WO2012102357A1 - 二環式化合物およびその医薬用途 - Google Patents
二環式化合物およびその医薬用途 Download PDFInfo
- Publication number
- WO2012102357A1 WO2012102357A1 PCT/JP2012/051721 JP2012051721W WO2012102357A1 WO 2012102357 A1 WO2012102357 A1 WO 2012102357A1 JP 2012051721 W JP2012051721 W JP 2012051721W WO 2012102357 A1 WO2012102357 A1 WO 2012102357A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- cyclopenta
- oxepin
- butanoic acid
- hydroxyoctahydro
- Prior art date
Links
- -1 Bicyclic compound Chemical class 0.000 title description 273
- 150000001875 compounds Chemical class 0.000 claims abstract description 411
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000012453 solvate Substances 0.000 claims abstract description 29
- 239000000651 prodrug Substances 0.000 claims abstract description 28
- 229940002612 prodrug Drugs 0.000 claims abstract description 28
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 21
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 107
- 239000000203 mixture Substances 0.000 claims description 92
- WPHQPILBUSXJGK-CWSKWRMQSA-N 4-[(3S,5aR,6R,7R,8aS)-6-[(E,3S)-4-(4-fluorophenoxy)-3-hydroxybut-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC1=CC=C(F)C=C1 WPHQPILBUSXJGK-CWSKWRMQSA-N 0.000 claims description 88
- DLYAYXGOTNKGIP-LGVFIEJVSA-N 4-[(3S,5aR,6R,7R,8aS)-6-[(E,3S)-4-(3-fluorophenoxy)-3-hydroxybut-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC1=CC=CC(F)=C1 DLYAYXGOTNKGIP-LGVFIEJVSA-N 0.000 claims description 75
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 40
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- DQJCSJBXVXQNDF-ODFQLVLFSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(3s)-3-hydroxy-5-[3-(trifluoromethyl)phenyl]pentyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)CC1=CC=CC(C(F)(F)F)=C1 DQJCSJBXVXQNDF-ODFQLVLFSA-N 0.000 claims description 24
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 21
- LJLLMEZGXRNUKF-CNLKNKJVSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(e,3s)-3-hydroxy-5-[3-(trifluoromethyl)phenyl]pent-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(C(F)(F)F)=C1 LJLLMEZGXRNUKF-CNLKNKJVSA-N 0.000 claims description 21
- AFRJKTGUXVDACI-LGVFIEJVSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC1=CC=CC(C(F)(F)F)=C1 AFRJKTGUXVDACI-LGVFIEJVSA-N 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 20
- KXXCRJZOJQYDBW-LQLZCIRRSA-N 4-[(3S,5aR,6R,7R,8aS)-6-[(E,3S)-4-(2-fluorophenoxy)-3-hydroxybut-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC1=CC=CC=C1F KXXCRJZOJQYDBW-LQLZCIRRSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 18
- SSFYYPKOXRTHPW-YZEDFJHOSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3r)-5-(3-chlorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(Cl)=C1 SSFYYPKOXRTHPW-YZEDFJHOSA-N 0.000 claims description 16
- 239000000556 agonist Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- WWTOKVFYBDRKGQ-WZRZNKSUSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3s)-5-cyclohexyl-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1CCCCC1 WWTOKