried out using a corresponding alcohol compound in place of oxetan-2-ylmethanol used in Example 14 and a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The following example compounds were obtained by performing the same operations as in Example 14→Example 10→Example 11.
実施例16(1):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(オキセタン-3-イルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
1H-NMR(CD3OD):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.04, 3.95, 4.10, 4.18, 4.36-4.40, 4.55, 4.63-4.67, 6.22, 6.55, 6.85-6.97, 7.16-7.21, 7.29, 7.40, 7.52-7.56, 7.62-7.67。
Example 16 (1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl] Propanoic acid HPLC retention time (min): 0.94;
1H -NMR ( CD3OD ): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.04, 3.95, 4.10, 4.18, 4.36-4.40, 4.55, 4.63-4.67, 6.22, 6.55, 6.85- 6.97, 7.16 -7.21, 7.29, 7.40, 7.52-7.56, 7.62-7.67.
実施例16(2):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(オキソラン-2-イルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.72, 1.84-1.99, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.57, 3.66-3.80, 3.89, 4.10, 4.18, 4.55, 6.22, 6.56, 6.87, 6.94-6.97, 7.05, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.64。
Example 16 (2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl] Propanoic acid HPLC retention time (min): 1.00;
1H -NMR (CD 3 OD): δ 1.72, 1.84-1.99, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.57, 3.66-3.80, 3.89, 4.10, 4.18, 4.55, 6.22, 6.56, 6.87, 6.94 -6.97, 7.05, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.64.
実施例16(3):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(オキソラン-3-イルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 1.74, 1.95, 2.06-2.11, 2.25, 2.57-2.61, 2.91-2.95, 3.57-3.61, 3.67-3.73, 3.87, 4.10, 4.19, 4.55, 6.23, 6.56, 6.87, 6.94-6.96, 7.02, 7.16-7.21, 7.30, 7.41, 7.50-7.54, 7.57-7.65。
Example 16 (3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl] Propanoic acid HPLC retention time (min): 0.97;
1H -NMR (CD 3 OD): δ 1.74, 1.95, 2.06-2.11, 2.25, 2.57-2.61, 2.91-2.95, 3.57-3.61, 3.67-3.73, 3.87, 4.10, 4.19, 4.55, 6.23, 6.56, 6.87 , 6.94-6.96, 7.02, 7.16-7.21, 7.30, 7.41, 7.50-7.54, 7.57-7.65.
実施例16(4):
3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(オキサン-2-イルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
1H-NMR(CD3OD):δ 1.26, 1.39-1.55, 1.68, 1.82, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.23-3.30, 3.51, 3.70, 3.87, 4.10, 4.18, 4.55, 6.20, 6.56, 6.87, 6.93-6.96, 7.02, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.63。
Example 16 (4):
3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min ):1.10;
1H -NMR ( CD3OD ): δ 1.26, 1.39-1.55, 1.68, 1.82, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.23-3.30, 3.51, 3.70, 3.87, 4.10, 4.18, 4.55, 6.20 , 6.56, 6.87, 6.93-6.96, 7.02, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.63.
実施例16(5):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(プロパン-2-イル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.31(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 1.04, 1.98-2.21, 2.67, 2.89-3.01, 4.10-4.24, 4.55-4.66, 6.22, 6.59, 6.85-6.92, 7.07, 7.16-7.28, 7.38-7.57, 7.76。
Example 16 (5): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(propan-2-yl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl] Propanoic acid TLC: Rf 0.31 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 1.04, 1.98-2.21, 2.67, 2.89-3.01, 4.10-4.24, 4.55-4.66, 6.22, 6.59, 6.85-6.92, 7.07, 7.16-7.28, 7.38-7. 57, 7.76.
実施例16(6):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(2-メチルプロピル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.34(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 0.91, 1.57, 2.08-2.15, 2.67, 2.97, 3.30, 4.10-4.24, 4.62, 6.20, 6.57, 6.83-6.92, 7.08, 7.16-7.25, 7.31, 7.40-7.47, 7.51-7.60。
Example 16 (6): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid TLC: Rf 0.34 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 0.91, 1.57, 2.08-2.15, 2.67, 2.97, 3.30, 4.10-4.24, 4.62, 6.20, 6.57, 6.83-6.92, 7.08, 7.16-7.25, 7.31, 7.40-7.47, 7.51-7.60.
実施例16(7):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(シクロプロピルメチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.79(酢酸エチル);
1H-NMR(CDCl3):δ 0.09-0.13, 0.38-0.43, 0.80-0.90, 2.09-2.18, 2.67, 2.97, 3.42, 4.11-4.23, 4.63, 6.22, 6.58, 6.86-6.93, 7.14-7.26, 7.33, 7.44, 7.55, 7.63。
Example 16 (7): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(cyclopropylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.79 (ethyl acetate);
1H -NMR ( CDCl3 ): δ 0.09-0.13, 0.38-0.43, 0.80-0.90, 2.09-2.18, 2.67, 2.97, 3.42, 4.11-4.23, 4.63, 6.22, 6.58, 6.86-6.93, 7 .14-7.26, 7.33, 7.44, 7.55, 7.63.
実施例16(8):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(2-フェニルエチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.74(酢酸エチル);
1H-NMR(CDCl3):δ 2.07-2.21, 2.64-2.71, 2.74-2.81, 2.94-3.01, 3.72-3.80, 4.11-4.24, 4.63, 6.22, 6.59, 6.81-6.93, 7.09-7.26, 7.31-7.45, 7.51-7.60。
Example 16 (8): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-phenylethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid TLC: Rf 0.74 (ethyl acetate);
1H -NMR ( CDCl3 ): δ 2.07-2.21, 2.64-2.71, 2.74-2.81, 2.94-3.01, 3.72-3.80, 4.11-4.24, 4.63, 6.22, 6.59, 6.81-6.93, 7.09-7.2 6, 7.31- 7.45, 7.51-7.60.
実施例17:N-(3-ブロモフェニル)-N-(2-オキソプロピル)ベンゼンスルホンアミド
実施例9で製造した化合物(1.00g)のDMF(6mL)溶液に、氷冷下、水素化ナトリウム(60%inミネラルオイル、141mg)を加え、室温で撹拌した。30分後、クロロアセトン(0.52mL)を加え、室温で4時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=80:20→50:50)によって精製することにより、以下の物性値を有する標題化合物(1.10g)を得た。
TLC:Rf 0.42(ヘキサン:酢酸エチル=2:1)
Example 17: N-(3-bromophenyl)-N-(2-oxopropyl)benzenesulfonamide A solution of the compound prepared in Example 9 (1.00 g) in DMF (6 mL) was hydrogenated under ice cooling. Sodium (60% in mineral oil, 141 mg) was added and stirred at room temperature. After 30 minutes, chloroacetone (0.52 mL) was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20→50:50) to obtain the title compound (1.10 g) having the following physical properties.
TLC: Rf 0.42 (hexane: ethyl acetate = 2:1)
実施例18:N-(3-ブロモフェニル)-N-(2-ヒドロキシ-2-メチルプロピル)ベンゼンスルホンアミド
実施例17で製造した化合物(313mg)のTHF(3mL)溶液に、氷冷下、メチルマグネシウムブロミド(0.95M THF溶液、1.0mL)を加え、室温で一晩撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=80:20→50:50)によって精製することにより、以下の物性値を有する標題化合物(50mg)を得た。
TLC:Rf 0.58(ヘキサン:酢酸エチル=1:1)。
Example 18: N-(3-bromophenyl)-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide A solution of the compound prepared in Example 17 (313 mg) in THF (3 mL) was added under ice cooling. Methylmagnesium bromide (0.95M THF solution, 1.0 mL) was added and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20→50:50) to obtain the title compound (50 mg) having the following physical properties.
TLC: Rf 0.58 (hexane: ethyl acetate = 1:1).
実施例19:3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル-(2-ヒドロキシ-2-メチルプロピル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに実施例18で製造した化合物を用いて、実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 1.18, 2.06-2.10, 2.58-2.62, 2.92-2.96, 3.66, 4.10, 4.18, 4.54, 6.20, 6.55, 6.87, 6.95, 6.99, 7.05, 7.17-7.21, 7.25, 7.35, 7.46-7.54, 7.60。
Example 19: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl-(2-hydroxy-2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl ] Propanoic acid Using the compound produced in Example 18 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, subjecting the same objective operation to Example 10 → Example 11. The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.93;
1H -NMR (CD 3 OD): δ 1.18, 2.06-2.10, 2.58-2.62, 2.92-2.96, 3.66, 4.10, 4.18, 4.54, 6.20, 6.55, 6.87, 6.95, 6.99, 7.05, 7.1 7-7.21, 7.25 , 7.35, 7.46-7.54, 7.60.
実施例20(1)~(4)
実施例17で使用したクロロアセトンの代わりに相当するハライド化合物を、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例17→実施例10→実施例11と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 20 (1) to (4)
Using a corresponding halide compound in place of chloroacetone used in Example 17 and a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10, Example 17 → Implementation The following example compounds were obtained by performing the same operations as in Example 10→Example 11.
実施例20(1):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(メチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.20, 4.10, 4.19, 4.55, 6.24, 6.57, 6.87, 6.93-7.00, 7.08, 7.17-7.20, 7.27, 7.36, 7.50-7.56, 7.63。
Example 20(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(methyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 0.99;
1H -NMR ( CDCl3 ): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.20, 4.10, 4.19, 4.55, 6.24, 6.57, 6.87, 6.93-7.00, 7.08, 7.17-7.20, 7.27, 7.36, 7.50-7.56, 7.63.
実施例20(2):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(エチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.01;
1H-NMR(CDCl3):δ 1.07, 2.06-2.11, 2.57-2.61, 2.92-2.96, 3.66, 4.11, 4.19, 4.55, 6.22, 6.57, 6.87, 6.92-6.96, 7.01, 7.16-7.21, 7.29, 7.39, 7.50-7.54, 7.59-7.65。
Example 20(2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(ethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 1.01;
1H -NMR ( CDCl3 ): δ 1.07, 2.06-2.11, 2.57-2.61, 2.92-2.96, 3.66, 4.11, 4.19, 4.55, 6.22, 6.57, 6.87, 6.92-6.96, 7.01, 7.16- 7.21, 7.29, 7.39, 7.50-7.54, 7.59-7.65.
実施例20(3):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(ベンジル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.07;
1H-NMR(CDCl3):δ 2.04-2.09, 2.57-2.61, 2.91-2.95, 4.08, 4.16, 4.52, 4.80, 6.14, 6.48, 6.85-6.89, 6.93-6.96, 7.14-7.28, 7.54-7.58, 7.63-7.69。
Example 20(3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(benzyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 1.07;
1H -NMR ( CDCl3 ): δ 2.04-2.09, 2.57-2.61, 2.91-2.95, 4.08, 4.16, 4.52, 4.80, 6.14, 6.48, 6.85-6.89, 6.93-6.96, 7.14-7.28, 7 .54-7.58, 7.63-7.69.
実施例20(4):3-[2-[(E,3R)-5-[3-[ベンゼンスルホニル(2,2,2-トリフルオロエチル)アミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.49(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.08-2.17, 2.62-2.70, 2.94-3.00, 4.11-4.26, 4.62, 6.21, 6.57, 6.83-6.93, 7.10, 7.17-7.25, 7.36, 7.47, 7.57-7.63。
Example 20 (4): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2,2,2-trifluoroethyl)amino]phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoic acid TLC: Rf 0.49 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 2.08-2.17, 2.62-2.70, 2.94-3.00, 4.11-4.26, 4.62, 6.21, 6.57, 6.83-6.93, 7.10, 7.17-7.25, 7.36, 7.47, 7 .57-7.63.
実施例21:(R)-1-(3-ブロモフェニル)-2-フェニルエタン-1-オール
1-(3-ブロモフェニル)-2-フェニルエタノン(CAS登録番号:40396-53-0)(2.00g)のTHF(70mL)溶液に、-20℃で(R)-メチルオキサザボロリジン(1.0Mトルエン溶液、3.6mL)およびボランジメチルスルフィド(2.0M THF溶液、3.6mL)を加え、同温で1時間撹拌した。反応溶液に-20℃でメタノール(1mL)を加え、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(1.91g、96%ee)を得た。得られた化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IA(10mm×250mm)、移動相:CO2:アセトニトリル:メタノール=90:9:1、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)で分析した結果、保持時間は5.6分であった。
HPLC保持時間(分):1.08。
Example 21: (R)-1-(3-bromophenyl)-2-phenylethan-1-ol 1-(3-bromophenyl)-2-phenylethanone (CAS registration number: 40396-53-0) (2.00 g) in THF (70 mL) at -20°C were (R)-methyloxazaborolidine (1.0 M toluene solution, 3.6 mL) and borane dimethyl sulfide (2.0 M THF solution, 3. 6 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hour. Methanol (1 mL) was added to the reaction solution at -20°C, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→2:1) to obtain the title compound (1.91 g, 96% ee) having the following physical properties. The obtained compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IA (10 mm x 250 mm), mobile phase: CO 2 : acetonitrile: methanol = 90:9:1, flow rate: 30 mL/min, pressure: 100 bar, wavelength: As a result of analysis at 220 nm (column temperature: 35° C.), the retention time was 5.6 minutes.
HPLC retention time (min): 1.08.
実施例22:イソプロピル 3-(2-(((R,E)-3-ヒドロキシ-5-(3-((R)-1-ヒドロキシ-2-フェニルエチル)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに実施例21で製造した化合物を用いて、実施例10と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.21。
Example 22: Isopropyl 3-(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-ene-1 -yl)oxy)phenyl)propanoate The same procedure as in Example 10 was carried out using the compound prepared in Example 21 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. As a result, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.21.
実施例23:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例22で製造した化合物を用いて、実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.28, 6.62, 6.86, 6.94, 7.10-7.31。
Example 23: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid Propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 By using the compound produced in Example 22 instead and subjecting it to the same objective operations as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
1H -NMR ( CD3OD ): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.28, 6.62, 6.86, 6.94, 7.10-7.31.
実施例24:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例21で使用した(R)-メチルオキサザボロリジンの代わりに(S)-メチルオキサザボロリジンを、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例21→実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.61, 6.86, 6.94, 7.10-7.31。
Example 24: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid: (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine used in Example 21, and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. Using the corresponding halide compound, the title compound having the following physical properties was obtained by performing the same operations as in Example 21 → Example 10 → Example 11.
HPLC retention time (min): 0.97;
1H -NMR ( CD3OD ): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.61, 6.86, 6.94, 7.10-7.31.
実施例25:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(2R)-2-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例21で使用した1-(3-ブロモフェニル)-2-フェニルエタノンの代わりに2-(3-ブロモフェニル)-1-フェニルエタノン(CAS登録番号:27798-44-3)を、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例21→実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 2.10-2.15, 2.64-2.68, 2.94-3.05, 4.10-4.21, 4.59-4.64, 4.92, 6.27, 6.61, 6.86-6.91, 7.05-7.24, 7.27-7.37。
Example 25: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2R)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid 2-(3-bromophenyl)-1-phenylethanone (CAS registration number: 27798-44-3) was used instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21. , by using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, and performing the same operation as in Example 21 → Example 10 → Example 11. , the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.99;
1H -NMR ( CDCl3 ): δ 2.10-2.15, 2.64-2.68, 2.94-3.05, 4.10-4.21, 4.59-4.64, 4.92, 6.27, 6.61, 6.86-6.91, 7.05-7.24, 7.27-7.3 7.
実施例26:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(2S)-2-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例25で使用した(R)-メチルオキサザボロリジンの代わりに(S)-メチルオキサザボロリジンを、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例25と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.98;
1H-NMR(CDCl3):δ 2.10-2.15, 2.63-2.67, 2.94-3.05, 4.10-4.22, 4.59-4.64, 4.91, 6.27, 6.61, 6.86-6.91, 7.06-7.08, 7.14-7.24, 7.28-7.38。
Example 26: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2S)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid: (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine used in Example 25, and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The title compound having the following physical properties was obtained by carrying out the same operations as in Example 25 using the corresponding halide compound.
HPLC retention time (min): 0.98;
1H -NMR ( CDCl3 ): δ 2.10-2.15, 2.63-2.67, 2.94-3.05, 4.10-4.22, 4.59-4.64, 4.91, 6.27, 6.61, 6.86-6.91, 7.06-7.08, 7.14-7.2 4, 7.28- 7.38.
実施例27:1-(3-ブロモフェニル)-3-フェニルプロパン-1-オール
3-ブロモベンズアルデヒド(500mg)のTHF(13.5mL)溶液を、0℃に冷却し、フェニルマグネシウムクロリド(1.0M THF溶液、3.5mL)を加え、反応混合物を0℃で30分間撹拌した。反応混合物を飽和塩化アンモニウム溶液に注ぎ、メチル-tert-ブチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→2:1)によって精製することにより、以下の物性値を有する標題化合物(610mg)を得た。
1H-NMR(CDCl3):δ 1.85, 1.98-2.15, 2.65-2.80, 4.65-4.69, 7.18-7.31, 7.39-7.42, 7.51。
Example 27: 1-(3-bromophenyl)-3-phenylpropan-1-ol A solution of 3-bromobenzaldehyde (500 mg) in THF (13.5 mL) was cooled to 0° C., and phenylmagnesium chloride (1. 0M THF solution, 3.5 mL) was added and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into saturated ammonium chloride solution and extracted with methyl-tert-butyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→2:1) to obtain the title compound (610 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.85, 1.98-2.15, 2.65-2.80, 4.65-4.69, 7.18-7.31, 7.39-7.42, 7.51.
実施例28:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(1-ヒドロキシ-3-フェニルプロピル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに実施例27で製造した化合物を用いて、実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.82-2.03, 2.36-2.40, 2.47-2.63, 2.81-2.85, 3.96-4.09, 4.46-4.51, 6.22, 6.54, 6.69-6.79, 6.98-7.29。
Example 28: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-3-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Example 10 By using the compound produced in Example 27 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and performing the same operations as in Example 10 → Example 11, the following physical property values were obtained. The title compound was obtained.
HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 1.82-2.03, 2.36-2.40, 2.47-2.63, 2.81-2.85, 3.96-4.09, 4.46-4.51, 6.22, 6.54, 6.69-6.79, 6.98-7.29.
実施例29:1-(3-ブロモフェニル)-2-メチル-2-フェニルプロパン-1-オール
1-(3-ブロモフェニル)-2-フェニル-エタノン(CAS登録番号:40396-53-0)(220mg)のトルエン(0.4mL)溶液に、水酸化カリウム(179mg)および18-クラウン-6-エーテル(4mg)およびヨウ化メチル(0.29mL)を加え、反応混合物を70℃で4時間撹拌した。反応混合物に水を加え、2-メトキシ-2-メチルプロパンで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さのメタノール(1.5mL)溶液に、水素化ホウ素ナトリウム(61mg)を加え、反応混合物を室温で1時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1)によって精製することにより、以下の物性値を有する標題化合物(129mg)を得た。
HPLC保持時間(分):1.15(条件)。
Example 29: 1-(3-bromophenyl)-2-methyl-2-phenylpropan-1-ol 1-(3-bromophenyl)-2-phenyl-ethanone (CAS registration number: 40396-53-0) (220 mg) in toluene (0.4 mL) were added potassium hydroxide (179 mg), 18-crown-6-ether (4 mg) and methyl iodide (0.29 mL), and the reaction mixture was heated at 70°C for 4 hours. Stirred. Water was added to the reaction mixture, and the mixture was extracted with 2-methoxy-2-methylpropane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Sodium borohydride (61 mg) was added to a solution of the obtained residue in methanol (1.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the title compound (129 mg) having the following physical properties.
HPLC retention time (min): 1.15 (conditions).
実施例30:3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(1-ヒドロキシ-2-メチル-2-フェニルプロピル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに、実施例29で製造した化合物を用いて、実施例10→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 2.08-2.13, 2.64-2.68, 2.94-2.97, 4.08-4.21, 4.59, 4.75, 6.15, 6.56, 6.86-6.91, 6.97-7.00, 7.09, 7.15-7.25, 7.30-7.38。
Example 30: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-methyl-2-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propane Acid By using the compound produced in Example 29 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, and subjecting the operation to the same purpose as in Example 10 → Example 11. , the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 2.08-2.13, 2.64-2.68, 2.94-2.97, 4.08-4.21, 4.59, 4.75, 6.15, 6.56, 6.86-6.91, 6.97-7.00, 7.09, 7.15-7. 25, 7.30- 7.38.
実施例31:3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパンアミド
実施例11で製造した化合物(50mg)のTHF(1mL)溶液に、氷冷下、トリエチルアミン(0.021mL)とイソブチルクロロホルマート(0.016mL)を加え、反応混合物を0℃で10分間撹拌した。アンモニア(0.5M 1,4-ジオキサン溶液、0.4mL)を0℃で加え,室温で30分間撹拌した。反応混合物を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1→0:1)によって精製することにより、以下の物性値を有する標題化合物(38mg)を得た。
HPLC保持時間(分):0.88;
1H-NMR(CDCl3):δ 2.09-2.21, 2.54-2.63, 3.01, 4.13-4.23, 4.59, 5.70, 6.36, 6.54, 6.87-6.94, 7.00-7.22, 7.40-7.53, 7.79-7.82, 7.93。
Example 31: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanamide Compound prepared in Example 11 ( Triethylamine (0.021 mL) and isobutyl chloroformate (0.016 mL) were added to a solution of 50 mg) in THF (1 mL) under ice cooling, and the reaction mixture was stirred at 0° C. for 10 minutes. Ammonia (0.5M 1,4-dioxane solution, 0.4 mL) was added at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1:1 → 0:1) to obtain the title compound (38 mg) having the following physical properties. .
HPLC retention time (min): 0.88;
1H -NMR ( CDCl3 ): δ 2.09-2.21, 2.54-2.63, 3.01, 4.13-4.23, 4.59, 5.70, 6.36, 6.54, 6.87-6.94, 7.00-7.22, 7.40-7.53, 7.79-7. 82, 7.93.
実施例32(1)~(3)
実施例31で使用したアンモニアの代わりに相当するアミン化合物を用いて、実施例31と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 32 (1) to (3)
The following example compounds were obtained by carrying out the same operations as in Example 31 using the corresponding amine compound instead of ammonia used in Example 31.
実施例32(1):N-[3-[(E,3R)-3-ヒドロキシ-5-[2-(3-モルホリン-4-イル-3-オキソプロピル)フェノキシ]ペンタ-1-エニル]フェニル]ベンゼンスルホンアミド
HPLC保持時間(分):0.94;
1H-NMR(CDCl3):δ 2.09-2.19, 2.60-2.65, 2.92-2.99, 3.41, 3.50-3.70, 4.09-4.23, 4.57, 6.30, 6.52, 6.85-6.91, 7.02-7.20, 7.40-7.56, 7.78-7.81。
Example 32 (1): N-[3-[(E,3R)-3-hydroxy-5-[2-(3-morpholin-4-yl-3-oxopropyl)phenoxy]pent-1-enyl] phenyl]benzenesulfonamide HPLC retention time (min): 0.94;
1H -NMR ( CDCl3 ): δ 2.09-2.19, 2.60-2.65, 2.92-2.99, 3.41, 3.50-3.70, 4.09-4.23, 4.57, 6.30, 6.52, 6.85-6.91, 7.02-7.20, 7. 40-7.56, 7.78-7.81.
実施例32(2):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-N,N-ジメチルプロパンアミド
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 2.09-2.19, 2.60-2.65, 2.86-3.03, 4.09-4.22, 4.55, 6.33, 6.51, 6.84-6.91, 6.98-7.00, 7.12-7.20, 7.23-7.26, 7.40-7.52, 7.78-7.83, 7.98。
Example 32 (2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N,N-dimethylpropane Amide HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 2.09-2.19, 2.60-2.65, 2.86-3.03, 4.09-4.22, 4.55, 6.33, 6.51, 6.84-6.91, 6.98-7.00, 7.12-7.20, 7.23-7.2 6, 7.40- 7.52, 7.78-7.83, 7.98.
実施例32(3):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-N-メチルプロパンアミド
HPLC保持時間(分):0.90;
1H-NMR(CDCl3):δ 2.07-2.19, 2.41-2.53, 2.82, 2.93-2.97, 4.10-4.22, 4.60, 5.58, 6.31, 6.54, 6.86-6.90, 7.02-7.20, 7.40-7.54, 7.78。
Example 32 (3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N-methylpropanamide HPLC Retention time (min): 0.90;
1H -NMR ( CDCl3 ): δ 2.07-2.19, 2.41-2.53, 2.82, 2.93-2.97, 4.10-4.22, 4.60, 5.58, 6.31, 6.54, 6.86-6.90, 7.02-7.20, 7.40-7. 54, 7.78.
実施例33:3-[2-[(3S)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸 Example 33: 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid
実施例11で製造した化合物(1.1g)のメタノール(10mL)溶液に、5%パラジウム-炭素(200mg)を加え、水素雰囲気下、室温で1時間撹拌した。反応溶液を濾過した後、濾液を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=70:30→酢酸エチル:メタノール=95:5)によって精製することにより、以下の物性値を有する標題化合物(1.05g)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76。
To a solution of the compound prepared in Example 11 (1.1 g) in methanol (10 mL) was added 5% palladium-carbon (200 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 → ethyl acetate: methanol = 95:5) to obtain the following physical properties. The title compound (1.05g) was obtained.
TLC: Rf 0.30 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.
実施例34:3-[2-[(3S)-5-[3-(ベンジルアミノ)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例12(6)で製造した化合物を用いて、実施例33と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
HPLC保持時間(分):0.81;
1H-NMR(CD3OD):δ 1.74-1.90, 2.00, 2.51-2.55, 2.59, 2.70, 2.85-2.89, 3.85, 4.07-4.16, 4.31, 6.47-6.56, 6.85, 6.92, 7.00, 7.13-7.23, 7.28-7.32, 7.36-7.38。
Example 34: 3-[2-[(3S)-5-[3-(benzylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid 3-[2-[(E ,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid using the compound prepared in Example 12(6), Example 33 The following example compounds were obtained by performing the same operations as above.
HPLC retention time (min): 0.81;
1H -NMR (CD 3 OD): δ 1.74-1.90, 2.00, 2.51-2.55, 2.59, 2.70, 2.85-2.89, 3.85, 4.07-4.16, 4.31, 6.47-6.56, 6.85, 6.92, 7.00, 7.13-7.23 , 7.28-7.32, 7.36-7.38.
実施例35:イソプロピル 3-(2-(((S)-3-ヒドロキシ-5-(3-((R)-1-ヒドロキシ-2-フェニルエチル)フェニル)ペンチル)オキシ)フェニル)プロパノエート
実施例22で製造した化合物(782mg)のTHF(10mL)溶液に、室温でp-トルエンスルホニルヒドラジド(2.66g)と酢酸ナトリウム(1.17g)を加え、80℃で19時間撹拌した。反応溶液を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→1:1)によって精製することにより、以下の物性値を有する標題化合物(515mg)を得た。
HPLC保持時間(分):1.22。
Example 35: Isopropyl 3-(2-(((S)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pentyl)oxy)phenyl)propanoate Example To a solution of the compound prepared in 22 (782 mg) in THF (10 mL) were added p-toluenesulfonyl hydrazide (2.66 g) and sodium acetate (1.17 g) at room temperature, and the mixture was stirred at 80° C. for 19 hours. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3→1:1) to obtain the title compound (515 mg) having the following physical properties.
HPLC retention time (min): 1.22.
実施例36:3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸 Example 36: 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例35で製造した化合物を用いて、実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.99;
1H-NMR(CD3OD):δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.82, 6.85, 6.94, 7.08-7.23。
Substitute for propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 The compound prepared in Example 35 was subjected to the same operations as in Example 11 to obtain the title compound having the following physical properties.
HPLC retention time (min): 0.99;
1H -NMR (CD 3 OD): δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.82, 6.85, 6.94 , 7.08-7.23 .
実施例37:3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸 Example 37: 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid
実施例21で使用した(R)-メチルオキサザボロリジンの代わりに(S)-メチルオキサザボロリジンを、実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例21→実施例10→実施例35→実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.99;
1H-NMR(CD3OD):δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.81, 6.85, 6.94, 7.08-7.23。
Corresponding to (S)-methyloxazaborolidine in place of (R)-methyloxazaborolidine used in Example 21 and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. Using the halide compound, the title compound having the following physical properties was obtained by performing the same operations as in Example 21 → Example 10 → Example 35 → Example 11.
HPLC retention time (min): 0.99;
1H -NMR (CD 3 OD): δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.81, 6.85, 6.94 , 7.08-7.23 .
実施例38:イソプロピル 3-(2-((3R)-3-ヒドロキシ-3-(2-(3-(フェニルスルホンアミド)フェニル)シクロプロピル)プロポキシ)フェニル)プロパノエート
実施例10で製造した化合物(50mg)のジクロロメタン(2mL)溶液を0℃に冷却し、ジエチル亜鉛(1Mヘキサン溶液、0.5mL)を加え、続けてジヨードメタン(128mg)を加え、得られた反応混合物を0℃で1時間半撹拌した。飽和塩化アンモニウム水溶液を0℃で加え、室温で5分間撹拌した。反応混合物を水にあけ、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→2:1)によって精製することにより、以下の物性値を有する標題化合物(15mg)を得た。
HPLC保持時間(分):1.10。
Example 38: Isopropyl 3-(2-((3R)-3-hydroxy-3-(2-(3-(phenylsulfonamido)phenyl)cyclopropyl)propoxy)phenyl)propanoate Compound prepared in Example 10 ( A solution of 50 mg) in dichloromethane (2 mL) was cooled to 0°C, diethylzinc (1M solution in hexane, 0.5 mL) was added, followed by diiodomethane (128 mg), and the resulting reaction mixture was incubated at 0°C for 1.5 hours. Stirred. A saturated aqueous ammonium chloride solution was added at 0°C, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→2:1) to obtain the title compound (15 mg) having the following physical properties.
HPLC retention time (min): 1.10.
実施例39: 3-[2-[(3R)-3-[2-[3-(ベンゼンスルホンアミド)フェニル]シクロプロピル]-3-ヒドロキシプロポキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例38で製造した化合物を用いて、実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.92;
1H-NMR(CD3OD):δ 0.85-0.92, 1.03-1.08, 1.72-1.75, 2.03-2.09, 2.57, 2.91, 4.06-4.15, 6.68-6.69, 6.73-6.75, 6.84-6.89, 7.06, 7.14-7.20, 7.44-7.57, 7.72-7.74。
Example 39: 3-[2-[(3R)-3-[2-[3-(benzenesulfonamido)phenyl]cyclopropyl]-3-hydroxypropoxy]phenyl]propanoic acid Propane used in Example 11- Compound prepared in Example 38 in place of 2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by carrying out the same operations as in Example 11.
HPLC retention time (min): 0.92;
1H -NMR ( CD3OD ): δ 0.85-0.92, 1.03-1.08, 1.72-1.75, 2.03-2.09, 2.57, 2.91, 4.06-4.15, 6.68-6.69, 6.73-6.75, 6.84-6.89, 7. 06, 7.14 -7.20, 7.44-7.57, 7.72-7.74.
実施例40:5-((3-ニトロベンジル)スルホニル)-1-フェニル-1H-テトラゾール
5-[(3-ニトロベンジル)チオ]-1-フェニル-1H-テトラゾール[J.Org.Chem.(2001),80,pp.11611-11617](8.50g)のアセトニトリル(150mL)とエタノール(150mL)溶液を0℃に冷却し、モリブデン酸アンモニウム四水和物(3.35g)の過酸化水素水溶液(35%、26mL)を10分間かけて滴下した。反応混合物を0℃で2時間,室温で2時間半撹拌した。反応液を再び0℃に冷却し、チオ硫酸ナトリウム水溶液(1M、150mL)を20分間かけてゆっくりと加た。減圧濃縮し,残さを酢酸エチルで抽出し、有機層を飽和食塩水で洗浄、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた油状物をヘキサンと酢酸エチルの混合溶媒に懸濁させ、青色固体を濾取した.固体をジクロロメタンに溶解させ、生じる固体をろ過し、ろ液を減圧濃縮し、以下の物性値を有する標題化合物(7.71g)を得た。
1H-NMR(CDCl3):δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35。
Example 40: 5-((3-nitrobenzyl)sulfonyl)-1-phenyl-1H-tetrazole 5-[(3-nitrobenzyl)thio]-1-phenyl-1H-tetrazole [J. Org. Chem. (2001), 80, pp. A solution of 11611-11617] (8.50 g) in acetonitrile (150 mL) and ethanol (150 mL) was cooled to 0°C, and a solution of ammonium molybdate tetrahydrate (3.35 g) in hydrogen peroxide (35%, 26 mL) was added. was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 2.5 hours. The reaction solution was again cooled to 0° C., and an aqueous sodium thiosulfate solution (1M, 150 mL) was slowly added over 20 minutes. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained oil was suspended in a mixed solvent of hexane and ethyl acetate, and the blue solid was collected by filtration. The solid was dissolved in dichloromethane, the resulting solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.71 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35.
実施例41:(R)-1-((tert-ブチルジメチルシリル)オキシ)-4-((4-メトキシベンジル)オキシ)ブタン-2-オール
(R)-4-[(4-メトキシベンジル)オキシ]ブタン-1,2-ジオール(CAS登録番号:213978-61-1)(13.5g)のDMF(300mL)溶液に、DMAP(0.73g)およびイミダゾール(6.08g)を加え、反応混合物を0℃で5分間撹拌した。クロロ-tert-ブチル-ジメチルシラン(8.93g)を加え,室温で終夜撹拌した。反応液に酢酸エチルを加え希釈した後、有機層を飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(18.1g)を得た。
1H-NMR(CDCl3):δ 0.02, 0.83, 1.65-1.71, 2.73, 3.62-3.41, 3.74, 3.74-3.76, 4.39, 6.82, 7.18-7.21。
Example 41: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-ol (R)-4-[(4-methoxybenzyl) DMAP (0.73 g) and imidazole (6.08 g) were added to a solution of DMF (300 mL) of oxy]butane-1,2-diol (CAS registration number: 213978-61-1) (13.5 g), and reaction was started. The mixture was stirred at 0°C for 5 minutes. Chloro-tert-butyl-dimethylsilane (8.93 g) was added, and the mixture was stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate, the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (18.1 g) having the following physical properties. I got it.
1H -NMR ( CDCl3 ): δ 0.02, 0.83, 1.65-1.71, 2.73, 3.62-3.41, 3.74, 3.74-3.76, 4.39, 6.82, 7.18-7.21.
実施例42:(R)-1-((tert-ブチルジメチルシリル)オキシ)-4-((4-メトキシベンジル)オキシ)ブタン-2-イル ベンゾエート
実施例41で製造した化合物(5.60g)とピリジン(27mL)のジクロロメタン(55mL)溶液を0℃に冷却し、N,N-ジイソプロピルエチルアミン(27mL)とDMAP(0.2g)を加えた。反応溶液にベンジルクロリド(2.5mL)を加え、室温で終夜撹拌した後、減圧濃縮した。得られた残さを酢酸エチルにあけ、有機層を1M塩酸,飽和炭酸水素ナトリウム水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→7:3)によって精製することにより、下の物性値を有する標題化合物(6.31g)を得た。
1H-NMR(CDCl3):δ 0.00, 0.01, 0.85, 2.02-2.08, 3.53-3.57, 3.76, 3.79, 4.40, 5.27-5.30, 6.81, 7.21, 7.42, 7.53-7.56, 8.01。
Example 42: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate Compound prepared in Example 41 (5.60 g) and pyridine (27 mL) in dichloromethane (55 mL) was cooled to 0° C., and N,N-diisopropylethylamine (27 mL) and DMAP (0.2 g) were added. Benzyl chloride (2.5 mL) was added to the reaction solution, stirred at room temperature overnight, and then concentrated under reduced pressure. The obtained residue was poured into ethyl acetate, and the organic layer was washed with 1M hydrochloric acid and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→7:3) to obtain the title compound (6.31 g) having the physical properties shown below.
1 H-NMR (CDCL 3 ): δ 0.00, 0.01, 0.85, 2.02-2.08, 3.53-3.57, 3.53-3.57, 3.76, 4.40, 5.27-5.30, 5.27-5.30, 6.81, 7.42, 7.53-7.56, 8.01.
実施例43:(R)-1-ヒドロキシ-4-((4-メトキシベンジル)オキシ)ブタン-2-イル ベンゾエート
実施例42で製造した化合物(6.31g)のTHF(170mL)溶液を0℃に冷却し、酢酸(3.6mL)とテトラブチルアンモニウムフルオリド(1.0M THF溶液、21.2mL)を加え、室温で終夜撹拌した。得られた残さを酢酸エチルにあけ、有機層を飽和アンモニア水,飽和炭酸水素ナトリウム水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、下の物性値を有する標題化合物(4.10g)を得た。
1H-NMR(CDCl3):δ 2.06-2.09, 2.57, 3.54-3.65, 3.78, 3.80-3.86, 4.41-4.46, 5.27-5.30, 6.84, 7.23, 7.43, 7.56, 8.02。
Example 43: (R)-1-hydroxy-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate A solution of the compound prepared in Example 42 (6.31 g) in THF (170 mL) was heated at 0°C. Acetic acid (3.6 mL) and tetrabutylammonium fluoride (1.0 M THF solution, 21.2 mL) were added, and the mixture was stirred at room temperature overnight. The obtained residue was poured into ethyl acetate, and the organic layer was washed with saturated aqueous ammonia and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:1) to obtain the title compound (4.10 g) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 2.06-2.09, 2.57, 3.54-3.65, 3.78, 3.80-3.86, 4.41-4.46, 5.27-5.30, 6.84, 7.23, 7.43, 7.56, 8.02.
実施例44:(R)-4-((4-メトキシベンジル)オキシ)-1-オキソブタン-2-イル ベンゾエート
二クロム酸ピリジニウム(10.6g)とモレキュラーシーブ(商品名)(21.7g)をジクロロメタン(30mL)に懸濁させ、その溶液に実施例43で製造した化合物(3.1 g)のジクロロメタン溶液(100mL)を滴下した。室温で2時間半撹拌した後、ジエチルエーテルで希釈し、ろ過した。ろ液を減圧濃縮し、以下の物性値を有する標題化合物を得た。
1H-NMR(CDCl3):δ 2.27-2.40, 3.57-3.70, 3.76, 4.43, 5.40, 6.82, 7.15-7.24, 7.45, 7.60, 8.03, 9.64。
Example 44: (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-yl benzoate Pyridinium dichromate (10.6 g) and Molecular Sieve (trade name) (21.7 g) It was suspended in dichloromethane (30 mL), and a dichloromethane solution (100 mL) of the compound prepared in Example 43 (3.1 g) was added dropwise to the solution. After stirring at room temperature for 2.5 hours, the mixture was diluted with diethyl ether and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound having the following physical properties.
1H -NMR ( CDCl3 ): δ 2.27-2.40, 3.57-3.70, 3.76, 4.43, 5.40, 6.82, 7.15-7.24, 7.45, 7.60, 8.03, 9.64.
実施例45:(R,E)-5-((4-メトキシベンジル)オキシ)-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエート
実施例40で製造した化合物(3.56g)のTHF(70mL)溶液を-70℃に冷却し、カリウムヘキサメチルジシラジド(0.5Mトルエン溶液、22.5mL)を加えた。反応液を-70℃で30分間撹拌し、実施例44で製造した化合物(3.09g)のTHF(20mL)溶液を5分かけて滴下し、反応溶液を室温で終夜撹拌した。反応液に酢酸エチルを加え希釈した後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、以下の物性値を有する標題化合物(2.23g)を得た。
1H-NMR(CDCl3):δ 2.11-2.24, 3.60, 3.75, 6.81, 7.22, 7.43-7.47, 7.56-7.63, 8.04-8.09, 8.21。
Example 45: (R,E)-5-((4-methoxybenzyl)oxy)-1-(3-nitrophenyl)pent-1-en-3-yl benzoate Compound prepared in Example 40 (3. A solution of 56 g) in THF (70 mL) was cooled to -70°C, and potassium hexamethyldisilazide (0.5M solution in toluene, 22.5 mL) was added. The reaction solution was stirred at −70° C. for 30 minutes, a solution of the compound prepared in Example 44 (3.09 g) in THF (20 mL) was added dropwise over 5 minutes, and the reaction solution was stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:0). →1:1) to obtain the title compound (2.23 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 2.11-2.24, 3.60, 3.75, 6.81, 7.22, 7.43-7.47, 7.56-7.63, 8.04-8.09, 8.21.
実施例46:(R,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエート、または(S,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエート
実施例45で製造した化合物(2.23g)のジクロロメタン(100mL)とリン酸バッファー(pH7,100mL)溶液に、室温で2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(2.26g)を加え、室温で3時間半激しく撹拌した。反応混合物を酢酸エチルにあけ、有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:4)によって精製することにより、標題化合物の混合物(1.25g)を得た。得られた混合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IA(20mm×250mm)、移動相:CO2:メタノール=90:10、流速:100mL/min、圧力:120bar、波長:254nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IA(10mm×250mm)、移動相:CO2:アセトニトリル:メタノール=75:22.5:2.5、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)で分析した結果、(R,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートおよび(S,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートの保持時間はそれぞれ5.4分および8.5分であった。
1H-NMR(CDCl3):δ 2.04, 2.10-2.14, 3.77-3.82, 5.92-5.95, 6.47, 6.79, 7.46-7.51, 7.60, 7.68, 8.08-8.12, 8.26。
Example 46: (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate, or (S,E)-5-hydroxy-1-(3-nitrophenyl) Phenyl)pent-1-en-3-
1H -NMR ( CDCl3 ): δ 2.04, 2.10-2.14, 3.77-3.82, 5.92-5.95, 6.47, 6.79, 7.46-7.51, 7.60, 7.68, 8.08-8.12, 8.26.
実施例47:メチル 2-(2-ヒドロキシフェニル)-2-メチルプロパノエート
メチル 2-(2-ヒドロキシフェニル)アセテート(CAS登録番号:22446-37-3)(1.5g)のTHF(120mL)溶液に、-78℃でリチウム ジイソプロピルアミド(2.0M THF溶液、18mL)を加え、同温で1.5時間撹拌した。反応溶液に、-78℃でヨウ化メチル(5.2g)を加え、室温で30分間撹拌した。反応溶液に水(40mL)と酢酸(1mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥し、減圧濃縮した。得られた残さ(1.8g)をTHF(150mL)に溶解後、-78℃でリチウム ジイソプロピルアミド(2.0M THF溶液、10mL)を加え、同温で1.5時間撹拌した。反応溶液に、-78℃でヨウ化メチル(2.85g)を加え、室温で30分間撹拌した。反応溶液に水(40mL)と酢酸(1mL)を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥し、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル=7:1)によって精製することにより、以下の物性値を有する標題化合物(538mg)を得た。
1H-NMR(DMSO-d6):δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49。
Example 47: Methyl 2-(2-hydroxyphenyl)-2-methylpropanoate Methyl 2-(2-hydroxyphenyl) acetate (CAS registration number: 22446-37-3) (1.5 g) in THF (120 mL) ) Lithium diisopropylamide (2.0M THF solution, 18 mL) was added to the solution at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (5.2 g) was added to the reaction solution at -78°C, and the mixture was stirred at room temperature for 30 minutes. Water (40 mL) and acetic acid (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the obtained residue (1.8 g) in THF (150 mL), lithium diisopropylamide (2.0 M THF solution, 10 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (2.85 g) was added to the reaction solution at -78°C, and the mixture was stirred at room temperature for 30 minutes. Water (40 mL) and acetic acid (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1) to obtain the title compound (538 mg) having the following physical properties.
1H -NMR (DMSO- d6 ): δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49.
実施例48:メチル 1-(2-ヒドロキシベンジル)シクロプロパン-1-カルボキシレート
シクロプロピルカルボニトリル(CAS登録番号:5500-21-0)(3.35g)のTHF(50mL)溶液に、室温でナトリウムビス(トリメチルシリル)アミド(1.0M THF溶液、75mL)を加え、20分間撹拌した。反応溶液に、室温で1-(クロロメチル)-2-メトキシベンゼン(CAS登録番号:7035-02-1)(7.83g)を加え、加熱還流下3時間撹拌した。室温まで冷却後、反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル=10:1)によって精製することにより、ニトリル化合物の粗生成物(6.00g)を得た。得られたニトリル化合物の粗生成物(4.50g)のメタノール(50mL)溶液に、室温で濃硫酸(20mL)を加え、加熱還流下5時間撹拌した。反応溶液を室温まで冷却後、減圧濃縮した。得られた残さに氷水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮することによりエステル化合物の粗生成物(3.20g)を得た。得られたエステル化合物の粗生成物(2.00g)のジクロロメタン(30mL)溶液に、-10℃で三臭化ホウ素(1.0Mジクロロメタン溶液、18.2mL)を滴下し、室温で1時間撹拌した。反応溶液を減圧濃縮後、得られた残さを高速液体クロマトグラフィー(移動相A(0.1%トリフルオロ酢酸(以下、TFAと略記)水溶液):移動相B(0.1%TFA/アセトニトリル)=95:5→5:95)にて分取精製することにより、以下の物性値を有する標題化合物(550mg)を得た。
1H-NMR(CDCl3):δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45。
Example 48: Methyl 1-(2-hydroxybenzyl)cyclopropane-1-carboxylate A solution of cyclopropylcarbonitrile (CAS Registration Number: 5500-21-0) (3.35 g) in THF (50 mL) at room temperature. Sodium bis(trimethylsilyl)amide (1.0 M THF solution, 75 mL) was added and stirred for 20 minutes. 1-(chloromethyl)-2-methoxybenzene (CAS registration number: 7035-02-1) (7.83 g) was added to the reaction solution at room temperature, and the mixture was stirred under heating under reflux for 3 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a crude product (6.00 g) of a nitrile compound. To a solution of the obtained crude nitrile compound (4.50 g) in methanol (50 mL) was added concentrated sulfuric acid (20 mL) at room temperature, and the mixture was stirred under heating under reflux for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure. Ice water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude ester compound (3.20 g). Boron tribromide (1.0 M dichloromethane solution, 18.2 mL) was added dropwise to a solution of the obtained crude ester compound (2.00 g) in dichloromethane (30 mL) at -10°C, and the mixture was stirred at room temperature for 1 hour. did. After concentrating the reaction solution under reduced pressure, the resulting residue was subjected to high performance liquid chromatography (mobile phase A (0.1% trifluoroacetic acid (hereinafter abbreviated as TFA) aqueous solution): mobile phase B (0.1% TFA/acetonitrile). =95:5→5:95) to obtain the title compound (550 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45.
実施例49:メチル 4-(2-ヒドロキシフェニル)-2,2-ジメチルブタノエート
メチル 4-(2-ヒドロキシフェニル)ブタノエート(CAS登録番号:93108-07-7)(3.00g)のTHF(150mL)溶液に、-78℃でリチウム ジイソプロピルアミド溶液(2.0M THF溶液、22.5mL)を加え、同温で30分間撹拌した。反応溶液に、-78℃でヨウ化メチル(6.3g)を加え、室温で2時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さを高速液体クロマトグラフィー(移動相A(0.1%TFA水溶液):移動相B(0.1%TFA/アセトニトリル)=95:5→5:95)にて分取精製することにより、以下の物性値を有する標題化合物(538mg)を得た。
1H-NMR(DMSO-d6):δ 1.17, 1.67-1.73, 2.38-2.43, 3.59, 6.66-6.76, 6.95-7.00, 9.19。
Example 49: Methyl 4-(2-hydroxyphenyl)-2,2-dimethylbutanoate Methyl 4-(2-hydroxyphenyl)butanoate (CAS registration number: 93108-07-7) (3.00 g) in THF A lithium diisopropylamide solution (2.0 M THF solution, 22.5 mL) was added to the solution (150 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (6.3 g) was added to the reaction solution at -78°C, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution): mobile phase B (0.1% TFA/acetonitrile) = 95:5 → 5:95). The title compound (538 mg) having the following physical property values was obtained.
1H -NMR (DMSO- d6 ): δ 1.17, 1.67-1.73, 2.38-2.43, 3.59, 6.66-6.76, 6.95-7.00, 9.19.
実施例50:メチル 1-(2-メトキシフェネチル)シクロプロパン-1-カルボキシレート
ビス(シクロペンタジエニル)チタン(IV)ジクロリド(CAS登録番号:1271-19-8)(34.6g)のTHF(200mL)溶液に、室温で亜鉛(18.2g)を加え、同温で1時間撹拌した。反応溶液に、室温でメチル 2-(1-アセトキシメチル)-2-プロペノエート(CAS登録番号:30982-08-2)(11.0g)と1-(クロロメチル)-2-メトキシベンゼン(CAS登録番号:7035-02-1)(10.9g)のTHF(200mL)溶液を加え、同温で終夜撹拌した。反応溶液に水を加え、ジエチルエーテルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル=5:1→2:1)によって精製することにより、エステル化合物の粗生成物(13.0g)を得た。得られたエステル化合物(3.00g)の粗生成物のジエチルエーテル(100mL)溶液に、氷冷下酢酸パラジウム(II)とジアゾメタン(0.5Mジエチルエーテル溶液、32.6mL)を加え、室温で4時間撹拌した。反応溶液に酢酸(4mL)と水を加え、ジエチルエーテルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮することにより、以下の物性値を有する標題化合物(3.00g)を得た。
1H-NMR(DMSO-d6):δ 0.70, 1.21, 1.76-1.88, 2.76-2.87, 3.70, 3.83, 6.80-6.96, 7.11-7.32。
Example 50: Methyl 1-(2-methoxyphenethyl)cyclopropane-1-carboxylate bis(cyclopentadienyl)titanium(IV) dichloride (CAS registration number: 1271-19-8) (34.6 g) in THF Zinc (18.2 g) was added to the (200 mL) solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Add methyl 2-(1-acetoxymethyl)-2-propenoate (CAS registration number: 30982-08-2) (11.0 g) and 1-(chloromethyl)-2-methoxybenzene (CAS registration number) to the reaction solution at room temperature. A solution of No. 7035-02-1) (10.9 g) in THF (200 mL) was added, and the mixture was stirred at the same temperature overnight. Water was added to the reaction solution and extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1→2:1) to obtain a crude ester compound (13.0 g). To a solution of the crude product of the obtained ester compound (3.00 g) in diethyl ether (100 mL) were added palladium (II) acetate and diazomethane (0.5M solution in diethyl ether, 32.6 mL) under ice cooling, and the mixture was stirred at room temperature. Stirred for 4 hours. Acetic acid (4 mL) and water were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (3.00 g) having the following physical properties.
1H -NMR (DMSO- d6 ): δ 0.70, 1.21, 1.76-1.88, 2.76-2.87, 3.70, 3.83, 6.80-6.96, 7.11-7.32.
実施例51:メチル 1-(2-ヒドロキシフェネチル)シクロプロパン-1-カルボキシレート
実施例50で製造した化合物(3.00g)のジクロロメタン(100mL)溶液に、-78℃で三臭化ホウ素(1.0Mジクロロメタン溶液、38.4mL)を滴下し、同温で5時間撹拌した。反応溶液にメタノール(30mL)と水を加え、ジクロロメタンで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さを高速液体クロマトグラフィー(移動相A(0.5%炭酸水素アンモニウム水溶液):移動相B(アセトニトリル)=80:20→25:75)にて分取精製することにより、以下の物性値を有する標題化合物(515mg)を得た。
1H-NMR(DMSO-d6):δ 0.73, 1.06, 1.67-1.79, 2.58-2.70, 3.58, 6.63-6.80, 6.95-7.01, 9.17。
Example 51: Methyl 1-(2-hydroxyphenethyl)cyclopropane-1-carboxylate Boron tribromide (1 0M dichloromethane solution (38.4 mL) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. Methanol (30 mL) and water were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (mobile phase A (0.5% ammonium bicarbonate aqueous solution): mobile phase B (acetonitrile) = 80:20 → 25:75) to produce the following: The title compound (515 mg) having physical properties was obtained.
1H -NMR (DMSO- d6 ): δ 0.73, 1.06, 1.67-1.79, 2.58-2.70, 3.58, 6.63-6.80, 6.95-7.01, 9.17.
実施例52:エチル (E)-3-(2-(ベンジルオキシ)-5-フルオロフェニル)アクリレート
水素化ナトリウム(60%inミネラルオイル、1.80g)をDMF(30mL)に懸濁させ溶液を0℃に冷却した。トリエチルホスホノアセテート(10.0g)を加え、0℃で30分間撹拌した後、2-ベンジルオキシ-5-フルオロ-ベンズアルデヒド(CAS登録番号:312314-37-7)(8.70g)のDMF(10mL)溶液を滴下し、0℃で1時間撹拌した。反応混合液を氷水にあけ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、下の物性値を有する標題化合物(13.2g)を得た。
1H-NMR(CDCl3):δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05。
Example 52: Ethyl (E)-3-(2-(benzyloxy)-5-fluorophenyl)acrylate Sodium hydride (60% in mineral oil, 1.80 g) was suspended in DMF (30 mL) to create a solution. Cooled to 0°C. After adding triethylphosphonoacetate (10.0 g) and stirring at 0°C for 30 minutes, 2-benzyloxy-5-fluoro-benzaldehyde (CAS registration number: 312314-37-7) (8.70 g) was added to DMF ( 10 mL) solution was added dropwise and stirred at 0°C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (13.2 g) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05.
実施例53:エチル 3-(5-フルオロ-2-ヒドロキシフェニル)プロパノエート
実施例52で製造した化合物(11.0g)のエタノール(18mL)の溶液にパラジウム炭素(1.95g)を加え、水素雰囲気下、室温で3時間撹拌した。反応液をセライト(商品名)でろ過し、ろ液を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1→2:1)によって精製することにより、下の物性値を有する標題化合物(5.8g)を得た。
1H-NMR(CDCl3):δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23。
Example 53: Ethyl 3-(5-fluoro-2-hydroxyphenyl)propanoate Palladium on carbon (1.95 g) was added to a solution of the compound prepared in Example 52 (11.0 g) in ethanol (18 mL), and a hydrogen atmosphere was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1→2:1) to obtain the title compound (5.8 g) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23.
実施例54:(R,E)-5-(2-((E)-3-メトキシ-3-オキソプロパ-1-エン-1-イル)フェノキシ)-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエート
実施例46で製造した(R,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエート(110mg)、メチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエート(CAS登録番号:6236-69-7)(90mg)並びにトリフェニルホスフィン(130mg)のTHF(1mL)溶液にアゾジカルボン酸ジイソプロピル(以下、DIADと略記)(0.1mL)を加え、室温で終夜撹拌した。減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:2)によって精製することにより、下の物性値を有する標題化合物(200mg)を得た。
1H-NMR(CDCl3):δ 2.43-2.55, 3.78, 4.24, 5.94-5.98, 6.46-6.53, 6.82, 6.90, 6.96, 7.29-7.33, 7.44-7.51, 7.57-7.60, 7.68, 8.00, 8.07-8.10, 8.23-8.24。
Example 54: (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)penta-1 -en-3-yl benzoate (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate (110 mg) prepared in Example 46, methyl (E)- Diisopropyl azodicarboxylate (hereinafter referred to as DIAD) was added to a solution of 3-(2-hydroxyphenyl)prop-2-enoate (CAS registration number: 6236-69-7) (90 mg) and triphenylphosphine (130 mg) in THF (1 mL). (abbreviation) (0.1 mL) was added, and the mixture was stirred at room temperature overnight. The residue was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:2) to obtain the title compound (200 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 2.43-2.55, 3.78, 4.24, 5.94-5.98, 6.46-6.53, 6.82, 6.90, 6.96, 7.29-7.33, 7.44-7.51, 7.57-7.60, 7.68, 8 .00, 8.07- 8.10, 8.23-8.24.
実施例55:(R,E)-1-(3-アミノフェニル)-5-(2-((E)-3-メトキシ-3-オキソプロパ-1-エン-1-イル)フェノキシ)ペンタ-1-エン-3-イル ベンゾエート
実施例54で製造した化合物(160mg)のエタノール溶液(7mL)に塩化第二すず(310mg)を加え、70℃で3時間半撹拌した。反応液を室温に戻した後、酢酸エチルにあけ、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:2)によって精製することにより、下の物性値を有する標題化合物(120mg)を得た。
1H-NMR(CDCl3):δ 2.39-2.52, 3.66, 3.79, 4.20, 5.90, 6.28, 6.53, 6.57-6.59, 6.68, 6.73, 6.79, 6.89, 6.94, 7.09, 7.28-7.32, 7.42-7.47, 7.49-7.50, 7.54-7.58, 8.01, 8.05-8.07。
Example 55: (R,E)-1-(3-aminophenyl)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)penta-1 -en-3-yl benzoate To an ethanol solution (7 mL) of the compound prepared in Example 54 (160 mg) was added stannic chloride (310 mg), and the mixture was stirred at 70° C. for 3.5 hours. After the reaction solution was returned to room temperature, it was poured into ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:2) to obtain the title compound (120 mg) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 2.39-2.52, 3.66, 3.79, 4.20, 5.90, 6.28, 6.53, 6.57-6.59, 6.68, 6.73, 6.79, 6.89, 6.94, 7.09, 7.28-7.32 , 7.42-7.47, 7.49-7.50, 7.54-7.58, 8.01, 8.05-8.07.
実施例56:(R,E)-5-(2-((E)-3-メトキシ-3-オキソプロパ-1-エン-1-イル)フェノキシ)-1-(3-(フェニルスルホンアミド)フェニル)ペンタ-1-エン-3-イル ベンゾエート
実施例55で製造した化合物(60mg)とピリジン(0.016mL)のジクロロメタン溶液(1mL)を0℃に冷却し、フェニルスルホニルクロリド(0.018mL)を加え、室温に戻しながら終夜撹拌した。反応溶液に1M塩酸と飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、下の物性値を有する標題化合物(62mg)を得た。
1H-NMR(CDCl3):δ 2.41-2.45, 3.87, 4.18-4.22, 5.84-5.88, 6.30-6.34, 6.51, 6.64, 6.89, 6.99, 7.05-7.19, 7.30-7.34, 7.38-7.50, 7.50-7.52, 7.56-7.59, 7.74-7.77, 8.04-8.07。
Example 56: (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamido)phenyl ) Pent-1-en-3-yl benzoate A dichloromethane solution (1 mL) of the compound prepared in Example 55 (60 mg) and pyridine (0.016 mL) was cooled to 0°C, and phenylsulfonyl chloride (0.018 mL) was added. The mixture was stirred overnight while returning to room temperature. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:1) to obtain the title compound (62 mg) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 2.41-2.45, 3.87, 4.18-4.22, 5.84-5.88, 6.30-6.34, 6.51, 6.64, 6.89, 6.99, 7.05-7.19, 7.30-7.34, 7.38-7. 50, 7.50- 7.52, 7.56-7.59, 7.74-7.77, 8.04-8.07.
実施例57:(E)-3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパ-2-エン酸
実施例56で製造した化合物(62mg)のTHF(1.5mL)とメタノール(0.5mL)の溶液に1M水酸化リチウム水溶液(0.5mL)を加え、室温で7時間撹拌した。反応溶液に1M塩酸と飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=10:0→9:1)によって精製することにより、下の物性値を有する標題化合物(29mg)を得た。
HPLC保持時間(分):0.89;
1H-NMR(DMSO-d6):δ 1.91-2.04, 4.10-4.22, 4.36, 5.12, 6.21-6.25, 6.44, 6.55, 6.93-6.99, 7.08-7.11, 7.16, 7.36-7.40, 7.52-7.55, 7.58-7.61, 7.66-7.68, 7.75-7.77, 7.85, 10.27, 12.31。
Example 57: (E)-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid A 1M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound produced in Example 56 (62 mg) in THF (1.5 mL) and methanol (0.5 mL), and the mixture was stirred at room temperature for 7 hours. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=10:0→9:1) to obtain the title compound (29 mg) having the physical properties shown below.
HPLC retention time (min): 0.89;
1H -NMR (DMSO- d6 ): δ 1.91-2.04, 4.10-4.22, 4.36, 5.12, 6.21-6.25, 6.44, 6.55, 6.93-6.99, 7.08-7.11, 7.16, 7.36-7.40, 7.52- 7.55, 7.58-7.61, 7.66-7.68, 7.75-7.77, 7.85, 10.27, 12.31.
実施例58:N-[3-[(E,3R)-5-[2-(2-シアノエチル)フェノキシ]-3-ヒドロキシペンタ-1-エニル]フェニル]ベンゼンスルホンアミド
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに相当するフェノール化合物を用いて、実施例54→実施例55→実施例56と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 2.07-2.19, 2.60-2.65, 2.89-3.00, 4.10-4.23, 4.58, 6.24, 6.44, 6.56, 6.89-6.95, 7.10-7.27, 7.42-7.46, 7.52-7.56, 7.75-7.78。
Example 58: N-[3-[(E,3R)-5-[2-(2-cyanoethyl)phenoxy]-3-hydroxypent-1-enyl]phenyl]benzenesulfonamide Methyl used in Example 54 By using the corresponding phenol compound instead of (E)-3-(2-hydroxyphenyl)prop-2-enoate and performing the same operations as in Example 54 → Example 55 → Example 56, The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.99;
1H -NMR ( CDCl3 ): δ 2.07-2.19, 2.60-2.65, 2.89-3.00, 4.10-4.23, 4.58, 6.24, 6.44, 6.56, 6.89-6.95, 7.10-7.27, 7.42-7.46, 7. 52-7.56, 7.75-7.78.
実施例59:メチル 1-[2-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]エチル]シクロプロパン-1-カルボキシレート
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例51で製造したフェノール化合物を用いて、実施例54→実施例55→実施例56と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 0.71, 1.22, 1.79-1.83, 2.07-2.15, 2.44, 2.77-2.81, 3.65, 4.10-4.23, 6.24, 6.44, 6.55, 6.83-6.94, 7.08-7.20, 7.41-7.45, 7.51-7.55, 7.75-7.77。
Example 59: Methyl 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1 -Carboxylate Using the phenol compound produced in Example 51 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54→Example 55→ By performing the same operations as in Example 56, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 0.71, 1.22, 1.79-1.83, 2.07-2.15, 2.44, 2.77-2.81, 3.65, 4.10-4.23, 6.24, 6.44, 6.55, 6.83-6.94, 7.08-7 .20, 7.41- 7.45, 7.51-7.55, 7.75-7.77.
実施例60:メチル 4-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2,2-ジメチルブタノエート
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例49で製造したフェノール化合物を用いて、実施例54→実施例55→実施例56と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.53, 1.56, 2.33-2.45, 3.63, 4.10-4.19, 5.95, 6.46, 6.71-6.91, 7.17-7.24, 7.45-7.52, 7.57-7.68。
Example 60: Methyl 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoate Using the phenol compound produced in Example 49 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 1.53, 1.56, 2.33-2.45, 3.63, 4.10-4.19, 5.95, 6.46, 6.71-6.91, 7.17-7.24, 7.45-7.52, 7.57-7.68.
実施例61(1)~(8)
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに相当するフェノール化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 61 (1) to (8)
Using the corresponding phenol compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 → Example 57 The following example compounds were obtained by performing the same operations as above.
実施例61(1):(E)-3-[4-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパ-2-エン酸
HPLC保持時間(分):0.85;
1H-NMR(DMSO-d6):δ 1.84-1.92, 4.06-4.17, 4.32-4.33, 5.07, 5.60-6.00, 6.10, 6.21, 6.37, 6.44, 6.94-6.97, 7.09-7.11, 7.16, 7.48-7.63, 7.75, 10.27, 12.15。
Example 61 (1): (E)-3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]proper-2 - Enoic acid HPLC retention time (min): 0.85;
1H -NMR (DMSO- d6 ): δ 1.84-1.92, 4.06-4.17, 4.32-4.33, 5.07, 5.60-6.00, 6.10, 6.21, 6.37, 6.44, 6.94-6.97, 7.09-7.11, 7.16, 7.48- 7.63, 7.75, 10.27, 12.15.
実施例61(2):3-[4-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.86;
1H-NMR(DMSO-d6):δ 1.80-1.84, 1.87-1.96, 2.48, 2.74, 3.95-4.01, 4.01-4.08, 4.28-4.34, 5.04, 6.21, 6.43, 6.82-6.94, 6.93-6.96, 7.08-7.13, 7.17, 7.51-7.56, 7.57-7.59, 7.75-7.78, 10.27, 12.04。
Example 61 (2): 3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min ): 0.86;
1H -NMR (DMSO- d6 ): δ 1.80-1.84, 1.87-1.96, 2.48, 2.74, 3.95-4.01, 4.01-4.08, 4.28-4.34, 5.04, 6.21, 6.43, 6.82-6.94, 6.93- 6.96, 7.08-7.13, 7.17, 7.51-7.56, 7.57-7.59, 7.75-7.78, 10.27, 12.04.
実施例61(3):(E)-3-[3-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパ-2-エン酸
HPLC保持時間(分):0.89;
1H-NMR(DMSO-d6):δ 1.83-1.98, 4.06-4.17, 4.31-4.35, 5.06, 6.20-6.25, 6.44, 6.54, 6.94-6.99, 7.09-7.11, 7.17, 7.23-7.26, 7.31, 7.52-7.61, 7.75-7.77, 10.27, 12.35。
Example 61 (3): (E)-3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]proper-2 - Enoic acid HPLC retention time (min): 0.89;
1H -NMR (DMSO- d6 ): δ 1.83-1.98, 4.06-4.17, 4.31-4.35, 5.06, 6.20-6.25, 6.44, 6.54, 6.94-6.99, 7.09-7.11, 7.17, 7.23-7.26, 7.31, 7.52-7.61, 7.75-7.77, 10.27, 12.35.
実施例61(4):3-[3-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.89;
1H-NMR(DMSO-d6):δ 1.81-1.95, 2.51, 2.78, 4.31, 5.05, 6.21, 6.43, 6.73-6.79, 6.93-6.96, 7.09-7.10, 7.14-7.18, 7.52-7.55, 7.58-7.61, 7.75-7.78, 10.25, 12.10。
Example 61 (4): 3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min ): 0.89;
1H -NMR (DMSO- d6 ): δ 1.81-1.95, 2.51, 2.78, 4.31, 5.05, 6.21, 6.43, 6.73-6.79, 6.93-6.96, 7.09-7.10, 7.14-7.18, 7.52-7.55, 7.58- 7.61, 7.75-7.78, 10.25, 12.10.
実施例61(5):2-[3-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2-メチルプロパン酸
HPLC保持時間(分):0.93;
1H-NMR(DMSO-d6):δ 1.44, 1.81-1.97, 3.99-4.10, 4.30-4.35, 5.05, 6.21, 6.44, 6.79-6.82, 6.84-6.85, 6.88-6.90, 6.93-6.96, 7.08-7.10, 7.16, 7.23, 7.51-7.55, 7.57-7.61, 7.75-7.78, 10.25, 12.30。
Example 61 (5): 2-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid HPLC Retention time (min): 0.93;
1H -NMR (DMSO- d6 ): δ 1.44, 1.81-1.97, 3.99-4.10, 4.30-4.35, 5.05, 6.21, 6.44, 6.79-6.82, 6.84-6.85, 6.88-6.90, 6.93-6.96, 7.08- 7.10, 7.16, 7.23, 7.51-7.55, 7.57-7.61, 7.75-7.78, 10.25, 12.30.
実施例61(6):
2-[4-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2-メチルプロパン酸
HPLC保持時間(分):0.92;
1H-NMR(DMSO-d6):δ 1.44, 1.83-1.93, 3.99-4.08, 4.29-4.33, 5.04, 6.21, 6.42, 6.86-6.88, 6.93-6.95, 7.07-7.09, 7.16, 7.23-7.25, 7.51-7.55, 7.57-7.60, 7.75-7.77, 10.25, 12.30。
Example 61 (6):
2-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid HPLC retention time (min): 0 .92;
1H -NMR (DMSO- d6 ): δ 1.44, 1.83-1.93, 3.99-4.08, 4.29-4.33, 5.04, 6.21, 6.42, 6.86-6.88, 6.93-6.95, 7.07-7.09, 7.16, 7.23- 7.25, 7.51-7.55, 7.57-7.60, 7.75-7.77, 10.25, 12.30.
実施例61(7):4-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]ブタン酸 Example 61 (7): 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 1.92-2.00, 2.12, 2.28-2.42, 2.68-2.71, 4.07-4.20, 4.63, 6.85-6.96, 7.08-7.19, 7.40-7.59, 7.59-7.63, 7.75-7.77。
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 1.92-2.00, 2.12, 2.28-2.42, 2.68-2.71, 4.07-4.20, 4.63, 6.85-6.96, 7.08-7.19, 7.40-7.59, 7.59-7.63, 7.7 5-7.77.
実施例61(8):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2,2-ジメチルプロパン酸
HPLC保持時間(分):0.95
1H-NMR(CDCl3):δ 1.21, 2.05-2.15, 2.96, 4.07-4.15, 4.60, 6.23, 6.53, 6.85-7.00, 7.07-7.20, 7.40-7.63, 7.76-7.78。
Example 61 (8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylpropane Acid HPLC retention time (min): 0.95
1H -NMR ( CDCl3 ): δ 1.21, 2.05-2.15, 2.96, 4.07-4.15, 4.60, 6.23, 6.53, 6.85-7.00, 7.07-7.20, 7.40-7.63, 7.76-7.78.
実施例62:2-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2-メチルプロパン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例47で製造したフェノール化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 1.63-1.65, 2.09-2.14, 4.13-4.21, 4.58, 6.28, 6.52, 6.82-6.84, 7.00-7.06, 7.15-7.19, 7.40-7.62, 7.76-7.78。
Example 62: 2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid in Example 54 Using the phenol compound produced in Example 47 instead of the used methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate, Example 54 → Example 55 → Example 56 → Example 57 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 1.63-1.65, 2.09-2.14, 4.13-4.21, 4.58, 6.28, 6.52, 6.82-6.84, 7.00-7.06, 7.15-7.19, 7.40-7.62, 7.76-7.7 8.
実施例63:1-[[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]メチル]シクロプロパン-1-カルボン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例48で製造した化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.38-1.40, 2.11-2.16, 4.13-4.18, 4.58, 6.28, 6.54, 6.85-7.20, 7.38-7.52, 7.74-7.76。
Example 63: 1-[[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]methyl]cyclopropane-1-carboxylic acid Using the compound prepared in Example 48 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 → By performing the same operations as in Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.38-1.40, 2.11-2.16, 4.13-4.18, 4.58, 6.28, 6.54, 6.85-7.20, 7.38-7.52, 7.74-7.76.
実施例64:4-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]-2,2-ジメチルブタン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例49で製造した化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 1.28, 1.74-1.91, 2.08-2.17, 2.61, 4.01-4.16, 4.62, 6.22, 6.51, 6.81-7.17, 7.39-7.43, 7.48-7.53, 7.75-7.78。
Example 64: 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoic acid Example Using the compound produced in Example 49 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 → Example By performing the same operations as in No. 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 1.28, 1.74-1.91, 2.08-2.17, 2.61, 4.01-4.16, 4.62, 6.22, 6.51, 6.81-7.17, 7.39-7.43, 7.48-7.53, 7.75-7. 78.
実施例65:1-[2-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]エチル]シクロプロパン-1-カルボン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例51で製造したフェノール化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 0.66-0.76, 1.19-1.30, 1.64-1.72, 1.79-1.88, 2.08-2.14, 2.75-2.89, 4.10-4.21, 4.65, 6.28, 6.55, 6.83-6.90, 6.96-7.00, 7.07-7.18, 7.35-7.39, 7.46-7.52, 7.73-7.76。
Example 65: 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1- Carboxylic acid Using the phenol compound produced in Example 51 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Implementation By performing the same operations as in Example 56→Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 0.66-0.76, 1.19-1.30, 1.64-1.72, 1.79-1.88, 2.08-2.14, 2.75-2.89, 4.10-4.21, 4.65, 6.28, 6.55, 6.83-6.9 0, 6.96- 7.00, 7.07-7.18, 7.35-7.39, 7.46-7.52, 7.73-7.76.
実施例66(1)~(3)
実施例1で使用した3,4-ジヒドロクマリンの代わりに相当するラクトン化合物を用いて、実施例1→実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 66 (1) to (3)
Using the corresponding lactone compound instead of 3,4-dihydrocoumarin used in Example 1, the same objective operation as in Example 1 → Example 54 → Example 55 → Example 56 → Example 57 is performed. As a result, the following example compounds were obtained.
実施例66(1):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-5-ブロモフェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CD3OD):δ 2.06-2.10, 2.56-2.60, 2.88-2.92, 4.07-4.19, 4.51, 6.23, 6.53, 6.86-6.88, 6.97-7.00, 7.11-7.19, 7.29-7.32, 7.46-7.50, 7.54-7.58, 7.76-7.78。
Example 66(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-bromophenyl]propanoic acid HPLC Retention time (min): 0.99;
1H -NMR ( CD3OD ): δ 2.06-2.10, 2.56-2.60, 2.88-2.92, 4.07-4.19, 4.51, 6.23, 6.53, 6.86-6.88, 6.97-7.00, 7.11-7.19, 7.29-7. 32, 7.46 -7.50, 7.54-7.58, 7.76-7.78.
実施例66(2):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-5-メチルフェニル]プロパン酸
HPLC保持時間(分):0.98;
1H-NMR(CD3OD):δ 1.92-1.96, 2.13, 2.42-2.46, 2.75-2.79, 3.63-4.03, 4.41, 6.11, 6.42, 6.69, 6.84-6.89, 6.99-7.06, 7.34-7.46, 7.64-7.66。
Example 66 (2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-methylphenyl]propanoic acid HPLC Retention time (min): 0.98;
1H -NMR ( CD3OD ): δ 1.92-1.96, 2.13, 2.42-2.46, 2.75-2.79, 3.63-4.03, 4.41, 6.11, 6.42, 6.69, 6.84-6.89, 6.99-7.06, 7.34-7 .46, 7.64 -7.66.
実施例66(3):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-4-メチルフェニル]プロパン酸
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 1.92-1.97, 2.18, 2.41-2.45, 2.74-2.78, 3.93-4.06, 4.42, 6.11, 6.41, 6.56, 6.64, 6.86-6.92, 7.00-7.07, 7.33-7.46, 7.64-7.66。
Example 66 (3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-4-methylphenyl]propanoic acid HPLC Retention time (min): 0.97;
1H -NMR ( CD3OD ): δ 1.92-1.97, 2.18, 2.41-2.45, 2.74-2.78, 3.93-4.06, 4.42, 6.11, 6.41, 6.56, 6.64, 6.86-6.92, 7.00-7.07, 7.33-7.46 , 7.64-7.66.
実施例67:3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-5-フルオロフェニル]プロパン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例53で製造したフェノール化合物を用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.94;
1H-NMR(CDCl3):δ 2.09-2.15, 2.67-2.71, 2.93-2.97, 4.10-4.15, 4.59, 6.27, 6.54, 6.77-6.80, 6.84-6.90, 6.95-7.00, 7.08-7.10, 7.16, 7.40-7.44, 7.50-7.55, 7.76-7.78。
Example 67: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-fluorophenyl]propanoic acid in Example 54 Using the phenol compound produced in Example 53 instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used, Example 54 → Example 55 → Example 56 → Example 57 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.94;
1H -NMR ( CDCl3 ): δ 2.09-2.15, 2.67-2.71, 2.93-2.97, 4.10-4.15, 4.59, 6.27, 6.54, 6.77-6.80, 6.84-6.90, 6.95-7.00, 7.08-7.1 0, 7.16, 7.40-7.44, 7.50-7.55, 7.76-7.78.
実施例68(1)~(2)
実施例52で使用した2-ベンジルオキシ-5-フルオロ-ベンズアルデヒドの代わりに相当するアルデヒド化合物を、実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに相当するフェノール化合物を用いて、実施例52→実施例53→実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 68 (1)-(2)
In place of 2-benzyloxy-5-fluoro-benzaldehyde used in Example 52, the corresponding aldehyde compound was substituted for methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. The following example compounds were prepared by using the corresponding phenol compound instead and performing the same operations as in Example 52 → Example 53 → Example 54 → Example 55 → Example 56 → Example 57. Obtained.
実施例68(1):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-6-フルオロフェニル]プロパン酸
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 2.09-2.15, 2.61-2.65, 2.97-3.01, 4.10-4.17, 4.60, 6.26, 6.54, 6.65-6.70, 6.97-7.00, 7.05-7.18, 7.41-7.44, 7.50-7.54, 7.76-7.79。
Example 68(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-6-fluorophenyl]propanoic acid HPLC Retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 2.09-2.15, 2.61-2.65, 2.97-3.01, 4.10-4.17, 4.60, 6.26, 6.54, 6.65-6.70, 6.97-7.00, 7.05-7.18, 7.41-7.4 4, 7.50- 7.54, 7.76-7.79.
実施例68(2):3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]-3-フルオロフェニル]プロパン酸
HPLC保持時間(分):0.94;
1H-NMR(CDCl3):δ 2.09-2.15, 2.69-2.73, 3.01-3.05, 4.22-4.24, 4.67, 6.30, 6.58, 6.95-7.01, 7.10-7.20, 7.42-7.45, 7.51-7.54, 7.77-7.79。
Example 68 (2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-3-fluorophenyl]propanoic acid HPLC Retention time (min): 0.94;
1H -NMR ( CDCl3 ): δ 2.09-2.15, 2.69-2.73, 3.01-3.05, 4.22-4.24, 4.67, 6.30, 6.58, 6.95-7.01, 7.10-7.20, 7.42-7.45, 7.51-7.5 4, 7.77- 7.79.
実施例69:3-[2-[(E,3S)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例1で製造した化合物を、実施例54で使用した(R,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートの代わりに実施例54で製造した(S,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートを用いて、実施例54→実施例55→実施例56→実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56, 7.75-7.78。
Example 69: 3-[2-[(E,3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Methyl used in Example 54 ( E)-3-(2-hydroxyphenyl)prop-2-enoate was replaced with the compound prepared in Example 1 (R,E)-5-hydroxy-1-(3-nitro) used in Example 54. (S,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate prepared in Example 54 was used instead of phenyl)pent-1-en-3-yl benzoate. The title compound having the following physical property values was obtained by performing the same operations as in Example 54 → Example 55 → Example 56 → Example 57.
HPLC retention time (min): 0.93;
1H -NMR (CD 3 OD): δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45- 7.50, 7.56 , 7.75-7.78.
実施例70:3-[2-[(3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸 Example 70: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid
実施例69で製造した化合物を用いて、実施例33と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76。
The compound produced in Example 69 was subjected to the same operations as in Example 33 to obtain the title compound having the following physical properties.
HPLC retention time (min): 0.93;
1H -NMR ( CD3OD ): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.
実施例71:イソプロピル (R,E)-3-(2-((5-(3-アミノフェニル)-3-((トリメチルシリル)オキシ)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例8で製造した化合物(1.00g)のTHF(10mL)溶液に、3-ブロモアニリン(421mg)、クロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(0.30g)および2Mリン酸三カリウム水溶液(5.7mL)を加え、70℃で19時間撹拌した。反応溶液を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(515mg)を得た。
HPLC保持時間(分):0.82。
Example 71: Isopropyl (R,E)-3-(2-((5-(3-aminophenyl)-3-((trimethylsilyl)oxy)pent-4-en-1-yl)oxy)phenyl)propanoate To a THF (10 mL) solution of the compound (1.00 g) produced in Example 8 were added 3-bromoaniline (421 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.30 g) and 2M aqueous tripotassium phosphate solution (5.7 mL) were added, and the mixture was heated at 70°C for 19 min. Stir for hours. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→2:1) to obtain the title compound (515 mg) having the following physical properties.
HPLC retention time (min): 0.82.
実施例72:イソプロピル (R,E)-3-(2-((5-(3-((4-フルオロフェニル)スルホンアミド)フェニル)-3-ヒドロキシペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例71で製造した化合物(50mg)のTHF(1mL)溶液に、室温でピリジン(0.018mL)、DMAP(2.7mg)および塩化 4-フルオロベンゼンスルホニル(CAS登録番号:349-88-2)(25.6mg)を加え、同温で16時間撹拌した。反応溶液に室温でTBAF(1.0M THF溶液、0.27mL)を加え、同温で1時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さを高速液体クロマトグラフィー(移動相A(0.1%TFA水溶液):移動相B(0.1%TFA/アセトニトリル)=90:0→10:90)にて分取精製することにより、以下の物性値を有する標題化合物(515mg)を得た。
HPLC保持時間(分):1.11。
Example 72: Isopropyl (R,E)-3-(2-((5-(3-((4-fluorophenyl)sulfonamido)phenyl)-3-hydroxypent-4-en-1-yl)oxy ) Phenyl) propanoate To a solution of the compound prepared in Example 71 (50 mg) in THF (1 mL) was added pyridine (0.018 mL), DMAP (2.7 mg) and 4-fluorobenzenesulfonyl chloride (CAS registration number: 349) at room temperature. -88-2) (25.6 mg) was added, and the mixture was stirred at the same temperature for 16 hours. TBAF (1.0M THF solution, 0.27 mL) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution): mobile phase B (0.1% TFA/acetonitrile) = 90:0 → 10:90). The title compound (515 mg) having the following physical properties was obtained.
HPLC retention time (min): 1.11.
実施例73:3-[2-[(E,3R)-5-[3-[(4-フルオロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに、実施例72で製造した化合物を用いて、実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.94
1H-NMR(CD3OD):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.25, 7.79-7.82。
Example 73: 3-[2-[(E,3R)-5-[3-[(4-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Example 11 Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in The compound produced in Example 72 was subjected to the same operations as in Example 11 to obtain the title compound having the following physical properties.
HPLC retention time (min): 0.94
1 H-NMR (CD 3 OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 2.91-2.95, 4.10, 4.55, 6.86, 6.86, 6.93, 6.93, 6.99, 7.13-7.25, 7.79-7.82
実施例74(1)~(21)
実施例72で使用した塩化 4-フルオロベンゼンスルホニルの代わりに相当するスルホニル化合物を用いて、実施例72→実施例11と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
Example 74 (1) to (21)
Using the corresponding sulfonyl compound instead of 4-fluorobenzenesulfonyl chloride used in Example 72, the following example compounds were obtained by performing the same operations as in Example 72→Example 11.
実施例74(1):3-[2-[(E,3R)-5-[3-[(4-クロロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.98;
1H-NMR(CD3OD):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.21, 7.48-7.51, 7.71-7.75。
Example 74(1): 3-[2-[(E,3R)-5-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.98;
1H -NMR ( CD3OD ): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.21, 7.48-7.51, 7.71-7.75 .
実施例74(2):
3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(4-メチルフェニル)スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
1H-NMR(CD3OD):δ 2.06-2.11, 2.37, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.27-7.30, 7.63-7.66。
Example 74 (2):
3-[2-[(E,3R)-3-hydroxy-5-[3-[(4-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96;
1H -NMR (CD 3 OD): δ 2.06-2.11, 2.37, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.27 -7.30, 7.63 -7.66.
実施例74(3):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[[4-(トリフルオロメチル)フェニル]スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.01;
1H-NMR(CD3OD):δ 2.06-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.27, 6.55, 6.86, 6.93, 6.99, 7.15-7.22, 7.80-7.83, 7.93-7.95。
Example 74(3): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[4-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 1.01;
1H -NMR ( CD3OD ): δ 2.06-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.27, 6.55, 6.86, 6.93, 6.99, 7.15-7.22, 7.80-7.83, 7.93-7.95 .
実施例74(4):3-[2-[(E,3R)-5-[3-[(4-ブチルフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.08;
1H-NMR(CD3OD):δ 0.93, 1.31-1.36, 1.55-1.63, 2.06-2.10, 2.57-2.67, 2.91-2.95, 4.11, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.28-7.30, 7.65-7.68。
Example 74 (4): 3-[2-[(E,3R)-5-[3-[(4-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.08;
1H -NMR (CD 3 OD): δ 0.93, 1.31-1.36, 1.55-1.63, 2.06-2.10, 2.57-2.67, 2.91-2.95, 4.11, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11 -7.20, 7.28-7.30, 7.65-7.68.
実施例74(5):3-[2-[(E,3R)-5-[3-[(3-フルオロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
MS(ESI,Pos.):482(M+H-H2O)+。
Example 74(5): 3-[2-[(E,3R)-5-[3-[(3-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96;
MS (ESI, Pos.): 482 (M+H- H2O ) + .
実施例74(6):3-[2-[(E,3R)-5-[3-[(3-クロロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
MS(ESI,Pos.):498(M+H-H2O)+。
Example 74(6): 3-[2-[(E,3R)-5-[3-[(3-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 1.00;
MS (ESI, Pos.): 498 (M+H- H2O ) + .
実施例74(7):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(3-メチルフェニル)スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
MS(ESI,Pos.):478(M+H-H2O)+。
Example 74(7): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(3-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97;
MS (ESI, Pos.): 478 (M+H- H2O ) + .
実施例74(8):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[[3-(トリフルオロメチル)フェニル]スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
MS(ESI,Pos.):532(M+H-H2O)+。
Example 74 (8): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 1.00;
MS (ESI, Pos.): 532 (M+H- H2O ) + .
実施例74(9):3-[2-[(E,3R)-5-[3-[(2-フルオロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.94;
MS(ESI,Pos.):482(M+H-H2O)+。
Example 74 (9): 3-[2-[(E,3R)-5-[3-[(2-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94;
MS (ESI, Pos.): 482 (M+H- H2O ) + .
実施例74(10):3-[2-[(E,3R)-5-[3-[(2-クロロフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
MS(ESI,Pos.):498(M+H-H2O)+。
Example 74 (10): 3-[2-[(E,3R)-5-[3-[(2-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC Retention time (min): 0.97;
MS (ESI, Pos.): 498 (M+H- H2O ) + .
実施例74(11):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(2-メチルフェニル)スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.97;
MS(ESI,Pos.):478(M+H-H2O)+。
Example 74 (11): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97;
MS (ESI, Pos.): 478 (M+H- H2O ) + .
実施例74(12):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[[2-(トリフルオロメチル)フェニル]スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
MS(ESI,Pos.):532(M+H-H2O)+。
Example 74 (12): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[2-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy] Phenyl]propanoic acid HPLC retention time (min): 0.99;
MS (ESI, Pos.): 532 (M+H- H2O ) + .
実施例74(13):3-[2-[(E,3R)-5-[3-(シクロペンチルスルホニルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸 Example 74 (13): 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 1.60-1.67, 1.74-1.81, 1.90-2.05, 2.08-2.13, 2.58-2.62, 2.92-2.96, 3.56, 4.13, 4.20, 4.58, 6.35, 6.62, 6.86, 6.94, 7.14-7.20, 7.26-7.32。
HPLC retention time (min): 0.93;
1H -NMR (CD 3 OD): δ 1.60-1.67, 1.74-1.81, 1.90-2.05, 2.08-2.13, 2.58-2.62, 2.92-2.96, 3.56, 4.13, 4.20, 4.58, 6.35, 6.62, 6.86, 6.94 , 7.14-7.20, 7.26-7.32.
実施例74(14):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(オキサン-4-イルスルホニルアミノ)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.48(酢酸エチル);
1H-NMR(CDCl3):δ 1.88-2.00, 2.15-2.20, 2.63-2.74, 2.90-3.02, 3.22-3.35, 4.04, 4.17, 6.38, 6.60, 6.88, 7.13-7.28。
Example 74 (14): 3-[2-[(E,3R)-3-hydroxy-5-[3-(oxan-4-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC :Rf 0.48 (ethyl acetate);
1H -NMR ( CDCl3 ): δ 1.88-2.00, 2.15-2.20, 2.63-2.74, 2.90-3.02, 3.22-3.35, 4.04, 4.17, 6.38, 6.60, 6.88, 7.13-7.28.
実施例74(15):3-[2-[(E,3R)-5-[3-(ベンジルスルホニルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.55(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.13-2.18, 2.67, 2.96, 4.13-4.22, 4.34, 4.64, 6.35, 6.61, 6.89, 6.96, 7.06, 7.13-7.36。
Example 74 (15): 3-[2-[(E,3R)-5-[3-(benzylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC:
1H -NMR ( CDCl3 ): δ 2.13-2.18, 2.67, 2.96, 4.13-4.22, 4.34, 4.64, 6.35, 6.61, 6.89, 6.96, 7.06, 7.13-7.36.
実施例74(16):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(ピリジン-2-イルスルホニルアミノ)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.36(酢酸エチル);
1H-NMR(CDCl3):δ 2.06-2.23, 2.72, 3.02, 4.16, 4.60, 6.31, 6.52, 6.86-6.93, 7.01, 7.10-7.22, 7.46, 7.85, 7.97, 8.41, 8.65。
Example 74 (16): 3-[2-[(E,3R)-3-hydroxy-5-[3-(pyridin-2-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC :Rf 0.36 (ethyl acetate);
1H -NMR ( CDCl3 ): δ 2.06-2.23, 2.72, 3.02, 4.16, 4.60, 6.31, 6.52, 6.86-6.93, 7.01, 7.10-7.22, 7.46, 7.85, 7.97, 8.41, 8.65 .
実施例74(17):3-[2-[(E,3R)-5-[3-(1-ベンゾフラン-3-イルスルホニルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.98;
1H-NMR(CDCl3):δ 2.08-2.13, 2.69, 2.96, 4.11, 4.55-4.62, 6.21, 6.52, 684-6.92, 6.99-7.03, 7.09-7.19, 7.30-7.40, 7.50, 7.70, 8.05。
Example 74 (17): 3-[2-[(E,3R)-5-[3-(1-benzofuran-3-ylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid HPLC retention time (min): 0.98;
1H -NMR ( CDCl3 ): δ 2.08-2.13, 2.69, 2.96, 4.11, 4.55-4.62, 6.21, 6.52, 684-6.92, 6.99-7.03, 7.09-7.19, 7.30-7.40, 7.50, 7. 70, 8.05.
実施例74(18):3-[2-[(E,3R)-5-[3-[(4-ブトキシフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.40(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 0.95, 1.40-1.50, 1.68-1.79, 2.10-2.14, 2.68, 2.96, 3.93, 4.10-4.19, 4.60, 6.26, 6.52, 6.81-6.91, 6.97-7.09, 7.12-7.24, 7.68。
Example 74 (18): 3-[2-[(E,3R)-5-[3-[(4-butoxyphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.40 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 0.95, 1.40-1.50, 1.68-1.79, 2.10-2.14, 2.68, 2.96, 3.93, 4.10-4.19, 4.60, 6.26, 6.52, 6.81-6.91, 6.97-7 .09, 7.12- 7.24, 7.68.
実施例74(19):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-(チオフェン-3-イルスルホニルアミノ)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.35(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.10-2.15, 2.68, 2.96, 4.09-4.20, 4.62, 6.27, 6.54, 6.84-6.92, 7.00-7.23, 7.27-7.32, 7.86。
Example 74 (19): 3-[2-[(E,3R)-3-hydroxy-5-[3-(thiophen-3-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC :Rf 0.35 (hexane:ethyl acetate=1:2);
1H -NMR ( CDCl3 ): δ 2.10-2.15, 2.68, 2.96, 4.09-4.20, 4.62, 6.27, 6.54, 6.84-6.92, 7.00-7.23, 7.27-7.32, 7.86.
実施例74(20):3-[2-[(E,3R)-3-ヒドロキシ-5-[3-[(2-プロピルフェニル)スルホニルアミノ]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.38(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 1.00, 1.64-1.74, 2.10-2.15, 2.70, 2.93-3.01, 4.10-4.19, 4.60, 6.26, 6.53, 6.85-6.92, 7.02-7.06, 7.10-7.24, 7.33, 7.45, 7.95。
Example 74 (20): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-propylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.38 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 1.00, 1.64-1.74, 2.10-2.15, 2.70, 2.93-3.01, 4.10-4.19, 4.60, 6.26, 6.53, 6.85-6.92, 7.02-7.06, 7.10-7. 24, 7.33, 7.45, 7.95.
実施例74(21):3-[2-[(E,3R)-5-[3-[(3-ブチルフェニル)スルホニルアミノ]フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
TLC:Rf 0.38(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 0.86, 1.18-1.28, 1.42-1.53, 2.08-2.14, 2.57, 2.69, 2.97, 4.10-4.21, 4.61, 6.25, 6.53, 6.84-6.92, 6.98, 7.04-7.21, 7.29-7.32, 7.55-7.60。
Example 74 (21): 3-[2-[(E,3R)-5-[3-[(3-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.38 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 0.86, 1.18-1.28, 1.42-1.53, 2.08-2.14, 2.57, 2.69, 2.97, 4.10-4.21, 4.61, 6.25, 6.53, 6.84-6.92, 6.98, 7.04-7.21, 7.29-7.32, 7.55-7.60.
実施例75:3-[2-[(3S)-5-[3-(シクロペンチルスルホニルアミノ)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例74(13)で製造した化合物を用いて、実施例33と同様の目的の操作を付すことにより、以下の実施例化合物を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 1.55-1.63, 1.74-2.07, 2.52-2.56, 2.73, 2.84, 2.85-2.89, 3.53, 3.89, 4.09-4.19, 6.85, 6.93, 7.02, 7.08-7.19, 7.23。
Example 75: 3-[2-[(3S)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid 3-[2-[( Example 74 (13) was used in place of E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. The following example compounds were obtained by carrying out the same operations as in No. 33.
HPLC retention time (min): 0.93;
1H -NMR (CD 3 OD): δ 1.55-1.63, 1.74-2.07, 2.52-2.56, 2.73, 2.84, 2.85-2.89, 3.53, 3.89, 4.09-4.19, 6.85, 6.93, 7.02, 7.08- 7.19, 7.23 .
実施例76:メチル (R,E)-3-(2-((3-ヒドロキシ-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例11で製造した化合物(500mg)のメタノール(10mL)溶液に、氷冷下トリメチルシリルジアゾメタン(2.0Mヘキサン溶液、2.6mL)を加え、室温で30分間撹拌した。反応溶液に氷冷下で酢酸を加え、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→1:1)によって精製することにより、以下の物性値を有する標題化合物(495mg)を得た。
HPLC保持時間(分):1.03。
Example 76: Methyl (R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Practice To a solution of the compound prepared in Example 11 (500 mg) in methanol (10 mL) was added trimethylsilyldiazomethane (2.0 M hexane solution, 2.6 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction solution under ice cooling, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3→1:1) to obtain the title compound (495 mg) having the following physical properties.
HPLC retention time (min): 1.03.
実施例77:メチル 3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-オキソペンタ-4-エノキシ]フェニル]プロパノエート
実施例76で製造した化合物(495mg)のジクロロメタン(10mL)溶液に、室温で二酸化マンガン(868mg)を加え、同温で20時間撹拌した。反応溶液をセライト(商品名)でろ過後、ろ液を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→1:1)によって精製することにより、以下の物性値を有する標題化合物(439mg)を得た。
HPLC保持時間(分):1.10。
1H-NMR(CDCl3):δ 2.59-2.63, 2.88-2.92, 3.08-3.11, 3.68, 4.31-4.34, 6.80, 6.85-6.92, 7.12, 7.18-7.34, 7.42-7.56, 7.77-7.80。
Example 77: Methyl 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoate of the compound prepared in Example 76 (495 mg) Manganese dioxide (868 mg) was added to a dichloromethane (10 mL) solution at room temperature, and the mixture was stirred at the same temperature for 20 hours. After filtering the reaction solution through Celite (trade name), the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3→1:1) to obtain the title compound (439 mg) having the following physical properties.
HPLC retention time (min): 1.10.
1H -NMR ( CDCl3 ): δ 2.59-2.63, 2.88-2.92, 3.08-3.11, 3.68, 4.31-4.34, 6.80, 6.85-6.92, 7.12, 7.18-7.34, 7.42-7.56, 7.77-7.8 0.
実施例78:3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-オキソペンタ-4-エノキシ]フェニル]プロパン酸
実施例77で使用したメチル (R,E)-3-(2-((3-ヒドロキシ-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエートの代わりに、実施例11で製造した化合物を用いて、実施例77と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 2.44-2.48, 2.81-2.85, 3.22, 3.25 ,4.33-4.37, 6.82, 6.86, 6.97, 7.14-7.21, 7.29, 7.33-7.39, 7.48-7.52, 7.56-7.63, 7.79-7.81。
Example 78: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoic acid Methyl (R,E )-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate prepared in Example 11 By subjecting the compound to the same intended operations as in Example 77, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.97;
1H -NMR ( CD3OD ): δ 2.44-2.48, 2.81-2.85, 3.22, 3.25, 4.33-4.37, 6.82, 6.86, 6.97, 7.14-7.21, 7.29, 7.33-7.39, 7.48-7.52, 7.56-7.63 , 7.79-7.81.
実施例79:3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]-3-オキソペントキシ]フェニル]プロパン酸
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに、実施例78で製造した化合物を用いて、実施例33と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.97;
1H-NMR(CD3OD):δ 2.47-2.51, 2.80-2.85, 2.88-2.91, 4.21-4.24, 6.85-6.95, 7.09-7.21, 7.44-7.48, 7.54, 7.74-7.76。
Example 79: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3-oxopentoxy]phenyl]propanoic acid 3-[2-[(E,3R) used in Example 33 -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]Propanoic acid was used for the same purpose as in Example 33, using the compound prepared in Example 78. By performing the operations, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.97;
1H -NMR ( CD3OD ): δ 2.47-2.51, 2.80-2.85, 2.88-2.91, 4.21-4.24, 6.85-6.95, 7.09-7.21, 7.44-7.48, 7.54, 7.74-7.76.
実施例80:3-[2-[5-[3-(1-ヒドロキシ-2-フェニルエチル)フェニル]-3-オキソペントキシ]フェニル]プロパン酸
実施例78で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例12(9)で製造した化合物を用いて、実施例78→実施例79と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.48-2.52, 2.80-2.96, 3.03-3.08, 4.25, 4.82, 6.85-6.94, 7.08-7.22。
Example 80: 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]-3-oxopentoxy]phenyl]propanoic acid 3-[2-[ used in Example 78 (E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid was used in place of the compound prepared in Example 12(9). The title compound having the following physical properties was obtained by performing the same operations as in Example 78→Example 79.
HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 2.48-2.52, 2.80-2.96, 3.03-3.08, 4.25, 4.82, 6.85-6.94, 7.08-7.22.
実施例81:イソプロピル 3-(2-(ペンタ-4-イン-1-イルオキシ)フェニル)プロパノエート
実施例1で製造した化合物(3.00g)のN,N-ジメチルアセトアミド(25mL)溶液に、室温で炭酸セシウム(9.39g)を加え、同温で15分間撹拌した。反応溶液に室温で5-クロロ-1-ペンチン(CAS登録番号:14267-92-6)(1.63g)を加え、60℃で3時間撹拌した。反応溶液に水を加え、ジエチルエーテルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0→5:1)によって精製することにより、以下の物性値を有する標題化合物(2.40g)を得た。
HPLC保持時間(分):1.13。
Example 81: Isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate The compound prepared in Example 1 (3.00 g) was added to a solution of N,N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added thereto, and the mixture was stirred at the same temperature for 15 minutes. 5-chloro-1-pentyne (CAS registration number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60° C. for 3 hours. Water was added to the reaction solution and extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0→5:1) to obtain the title compound (2.40 g) having the following physical properties.
HPLC retention time (min): 1.13.
実施例82:イソプロピル (E)-3-(2-((5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例81で製造した化合物(1.00g)のヘプタン(2mL)溶液に、室温で4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(1.17g)と4-ジメチルアミノ安息香酸(60.2mg)を加え、100℃で4時間撹拌した。反応溶液を室温まで冷却後、濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:1→4:1)によって精製することにより、以下の物性値を有する標題化合物(503mg)を得た。
HPLC保持時間(分):1.38。
Example 82: Isopropyl (E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-1- yl)oxy)phenyl)propanoate To a solution of the compound prepared in Example 81 (1.00 g) in heptane (2 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1→4:1) to obtain the title compound (503 mg) having the following physical properties.
HPLC retention time (min): 1.38.
実施例83:イソプロピル (E)-3-(2-((5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例82で製造した化合物(180mg)のTHF(3mL)溶液に、実施例9で製造した化合物(168mg)、クロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(0.035g)および2Mリン酸三カリウム水溶液(0.67mL)を加え、60℃で1時間撹拌した。反応溶液を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(113mg)を得た。
HPLC保持時間(分):1.24。
Example 83: Isopropyl (E)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Compound prepared in Example 82 (180 mg) in THF (3 mL), the compound prepared in Example 9 (168 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [ 2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.035 g) and 2M aqueous tripotassium phosphate solution (0.67 mL) were added, and the mixture was stirred at 60° C. for 1 hour. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1) to obtain the title compound (113 mg) having the following physical properties.
HPLC retention time (min): 1.24.
実施例84:3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸 Example 84: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid
実施例83で製造した化合物(146mg)のTHF(0.5mL)とメタノール(0.1mL)の溶液に、1M水酸化リチウム水溶液(0.5mL)を加え、50℃で8時間撹拌した。1M塩酸を加え酸性にし、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮することにより、以下の物性値を有する標題化合物(105mg)を得た。
HPLC保持時間(分):1.10
1H-NMR(CD3OD):δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45-7.49, 7.55, 7.75-7.78。
A 1M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound produced in Example 83 (146 mg) in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50° C. for 8 hours. The mixture was made acidic by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (105 mg) having the following physical properties.
HPLC retention time (min): 1.10
1H -NMR (CD 3 OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7. 19, 7.45 -7.49, 7.55, 7.75-7.78.
実施例85:3-[2-[(E)-5-[4-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに1-(4-ブロモフェニル)-2-フェニルエタン-1-オール(CAS登録番号:20498-64-0)を用いて、実施例83→実施例84と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.97-2.03, 2.41-2.45, 2.67-2.71, 2.96-3.03, 4.04, 4.86-4.90, 6.23-6.30, 6.44, 6.83-6.89, 7.16-7.34。
Example 85: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid N-( used in Example 83) Using 1-(4-bromophenyl)-2-phenylethan-1-ol (CAS registration number: 20498-64-0) in place of 3-bromophenyl)benzenesulfonamide, Example 83 → Example 84 The following example compounds were obtained by subjecting them to the same operations as above.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 1.97-2.03, 2.41-2.45, 2.67-2.71, 2.96-3.03, 4.04, 4.86-4.90, 6.23-6.30, 6.44, 6.83-6.89, 7.16-7.34.
実施例86:3-[2-[(E)-5-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに実施例21で製造した化合物を用いて、実施例83→実施例84と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.20;
1H-NMR(CDCl3):δ 2.00, 2.43, 2.64-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.44, 6.83-6.89, 7.15-7.39。
Example 86: 3-[2-[(E)-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Used in Example 83 By using the compound produced in Example 21 instead of the N-(3-bromophenyl)benzenesulfonamide obtained and subjecting it to the same operation as in Example 83 → Example 84, a product having the following physical property values was obtained. The title compound was obtained.
HPLC retention time (min): 1.20;
1H -NMR ( CDCl3 ): δ 2.00, 2.43, 2.64-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.44, 6.83-6.89, 7.15-7.39.
実施例87:3-[2-[(E)-5-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例21で使用した(R)-メチルオキサザボロリジンの代わりに(S)-メチルオキサザボロリジンを、実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例21→実施例83→実施例84と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.20;
1H-NMR(CDCl3):δ 2.00, 2.44, 2.66-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.45, 6.83-8.89, 7.15-7.40。
Example 87: 3-[2-[(E)-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Used in Example 21 (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine, and a corresponding halide compound was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. Then, the title compound having the following physical property values was obtained by subjecting it to the same operations as in Example 21→Example 83→Example 84.
HPLC retention time (min): 1.20;
1H -NMR ( CDCl3 ): δ 2.00, 2.44, 2.66-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.45, 6.83-8.89, 7.15-7.40.
実施例87(1)~(10)
実施例9で使用した3-ブロモアニリンの代わりに相当するアミン化合物を用いて、実施例9→実施例83→実施例84と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
Example 87 (1) to (10)
By using the corresponding amine compound instead of 3-bromoaniline used in Example 9 and subjecting it to the same operation as in Example 9 → Example 83 → Example 84, a title having the following physical property values was obtained. The compound was obtained.
実施例87(1):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-2-(トリフルオロメチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.08;
1H-NMR(CDCl3):δ 1.92-1.99, 2.36-2.42, 2.64-2.68, 2.93-2.97, 3.99, 5.98, 6.02, 6.58-6.65, 6.81, 6.88, 7.00, 7.15-7.20, 7.39-7.45, 7.51-7.56, 7.65, 7.70-7.73。
Example 87(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.08;
1H -NMR ( CDCl3 ): δ 1.92-1.99, 2.36-2.42, 2.64-2.68, 2.93-2.97, 3.99, 5.98, 6.02, 6.58-6.65, 6.81, 6.88, 7.00, 7.15-7.20, 7 .39-7.45, 7.51-7.56, 7.65, 7.70-7.73.
実施例87(2):3-[2-[(E)-5-[5-(ベンゼンスルホンアミド)-2-(トリフルオロメチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.97-2.04, 2.43-2.49, 2.74-2.78, 3.00-3.04, 4.04, 6.25-6.32, 6.66, 6.85, 6.91, 7.10-7.25, 7.44-7.48, 7.53-7.58, 7.84-7.87。
Example 87 (2): 3-[2-[(E)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.10;
1H -NMR ( CDCl3 ): δ 1.97-2.04, 2.43-2.49, 2.74-2.78, 3.00-3.04, 4.04, 6.25-6.32, 6.66, 6.85, 6.91, 7.10-7.25, 7.44-7.48, 7. 53-7.58, 7.84-7.87.
実施例87(3):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-5-(トリフルオロメチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.11;
1H-NMR(CDCl3):δ 1.96-2.02, 2.41-2.46, 2.72-2.76, 2.97-3.01, 4.03, 6.31-6.40, 6.84, 6.90, 7.15-7.25, 7.43-7.48, 7.52-7.57, 7.79-7.82。
Example 87 (3): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.11;
1H -NMR ( CDCl3 ): δ 1.96-2.02, 2.41-2.46, 2.72-2.76, 2.97-3.01, 4.03, 6.31-6.40, 6.84, 6.90, 7.15-7.25, 7.43-7.48, 7.52-7.5 7, 7.79- 7.82.
実施例87(4):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-4-(トリフルオロメチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.98-2.05, 2.45-2.50, 2.68-2.72, 2.97-3.01, 4.04, 6.36-6.47, 6.80-6.91, 7.15-7.22, 7.37-7.44, 7.51-7.55, 7.74-7.79。
Example 87 (4): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.10;
1H -NMR ( CDCl3 ): δ 1.98-2.05, 2.45-2.50, 2.68-2.72, 2.97-3.01, 4.04, 6.36-6.47, 6.80-6.91, 7.15-7.22, 7.37-7.44, 7.51-7.55 , 7.74- 7.79.
実施例87(5):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-2-シアノフェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.01;
1H-NMR(CDCl3):δ 1.95-2.02, 2.44-2.49, 2.64-2.68, 2.93-2.97, 4.01, 6.44, 6.60, 6.82, 6.88, 7.15-7.20, 7.31-7.32, 7.42-7.50, 7.52-7.60, 7.82-7.85。
Example 87 (5): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01;
1H -NMR ( CDCl3 ): δ 1.95-2.02, 2.44-2.49, 2.64-2.68, 2.93-2.97, 4.01, 6.44, 6.60, 6.82, 6.88, 7.15-7.20, 7.31-7.32, 7.42-7. 50, 7.52- 7.60, 7.82-7.85.
実施例87(6):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-4-シアノフェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.98-2.04, 2.46-2.51, 2.57-2.61, 2.92-2.96, 4.04-4.07, 6.38-6.46, 6.87, 6.92, 7.16-7.20, 7.24, 7.34, 7.49-7.55, 7.60, 7.75-7.78。
Example 87 (6): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00;
1H -NMR (CD 3 OD): δ 1.98-2.04, 2.46-2.51, 2.57-2.61, 2.92-2.96, 4.04-4.07, 6.38-6.46, 6.87, 6.92, 7.16-7.20, 7.24, 7.34, 7 .49-7.55 , 7.60, 7.75-7.78.
実施例87(7):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-2,4-ジクロロフェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.07;
1H-NMR(CD3OD):δ 1.87-1.94, 2.36-2.41, 2.44-2.48, 2.81, 3.95, 6.25, 6.59, 6.74, 6.79, 7.03-7.08, 7.22, 7.39-7.43, 7.49-7.53, 7.67-7.70。
Example 87 (7): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2,4-dichlorophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :1.07;
1H -NMR (CD 3 OD): δ 1.87-1.94, 2.36-2.41, 2.44-2.48, 2.81, 3.95, 6.25, 6.59, 6.74, 6.79, 7.03-7.08, 7.22, 7.39-7.43, 7.49- 7.53, 7.67 -7.70.
実施例87(8):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-4-メチルスルホニルフェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.98-2.05, 2.46-2.50, 2.67-2.50, 2.77, 2.96-3.00, 4.03, 6.40-6.42, 6.84, 6.90, 7.16-7.22, 7.47-7.52, 7.58, 7.64, 7.71, 7.91-7.94。
Example 87 (8): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :1.10;
1H -NMR ( CDCl3 ): δ 1.98-2.05, 2.46-2.50, 2.67-2.50, 2.77, 2.96-3.00, 4.03, 6.40-6.42, 6.84, 6.90, 7.16-7.22, 7.47-7.52, 7. 58, 7.64, 7.71, 7.91-7.94.
実施例87(9):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)-5-メチルスルホニルフェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 1.97-2.03, 2.44-2.49, 2.72-2.76, 2.97-3.03, 4.04, 6.36, 6.41-6.48, 6.84, 6.90, 7.15-7.22, 7.40, 7.45-7.49, 7.54-7.58, 7.77, 7.82-7.84。
Example 87 (9): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :0.99;
1H -NMR ( CDCl3 ): δ 1.97-2.03, 2.44-2.49, 2.72-2.76, 2.97-3.03, 4.04, 6.36, 6.41-6.48, 6.84, 6.90, 7.15-7.22, 7.40, 7.45-7. 49, 7.54- 7.58, 7.77, 7.82-7.84.
実施例87(10):3-[2-[(E)-5-[3-(ベンゼンスルホンアミドメチル)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.96-2.02, 2.39-2.44, 2.66-2.70, 2.93-2.97, 4.03, 4.12, 5.33, 6.24, 6.36, 6.83-6.90, 6.96-6.99, 7.14-7.21, 7.47-7.52, 7.54-7.59, 7.84-7.88。
Example 87 (10): 3-[2-[(E)-5-[3-(benzenesulfonamidomethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10 ;
1H -NMR ( CDCl3 ): δ 1.96-2.02, 2.39-2.44, 2.66-2.70, 2.93-2.97, 4.03, 4.12, 5.33, 6.24, 6.36, 6.83-6.90, 6.96-6.99, 7.14-7. 21, 7.47- 7.52, 7.54-7.59, 7.84-7.88.
実施例88(1)~(2)
実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例83→実施例35→実施例84と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
Example 88 (1)-(2)
By using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83, and subjecting it to the same objective operation as Example 83 → Example 35 → Example 84, The title compound having the following physical properties was obtained.
実施例88(1):3-[2-[5-[3-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペントキシ]フェニル]プロパン酸
TLC:Rf 0.61(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 1.47-1.55, 1.67-1.74, 1.79-1.85, 2.58, 2.65, 2.88, 2.97-3.07, 3.96, 4.89, 6.79-6.88, 7.09-7.33。
Example 88 (1): 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid TLC: Rf 0.61 (hexane: ethyl acetate = 1: 2);
1H -NMR ( CDCl3 ): δ 1.47-1.55, 1.67-1.74, 1.79-1.85, 2.58, 2.65, 2.88, 2.97-3.07, 3.96, 4.89, 6.79-6.88, 7.09-7.33.
実施例88(2):3-[2-[5-[4-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペントキシ]フェニル]プロパン酸
HPLC保持時間(分):1.1;
1H-NMR(CDCl3):δ 1.47-1.80, 2.48-2.56, 2.64-2.69, 2.82-2.88, 3.02-3.06, 3.95, 4.89-4.93, 6.79-6.87, 7.11-7.34。
Example 88 (2): 3-[2-[5-[4-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid HPLC retention time (min): 1.1;
1H -NMR ( CDCl3 ): δ 1.47-1.80, 2.48-2.56, 2.64-2.69, 2.82-2.88, 3.02-3.06, 3.95, 4.89-4.93, 6.79-6.87, 7.11-7.34.
実施例89:(R)-3-[2-[5-[3-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペントキシ]フェニル]プロパン酸、または(S)-3-[2-[5-[3-(1-ヒドロキシ-2-フェニルエチル)フェニル]ペントキシ]フェニル]プロパン酸
実施例88(1)で製造した化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IF(10mm×250mm)、移動相:CO2:アセトニトリル:メタノール=75:22.5:2.5、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた実施例88(1)の光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IF(10mm×250mm)、移動相:CO2:アセトニトリル:メタノール=75:22.5:2.5、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)で分析した結果、第一ピークおよび第二ピークの保持時間はそれぞれ14.9分および19.1分であった。
Example 89: (R)-3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid, or (S)-3-[2-[5 -[3-(1-Hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid The compound produced in Example 88 (1) was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IF (10 mm x 250 mm), Optical resolution was performed using a mobile phase: CO 2 :acetonitrile:methanol=75:22.5:2.5, flow rate: 30 mL/min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35° C.). The optically active substance of Example 88 (1) obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IF (10 mm x 250 mm), mobile phase: CO 2 :acetonitrile:methanol=75:22. As a result of analysis, the retention times of the first peak and second peak were 14.9 minutes and 19.5 minutes, respectively. It was 1 minute.
実施例90:4-ブロモ-N-メトキシ-N-メチルチアゾール-2-カルボキサミド
4-ブロモチアゾール-2-カルボン酸(1.0g)のジクロロメタン(9.6mL)溶液に、N,O-ジメチルヒドロキシルアミン塩酸塩(609mg)およびジイソプロピルエチルアミン(2.5mL)および1-(クロロ-1-ピロリジニルメチレン)ピロリジニウムヘキサフルオロホスファート(2.4g)を加え、室温で5時間撹拌した。反応混合物を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)によって精製することにより、以下の物性値を有する標題化合物(1.0g)を得た。
TLC:Rf 0.3(ヘキサン:酢酸エチル=2:1)。
Example 90: 4-Bromo-N-methoxy-N-methylthiazole-2-carboxamide To a solution of 4-bromothiazole-2-carboxylic acid (1.0 g) in dichloromethane (9.6 mL) was added N,O-dimethylhydroxyl. Amine hydrochloride (609 mg), diisopropylethylamine (2.5 mL) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (2.4 g) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1) to obtain the title compound (1.0 g) having the following physical properties.
TLC: Rf 0.3 (hexane: ethyl acetate = 2:1).
実施例91:1-(4-ブロモチアゾール-2-イル)-2-フェニルエタン-1-オン
実施例90で製造した化合物(300mg)のジエチルエーテル(1mL)溶液に、ベンジルマグネシウムブロミド(0.1Mジエチルエーテル溶液、40mL)を0℃で加え、室温で1時間撹拌した。反応混合物に飽和塩化アンモニウム溶液を加え、ジエチルエーテルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=8:1)によって精製することにより、以下の物性値を有する標題化合物(181mg)を得た。
TLC:Rf 0.7(ヘキサン:酢酸エチル=4:1)。
Example 91: 1-(4-bromothiazol-2-yl)-2-phenylethan-1-one To a solution of the compound prepared in Example 90 (300 mg) in diethyl ether (1 mL) was added benzylmagnesium bromide (0. 1M diethyl ether solution (40 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (181 mg) having the following physical properties.
TLC: Rf 0.7 (hexane: ethyl acetate = 4:1).
実施例92:3-[2-[(E)-5-[2-(1-ヒドロキシ-2-フェニルエチル)-1,3-チアゾール-4-イル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例21で使用した1-(3-ブロモフェニル)-2-フェニルエタノンの代わりに実施例91で製造した化合物を、実施例21で使用した(R)-メチルオキサザボロリジンの代わりに(RS)-メチルオキサザボロリジンを、実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例21→実施例83→実施例84と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.98;
1H-NMR(DMSO-d6):δ 1.92-2.00, 2.41-2.48, 2.80-2.84, 2.85-2.90, 3.10-3.15, 4.01-4.06, 4.80-4.85, 5.83, 6.60-6.72, 6.85, 6.95, 7.14-7.18, 7.21-7.25。
Example 92: 3-[2-[(E)-5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-4-yl]pent-4-enoxy]phenyl]propanoic acid The compound prepared in Example 91 was used instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21, and the compound prepared in Example 91 was used instead of (R)-methyloxazaborolidine used in Example 21. Example 21 → Example 83 → Example 84 (RS)-methyloxazaborolidine was added using a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.98;
1H -NMR (DMSO- d6 ): δ 1.92-2.00, 2.41-2.48, 2.80-2.84, 2.85-2.90, 3.10-3.15, 4.01-4.06, 4.80-4.85, 5.83, 6.60-6.72, 6.85, 6 .95, 7.14-7.18, 7.21-7.25.
実施例93:3-[2-[(E)-5-[4-(1-ヒドロキシ-2-フェニルエチル)-1,3-チアゾール-2-イル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例90で使用した4-ブロモチアゾール-2-カルボン酸の代わりに2-ブロモチアゾール-4-カルボン酸を、実施例83で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに相当するハライド化合物を用いて、実施例90→実施例91→実施例21(ただし、(R)-メチルオキサザボロリジンの代わりに(RS)-メチルオキサザボロリジンを使用)→実施例83→実施例84と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 1.98-2.05, 2.41-2.47, 2.66-2.70, 2.96-3.00, 3.08, 3.34, 4.03, 5.18, 6.42-6.46, 6.58, 6.62, 6.83-6.89, 6.93, 7.16-7.25, 7.27-7.34。
Example 93: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pent-4-enoxy]phenyl]propanoic acid Corresponding to 2-bromothiazole-4-carboxylic acid in place of 4-bromothiazole-2-carboxylic acid used in Example 90 and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. Example 90 → Example 91 → Example 21 (however, (RS)-methyloxazaborolidine was used instead of (R)-methyloxazaborolidine) → Example 83 → By performing the same operations as in Example 84, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 1.98-2.05, 2.41-2.47, 2.66-2.70, 2.96-3.00, 3.08, 3.34, 4.03, 5.18, 6.42-6.46, 6.58, 6.62, 6.83-6.89, 6 .93, 7.16- 7.25, 7.27-7.34.
実施例94:3-[2-[5-[5-(1-ヒドロキシ-2-フェニルエチル)-1,3-チアゾール-2-イル]ペントキシ]フェニル]プロパン酸
実施例35で使用したイソプロピル 3-(2-(((R,E)-3-ヒドロキシ-5-(3-((R)-1-ヒドロキシ-2-フェニルエチル)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエートの代わりに実施例93で製造した化合物を用いて,実施例35と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.56-1.64, 1.80-1.90, 2.57-2.61, 2.94, 3.05, 3.09-3.11, 3.96, 5.14, 6.80, 6.86, 7.14-7.25, 7.29-7.33, 7.46。
Example 94: 3-[2-[5-[5-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pentoxy]phenyl]propanoic acid Isopropyl used in Example 35 3 -(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl ) Using the compound prepared in Example 93 instead of propanoate, the following example compound was obtained by subjecting it to the same operation as in Example 35.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.56-1.64, 1.80-1.90, 2.57-2.61, 2.94, 3.05, 3.09-3.11, 3.96, 5.14, 6.80, 6.86, 7.14-7.25, 7.29-7.33, 7 .46.
実施例95:3-[2-[5-[2-(1-ヒドロキシ-2-フェニルエチル)-1,3-チアゾール-5-イル]ペントキシ]フェニル]プロパン酸
実施例35で使用したイソプロピル 3-(2-(((R,E)-3-ヒドロキシ-5-(3-((R)-1-ヒドロキシ-2-フェニルエチル)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエートの代わりに実施例92で製造した化合物を用いて,実施例35と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 1.51-1.59, 1.68-1.85, 2.57-2.61, 2.84, 2.90, 3.09, 3.27, 3.97, 5.14, 6.81, 6.86, 7.13-7.25, 7.28-7.32, 7.39。
Example 95: 3-[2-[5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-5-yl]pentoxy]phenyl]propanoic acid Isopropyl used in Example 35 3 -(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl ) Using the compound prepared in Example 92 instead of propanoate, the following example compound was obtained by subjecting it to the same operation as in Example 35.
HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 1.51-1.59, 1.68-1.85, 2.57-2.61, 2.84, 2.90, 3.09, 3.27, 3.97, 5.14, 6.81, 6.86, 7.13-7.25, 7.28-7.32, 7.39.
実施例95(1):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]-N-メチルスルホニルプロパンアミド
実施例84で製造した化合物(100mg)のDMF(1mL)溶液に、メタンスルホンアミド(102mg)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(124mg)およびDMAP(78.7mg)を加え、室温で23時間撹拌した。反応混合物に1M塩酸を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)によって精製することにより、以下の物性値を有する標題化合物(80.7mg)を得た。HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 1.97-2.04, 2.37-2.42, 2.64-2.67, 2.96-2.99, 3.19, 4.05, 6.22, 6.33, 6.73, 6.85-6.92, 7.06-7.08, 7.13-7.17, 7.21, 7.41-7.45, 7.50-7.54, 7.76-7.78。
Example 95 (1): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]-N-methylsulfonylpropanamide Produced in Example 84 Methanesulfonamide (102 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (124 mg) and DMAP (78.7 mg) were added to a solution of the compound (100 mg) in DMF (1 mL), and the mixture was stirred at room temperature. Stirred for 23 hours. 1M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→0:1) to obtain the title compound (80.7 mg) having the following physical properties. HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 1.97-2.04, 2.37-2.42, 2.64-2.67, 2.96-2.99, 3.19, 4.05, 6.22, 6.33, 6.73, 6.85-6.92, 7.06-7.08, 7.13-7. 17, 7.21, 7.41-7.45, 7.50-7.54, 7.76-7.78.
実施例95(2):3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパンアミド
実施例31で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例84で製造した化合物を用いて、実施例31と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.98;
1H-NMR(CDCl3):δ 1.95-2.02, 2.40-2.45, 2.60-2.64, 3.03-3.07, 4.04, 5.55, 5.82, 6.29, 6.34-6.41, 6.86, 6.89-6.95, 7.03-7.06, 7.11-7.22, 7.41-7.44, 7.49-7.53, 7.82-7.85, 8.25。
Example 95 (2): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanamide 3-[2- used in Example 31 Example 31 by using the compound prepared in Example 84 in place of [(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. By subjecting it to the same operations as above, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.98;
1H -NMR ( CDCl3 ): δ 1.95-2.02, 2.40-2.45, 2.60-2.64, 3.03-3.07, 4.04, 5.55, 5.82, 6.29, 6.34-6.41, 6.86, 6.89-6.95, 7.03-7. 06, 7.11- 7.22, 7.41-7.44, 7.49-7.53, 7.82-7.85, 8.25.
実施例95(3):N-[3-[(E)-5-[2-(2-シアノエチル)フェノキシ]ペンタ-1-エンイル]フェニル]ベンゼンスルホンアミド
実施例95(2)で製造した化合物(100mg)のTHF(1mL)溶液に、氷冷下、ピリジン(0.052mL)とトリフルオロ酢酸無水物(67.8mg)を加え、同温で1時間撹拌した。メタノールと1M水酸化ナトリウム水溶液を加え、室温で1時間撹拌した。反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1→1:1)によって精製することにより、以下の物性値を有する標題化合物(91.0mg)を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 1.95-2.02, 2.37-2.42, 2.61-2.65, 2.95-2.99, 4.03, 6.20, 6.34, 6.49, 6.84-6.94, 7.05-7.25, 7.41-7.46, 7.51-7.55, 7.75-7.78。
Example 95(3): N-[3-[(E)-5-[2-(2-cyanoethyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide Compound produced in Example 95(2) (100 mg) in THF (1 mL) were added pyridine (0.052 mL) and trifluoroacetic anhydride (67.8 mg) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Methanol and 1M aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1→1:1) to obtain the title compound (91.0 mg) having the following physical properties.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 1.95-2.02, 2.37-2.42, 2.61-2.65, 2.95-2.99, 4.03, 6.20, 6.34, 6.49, 6.84-6.94, 7.05-7.25, 7.41-7.46, 7. 51-7.55, 7.75-7.78.
実施例95(4):N-[3-[(E)-5-[2-[2-(1H-テトラゾール-5-イル)エチル]フェノキシ]ペンタ-1-エンイル]フェニル]ベンゼンスルホンアミド
実施例95(3)で製造した化合物(43.0mg)のトルエン(0.5mL)溶液に、トリメチルシリルアジド(44.0mg)とジブチルすずオキシド(24.0mg)を加え、100℃で一晩撹拌した。反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル:メタノール=50:50:3→0:100:3)によって精製することにより、以下の物性値を有する標題化合物(15.0mg)を得た。
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 1.92-1.99, 2.34-2.39, 3.11-3.15, 3.30-3.34, 4.02, 6.20, 6.30, 6.83-6.90, 7.30-7.22, 7.39-7.43, 7.49-7.53, 7.76-7.78。
Example 95 (4): N-[3-[(E)-5-[2-[2-(1H-tetrazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl]benzenesulfonamide
Trimethylsilyl azide (44.0 mg) and dibutyltin oxide (24.0 mg) were added to a toluene (0.5 mL) solution of the compound (43.0 mg) produced in Example 95 (3), and the mixture was stirred at 100°C overnight. did. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 50:50:3 → 0:100:3) to obtain the title compound (15.0 mg) having the following physical properties.
HPLC retention time (min): 0.99;
1H -NMR ( CDCl3 ): δ 1.92-1.99, 2.34-2.39, 3.11-3.15, 3.30-3.34, 4.02, 6.20, 6.30, 6.83-6.90, 7.30-7.22, 7.39-7.43, 7.49-7.5 3, 7.76- 7.78.
実施例95(5):イソブチル (E)-(3-(5-(2-(3-アミノ-3-オキソプロピル)フェノキシ)ペンタ-1-エン-1-イル)フェニル)(フェニルスルホニル)カーバメート
実施例84で製造した化合物(100mg)のTHF(1mL)溶液に、氷冷下、トリエチルアミン(0.20mL)とイソブチルクロロホルマート(110mg)を加え、反応混合物を室温で10分間撹拌した。反応溶液に氷冷下、アンモニア(28%水溶液、0.5mL)を加え,室温で30分間撹拌した。反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1→0:1)によって精製することにより、以下の物性値を有する標題化合物(120mg)を得た。
HPLC保持時間(分):1.11。
Example 95 (5): Isobutyl (E)-(3-(5-(2-(3-amino-3-oxopropyl)phenoxy)pent-1-en-1-yl)phenyl)(phenylsulfonyl)carbamate To a solution of the compound prepared in Example 84 (100 mg) in THF (1 mL) were added triethylamine (0.20 mL) and isobutyl chloroformate (110 mg) under ice cooling, and the reaction mixture was stirred at room temperature for 10 minutes. Ammonia (28% aqueous solution, 0.5 mL) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1→0:1) to obtain the title compound (120 mg) having the following physical properties.
HPLC retention time (min): 1.11.
実施例95(6):N-[3-[(E)-5-[2-[2-(1H-1,2,4-トリアゾール-5-イル)エチル]フェノキシ]ペンタ-1-エンイル]フェニル]ベンゼンスルホンアミド 実施例95(5)で製造した化合物(120mg)のDMF(0.2mL)溶液に、N,N-ジメチルホルムアミドジメチルアセタール(0.5mL)を加え、100℃で4時間撹拌した。反応溶液を減圧濃縮後、酢酸(1mL)とヒドラジン一水和物(0.1mL)を加え、100℃で3時間撹拌した。室温まで冷却後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1→0:1)によって精製した。得られた残さ(48mg)のメタノール(1mL)溶液に、2M水酸化ナトリウム水溶液(0.2mL)を加え、室温で一晩撹拌した。反応混合物を1Mリン酸二水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル:メタノール=50:50:3→0:100:3)によって精製することにより、以下の物性値を有する標題化合物(24.0mg)を得た。
HPLC保持時間(分):0.90;
1H-NMR(CDCl3):δ 1.95-2.02, 2.38-2.43, 3.08-3.18, 4.04, 6.22, 6.32, 6.84-6.89, 6.94-6.97, 7.02, 7.07-7.21, 7.39-7.43, 7.49-7.53, 7.67, 7.75-7.77, 8.04。
Example 95(6): N-[3-[(E)-5-[2-[2-(1H-1,2,4-triazol-5-yl)ethyl]phenoxy]pent-1-enyl] Phenyl]benzenesulfonamide To a solution of the compound prepared in Example 95 (5) (120 mg) in DMF (0.2 mL) was added N,N-dimethylformamide dimethyl acetal (0.5 mL), and the mixture was stirred at 100°C for 4 hours. did. After the reaction solution was concentrated under reduced pressure, acetic acid (1 mL) and hydrazine monohydrate (0.1 mL) were added, and the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). A 2M aqueous sodium hydroxide solution (0.2 mL) was added to a solution of the obtained residue (48 mg) in methanol (1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1M aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 50:50:3 → 0:100:3) to obtain the title compound (24.0 mg) having the following physical properties. Ta.
HPLC retention time (min): 0.90;
1H -NMR ( CDCl3 ): δ 1.95-2.02, 2.38-2.43, 3.08-3.18, 4.04, 6.22, 6.32, 6.84-6.89, 6.94-6.97, 7.02, 7.07-7.21, 7.39-7.43, 7. 49-7.53, 7.67, 7.75-7.77, 8.04.
実施例96:イソプロピル (E)-3-(2-((4-ヒドロキシ-6-(3-(フェニルスルホンアミド)フェニル)ヘキサ-5-エン-1-イル)オキシ)フェニル)プロパノエート
実施例2で使用した2-(2-ブロモエチル)-1,3-ジオキサンの代わりに2-(3-ブロモプロピル)-1,3-ジオキサンを用いて、実施例2→実施例3→実施例4→実施例5→実施例7→実施例8→実施例10と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.43(ヘキサン:酢酸エチル=1:1)。
Example 96: Isopropyl (E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate Example 2 Using 2-(3-bromopropyl)-1,3-dioxane instead of 2-(2-bromoethyl)-1,3-dioxane used in Example 2 → Example 3 → Example 4 → Implementation The title compound having the following physical properties was obtained by subjecting it to the same operations as in Example 5→Example 7→Example 8→Example 10.
TLC: Rf 0.43 (hexane: ethyl acetate = 1:1).
実施例97:3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例96で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81。
Example 97: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 Using the compound prepared in Example 96 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate By subjecting the mixture to the same operations as in Example 11, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.
実施例98:イソプロピル (R,E)-3-(2-((4-ヒドロキシ-6-(3-(フェニルスルホンアミド)フェニル)ヘキサ-5-エン-1-イル)オキシ)フェニル)プロパノエート、またはイソプロピル (S,E)-3-(2-((4-ヒドロキシ-6-(3-(フェニルスルホンアミド)フェニル)ヘキサ-5-エン-1-イル)オキシ)フェニル)プロパノエート
実施例96で製造した化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IC(20mm×250mm)、移動相:CO2:メタノール=85:15、流速:100mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた実施例96の光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IC(10mm×250mm)、移動相:CO2:メタノール=85:15、流速:30mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)で分析した結果、第一ピークおよび第二ピークの保持時間はそれぞれ13.6分および15.8分であった。
Example 98: Isopropyl (R,E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate, or isopropyl (S,E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate in Example 96. The produced compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm x 250 mm), mobile phase: CO 2 : methanol = 85:15, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column temperature: Optical resolution was performed using a temperature of 35°C. The optically active substance of Example 96 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm x 250 mm), mobile phase: CO 2 : methanol = 85:15, flow rate: 30 mL/min , pressure: 120 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 13.6 minutes and 15.8 minutes, respectively.
実施例99:(R)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エノキシ]フェニル]プロパン酸、または(S)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例98で製造した第一ピークの光学活性体を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81。
Example 99: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid, or (S)- 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Propan-2-yl 3-[ used in Example 11 Optically active compound of the first peak produced in Example 98 instead of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.
実施例100:(R)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エノキシ]フェニル]プロパン酸、または(S)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例98で製造した第二ピークの光学活性体を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81。
Example 100: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid, or (S)- 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Propan-2-yl 3-[ used in Example 11 The optically active substance with the second peak produced in Example 98 instead of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.
実施例101: 3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキソキシ]フェニル]プロパン酸
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例97で製造した化合物を用いて、実施例33と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.96;
1H-NMR(CDCl3):δ 1.58-1.67, 1.72-2.00, 2.65-2.09, 2.93-3.07, 3.59-3.65, 3.95-4.05, 6.82-6.93, 6.98-7.01, 7.12-7.22, 7.40-7.45, 7.50-7.54, 7.77-7.80。
Example 101: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid 3-[2-[(E,3R) used in Example 33 -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, using the compound prepared in Example 97, and the same objective operation as in Example 33. The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.96;
1H -NMR ( CDCl3 ): δ 1.58-1.67, 1.72-2.00, 2.65-2.09, 2.93-3.07, 3.59-3.65, 3.95-4.05, 6.82-6.93, 6.98-7.01, 7.12-7.22, 7.40 -7.45, 7.50-7.54, 7.77-7.80.
実施例102:(R)-3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキソキシ]フェニル]プロパン酸、または(S)-3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキソキシ]フェニル]プロパン酸
実施例101で製造した化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IB(20mm×250mm)、移動相:CO2:アセトニトリル:メタノール=80:18:2、流速:100mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた実施例101の光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IB(20mm×250mm)、移動相:CO2:アセトニトリル:メタノール=80:18:2、流速:100mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)で分析した結果、第一ピークおよび第二ピークの保持時間はそれぞれ9.6分および12.3分であった。
Example 102: (R)-3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid, or (S)-3-[2-[6 -[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid The compound produced in Example 101 was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: Optical resolution was performed using CO 2 :acetonitrile:methanol=80:18:2, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35° C.). The optically active substance of Example 101 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO 2 :acetonitrile:methanol=80:18:2, flow rate : 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 9.6 minutes and 12.3 minutes, respectively.
実施例103:3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-オキソヘキソキシ]フェニル]プロパン酸
実施例78で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例97で製造した化合物を用いて、実施例78→実施例79と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.45(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.01-2.10, 2.61-2.75, 2.83, 2.96, 3.96, 6.78-6.82, 6.86-6.91, 6.96, 7.10, 7.14-7.21, 7.42, 7.51, 7.68-7.84。
Example 103: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexoxy]phenyl]propanoic acid 3-[2-[(E,3R)-5 used in Example 78 - [3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid was used for the same purpose as Example 78 → Example 79, using the compound prepared in Example 97 The title compound having the following physical properties was obtained.
TLC: Rf 0.45 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 2.01-2.10, 2.61-2.75, 2.83, 2.96, 3.96, 6.78-6.82, 6.86-6.91, 6.96, 7.10, 7.14-7.21, 7.42, 7.51, 7.68-7 .84.
実施例104(1)~(2)
実施例81で使用したイソプロピル 3-(2-ヒドロキシフェニル)プロパノエートの代わりに相当するフェノール化合物を用いて、実施例81→実施例82→実施例83→実施例84と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
Example 104 (1)-(2)
Using the corresponding phenol compound instead of isopropyl 3-(2-hydroxyphenyl)propanoate used in Example 81, the procedure was carried out for the same purpose as in Example 81 → Example 82 → Example 83 → Example 84. As a result, the following example compounds were obtained.
実施例104(1):2-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]酢酸
HPLC保持時間(分):1.01;
1H-NMR(CDCl3):δ 1.89-1.96, 2.33-2.38, 3.67, 4.01, 6.14, 6.29, 6.68, 6.85-6.94, 7.00-7.28, 7.39-7.43, 7.48-7.52, 7.74-7.77。
Example 104 (1): 2-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]acetic acid HPLC retention time (min): 1.01;
1H -NMR ( CDCl3 ): δ 1.89-1.96, 2.33-2.38, 3.67, 4.01, 6.14, 6.29, 6.68, 6.85-6.94, 7.00-7.28, 7.39-7.43, 7.48-7.52, 7.74-7. 77.
実施例104(2):4-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]ブタン酸
HPLC保持時間(分):1.07;
1H-NMR(CDCl3):δ 1.93-2.00, 2.37-2.43, 2.70, 4.00, 6.21, 6.33, 6.82-6.92, 7.04-7.19, 7.40-7.44, 7.49-7.53, 7.75-7.78。
Example 104 (2): 4-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]butanoic acid HPLC retention time (min): 1.07;
1H -NMR ( CDCl3 ): δ 1.93-2.00, 2.37-2.43, 2.70, 4.00, 6.21, 6.33, 6.82-6.92, 7.04-7.19, 7.40-7.44, 7.49-7.53, 7.75-7.78.
実施例105(1)~(3)
実施例81で使用した5-クロロ-1-ペンチンの代わりに相当するハライド化合物を用いて、実施例81→実施例82→実施例83→実施例84と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
Example 105 (1) to (3)
By using the corresponding halide compound instead of 5-chloro-1-pentyne used in Example 81, and subjecting it to the same objective operation as in Example 81 → Example 82 → Example 83 → Example 84, The following example compounds were obtained.
実施例105(1):3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]ブタ-3-エノキシ]フェニル]プロパン酸
HPLC保持時間(分):1.01;
1H-NMR(CD3OD):δ 2.52-2.56, 2.67-2.71, 2.88-2.92, 4.10-4.13, 6.31, 6.46, 6.86, 6.93-6.98, 7.09-7.20, 7.44-7.49, 7.52-7.57, 7.75-7.78。
Example 105 (1): 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]but-3-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01;
1H -NMR ( CD3OD ): δ 2.52-2.56, 2.67-2.71, 2.88-2.92, 4.10-4.13, 6.31, 6.46, 6.86, 6.93-6.98, 7.09-7.20, 7.44-7.49, 7.52-7. 57, 7.75 -7.78.
実施例105(2):3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]ヘキサ-5-エノキシ]フェニル]プロパン酸
TLC:Rf 0.44(ヘキサン:酢酸エチル=1:1);
1H-NMR(CDCl3):δ 1.65-1.76, 1.77-1.88, 2.25-2.31, 2.69-2.75, 2.99-3.05, 3.99, 6.18, 6.33, 6.83, 6.89, 6.95-7.00, 7.10-7.21, 7.44, 7.53, 7.67, 7.81。
Example 105(2): 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]hex-5-enoxy]phenyl]propanoic acid TLC: Rf 0.44 (hexane: ethyl acetate =1:1);
1H -NMR ( CDCl3 ): δ 1.65-1.76, 1.77-1.88, 2.25-2.31, 2.69-2.75, 2.99-3.05, 3.99, 6.18, 6.33, 6.83, 6.89, 6.95-7.00, 7.10-7. 21, 7.44, 7.53, 7.67, 7.81.
実施例105(3):3-[2-[(E)-7-[3-(ベンゼンスルホンアミド)フェニル]ヘプタ-6-エノキシ]フェニル]プロパン酸
TLC:Rf 0.44(ヘキサン:酢酸エチル=1:1);
1H-NMR(CDCl3):δ 1.61-1.73, 1.77-1.88, 2.27, 2.76-2.82, 3.02-3.07, 4.01, 6.29-6.33, 6.83-6.93, 7.08-7.23, 7.45, 7.53, 7.84, 8.75。
Example 105(3): 3-[2-[(E)-7-[3-(benzenesulfonamido)phenyl]hept-6-enoxy]phenyl]propanoic acid TLC: Rf 0.44 (hexane: ethyl acetate =1:1);
1H -NMR ( CDCl3 ): δ 1.61-1.73, 1.77-1.88, 2.27, 2.76-2.82, 3.02-3.07, 4.01, 6.29-6.33, 6.83-6.93, 7.08-7.23, 7.45, 7.53, 7. 84, 8.75.
実施例106:メチル 3-(2-((4-ヒドロキシ-5-(3-(フェニルスルホンアミド)フェニル)ペンチル)オキシ)フェニル)プロパノエート
実施例84で製造した化合物(200mg)を酢酸エチル(1mL)に溶解した。メタノール(1mL)、トリメチルシリルジアゾメタン(2Mヘキサン溶液、0.3mL)を加え、室温で一晩撹拌した。反応液を減圧濃縮し、得られた残渣をジクロロメタン(2mL)に溶解した。飽和重炭酸ナトリウム水溶液(2mL)、メタクロロ過安息香酸(171mg)を加え、室温で5時間撹拌した。反応溶液に、飽和チオ硫酸ナトリウム水溶液を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をメタノール(2mL)に溶解し、5%パラジウム-炭素(20mg)を加え、水素雰囲気下、室温で3時間撹拌した。反応溶液を濾過した後、濾液を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=70:30→酢酸エチル)によって精製することにより、以下の物性値を有する標題化合物(53mg)を得た。
TLC:Rf 0.31(ヘキサン:酢酸エチル=1:1)。
Example 106: Methyl 3-(2-((4-hydroxy-5-(3-(phenylsulfonamido)phenyl)pentyl)oxy)phenyl)propanoate The compound prepared in Example 84 (200 mg) was added to ethyl acetate (1 mL). ) dissolved in Methanol (1 mL) and trimethylsilyldiazomethane (2M hexane solution, 0.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 mL). Saturated aqueous sodium bicarbonate solution (2 mL) and metachloroperbenzoic acid (171 mg) were added and stirred at room temperature for 5 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 → ethyl acetate) to obtain the title compound ( 53 mg) was obtained.
TLC: Rf 0.31 (hexane: ethyl acetate = 1:1).
実施例107:3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシペントキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例106で製造した化合物を用いて、実施例11と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.60(酢酸エチル);
1H-NMR(CDCl3):δ 1.50-1.68, 1.68-1.74, 1.77-2.00, 2.61-2.70, 2.72-2.79, 2.92-2.99, 3.87, 3.95-4.05, 6.82-7.03, 7.15-7.21, 7.38-7.45, 7.48-7.53, 7.77。
Example 107: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-hydroxypentoxy]phenyl]propanoic acid Propan-2-yl 3-[2-[ used in Example 11) Same as Example 11, using the compound prepared in Example 106 instead of (E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate. By performing the desired operations, the title compound having the following physical properties was obtained.
TLC: Rf 0.60 (ethyl acetate);
1H -NMR ( CDCl3 ): δ 1.50-1.68, 1.68-1.74, 1.77-2.00, 2.61-2.70, 2.72-2.79, 2.92-2.99, 3.87, 3.95-4.05, 6.82-7.03, 7.15-7.21 , 7.38- 7.45, 7.48-7.53, 7.77.
実施例108:エチル 3-(2-(4-オキソブチル)フェニル)プロパノエート
エチル 3-[2-(4-ヒドロキシブチル)フェニル]プロパノエート(CAS登録番号:864677-94-1)(0.56g)のジクロロメタン(9mL)溶液に、炭酸水素ナトリウム(0.56g)および1,1,1-トリアセトキシ-1,1-ジヒドロ-1,2-ベンズヨードキソール-3(1H)-オン(CAS登録番号:87413-09-0)(1.13g)を0℃で加え、反応混合物を室温で1時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで抽出した。有機層を、飽和チオ硫酸ナトリウム水溶液で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(0.34g)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=4:1)。
Example 108: Ethyl 3-(2-(4-oxobutyl)phenyl)propanoate Ethyl 3-[2-(4-hydroxybutyl)phenyl]propanoate (CAS Registration Number: 864677-94-1) (0.56 g) Sodium bicarbonate (0.56 g) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (CAS Registration No. :87413-09-0) (1.13 g) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to obtain the title compound (0.34 g) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 4:1).
実施例109:3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸
実施例4で使用したイソプロピル 3-(2-(3-オキソプロポキシ)フェニル)プロパノエートの代わりに実施例108で製造した化合物を用いて、実施例4→実施例5→実施例7→実施例8→実施例10→実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 1.60-1.79, 2.66-2.72, 2.97-3.01, 4.30-4.35, 6.16, 6.49, 6.98-7.07, 7.13-7.17, 7.40-7.53, 7.77-7.79。
Example 109: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid Isopropyl 3-( used in Example 4) Same as Example 4→Example 5→Example 7→Example 8→Example 10→Example 11 using the compound produced in Example 108 instead of 2-(3-oxopropoxy)phenyl)propanoate By subjecting it to the desired operation, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 1.60-1.79, 2.66-2.72, 2.97-3.01, 4.30-4.35, 6.16, 6.49, 6.98-7.07, 7.13-7.17, 7.40-7.53, 7.77-7.79.
実施例110:(R)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸、または(S)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸 Example 110: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, or (S)- 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid
実施例109で製造した化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IC(20mm×250mm)、移動相:CO2:メタノール=85:15、流速:100mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた実施例109の光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IC(10mm×250mm)、移動相:CO2:メタノール=85:15、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)で分析した結果、第一ピークおよび第二ピークの保持時間はそれぞれ12.4分および14.4分であった。 The compound produced in Example 109 was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm x 250 mm), mobile phase: CO 2 : methanol = 85:15, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm). , column temperature: 35°C). The optically active substance of Example 109 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm x 250 mm), mobile phase: CO 2 : methanol = 85:15, flow rate: 30 mL/min , pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 12.4 minutes and 14.4 minutes, respectively.
実施例111:3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキシル]フェニル]プロパン酸
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例109で製造した化合物を用いて、実施例33と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CD3OD):δ 1.37-1.61, 2.39-2.58, 2.84, 6.79-6.81, 6.98-7.08, 7.30-7.42, 7.61-7.63。
Example 111: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexyl]phenyl]propanoic acid 3-[2-[(E,3R)- used in Example 33 The same objective procedure as in Example 33 was carried out using the compound prepared in Example 109 in place of 5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. As a result, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
1H -NMR ( CD3OD ): δ 1.37-1.61, 2.39-2.58, 2.84, 6.79-6.81, 6.98-7.08, 7.30-7.42, 7.61-7.63.
実施例112:3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-オキソヘキシル]フェニル]プロパン酸 Example 112: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid
実施例78で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例109で製造した化合物を用いて、実施例78→実施例79と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 1.75-1.83, 2.44-2.47, 2.54-2.61, 2.65-2.69, 2.75-2.79, 2.92-2.96, 6.90-6.94, 7.09-7.14, 7.18, 7.43-7.48, 7.54, 7.74-7.76。
Example 109 in place of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 78 By using the compound prepared in Example 78 and subjecting it to the same objective operations as in Example 79, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
1H -NMR (CD 3 OD): δ 1.75-1.83, 2.44-2.47, 2.54-2.61, 2.65-2.69, 2.75-2.79, 2.92-2.96, 6.90-6.94, 7.09-7.14, 7.18, 7.43-7.4 8, 7.54 , 7.74-7.76.
実施例113:イソプロピル 3-(2-((5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例81で製造した化合物(1.5g)および実施例9で製造した化合物(1.7g)のDMF(6mL)溶液に、トリエチルアミン(6mL)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(100mg)、ヨウ化銅(I)(50mg)を加え、60℃で一晩撹拌した。反応溶液に水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)によって精製することにより、以下の物性値を有する標題化合物(1.57g)を得た。
TLC:Rf 0.39(ヘキサン:酢酸エチル=2:1)。
Example 113: Isopropyl 3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate Compound prepared in Example 81 (1.5 g ) and the compound prepared in Example 9 (1.7 g) in DMF (6 mL), triethylamine (6 mL), bis(triphenylphosphine)palladium(II) dichloride (100 mg), copper(I) iodide (50 mg). ) and stirred at 60°C overnight. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→0:1) to obtain the title compound (1.57 g) having the following physical properties.
TLC: Rf 0.39 (hexane: ethyl acetate = 2:1).
実施例114:3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-イノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例113で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CD3OD):δ 2.06-2.12, 2.55-2.59, 2.64-2.67, 2.92-2.96, 4.13-4.16, 6.87, 6.95, 7.03-7.07, 7.12-7.20, 7.45-7.50, 7.56, 7.74-7.77。
Example 114: 3-[2-[5-[3-(benzenesulfonamido)phenyl]pent-4-inoxy]phenyl]propanoic acid Propan-2-yl 3-[2-[( The same procedure as in Example 11 was carried out using the compound prepared in Example 113 in place of E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate. By subjecting it to the intended operations, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
1H -NMR ( CD3OD ): δ 2.06-2.12, 2.55-2.59, 2.64-2.67, 2.92-2.96, 4.13-4.16, 6.87, 6.95, 7.03-7.07, 7.12-7.20, 7.45-7.50, 7. 56, 7.74 -7.77.
実施例115:イソプロピル (R)-3-(2-((5-(3-(フェニルスルホンアミド)フェニル)-3-((トリメチルシリル)オキシ)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例113で使用したイソプロピル 3-(2-(ペンタ-4-イン-1-イルオキシ)フェニル)プロパノエートの代わりに実施例7で製造した化合物を用いて、実施例113と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.12。
Example 115: Isopropyl (R)-3-(2-((5-(3-(phenylsulfonamido)phenyl)-3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl ) Propanoate The same purpose as in Example 113 was obtained by using the compound prepared in Example 7 instead of isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate used in Example 113. By subjecting it to the operation, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.12.
実施例116:イソプロピル (R)-3-(2-((3-ヒドロキシ-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエート
実施例115で製造した化合物(170mg)のTHF(1mL)溶液に、室温でTBAF(1.0M THF溶液、0.48mL)を加え、同温で20分間撹拌した。反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→ヘキサン:酢酸エチル=1:1)によって精製することにより、以下の物性値を有する標題化合物(82.8mg)を得た。
HPLC保持時間(分):1.12。
Example 116: Isopropyl (R)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate Example 115 TBAF (1.0 M THF solution, 0.48 mL) was added to a THF (1 mL) solution of the compound (170 mg) prepared above at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 7:3 → hexane: ethyl acetate = 1:1) to obtain the title compound (82.8 mg) having the following physical properties.
HPLC retention time (min): 1.12.
実施例117:3-[2-[(3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-イノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例116で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.93;
1H-NMR(CD3OD):δ 2.19-2.30, 2.57-2.60, 2.91-2.95, 4.16-4.26, 4.85, 6.88, 6.96, 7.07-7.22, 7.46-7.51, 7.57, 7.75-7.77。
Example 117: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-inoxy]phenyl]propanoic acid Propane-2- used in Example 11 Using the compound prepared in Example 116 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate By subjecting the mixture to the same operations as in Example 11, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.93;
1H -NMR ( CD3OD ): δ 2.19-2.30, 2.57-2.60, 2.91-2.95, 4.16-4.26, 4.85, 6.88, 6.96, 7.07-7.22, 7.46-7.51, 7.57, 7.75-7.77.
実施例118:3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]ペントキシ]フェニル]プロパン酸 Example 118: 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例114で製造した化合物を用いて、実施例33と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.42(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 1.42-1.49, 1.58-1.65, 1.75-1.82, 2.55, 2.67, 2.95, 3.95, 6.80-6.97, 7.10-7.21, 7.27, 7.40, 7.49, 7.76。
Example 114 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 Using the compound prepared in Example 33, the title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 33.
TLC: Rf 0.42 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 1.42-1.49, 1.58-1.65, 1.75-1.82, 2.55, 2.67, 2.95, 3.95, 6.80-6.97, 7.10-7.21, 7.27, 7.40, 7.49, 7.76.
実施例119:イソプロピル (Z)-3-(2-((5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例113で製造した化合物(100mg)の酢酸エチル(10mL)溶液に、室温でリンドラー触媒(パラジウム5重量%含有)(10.0mg)とキノリン(12.8mg)を加え、同温、水素雰囲気下で5時間撹拌した。反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→1:1)によって精製することにより、以下の物性値を有する標題化合物(92.3mg)を得た。
HPLC保持時間(分):1.23。
Example 119: Isopropyl (Z)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Compound prepared in Example 113 (100 mg) in ethyl acetate (10 mL) at room temperature were added Lindlar catalyst (containing 5% by weight of palladium) (10.0 mg) and quinoline (12.8 mg), and the mixture was stirred at the same temperature under a hydrogen atmosphere for 5 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3→1:1) to obtain the title compound (92.3 mg) having the following physical properties.
HPLC retention time (min): 1.23.
実施例120:3-[2-[(Z)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例119で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CD3OD):δ 1.89-1.95, 2.37-2.43, 2.49-2.53, 2.83-2.87, 3.97-4.00, 5.74, 6.38, 6.83-6.89, 6.96-7.02, 7.13-7.19, 7.41-7.45, 7.51, 7.72-7.76。
Example 120: 3-[2-[(Z)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid Propan-2-yl 3-[ used in Example 11 Using the compound prepared in Example 119 in place of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate, Example The title compound having the following physical properties was obtained by subjecting it to the same operation as in No. 11.
HPLC retention time (min): 1.10;
1H -NMR (CD 3 OD): δ 1.89-1.95, 2.37-2.43, 2.49-2.53, 2.83-2.87, 3.97-4.00, 5.74, 6.38, 6.83-6.89, 6.96-7.02, 7.13-7.19, 7. 41-7.45 , 7.51, 7.72-7.76.
実施例121:3-[2-[(Z,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例119で使用したイソプロピル 3-(2-((5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-イン-1-イル)オキシ)フェニル)プロパノエートの代わりに実施例116で製造した化合物を用いて、実施例119→実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.92;
1H-NMR(CD3OD):δ 2.00-2.07, 2.44-2.48, 2.77-2.80, 4.02, 4.11, 4.75, 5.72, 6.46,6.83-6.88, 6.92-7.04, 7.12-7.18, 7.42-7.47, 7.52, 7.74-7.77。
Example 121: 3-[2-[(Z,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Isopropyl used in Example 119 3 Example 119 using the compound prepared in Example 116 in place of -(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate →The title compound having the following physical properties was obtained by subjecting it to the same operations as in Example 11.
HPLC retention time (min): 0.92;
1H -NMR (CD 3 OD): δ 2.00-2.07, 2.44-2.48, 2.77-2.80, 4.02, 4.11, 4.75, 5.72, 6.46, 6.83-6.88, 6.92-7.04, 7.12-7.18, 7.42-7. 47, 7.52 , 7.74-7.77.
実施例122:エチル (E)-3-(2-(3-(ベンジルオキシ)-2-ヒドロキシプロポキシ)フェニル)アクリレート
エチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエート(CAS登録番号:6236-62-0)(1.92g)およびジイソプロピルエチルアミン(0.69mL)のヘキサメチルホスホルアミド(20mL)溶液に、ベンジル グリシジル エーテル(6.57g)を加え、反応混合物を80℃で19時間撹拌した。反応液を室温まで冷却後、水に注ぎ、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)によって精製することにより、以下の物性値を有する標題化合物(2.66g)を得た。
TLC:Rf 0.33(ヘキサン:酢酸エチル=2:1)。
Example 122: Ethyl (E)-3-(2-(3-(benzyloxy)-2-hydroxypropoxy)phenyl)acrylate Ethyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS Benzyl glycidyl ether (6.57 g) was added to a solution of Registration Number: 6236-62-0) (1.92 g) and diisopropylethylamine (0.69 mL) in hexamethylphosphoramide (20 mL), and the reaction mixture was heated at 80°C. The mixture was stirred for 19 hours. After cooling the reaction solution to room temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (2.66 g) having the following physical properties.
TLC: Rf 0.33 (hexane: ethyl acetate = 2:1).
実施例123:エチル (E)-3-(2-(3-(ベンジルオキシ)-2-((tert-ブチルジメチルシリル)オキシ)プロポキシ)フェニル)アクリレート
実施例122で製造した化合物(300mg)およびイミダゾ-ル(200mg)のDMF(3mL)溶液に、tert-ブチルジメチルシリル クロライド(330mg)を0℃で加え、反応混合物を室温で5日間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1)によって精製することにより、以下の物性値を有する標題化合物(380mg)を得た。
TLC:Rf 0.41(ヘキサン:酢酸エチル=9:1)。
Example 123: Ethyl (E)-3-(2-(3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)acrylate Compound prepared in Example 122 (300 mg) and To a solution of imidazole (200 mg) in DMF (3 mL) was added tert-butyldimethylsilyl chloride (330 mg) at 0°C, and the reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the title compound (380 mg) having the following physical properties.
TLC: Rf 0.41 (hexane: ethyl acetate = 9:1).
実施例124:エチル 3-(2-(2-((tert-ブチルジメチルシリル)オキシ)-3-ヒドロキシプロポキシ)フェニル)プロパノエート
実施例123で製造した化合物(380mg)および5%パラジウム炭素(50%wet、180mg)のエタノール(8mL)溶液を、水素雰囲気下、室温で1.5時間撹拌した。反応混合物をセライト(商品名)でろ過後、ろ液を濃縮することにより、以下の物性値を有する標題化合物(290mg)を得た。
TLC:Rf 0.34(ヘキサン:酢酸エチル=4:1)。
Example 124: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-hydroxypropoxy)phenyl)propanoate The compound prepared in Example 123 (380 mg) and 5% palladium on carbon (50% A solution of 180 mg) in ethanol (8 mL) was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. After filtering the reaction mixture through Celite (trade name), the filtrate was concentrated to obtain the title compound (290 mg) having the following physical properties.
TLC: Rf 0.34 (hexane: ethyl acetate = 4:1).
実施例125:エチル 3-(2-(2-((tert-ブチルジメチルシリル)オキシ)-3-オキソプロポキシ)フェニル)プロパノエート
実施例124で製造した化合物(290mg)および炭酸水素ナトリウム(190mg)の塩化メチレン(3mL)溶液に、1,1,1-トリアセトキシ-1,1-ジヒドロ-1,2-ベンズヨードキソール-3(1H)-オン(390mg)を0℃で加え、反応混合物を室温で1時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、塩化メチレンで抽出した。有機層を、飽和チオ硫酸ナトリウム水溶液で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(250mg)を得た。
TLC:Rf 0.40(ヘキサン:酢酸エチル=4:1)。
Example 125: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)propanoate The compound prepared in Example 124 (290 mg) and sodium hydrogen carbonate (190 mg) 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (390 mg) was added to a methylene chloride (3 mL) solution at 0°C, and the reaction mixture was Stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the title compound (250 mg) having the following physical properties.
TLC: Rf 0.40 (hexane: ethyl acetate = 4:1).
実施例126:エチル (E)-3-(2-((2-ヒドロキシ-4-(3-(フェニルスルホンアミド)フェニル)ブタ-3-エン-1-イル)オキシ)フェニル)プロパノエート
実施例45で使用した(R)-4-((4-メトキシベンジル)オキシ)-1-オキソブタン-2-イル ベンゾエートの代わりに実施例125で製造した化合物を用いて、実施例45→実施例55→実施例56→実施例116と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.43(ヘキサン:酢酸エチル=1:1)。
Example 126: Ethyl (E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate Example 45 Using the compound prepared in Example 125 in place of (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-yl benzoate used in Example 45 → Example 55 → Implementation The title compound having the following physical properties was obtained by subjecting it to the same operations as in Example 56→Example 116.
TLC: Rf 0.43 (hexane: ethyl acetate = 1:1).
実施例127:3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシブタ-3-エノキシ]フェニル]プロパン酸 Example 127: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例126で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79。
Substitute for propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 By using the compound produced in Example 126 and subjecting it to the same objective operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7. 52, 7.76- 7.79.
実施例128:エチル (S,E)-3-(2-((2-ヒドロキシ-4-(3-(フェニルスルホンアミド)フェニル)ブタ-3-エン-1-イル)オキシ)フェニル)プロパノエート、またはエチル (R,E)-3-(2-((2-ヒドロキシ-4-(3-(フェニルスルホンアミド)フェニル)ブタ-3-エン-1-イル)オキシ)フェニル)プロパノエート
実施例126で製造した化合物をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IB(20mm×250mm)、移動相:CO2:2-プロパノール=83:17、流速:100mL/min、圧力:120bar、波長:220nm、カラム温度:35℃)を用いて光学分割を行った。前記光学分割条件において得られた実施例126の光学活性体をSFC(使用カラム:株式会社ダイセル CHIRALPAK-IB(10mm×250mm)、移動相:CO2:2-プロパノール=83:17、流速:30mL/min、圧力:100bar、波長:220nm、カラム温度:35℃)で分析した結果、第一ピークおよび第二ピークの保持時間はそれぞれ12.6分および14.6分であった。
Example 128: Ethyl (S,E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate, or ethyl (R,E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate in Example 126 The produced compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO 2 :2-propanol = 83:17, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column Optical resolution was performed using a temperature of 35°C. The optically active substance of Example 126 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (10 mm x 250 mm), mobile phase: CO 2 :2-propanol = 83:17, flow rate: 30 mL /min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 12.6 minutes and 14.6 minutes, respectively.
実施例129:3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシブタ-3-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例128で製造した第一ピークの光学活性体を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79。
Example 129: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 The first peak prepared in Example 128 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 11 using the optically active form of .
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7. 52, 7.76- 7.79.
実施例130:3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシブタ-3-エノキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例128で製造した第二ピークの光学活性体を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79。
Example 130: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 The second peak prepared in Example 128 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 11 using the optically active form of .
HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7. 52, 7.76- 7.79.
実施例131:N-(3-ブロモフェニル)-N-(フェニルスルホニル)ベンゼンスルホンアミド
3-ブロモアニリン(500mg)のジクロロメタン(10mL)溶液に、トリエチルアミン(1.6mL)およびDMAP(177mg)およびベンゼンスルホン酸無水物(1.9g)を加え、室温で18時間撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(950mg)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=4:1)。
Example 131: N-(3-bromophenyl)-N-(phenylsulfonyl)benzenesulfonamide To a solution of 3-bromoaniline (500 mg) in dichloromethane (10 mL) is added triethylamine (1.6 mL) and DMAP (177 mg) and benzene. Sulfonic anhydride (1.9 g) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the title compound (950 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 4:1).
実施例132:N-(3-(4-ヒドロキシブタ-1-イン-1-イル)フェニル)-N-(フェニルスルホニル)ベンゼンスルホンアミド
実施例131で製造した化合物(949mg)のDMF(4mL)溶液に、トリエチルアミン(1.5mL)および3-ブチン-1-オール(220mg)およびヨウ化銅(40mg)およびビス(トリフェニルホスフィンパラジウム)ジクロリド(147mg)を加え、80℃で2時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した.有機層を、水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)によって精製することにより、以下の物性値を有する標題化合物(771mg)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=2:1)。
Example 132: N-(3-(4-hydroxybut-1-yn-1-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide The compound prepared in Example 131 (949 mg) in DMF (4 mL) Triethylamine (1.5 mL), 3-butyn-1-ol (220 mg), copper iodide (40 mg) and bis(triphenylphosphine palladium) dichloride (147 mg) were added to the solution, and the mixture was stirred at 80° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (771 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 2:1).
実施例133:N-(3-(4-ヒドロキシブチル)フェニル)-N-(フェニルスルホニル)ベンゼンスルホンアミド
実施例132で製造した化合物(600mg)および20%水酸化パラジウム炭素(50%wet、150mg)のメタノール(5mL)溶液を、水素雰囲気下、室温で9時間撹拌した.反応混合物をセライト(商品名)でろ過後、ろ液を濃縮することにより、以下の物性値を有する標題化合物(575mg)を得た。
HPLC保持時間(分):1.00。
Example 133: N-(3-(4-hydroxybutyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide The compound prepared in Example 132 (600 mg) and 20% palladium hydroxide on carbon (50% wet, 150 mg) ) in methanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 9 hours. After filtering the reaction mixture through Celite (trade name), the filtrate was concentrated to obtain the title compound (575 mg) having the following physical properties.
HPLC retention time (min): 1.00.
実施例134:3-[3-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]プロパン酸
実施例133で製造した化合物(45mg)のTHF(0.5mL)溶液に、メチル 3-(3-ヒドロキシフェニル)プロパノエート(22mg)およびDIAD(82mg)およびトリフェニルホスフィン(40mg)を加え、室温で2時間撹拌した。反応混合物を、減圧濃縮した。得られた残さのメタノール(0.5mL)および1,2-ジメトキシエタン(0.5mL)溶液に、5N水酸化ナトリウム水溶液(0.4mL)を加え、45℃で19時間撹拌した。反応混合物に、2M塩酸を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥した後に、減圧濃縮した。得られた残さを、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)によって精製することにより、以下の物性値を有する標題化合物(14mg)を得た。
HPLC保持時間(分):0.97;
1H-NMR(CDCl3):δ 1.66-1.75, 2.61, 2.74, 2.94, 3.94, 6.71-6.73, 6.79-6.86, 6.91-7.00, 7.14, 7.21, 7.37-7.41, 7.47-7.52, 7.72-7.74。
Example 134: 3-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid To a solution of the compound prepared in Example 133 (45 mg) in THF (0.5 mL) was added methyl 3 -(3-Hydroxyphenyl)propanoate (22 mg), DIAD (82 mg) and triphenylphosphine (40 mg) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A 5N aqueous sodium hydroxide solution (0.4 mL) was added to a solution of the obtained residue in methanol (0.5 mL) and 1,2-dimethoxyethane (0.5 mL), and the mixture was stirred at 45° C. for 19 hours. 2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (14 mg) having the following physical properties.
HPLC retention time (min): 0.97;
1H -NMR ( CDCl3 ): δ 1.66-1.75, 2.61, 2.74, 2.94, 3.94, 6.71-6.73, 6.79-6.86, 6.91-7.00, 7.14, 7.21, 7.37-7.41, 7.47-7.52, 7 .72-7.74.
実施例135(1)~(6)
実施例134で使用したメチル 3-(3-ヒドロキシフェニル)プロパノエートの代わりに相当するフェノール化合物を用いて、実施例134と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
Example 135 (1) to (6)
The following example compound was obtained by subjecting it to the same operation as in Example 134, using the corresponding phenol compound instead of methyl 3-(3-hydroxyphenyl)propanoate used in Example 134.
実施例135(1):3-[4-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]プロパン酸
HPLC保持時間(分):0.96;
1H-NMR(CD3OD):δ 1.64-1.74, 2.55-2.61, 2.86, 3.91, 6.80-6.84, 6.92-6.94, 7.11-7.15, 7.42-7.46, 7.50-7.54, 7.73-7.76。
Example 135 (1): 3-[4-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.96;
1H -NMR ( CD3OD ): δ 1.64-1.74, 2.55-2.61, 2.86, 3.91, 6.80-6.84, 6.92-6.94, 7.11-7.15, 7.42-7.46, 7.50-7.54, 7.73-7.76.
実施例135(2):4-[2-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]ブタン酸
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 1.77-1.83, 1.96-2.03, 2.48, 2.60, 2.71-2.75, 3.97, 6.82, 6.87-6.90, 7.05-7.07, 7.11-7.20, 7.39-7.43, 7.47-7.52, 7.78-7.81。
Example 135 (2): 4-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 1.77-1.83, 1.96-2.03, 2.48, 2.60, 2.71-2.75, 3.97, 6.82, 6.87-6.90, 7.05-7.07, 7.11-7.20, 7.39-7.43, 7. 47-7.52, 7.78-7.81.
実施例135(3):4-[3-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]ブタン酸
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 1.70-1.74, 1.95-2.02, 2.40, 2.59, 2.65, 3.93, 6.71-6.78, 6.86, 6.93-6.95, 7.12-7.21, 7.39-7.43, 7.48-7.52, 7.74-7.77。
Example 135 (3): 4-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 0.99;
1H -NMR ( CDCl3 ): δ 1.70-1.74, 1.95-2.02, 2.40, 2.59, 2.65, 3.93, 6.71-6.78, 6.86, 6.93-6.95, 7.12-7.21, 7.39-7.43, 7.48-7. 52, 7.74- 7.77.
実施例135(4):2-[2-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]酢酸
HPLC保持時間(分):0.94;
1H-NMR(CDCl3):δ 1.68-1.72, 2.57, 3.65, 3.96, 6.80-6.94, 7.13, 7.21-7.24, 7.37-7.42, 7.47-7.52, 7.74-7.77。
Example 135 (4): 2-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid HPLC retention time (min): 0.94;
1H -NMR ( CDCl3 ): δ 1.68-1.72, 2.57, 3.65, 3.96, 6.80-6.94, 7.13, 7.21-7.24, 7.37-7.42, 7.47-7.52, 7.74-7.77.
実施例135(5):2-[3-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]酢酸
HPLC保持時間(分):0.95;
1H-NMR(CDCl3):δ 1.74-1.77, 2.57-2.60, 3.66, 3.98, 6.83-6.86, 6.91-6.96, 7.11, 7.19-7.26, 7.36-7.43, 7.48-7.52, 7.75-7.78。
Example 135 (5): 2-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid HPLC retention time (min): 0.95;
1H -NMR ( CDCl3 ): δ 1.74-1.77, 2.57-2.60, 3.66, 3.98, 6.83-6.86, 6.91-6.96, 7.11, 7.19-7.26, 7.36-7.43, 7.48-7.52, 7.75-7.7 8.
実施例135(6):3-[2-[4-[3-(ベンゼンスルホンアミド)フェニル]ブトキシ]フェニル]プロパン酸
HPLC保持時間(分):0.99;
1H-NMR(CDCl3):δ 1.70-1.86, 2.61, 2.66-2.70, 2.97-3.01, 3.97, 6.82, 6.87-6.91, 7.03-7.06, 7.12-7.21, 7.40-7.44, 7.48-7.53, 7.60, 7.78-7.81。
Example 135 (6): 3-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.99;
1H -NMR ( CDCl3 ): δ 1.70-1.86, 2.61, 2.66-2.70, 2.97-3.01, 3.97, 6.82, 6.87-6.91, 7.03-7.06, 7.12-7.21, 7.40-7.44, 7.48-7.5 3, 7.60, 7.78-7.81.
実施例136:イソプロピル (E)-3-(2-((5-(3-ニトロフェニル)-3-オキソペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例10で使用したN-(3-ブロモフェニル)ベンゼンスルホンアミドの代わりに3-ブロモニトロベンゼンを用いて、実施例10→実施例77と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.43(ヘキサン:酢酸エチル=2:1)。
Example 136: Isopropyl (E)-3-(2-((5-(3-nitrophenyl)-3-oxopent-4-en-1-yl)oxy)phenyl)propanoate N- used in Example 10 By using 3-bromonitrobenzene in place of (3-bromophenyl)benzenesulfonamide and subjecting it to the same operations as in Example 10→Example 77, the title compound having the following physical properties was obtained.
TLC: Rf 0.43 (hexane: ethyl acetate = 2:1).
実施例137:イソプロピル (E)-3-(2-((3,3-ジフルオロ-5-(3-ニトロフェニル)ペンタ-4-エン-1-イル)オキシ)フェニル)プロパノエート
実施例136で製造した化合物(205mg)をジクロロメタン(0.4mL)に溶解し、ビス(2-メトキシエチル)アミノ硫黄トリフルオリド(1.5mL)を加え、室温で3日間撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=90:10→酢酸エチル)によって精製することにより、以下の物性値を有する標題化合物(29mg)を得た。
TLC:Rf 0.66(ヘキサン:酢酸エチル=2:1)。
Example 137: Isopropyl (E)-3-(2-((3,3-difluoro-5-(3-nitrophenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Prepared in Example 136 The obtained compound (205 mg) was dissolved in dichloromethane (0.4 mL), bis(2-methoxyethyl)aminosulfur trifluoride (1.5 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10→ethyl acetate) to obtain the title compound (29 mg) having the following physical properties.
TLC: Rf 0.66 (hexane: ethyl acetate = 2:1).
実施例138:3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]-3,3-ジフルオロペンタ-4-エノキシ]フェニル]プロパン酸
実施例55で使用した(R,E)-5-(2-((E)-3-メトキシ-3-オキソプロパ-1-エン-1-イル)フェノキシ)-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートの代わりに実施例137で製造した化合物を用いて、実施例55→実施例56→実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.22(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.50-2.62, 2.72, 2.93, 4.20, 6.30, 6.80-6.95, 7.05, 7.12-7.25, 7.43, 7.53, 7.78, 7.89。
Example 138: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropent-4-enoxy]phenyl]propanoic acid used in Example 55 (R ,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)pent-1-en-3-yl By using the compound produced in Example 137 instead of benzoate and subjecting it to the same operations as in Example 55 → Example 56 → Example 11, the title compound having the following physical properties was obtained.
TLC: Rf 0.22 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 2.50-2.62, 2.72, 2.93, 4.20, 6.30, 6.80-6.95, 7.05, 7.12-7.25, 7.43, 7.53, 7.78, 7.89.
実施例139:3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]-3,3-ジフルオロペントキシ]フェニル]プロパン酸 Example 139: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid
実施例33で使用した3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸の代わりに実施例138で製造した化合物を用いて、実施例33と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
TLC:Rf 0.20(ヘキサン:酢酸エチル=1:2);
1H-NMR(CDCl3):δ 2.14-2.47, 2.67-2.74, 2.76-2.84, 2.88-2.98, 4.13-4.21, 6.79-6.88, 6.89-7.07, 7.11-7.25, 7.42, 7.52, 7.79。
Example 138 in place of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 Using the compound prepared in Example 33, the title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 33.
TLC: Rf 0.20 (hexane: ethyl acetate = 1:2);
1H -NMR ( CDCl3 ): δ 2.14-2.47, 2.67-2.74, 2.76-2.84, 2.88-2.98, 4.13-4.21, 6.79-6.88, 6.89-7.07, 7.11-7.25, 7.42, 7.52, 7.7 9.
実施例140:(S)-5-((2-(2,2-ジメチル-1,3-ジオキソラン-4-イル)エチル)チオ)-1-フェニル-1H-テトラゾール
2-[(S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール(CAS登録番号:32233-43-5)(2.00g)のTHF(25mL)溶液に、室温で1-フェニル-1H-テトラゾール-5-チオール(CAS登録番号:86-93-1)(3.66g)、トリフェニルホスフィン(5.38g)およびDIAD(1.10g)を加え、同温で1時間撹拌した。反応溶液を減圧濃縮後、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(4.14g)を得た。
HPLC保持時間(分):0.97。
Example 140: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)thio)-1-phenyl-1H-tetrazole 2-[(S)- 1-Phenyl-1H-tetrazole was added to a solution of 2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (CAS registration number: 32233-43-5) (2.00 g) in THF (25 mL) at room temperature. -5-thiol (CAS registration number: 86-93-1) (3.66 g), triphenylphosphine (5.38 g) and DIAD (1.10 g) were added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1) to obtain the title compound (4.14 g) having the following physical properties.
HPLC retention time (min): 0.97.
実施例141:(S)-5-((2-(2,2-ジメチル-1,3-ジオキソラン-4-イル)エチル)スルホニル)-1-フェニル-1H-テトラゾール
実施例140で製造した化合物(4.14g)のアセトニトリル(15mL)とエタノール(15mL)溶液に、氷冷下モリブデン酸アンモニウム四水和物(1.57g)と30重量%過酸化水素水(8.3mL)を加え、室温で16時間撹拌した。反応溶液を減圧濃縮後、得られた水層を酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さを2,2-ジメトキシプロパン(8.3mL)に溶解後、室温でp-トルエンスルホン酸一水和物(129mg)を加え、同温で1時間撹拌した。反応溶液を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(3.96g)を得た。
HPLC保持時間(分):0.96。
Example 141: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole Compound prepared in Example 140 To a solution of (4.14 g) in acetonitrile (15 mL) and ethanol (15 mL), ammonium molybdate tetrahydrate (1.57 g) and 30% by weight hydrogen peroxide solution (8.3 mL) were added under ice cooling, and the mixture was heated to room temperature. The mixture was stirred for 16 hours. After concentrating the reaction solution under reduced pressure, the resulting aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. After dissolving the obtained residue in 2,2-dimethoxypropane (8.3 mL), p-toluenesulfonic acid monohydrate (129 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1) to obtain the title compound (3.96 g) having the following physical properties.
HPLC retention time (min): 0.96.
実施例142:(S,E)-N-(3-(4,5-ジヒドロキシペンタ-1-エン-1-イル)フェニル)ベンゼンスルホンアミド
実施例141で製造した化合物(1.04g)の1,2-ジメトキシエタン(15mL)溶液に、-78℃でカリウム ビス(トリメチルシリル)アミド(0.5Mトルエン溶液、15.3mL)を加え、同温で10分間撹拌した。反応溶液に、-78℃でN-(3-ホルミルフェニル)ベンゼンスルホンアミド(CAS登録番号:151721-35-6)(800mg)の1,2-ジメトキシエタン(5mL)溶液を加え、室温で1時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1)によって精製した。得られた残さをメタノール(3mL)に溶解後、室温で2M塩酸(3mL)を加え、50℃で30分間撹拌した。反応溶液を氷冷後、2M水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0→9:1)によって精製することにより、以下の物性値を有する標題化合物(675mg)を得た。
HPLC保持時間(分):0.73。
Example 142: (S,E)-N-(3-(4,5-dihydroxypent-1-en-1-yl)phenyl)benzenesulfonamide 1 of the compound prepared in Example 141 (1.04 g) Potassium bis(trimethylsilyl)amide (0.5M toluene solution, 15.3 mL) was added to a solution of ,2-dimethoxyethane (15 mL) at -78°C, and the mixture was stirred at the same temperature for 10 minutes. A solution of N-(3-formylphenyl)benzenesulfonamide (CAS registration number: 151721-35-6) (800 mg) in 1,2-dimethoxyethane (5 mL) was added to the reaction solution at -78°C, and 1 Stir for hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). After dissolving the obtained residue in methanol (3 mL), 2M hydrochloric acid (3 mL) was added at room temperature, and the mixture was stirred at 50°C for 30 minutes. The reaction solution was cooled with ice, neutralized with a 2M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0→9:1) to obtain the title compound (675 mg) having the following physical properties.
HPLC retention time (min): 0.73.
実施例143:(S,E)-1-ヒドロキシ-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-2-イル ベンゾエート
実施例142で製造した化合物(450mg)とイミダゾール(131mg)のDMF(5mL)溶液に、氷冷下でt-ブチルジメチルクロロシラン(0.7M DMF溶液、2mL)を5分間かけて滴下後、室温で24時間撹拌した。反応溶液を氷冷後、イミダゾール(131mg)とt-ブチルジメチルクロロシラン(213mg)を加え、室温で5時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをジクロロメタン(5mL)に溶解後、氷冷下でピリジン(0.42mL)、塩化ベンゾイル(215mg)およびDMAP(15.7mg)を加え、室温で1.5時間撹拌した。反応溶液を氷冷後、塩化ベンゾイル(215mg)を加え,室温で1.5時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→2:1)によって精製した。得られた残さをTHF(3mL)と酢酸(0.30mL)に溶解後、氷冷下でTBAF(1.0M THF溶液1.6mL)を加え、室温で12時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→2:1)によって精製することにより、以下の物性値を有する標題化合物(292mg)を得た。
HPLC保持時間(分):0.97。
Example 143: (S,E)-1-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate The compound prepared in Example 142 (450 mg) and imidazole (131 mg) ) to a DMF (5 mL) solution under ice-cooling, t-butyldimethylchlorosilane (0.7M DMF solution, 2 mL) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 24 hours. After cooling the reaction solution with ice, imidazole (131 mg) and t-butyldimethylchlorosilane (213 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. After dissolving the obtained residue in dichloromethane (5 mL), pyridine (0.42 mL), benzoyl chloride (215 mg) and DMAP (15.7 mg) were added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After cooling the reaction solution with ice, benzoyl chloride (215 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1). After dissolving the obtained residue in THF (3 mL) and acetic acid (0.30 mL), TBAF (1.6 mL of 1.0 M THF solution) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1) to obtain the title compound (292 mg) having the following physical properties.
HPLC retention time (min): 0.97.
実施例144:(S,E)-1-ヨード-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-2-イル ベンゾエート
実施例143で製造した化合物(147mg)のDMF(1mL)溶液に、室温でイミダゾール(68.6mg)とトリフェニルホスフィン(106mg)を加えた。反応溶液に氷冷下でヨウ素(102mg)を加え、50℃で1.5時間撹拌した。反応溶液を氷冷後、トリフェニルホスフィン(26.0mg)とヨウ素(25.0mg)を加え、50℃で30分間撹拌した。反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→3:2)によって精製することにより、以下の物性値を有する標題化合物(121mg)を得た。
HPLC保持時間(分):1.20。
Example 144: (S,E)-1-iodo-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate The compound prepared in Example 143 (147 mg) in DMF (1 mL) ) Imidazole (68.6 mg) and triphenylphosphine (106 mg) were added to the solution at room temperature. Iodine (102 mg) was added to the reaction solution under ice cooling, and the mixture was stirred at 50°C for 1.5 hours. After cooling the reaction solution on ice, triphenylphosphine (26.0 mg) and iodine (25.0 mg) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→3:2) to obtain the title compound (121 mg) having the following physical properties.
HPLC retention time (min): 1.20.
実施例145:(S,E)-1-(2-(3-イソプロポキシ-3-オキソプロピル)フェノキシ)-5-(3-(フェニルスルホンアミド)フェニル)ペンタ-4-エン-2-イル ベンゾエート
実施例1で製造した化合物(68.4mg)のDMF(0.5mL)溶液に、氷冷下で水素化ナトリウム(60%inミネラルオイル、13.1mg)を加え、室温で15分間撹拌した。反応溶液に、室温で実施例144で製造した化合物(60mg)のDMF(0.5mL)溶液を加え、60℃で2時間撹拌した。反応溶液を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→3:2)によって精製することにより、以下の物性値を有する標題化合物(12.1mg)を得た。
HPLC保持時間(分):1.29。
Example 145: (S,E)-1-(2-(3-isopropoxy-3-oxopropyl)phenoxy)-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl Benzoate To a solution of the compound prepared in Example 1 (68.4 mg) in DMF (0.5 mL) was added sodium hydride (60% in mineral oil, 13.1 mg) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. . A solution of the compound prepared in Example 144 (60 mg) in DMF (0.5 mL) was added to the reaction solution at room temperature, and the mixture was stirred at 60° C. for 2 hours. After cooling the reaction solution to room temperature, it was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→3:2) to obtain the title compound (12.1 mg) having the following physical properties.
HPLC retention time (min): 1.29.
実施例146:3-[2-[(E,2S)-5-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸
実施例57で使用した(R,E)-5-(2-((E)-3-メトキシ-3-オキソプロパ-1-エン-1-イル)フェノキシ)-1-(3-(フェニルスルホンアミド)フェニル)ペンタ-1-エン-3-イル ベンゾエートの代わりに実施例145で製造した化合物を用いて、実施例57と同様の目的の操作を付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.95
1H-NMR(CD3OD):δ 2.50, 2.59-2.65, 2.95-2.99, 3.95-4.02, 4.09, 6.29, 6.43, 6.86-6.96, 7.08-7.10, 7.12-7.20, 7.44-7.48, 7.54, 7.75-7.77。
Example 146: 3-[2-[(E,2S)-5-[3-(benzenesulfonamido)phenyl]-2-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 57 (R ,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamido)phenyl)pent-1-ene By using the compound prepared in Example 145 in place of -3-yl benzoate and carrying out the same operation as in Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.95
1H -NMR (CD 3 OD): δ 2.50, 2.59-2.65, 2.95-2.99, 3.95-4.02, 4.09, 6.29, 6.43, 6.86-6.96, 7.08-7.10, 7.12-7.20, 7.44-7.48, 7 .54, 7.75 -7.77.
実施例147:2-(3-ニトロフェネトキシ)酢酸
2-(3-ニトロフェニル)エタノール(CAS登録番号:52022-77-2)(2.00g)のDMF(4mL)溶液を0℃に冷却し、水素化ナトリウム(60% inミネラルオイル、0.7g)を加え、0℃で15分撹拌した。イソプロピルブロモアセテート(2.6g)を滴下し、0℃で1時間、室温で2時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→2:1)によって精製することにより、エステル化合物(1.80g)を得た。メタノール(15mL)に溶解させ、水酸化ナトリウム(2N水溶液、10mL)を加え室温で終夜撹拌した。反応混合物を2M塩酸に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(1.15g)を得た。
1H-NMR(CDCl3):δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14。
Example 147: A solution of 2-(3-nitrophenethoxy)acetic acid 2-(3-nitrophenyl)ethanol (CAS registration number: 52022-77-2) (2.00 g) in DMF (4 mL) was cooled to 0 °C. Then, sodium hydride (60% in mineral oil, 0.7 g) was added, and the mixture was stirred at 0°C for 15 minutes. Isopropyl bromoacetate (2.6 g) was added dropwise, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→2:1) to obtain an ester compound (1.80 g). The mixture was dissolved in methanol (15 mL), added with sodium hydroxide (2N aqueous solution, 10 mL), and stirred at room temperature overnight. The reaction mixture was poured into 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.15 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14.
実施例148:2-(3-ニトロフェネトキシ)エタン-1-オール
実施例147で製造した化合物(1.15g)と4-メチルモルホリン(0.8mL)のTHF(10mL)溶液を0℃に冷却し、イソブチルクロロホルメート(0.8mL)を滴下した。室温で30分間撹拌し、生成する白色固体を濾取した。ろ液を0℃に冷却し、水素化ホウ素ナトリウム(1.15g)を加え0℃で10分間撹拌した後,少量の水を加え室温で30分間撹拌した.反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、以下の物性値を有する標題化合物(1.15g)を得た。
1H-NMR(CDCl3):δ 1.82, 3.00-3.03, 3.56-3.58, 3.69-3.78, 7.47, 7.56-7.58, 8.07-8.13。
Example 148: 2-(3-nitrophenethoxy)ethane-1-ol A solution of the compound prepared in Example 147 (1.15 g) and 4-methylmorpholine (0.8 mL) in THF (10 mL) was heated to 0°C. After cooling, isobutyl chloroformate (0.8 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and the resulting white solid was collected by filtration. The filtrate was cooled to 0°C, sodium borohydride (1.15g) was added, and the mixture was stirred at 0°C for 10 minutes, then a small amount of water was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:1) to obtain the title compound (1.15 g) having the following physical properties.
1H -NMR ( CDCl3 ): δ 1.82, 3.00-3.03, 3.56-3.58, 3.69-3.78, 7.47, 7.56-7.58, 8.07-8.13.
実施例149:3-[2-[2-[2-[3-(ベンゼンスルホンアミド)フェニル]エトキシ]エトキシ]フェニル]プロパン酸 Example 149: 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid
実施例54で使用した(R,E)-5-ヒドロキシ-1-(3-ニトロフェニル)ペンタ-1-エン-3-イル ベンゾエートの代わりに実施例148で製造した化合物を、実施例54で使用したメチル (E)-3-(2-ヒドロキシフェニル)プロパ-2-エノエートの代わりに実施例1で製造した化合物を用いて、実施例54→実施例55→実施例56→実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):0.99;
1H-NMR(DMSO-d6):δ 2.70-2.80, 3.17-3.18, 3.56-3.60, 3.68-3.71, 4.05-4.08, 6.84-6.96, 7.09-7.19, 7.50-7.60, 7.74-7.76。
In place of (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 54, the compound prepared in Example 148 was used in Example 54. Using the compound prepared in Example 1 instead of the used methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate, Example 54→Example 55→Example 56→Example 11 By subjecting it to a similar operation, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.99;
1H -NMR (DMSO- d6 ): δ 2.70-2.80, 3.17-3.18, 3.56-3.60, 3.68-3.71, 4.05-4.08, 6.84-6.96, 7.09-7.19, 7.50-7.60, 7.74-7.76.
実施例150:tert-ブチル (S)-2-(3-(1-ヒドロキシ-2-フェニルエチル)フェニル)アセテート
(1S)-1-(3-ブロモフェニル)-2-フェニル-エタノール(412mg)のTHF(0.5mL)溶液にブロモ-(2-tert-ブトキシ-2-オキソ-エチル)亜鉛(0.5M THF溶液、9mL)およびビス(トリ-tert-ブチルホスフィン)パラジウム(76mg)を加え、70℃で2時間撹拌した。反応混合物を室温に冷却し、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(296mg)を得た。
TLC:Rf 0.40(ヘキサン:酢酸エチル=4:1)。
Example 150: tert-butyl (S)-2-(3-(1-hydroxy-2-phenylethyl)phenyl)acetate (1S)-1-(3-bromophenyl)-2-phenyl-ethanol (412 mg) To a THF (0.5 mL) solution were added bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.5 M THF solution, 9 mL) and bis(tri-tert-butylphosphine) palladium (76 mg). , and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the title compound (296 mg) having the following physical properties.
TLC: Rf 0.40 (hexane: ethyl acetate = 4:1).
実施例151:tert-ブチル 2-(3-((1S)-2-フェニル-1-((テトラヒドロ-2H-ピラン-2-イル)オキシ)エチル)フェニル)アセテート
実施例150で製造した化合物(296mg)のジクロロメタン(2mL)溶液に、3,4-ジヒドロ-2H-ピラン(239mg)および4-トルエンスルホン酸ピリジニウム(71mg)を加え、室温で1.5時間撹拌した。反応混合物に、飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(341mg)を得た。
TLC:Rf 0.60(ヘキサン:酢酸エチル=4:1)。
Example 151: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)acetate Compound prepared in Example 150 ( 3,4-dihydro-2H-pyran (239 mg) and pyridinium 4-toluenesulfonate (71 mg) were added to a solution of 296 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (341 mg) having the following physical properties.
TLC: Rf 0.60 (hexane: ethyl acetate = 4:1).
実施例152:2-(3-((1S)-2-フェニル-1-((テトラヒドロ-2H-ピラン-2-イル)オキシ)エチル)フェニル)エタン-1-オール
実施例151で製造した化合物(341mg)のTHF(4mL)溶液に、水(0.15mL)および水素化ホウ素リチウム(187mg)加え、40℃で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)によって精製することにより、以下の物性値を有する標題化合物(236mg)を得た。
TLC:Rf 0.50(ヘキサン:酢酸エチル=1:1)。
Example 152: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)ethan-1-ol Compound prepared in Example 151 (341 mg) in THF (4 mL), water (0.15 mL) and lithium borohydride (187 mg) were added, and the mixture was stirred at 40°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain the title compound (236 mg) having the following physical properties.
TLC: Rf 0.50 (hexane: ethyl acetate = 1:1).
実施例153:tert-ブチル 2-(3-((1S)-2-フェニル-1-((テトラヒドロ-2H-ピラン-2-イル)オキシ)エチル)フェネトキシ)アセテート
実施例152で製造した化合物(236mg)のDMF(2mL)溶液に、ブロモ酢酸tert-ブチル(424mg)および水素化ナトリウム(60%inミネラルオイル、87mg)を加え、室温で2.5時間撹拌した。反応混合物に、飽和塩化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(250mg)を得た。
TLC:Rf 0.60(ヘキサン:酢酸エチル=4:1)。
Example 153: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenetoxy)acetate Compound prepared in Example 152 ( Tert-butyl bromoacetate (424 mg) and sodium hydride (60% in mineral oil, 87 mg) were added to a solution of 236 mg) in DMF (2 mL), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the title compound (250 mg) having the following physical properties.
TLC: Rf 0.60 (hexane: ethyl acetate = 4:1).
実施例154:2-(3-((1S)-2-フェニル-1-((テトラヒドロ-2H-ピラン-2-イル)オキシ)エチル)フェネトキシ)エタン-1-オール
実施例153で製造した化合物(250mg)のTHF(0.5mL)溶液に、水(0.1mL)および水素化ホウ素リチウム(123mg)を加え、40℃で2.5時間撹拌した。反応混合物に、水を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)によって精製することにより、以下の物性値を有する標題化合物(107mg)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=1:1)。
Example 154: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenetoxy)ethane-1-ol Compound prepared in Example 153 (250 mg) in THF (0.5 mL) were added water (0.1 mL) and lithium borohydride (123 mg), and the mixture was stirred at 40°C for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (107 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 1:1).
実施例155:イソプロピル (S)-3-(2-(2-(3-(1-ヒドロキシ-2-フェニルエチル)フェネトキシ)エトキシ)フェニル)プロパノエート
実施例154で製造した化合物(107mg)のジクロロメタン(1mL)溶液に、実施例1で製造した化合物(90mg)、トリフェニルホスフィン(114mg)および1,1-(アゾジカルボニル)ジピぺリジン(110mg)を加え、室温で1.5時間撹拌した。反応混合物を、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1)によって精製することによりエステル化合物(181mg)を得た。得られたエステル化合物(181mg)のTHF(0.6mL)溶液に、水(0.8mL)および酢酸(3.2mL)を加え、50℃で7時間撹拌した。反応混合物に、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)によって精製することにより、以下の物性値を有する標題化合物(97mg)を得た。
TLC:Rf 0.20(ヘキサン:酢酸エチル=4:1)。
Example 155: Isopropyl (S)-3-(2-(2-(3-(1-hydroxy-2-phenylethyl)phenetoxy)ethoxy)phenyl)propanoate The compound prepared in Example 154 (107 mg) was dissolved in dichloromethane ( The compound prepared in Example 1 (90 mg), triphenylphosphine (114 mg) and 1,1-(azodicarbonyl)dipiperidine (110 mg) were added to the 1 mL) solution, and the mixture was stirred at room temperature for 1.5 hours. . The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain an ester compound (181 mg). To a solution of the obtained ester compound (181 mg) in THF (0.6 mL) were added water (0.8 mL) and acetic acid (3.2 mL), and the mixture was stirred at 50°C for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to obtain the title compound (97 mg) having the following physical properties.
TLC: Rf 0.20 (hexane: ethyl acetate = 4:1).
実施例156:3-[2-[2-[2-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]エトキシ]エトキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例155で製造した化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.10;
1H-NMR(CDCl3):δ 2.59-2.63, 2.90-2.94, 3.00-3.03, 3.76-3.80, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 7.13-7.21, 7.22-7.32。
Example 156: 3-[2-[2-[2-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid Propane used in Example 11 Compound prepared in Example 155 in place of 2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
HPLC retention time (min): 1.10;
1H -NMR ( CDCl3 ): δ 2.59-2.63, 2.90-2.94, 3.00-3.03, 3.76-3.80, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 7.13-7.21, 7.22-7.32.
実施例157:3-[2-[2-[2-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]エトキシ]エトキシ]フェニル]プロパン酸
実施例150で使用した(1S)-1-(3-ブロモフェニル)-2-フェニル-エタノールの代わりに実施例21で製造した化合物を用いて、実施例150→実施例151→実施例152→実施例153→実施例154→実施例155→実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.00;
1H-NMR(CDCl3):δ 2.58-2.62, 2.90-2.95, 2.99-3.06, 3.77-3.81, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 6.88, 7.13-7.21, 7.25-7.32。
Example 157: 3-[2-[2-[2-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid used in Example 150 (1S )-1-(3-Bromophenyl)-2-phenyl-ethanol using the compound produced in Example 21, Example 150 → Example 151 → Example 152 → Example 153 → Example 154 → Example 155 was subjected to the same operation as in Example 11 to obtain the title compound having the following physical properties.
HPLC retention time (min): 1.00;
1H -NMR ( CDCl3 ): δ 2.58-2.62, 2.90-2.95, 2.99-3.06, 3.77-3.81, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 6.88, 7.13-7.21, 7.25-7.3 2.
実施例158:tert-ブチル (トランス-4-(3-ヒドロキシプロピル)シクロヘキシル)カルバメート
メチル トランス-3-[4-(tert-ブトキシカルボニルアミノ)シクロヘキシル]プロパノエート(500mg)のTHF(5mL)溶液を0℃に冷却し、水素化ホウ素リチウム(72.8mg)のTHF(1mL)溶液を加え、室温で15分間,50℃で3時間半撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(429mg)を得た。
1H-NMR(CDCl3):δ 0.95-1.28, 1.44, 1.53-1.60, 1.75-1.78, 1.98-2.01, 2.27-2.31, 3.36, 3.62, 4.36。
Example 158: A solution of tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate methyl trans-3-[4-(tert-butoxycarbonylamino)cyclohexyl]propanoate (500 mg) in THF (5 mL) was The mixture was cooled to .degree. C., a solution of lithium borohydride (72.8 mg) in THF (1 mL) was added, and the mixture was stirred at room temperature for 15 minutes and at 50.degree. C. for 3.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (429 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.95-1.28, 1.44, 1.53-1.60, 1.75-1.78, 1.98-2.01, 2.27-2.31, 3.36, 3.62, 4.36.
実施例159:tert-ブチル (トランス-4-(3-オキソプロピル)シクロヘキシル)カルバメート
実施例158で製造した化合物(429mg)のジクロロメタン(8.3mL)溶液を0℃に冷却し、1,1,1-トリアセトキシ-1,1-ジヒドロ-1,2-ベンズヨードキソール-3(1H)-オン(848mg)を加え、室温で3時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、以下の物性値を有する標題化合物(429mg)を得た。
1H-NMR(CDCl3):δ 0.96-1.28, 1.44, 1.53-1.60, 1.62-1.75, 1.98-2.01, 2.42-2.46, 3.36, 4.38。
Example 159: tert-butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate A solution of the compound prepared in Example 158 (429 mg) in dichloromethane (8.3 mL) was cooled to 0°C, and 1,1, 1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (848 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:1) to obtain the title compound (429 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.96-1.28, 1.44, 1.53-1.60, 1.62-1.75, 1.98-2.01, 2.42-2.46, 3.36, 4.38.
実施例160:エチル (E)-5-(トランス-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシル)ペンタ-2-エノエート
エチル ジエチルホスホノアセテート(747mg)のTHF(5mL)溶液を0℃に冷却し、水素化ナトリウム(60%inミネラルオイル、145mg)を加え、0℃で15分間撹拌した。反応混合物に実施例159で製造した化合物(429mg)のTHF(5mL)溶液を加え、室温で2時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→1:1)によって精製することにより、以下の物性値を有する標題化合物(270mg)を得た。
1H-NMR(CDCl3):δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00。
Example 160: Ethyl (E)-5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pent-2-enoate A solution of ethyl diethylphosphonoacetate (747 mg) in THF (5 mL) was heated to 0°C. After cooling, sodium hydride (60% in mineral oil, 145 mg) was added and stirred at 0° C. for 15 minutes. A solution of the compound prepared in Example 159 (429 mg) in THF (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:1) to obtain the title compound (270 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.0 0.
実施例161:エチル 5-(トランス-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシル)ペンタノエート
実施例160で製造した化合物(270mg)のエタノール(10mL)の溶液にパラジウム炭素(54mg)を加え、水素雰囲気下、室温で1時間半撹拌した。反応液をセライト(商品名)でろ過し、ろ液を減圧濃縮し、下の物性値を有する標題化合物(282mg)を得た。
1H-NMR(CDCl3):δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00。
Example 161: Ethyl 5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pentanoate Palladium on carbon (54 mg) was added to a solution of the compound prepared in Example 160 (270 mg) in ethanol (10 mL), The mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to obtain the title compound (282 mg) having the physical properties shown below.
1H -NMR ( CDCl3 ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.0 0.
実施例162:tert-ブチル (トランス-4-(5-ヒドロキシペンチル)シクロヘキシル)カルバメート
実施例161で製造した化合物(282mg)のTHF(5mL)溶液を0℃に冷却し、水素化ホウ素リチウム(36mg)を加え、50℃で3時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(270mg)を得た。
1H-NMR(CDCl3):δ 0.92-1.32, 1.44, 1.53-1.60, 1.73-1.78, 1.98-2.01, 2.26-2.31, 3.36, 3.64, 4.36。
Example 162: tert-Butyl (trans-4-(5-hydroxypentyl)cyclohexyl)carbamate A solution of the compound prepared in Example 161 (282 mg) in THF (5 mL) was cooled to 0°C, and lithium borohydride (36 mg ) and stirred at 50°C for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (270 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.92-1.32, 1.44, 1.53-1.60, 1.73-1.78, 1.98-2.01, 2.26-2.31, 3.36, 3.64, 4.36.
実施例163:5-(トランス-4-アミノシクロヘキシル)ペンタン-1-オール 塩酸塩
実施例162で製造した化合物(140mg)に塩化水素(4.0Mジオキサン溶液、6mL)を加え、反応混合物を室温で1時間半撹拌後、濃縮し、以下の物性値を有する標題化合物(180mg)を得た。
1H-NMR(DMSO-d6):δ 0.88-0.97, 1.15-1.42, 1.73-1.76, 1.90-1.93, 2.91, 3.36-3.75, 7.86。
Example 163: 5-(trans-4-aminocyclohexyl)pentan-1-ol hydrochloride Hydrogen chloride (4.0 M solution in dioxane, 6 mL) was added to the compound prepared in Example 162 (140 mg), and the reaction mixture was heated to room temperature. After stirring for 1.5 hours, the mixture was concentrated to obtain the title compound (180 mg) having the following physical properties.
1H -NMR (DMSO- d6 ): δ 0.88-0.97, 1.15-1.42, 1.73-1.76, 1.90-1.93, 2.91, 3.36-3.75, 7.86.
実施例164:5-(トランス-4-(フェニルスルホンアミド)シクロヘキシル)ペンチル ベンゼンスルホネート
実施例163で製造した化合物(180mg)ピリジン(2mL)とジクロロメタン(2mL)の溶液を0℃に冷却し、DMAP(5mg)を加えた。ベンゼンスルホニルクロリド(0.14mL)を滴下し、室温で終夜撹拌した。反応混合物を1M塩酸に注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(180mg)を得た。
1H-NMR(CDCl3):δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07。
Example 164: 5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl benzenesulfonate A solution of the compound prepared in Example 163 (180 mg) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0 °C, and DMAP was added. (5 mg) was added. Benzenesulfonyl chloride (0.14 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (180 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07.
実施例165:イソプロピル 3-(2-((5-(トランス-4-(フェニルスルホンアミド)シクロヘキシル)ペンチル)オキシ)フェニル)プロパノエート
実施例164で製造した化合物(180mg)と1-メチル-2-ピロリジノン(2mL)溶液に、炭酸セシウム(377mg)を加え、反応混合物を50℃で2時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→2:1)によって精製することにより、以下の物性値を有する標題化合物(60mg)を得た。
1H-NMR(CDCl3):δ 0.83-0.92, 1.07-1.84, 2.53-2.57, 2.89-2.93, 3.04-3.12, 3.92-3.95, 4.26-4.27, 4.96-5.02, 6.79-6.86, 7.13-7.17, 7.48-7.59, 7.87-7.89。
Example 165: Isopropyl 3-(2-((5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl)oxy)phenyl)propanoate The compound prepared in Example 164 (180 mg) and 1-methyl-2- Cesium carbonate (377 mg) was added to the pyrrolidinone (2 mL) solution, and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→2:1) to obtain the title compound (60 mg) having the following physical properties.
1H -NMR ( CDCl3 ): δ 0.83-0.92, 1.07-1.84, 2.53-2.57, 2.89-2.93, 3.04-3.12, 3.92-3.95, 4.26-4.27, 4.96-5.02, 6.79-6.86, 7.13 -7.17, 7.48-7.59, 7.87-7.89.
実施例166:3-[2-[5-[4-(ベンゼンスルホンアミド)シクロヘキシル]ペントキシ]フェニル]プロパン酸
実施例11で使用したプロパン-2-イル 3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパノエートの代わりに実施例165で製造したエステル化合物を用いて、実施例11と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間(分):1.20;
1H-NMR(CDCl3):δ 0.83-0.92, 1.07-1.83, 2.64-2.68, 2.92-2.96, 3.05-3.13, 3.93-3.96, 4.42-4.43, 6.80-6.88, 7.14-7.20, 7.48-7.59, 7.87-7.89。
Example 166: 3-[2-[5-[4-(benzenesulfonamido)cyclohexyl]pentoxy]phenyl]propanoic acid Propan-2-yl used in Example 11 3-[2-[(E,3R) -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate using the ester compound prepared in Example 165, and the same objective operation as in Example 11. The title compound having the following physical properties was obtained.
HPLC retention time (min): 1.20;
1H -NMR ( CDCl3 ): δ 0.83-0.92, 1.07-1.83, 2.64-2.68, 2.92-2.96, 3.05-3.13, 3.93-3.96, 4.42-4.43, 6.80-6.88, 7.14-7.20, 7.48 -7.59, 7.87-7.89.
以下に生物学的実験例を示し、これらの実験方法に基づいて、本発明化合物の効果を確認した。 Biological experimental examples are shown below, and the effects of the compounds of the present invention were confirmed based on these experimental methods.
生物学的実験例1:シュワン細胞を用いたin vitro試験
(試験方法)
1)ラットシュワン細胞の調製
クリーンベンチ内で生後0~2日の新生仔ラットの後根神経節(以下DRGと略す)を摘出し、DMEM中に回収した。回収後のチューブを室温にて400g、3分間、遠心分離し、上清を除去後、0.25%コラゲナーゼ溶液を添加した。37℃、30分間のインキュベートにより摘出DRGを分散・分離させた後、室温にて400g、3分間遠心分離し、上清を除去後、0.25%Trypsin/EDTAとDNaseIを添加した。37℃、30分間のインキュベート後、10%FBSを添加したDMEM(10%FBS-DMEM)でtrypsinを不活化し、室温にて400g、3分間遠心分離した。上清を除去後、10%FBS-DMEMを添加して細胞懸濁液を調製し、フィルター(直径70μm)に通した。フィルターを通した細胞懸濁液の細胞数をカウントし、2.0×105 cells/mLに調製した後、ポリ-D-リジンコート96-well black-clear plateに100μL/wellずつ播種し、CO2インキュベーターにて5%CO2、95%Air、37℃の条件下で静置培養した。
2)化合物添加
細胞培養プレートの培地をアスピレーターで吸引除去し、1%透析済みFBSと100μmol/L dibutyryl cyclic AMPを添加したDMEMを添加した。その後、DMSOに溶解した本発明化合物溶液を添加し、CO2インキュベーターにて5%CO2、95%Air、37℃の条件下で静置培養した。なお、細胞培養プレートwell中における本発明化合物の終濃度は、0.1、0.3、1または3μmol/Lとした。
3)細胞免疫染色
化合物処置後3日に細胞培養プレートの各wellにホルムアルデヒドを添加し、室温で30分以上静置した。上清を除去後、0.3%TritonX-100溶液を添加し、室温で20分以上静置した。上清を除去後、5μg/mL 抗myeline-associated glycoprotein抗体(抗MAG抗体)溶液を添加し、室温で60分以上または4℃(許容範囲:1~9℃)で一晩静置した。0.1%TritonX-100溶液で3回洗浄した後、10μg/mL Alexa fluor 488 anti-mouse IgG溶液を添加し、室温で60分以上または4℃で一晩静置した。0.1%TritonX-100溶液で4回洗浄した後、1μg/mL Hoechst33342溶液を添加し、核を染色した。
(評価方法)
蛍光画像のMAG陽性面積と細胞核数を算出し、それぞれ5視野/wellの総和を各wellのMAG陽性面積及び細胞核数とした。その後、各wellのMAG陽性面積を細胞核数で除した値(MAG/細胞核数値)を算出し、以下の式により媒体群に対するシュワン細胞分化促進率を求めた。
Biological experiment example 1: In vitro test using Schwann cells (test method)
1) Preparation of rat Schwann cells Dorsal root ganglia (hereinafter abbreviated as DRG) of
2) Compound addition The medium in the cell culture plate was removed by suction using an aspirator, and DMEM containing 1% dialyzed FBS and 100 μmol/L dibutyryl cyclic AMP was added. Thereafter, a solution of the compound of the present invention dissolved in DMSO was added, and the mixture was statically cultured in a CO 2 incubator under conditions of 5% CO 2 , 95% Air, and 37° C. The final concentration of the compound of the present invention in the cell culture plate well was 0.1, 0.3, 1 or 3 μmol/L.
3) Cell immunostaining Formaldehyde was added to each well of the cell culture plate 3 days after compound treatment, and the plate was left standing at room temperature for 30 minutes or more. After removing the supernatant, 0.3% Triton After removing the supernatant, a 5 μg/mL anti-myeline-associated glycoprotein antibody (anti-MAG antibody) solution was added and allowed to stand at room temperature for 60 minutes or more or at 4° C. (acceptable range: 1 to 9° C.) overnight. After washing three times with 0.1% Triton After washing four times with 0.1% Triton X-100 solution, 1 μg/mL Hoechst 33342 solution was added to stain the nucleus.
(Evaluation method)
The MAG positive area and the number of cell nuclei in the fluorescence image were calculated, and the sum of 5 fields/well was defined as the MAG positive area and the number of cell nuclei in each well. Thereafter, the MAG positive area of each well divided by the number of cell nuclei (MAG/cell nucleus number) was calculated, and the Schwann cell differentiation promotion rate for the medium group was determined using the following formula.
(結果)
0.3または3μmol/Lの本発明化合物溶液を添加した場合の媒体群に対するシュワン細胞分化促進率(% of vehicle値)は、以下のとおりであった。このことから、本発明化合物は強力な神経保護および/または修復作用を有すると考えられる。
(result)
The Schwann cell differentiation promotion rate (% of vehicle value) for the vehicle group when 0.3 or 3 μmol/L of the present invention compound solution was added was as follows. From this, it is thought that the compounds of the present invention have strong neuroprotective and/or repair effects.
生物学的実験例2:ストレプトゾトシン誘発ラットモデルを用いた試験
本発明化合物の糖尿病性末梢神経障害における治療効果を評価するため、ストレプトゾトシンモデルを用いたin vivo試験を行った。
(試験方法)
1)モデル作製法
ラットに55mg/kgのストレプトゾトシン(以下STZと略す)を単回静脈内投与することで作製した。
2)侵害受容閾値の測定
STZ投与までに1回以上、ラットを測定用の透明アクリルケージに10分間以上入れ、測定環境にラットを馴化させた。0.4、0.6、1、2、4、6、8、15gの8本のvon Freyフィラメントを、金網床の下から後肢足底部に垂直に適用した。すばやい逃避反応あるいは足振り反応を陽性反応(反応あり)とした。本発明化合物は、STZ投与後14日から28日まで1日1回経口投与し、投与量は0.03、0.3、または3mg/kgとした。また侵害受容閾値は、STZ投与前、STZ投与後14日(本発明化合物の投薬開始日)、21日(投薬開始後7日)、28日(投薬開始後14日)および35日(休薬後7日)において、本発明化合物の投与2時間後に測定した。
(評価方法)
Chaplanらの方法(J Neurosci Methods. 1994;53:55-63)に従い,up-down法にて侵害受容閾値を測定した。また、侵害受容閾値の改善率は以下の式に基づき算出した。
Biological Experiment Example 2: Test using a streptozotocin-induced rat model In order to evaluate the therapeutic effect of the compound of the present invention on diabetic peripheral neuropathy, an in vivo test using a streptozotocin model was conducted.
(Test method)
1) Model Preparation Method A model was prepared by intravenously administering 55 mg/kg of streptozotocin (hereinafter abbreviated as STZ) to rats.
2) Measurement of nociceptive threshold Rats were placed in a transparent acrylic cage for measurement for 10 minutes or more at least once before STZ administration to acclimatize the rats to the measurement environment. Eight von Frey filaments of 0.4, 0.6, 1, 2, 4, 6, 8, 15 g were applied vertically to the plantar hind paw from beneath the wire mesh floor. A quick escape response or leg-shaking response was considered a positive response (response). The compound of the present invention was orally administered once a day from
(Evaluation method)
Nociceptive thresholds were measured using the up-down method according to the method of Chaplan et al. (J Neurosci Methods. 1994; 53:55-63). In addition, the improvement rate of nociceptive threshold was calculated based on the following formula.
(結果)
本発明化合物を0.3mg/kgの投与量で投与した場合の侵害受容閾値の結果を図1に、侵害受容閾値改善率を表2に示す。いずれの化合物においても末梢神経障害において強力な鎮痛作用が認められた。また、例えば実施例11の化合物では投薬開始後7日から侵害受容閾値の改善が認められ、その作用は休薬後7日においても持続しており、持続的な鎮痛作用が認められた。
(result)
The nociceptive threshold results obtained when the compound of the present invention was administered at a dose of 0.3 mg/kg are shown in FIG. 1, and the nociceptive threshold improvement rate is shown in Table 2. A strong analgesic effect on peripheral neuropathy was observed in all compounds. Furthermore, for example, with the compound of Example 11, an improvement in nociceptive threshold was observed from 7 days after the start of administration, and this effect continued even 7 days after discontinuation of administration, indicating a sustained analgesic effect.
生物学的実験例3:反応性代謝物測定試験
本発明化合物の反応性代謝物とquaternary ammonium glutathione(QA-GSH)との複合体をLC/MS/MSで半定量し(Soglia JR et al.,Chem.Res.Toxicol.19(3),480-490,2006)、NADPHに依存した反応性代謝物量を測定した。
Biological Experiment Example 3: Reactive Metabolite Measurement Test The complex of the reactive metabolite of the compound of the present invention and quaternary ammonium glutathione (QA-GSH) was semi-quantitated by LC/MS/MS (Soglia JR et al. , Chem. Res. Toxicol. 19(3), 480-490, 2006), the amount of reactive metabolites dependent on NADPH was measured.
100mM リン酸バッファー(pH7.4)187.5μLに20mg/mLのヒト肝ミクロソーム(Xenotech)を12.5μL(終濃度:1mg/mL)、10mmol/L QA-GSHを25μL(終濃度:1mmol/L)、0.5mmol/L 本発明化合物溶液(DMSO:アセトニトリル:水 =5:38:57)を5μL(本発明化合物の終濃度:10μmol/L)添加した。37℃の水浴で3分間プレインキュベーション後、25mmol/L NADPHを20μL(終濃度:2mmol/L)添加して反応を開始した。反応1時間後にQA-GS付加体内部標準物質(IS)含有アセトニトリル500μLを混和して反応を停止した。反応を停止した試料中に生成した反応性代謝物とQA-GSHとの複合体(QA-GS付加体)をLC/MS/MSで分析した。測定はQA-GS付加体内部標準物質(IS)とともに実施した。 Add 12.5 μL of 20 mg/mL human liver microsomes (Xenotech) to 187.5 μL of 100 mM phosphate buffer (pH 7.4) (final concentration: 1 mg/mL), and 25 μL of 10 mmol/L QA-GSH (final concentration: 1 mmol/mL). L), 0.5 mmol/L 5 μL of a solution of the present compound (DMSO:acetonitrile:water = 5:38:57) (final concentration of the present compound: 10 μmol/L) was added. After preincubation for 3 minutes in a 37°C water bath, 20 μL of 25 mmol/L NADPH (final concentration: 2 mmol/L) was added to initiate the reaction. One hour after the reaction, 500 μL of acetonitrile containing QA-GS adduct internal standard substance (IS) was mixed to stop the reaction. A complex of reactive metabolites and QA-GSH (QA-GS adduct) produced in the sample after the reaction was stopped was analyzed by LC/MS/MS. Measurements were performed with a QA-GS adduct internal standard (IS).
下式より、QA-GS付加体濃度を算出した。 The QA-GS adduct concentration was calculated from the following formula.
(結果)
本発明化合物のQA-GS付加体濃度は低く、例えば、実施例11、36、37、74(13)、84および149の化合物のQA-GS付加体濃度はいずれも200nmol/L以下であった。
(result)
The QA-GS adduct concentrations of the compounds of the present invention were low; for example, the QA-GS adduct concentrations of the compounds of Examples 11, 36, 37, 74 (13), 84, and 149 were all below 200 nmol/L. .
生物学的実験例4:Hand-1EST試験
本発明化合物の生殖発生毒性を、マウスES細胞から心筋への分化過程における生細胞数と分化効率を指標にしたPOCA(登録商標) Hand1-EST(DS ファーマバイオメディカル株式会社)を用いて測定した(Le Coz F et al.,J. Toxicol.,40(2):251-61.2015)。
Biological Experiment Example 4: Hand-1 EST test POCA (registered trademark) Hand1-EST (DS Pharma Biomedical Co., Ltd.) (Le Coz F et al., J. Toxicol., 40(2):251-61.2015).
本発明化合物の1000mg/mL DMSO溶液を調製した。本発明化合物の1000mg/mL DMSO溶液を心筋分化培地で希釈し、本発明化合物の1000μg/mL液(DMSOの終濃度0.1%)を調製した。目視で沈殿物の有無を確認しながら、心筋分化培地(DMSOの終濃度0.1%)で順次3倍希釈し、沈殿物が無い濃度を最大溶解度として記録した。 A 1000 mg/mL DMSO solution of the compound of the present invention was prepared. A 1000 mg/mL DMSO solution of the compound of the present invention was diluted with myocardial differentiation medium to prepare a 1000 μg/mL solution of the compound of the present invention (final concentration of DMSO 0.1%). While visually checking for the presence of precipitates, the mixture was sequentially diluted 3 times with myocardial differentiation medium (DMSO final concentration 0.1%), and the concentration at which no precipitate was present was recorded as the maximum solubility.
融解したHand1-ES細胞(pGL4.17をベクターとし心筋分化マーカーHand1遺伝子のプロモーター領域とその下流にルシフェラーゼ遺伝子を形質転換したマウスES細胞)を未分化維持培地に懸濁後、ゼラチンコートした60mm Dishに播種し、2-3日培養した。培養2-3日後、トリプシン処理をしたHand1-ES細胞をゼラチンコートした60mm Dishに2×106cells/5mLで継代し、一晩培養した。その後、トリプシン処理をしたHand1-ES細胞を、心筋分化培地に懸濁後、PrimeSurface(登録商標)U底96wellプレートに750cells/50μL/wellで播種し、2時間培養した。2時間後、本発明化合物あるいは陽性対照である5-FUを含む心筋分化培地50μLを添加し(本発明化合物の終濃度:1000、333、111、37.0、12.3、4.12及び1.37μg/mL、5-FUの終濃度:1、0.333、0.111、0.0370、0.0123、0.00412及び0.00137μg/mL、DMSOの終濃度:0.1%)、5日間培養した。本発明化合物あるいは5-FUを5日間曝露した後、生細胞数を測定するためにCellTiter-Fluor(登録商標)(Promega)を添加し、SpectraMax M5e plate reader(Molecular Devices)を用いて、励起波長Ex 390nm及び蛍光波長Em 505nmの蛍光を測定した。さらに、分化効率を測定するためにSteady-Glo(登録商標)(Promega)を添加し、SpectraMax M5e plate readerを用いて、発光を測定した。専用解析ソフトPOCA Hand1-EST Analysis Softwareに、求めた最大溶解度、生細胞数の50%阻害濃度及び分化効率の50%阻害濃度を入力し、催奇形性リスクを判定した。判定の基準はProvability 0.52未満を低リスク、0.52以上を高リスクとした(Nagahori et al.,Toxicology Letters 259,44-51)。 Thawed Hand1-ES cells (mouse ES cells transformed with the promoter region of the cardiac differentiation marker Hand1 gene and the luciferase gene downstream thereof using pGL4.17 as a vector) were suspended in an undifferentiation maintenance medium and placed in a gelatin-coated 60 mm dish. and cultured for 2-3 days. After 2-3 days of culture, the trypsin-treated Hand1-ES cells were passaged into a gelatin-coated 60 mm dish at 2×10 6 cells/5 mL and cultured overnight. Thereafter, trypsin-treated Hand1-ES cells were suspended in myocardial differentiation medium, then seeded on a PrimeSurface (registered trademark) U-bottom 96-well plate at 750 cells/50 μL/well and cultured for 2 hours. After 2 hours, 50 μL of myocardial differentiation medium containing the compound of the present invention or 5-FU as a positive control was added (final concentration of the compound of the present invention: 1000, 333, 111, 37.0, 12.3, 4.12, 1.37 μg/mL, final concentration of 5-FU: 1, 0.333, 0.111, 0.0370, 0.0123, 0.00412 and 0.00137 μg/mL, final concentration of DMSO: 0.1% ), and cultured for 5 days. After exposing the compound of the present invention or 5-FU for 5 days, CellTiter-Fluor® (Promega) was added to measure the number of viable cells, and the excitation wavelength was adjusted using a SpectraMax M5e plate reader (Molecular Devices). Fluorescence was measured at Ex 390 nm and fluorescence wavelength Em 505 nm. Furthermore, in order to measure differentiation efficiency, Steady-Glo (registered trademark) (Promega) was added, and luminescence was measured using a SpectraMax M5e plate reader. The determined maximum solubility, 50% inhibitory concentration of viable cell number, and 50% inhibitory concentration of differentiation efficiency were input into the dedicated analysis software POCA Hand1-EST Analysis Software, and the teratogenic risk was determined. The criteria for determination was that Provacability of less than 0.52 was considered low risk, and that of 0.52 or more was considered high risk (Nagahori et al., Toxicology Letters 259, 44-51).
(結果)
本発明化合物のうち、例えば、実施例84、86および87の化合物は、probabilityが0.52未満であり、催奇形性のリスクは低いと考えられた。
[製剤例]
製剤例1
以下の各成分を常法により混合した後打錠して、一錠中に10mgの活性成分を含有する錠剤1万錠を得る。
・3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸…100g
・カルボキシメチルセルロースカルシウム … 20g
・ステアリン酸マグネシウム … 10g
・微結晶セルロース … 870g
(result)
Among the compounds of the present invention, for example, the compounds of Examples 84, 86, and 87 had a probability of less than 0.52, and were considered to have a low risk of teratogenicity.
[Formulation example]
Formulation example 1
The following ingredients are mixed in a conventional manner and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
・3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid...100g
・Carboxymethylcellulose calcium...20g
・Magnesium stearate … 10g
・Microcrystalline cellulose...870g
製剤例2
以下の各成分を常法により混合した後、除塵フィルターでろ過し、5mlずつアンプルに充填し、オートクレーブで加熱滅菌して、1アンプル中20mgの活性成分を含有するアンプル1万本を得る。
・3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸…200g
・マンニトール … 20g
・蒸留水 … 50L
Formulation example 2
The following components are mixed in a conventional manner, filtered through a dust removal filter, filled into ampoules of 5 ml each, and sterilized by heating in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient per ampoule.
・3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid...200g
・Mannitol…20g
・Distilled water…50L
本発明化合物を含有する医薬組成物は、強力な神経保護および/または修復作用を有するため、神経障害を伴う疾患の予防および/または治療に有用である。 A pharmaceutical composition containing the compound of the present invention has a strong neuroprotective and/or restorative effect and is therefore useful for the prevention and/or treatment of diseases accompanied by neurological disorders.
Claims (38)
R 2 は、(1)ハロゲン原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表し、pは0から3の整数を表し、pが2以上のとき複数のR 2 はそれぞれ同じでも異なっていてもよく、
Xは、(1)CH 2 、または(2)酸素原子を表し、
R L1a は、(1)ハロゲン原子、(2)水酸基、(3)オキソ基、または(4)C1~2アルキル基を表し、R L1a が2個以上のとき複数のR L1a は同じでも異なっていてもよく、さらに同一の炭素原子に結合する2個のR L1a がそれぞれC1~2アルキル基のとき、該C1~2アルキル基は結合する炭素原子と一緒になってC3~5の飽和炭素環を形成してもよく、
R 3 は、(1)水素原子、(2)ハロゲン原子、(3)水酸基、(4)C1~2アルキル基、または(5)メチリデン基を表し、qは0から2の整数を表し、
R 4 は、(1)ハロゲン原子、(2)水酸基、(3)C1~4アルキル基、(4)C1~4ハロアルキル基、(5)C1~4アルコキシ基、(6)C1~4ハロアルコキシ基、(7)シアノ基、または(8)-SO 2 -C1~2アルキル基を表し、rは0から6の整数を表し、rが2以上のとき複数のR 4 はそれぞれ同じでも異なっていてもよく、
R 5 は、(1)ハロゲン原子、(2)C1~6アルキル基、(3)C2~6アルケニル基、(4)C2~6アルキニル基、(5)C1~6ハロアルキル基、(6)C2~6ハロアルケニル基、(7)C2~6ハロアルキニル基、(8)C1~6アルコキシ基、または(9)C1~6ハロアルコキシ基を表し、tは0から6の整数を表し、tが2以上のとき複数のR 5 はそれぞれ同じでも異なっていてもよく、
R 12 は、(1)水素原子、(2)C1~4アルキル基、または(3)C1~4ハロアルキル基を表す。]
で示される化合物またはその塩を含有する医薬組成物。 General formula (I-1)
R 2 represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, p represents an integer from 0 to 3, and when p is 2 or more, multiple R 2 may be the same or different,
X represents (1) CH 2 or (2) oxygen atom,
R L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group, and when R L1a is two or more, multiple R L1a may be the same or different . Furthermore, when two R L1a bonded to the same carbon atom are each a C1-2 alkyl group, the C1-2 alkyl group together with the bonded carbon atom forms a C3-5 saturated carbocyclic ring . may be formed,
R 3 represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group, and q represents an integer from 0 to 2;
R 4 is (1) halogen atom, (2) hydroxyl group, (3) C1-4 alkyl group, (4) C1-4 haloalkyl group, (5) C1-4 alkoxy group, (6) C1-4 haloalkoxy group, (7) cyano group, or (8) -SO 2 -C1-2 alkyl group, r represents an integer from 0 to 6, and when r is 2 or more, multiple R 4s are the same or different. It's okay,
R 5 is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2 -6 haloalkenyl group, (7) C2-6 haloalkynyl group, (8) C1-6 alkoxy group, or (9) C1-6 haloalkoxy group, t represents an integer from 0 to 6, and t When 2 or more, the plurality of R5s may be the same or different,
R 12 represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group . ]
A pharmaceutical composition containing a compound represented by or a salt thereof .
(1)3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(2)3-[2-[(3S)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸、
(3)3-[2-[(3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペントキシ]フェニル]プロパン酸、
(4)3-[2-[(E,3R)-5-[4-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(5)3-[2-[(E,3R)-5-[3-(シクロペンチルスルホニルアミノ)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(6)3-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)-2-メチルフェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]プロパン酸、
(7)4-[2-[(E,3R)-5-[3-(ベンゼンスルホンアミド)フェニル]-3-ヒドロキシペンタ-4-エノキシ]フェニル]ブタン酸、
(8)3-[2-[(E)-4-[3-(ベンゼンスルホンアミド)フェニル]-2-ヒドロキシブタ-3-エノキシ]フェニル]プロパン酸、
(9)(R)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸、
(10)(S)-3-[2-[(E)-6-[3-(ベンゼンスルホンアミド)フェニル]-4-ヒドロキシヘキサ-5-エニル]フェニル]プロパン酸、
(11)3-[2-[(E)-5-[3-(ベンゼンスルホンアミド)フェニル]ペンタ-4-エノキシ]フェニル]プロパン酸、
(12)3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]ペントキシ]フェニル]プロパン酸、
(13)3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1R)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸、
(14)3-[2-[(3S)-3-ヒドロキシ-5-[3-[(1S)-1-ヒドロキシ-2-フェニルエチル]フェニル]ペントキシ]フェニル]プロパン酸、
(15)3-[2-[2-[2-[3-(ベンゼンスルホンアミド)フェニル]エトキシ]エトキシ]フェニル]プロパン酸、
(16)3-[2-[6-[3-(ベンゼンスルホンアミド)フェニル]-4-オキソヘキシル]フェニル]プロパン酸、もしくは
(17)3-[2-[5-[3-(ベンゼンスルホンアミド)フェニル]-3,3-ジフルオロペントキシ]フェニル]プロパン酸またはその塩である、請求項1に記載の医薬組成物。 The compound represented by the general formula (I -1 ) or a salt thereof is
(1) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(2) 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid,
(3) 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid,
(4) 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(5) 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(6) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid,
(7) 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid,
(8) 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid,
(9) (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid,
(10) (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid,
(11) 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid,
(12) 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid,
(13) 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid,
(14) 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid,
(15) 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid,
(16) 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid, or (17) 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid The pharmaceutical composition according to claim 1, which is amido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2020012078 | 2020-01-29 | ||
JP2020012078 | 2020-01-29 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2021119131A JP2021119131A (en) | 2021-08-12 |
JP2021119131A5 JP2021119131A5 (en) | 2022-06-02 |
JP7384179B2 true JP7384179B2 (en) | 2023-11-21 |
Family
ID=77195334
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021012154A Active JP7384179B2 (en) | 2020-01-29 | 2021-01-28 | Pharmaceutical composition containing benzene derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP7384179B2 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003016254A1 (en) | 2001-08-09 | 2003-02-27 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
JP2008504312A (en) | 2004-06-28 | 2008-02-14 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Phenylcarboxylic acid derivatives and their use for the treatment of diabetes |
JP2011503030A (en) | 2007-11-12 | 2011-01-27 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | Drugs active against neuropathic pain |
CN105622488A (en) | 2016-04-01 | 2016-06-01 | 南阳师范学院 | 4-cycloaminoalkoxy-3-methoxycinnamates, and preparation method and application thereof |
WO2017068070A1 (en) | 2015-10-20 | 2017-04-27 | Vassilatis Demetrios K | Nurr1:rxr activating compounds for simultaneous treatment of symptoms and pathology of parkinson's disease |
-
2021
- 2021-01-28 JP JP2021012154A patent/JP7384179B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003016254A1 (en) | 2001-08-09 | 2003-02-27 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
JP2008504312A (en) | 2004-06-28 | 2008-02-14 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Phenylcarboxylic acid derivatives and their use for the treatment of diabetes |
JP2011503030A (en) | 2007-11-12 | 2011-01-27 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | Drugs active against neuropathic pain |
WO2017068070A1 (en) | 2015-10-20 | 2017-04-27 | Vassilatis Demetrios K | Nurr1:rxr activating compounds for simultaneous treatment of symptoms and pathology of parkinson's disease |
CN105622488A (en) | 2016-04-01 | 2016-06-01 | 南阳师范学院 | 4-cycloaminoalkoxy-3-methoxycinnamates, and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2021119131A (en) | 2021-08-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6149975B2 (en) | Bicyclic compounds and their pharmaceutical uses | |
US20220089532A1 (en) | Benzene derivative | |
WO2006064757A1 (en) | Aminocarboxylic acid derivative and medicinal use thereof | |
WO2005058790A1 (en) | Compounds having lysophosphatidic acid receptor antagonism and uses thereof | |
JP5835236B2 (en) | Bicyclic compounds and their pharmaceutical uses | |
JP6950534B2 (en) | Tetrahydronaphthalene derivative | |
JP5907077B2 (en) | Bicyclic compounds and their pharmaceutical uses | |
EP3228615B1 (en) | Dihydronaphthalene derivatives useful in the treatment of s1p5-mediated diseases | |
JP7384179B2 (en) | Pharmaceutical composition containing benzene derivative | |
RU2811803C2 (en) | Benzene derivative | |
RU2811803C9 (en) | Benzene derivative | |
JPWO2017014315A1 (en) | Compound having EP2 agonist activity | |
EP3447045B1 (en) | 1-(1-hydroxy-2,3-dihydro-1h-inden-5-yl)-urea derivatives and related compounds kcnq 2-5 channel activators for treating dysuria | |
BR112021001853B1 (en) | BENZENE DERIVATIVE COMPOUNDS, SALTS THEREOF, USE THEREOF TO PREVENT OR TREAT NEUROPATHY, PHARMACEUTICAL COMPOSITION AND PROPHYLACTIC AND/OR THERAPEUTIC AGENTS AND FOR PROMOTING SCHWANN CELL DIFFERENTIATION | |
WO2024190780A1 (en) | Prophylactic and/or therapeutic agent for kidney diseases containing tricyclic compound | |
WO2024190777A1 (en) | Tricyclic compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220525 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220525 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230613 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230719 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231010 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231023 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7384179 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |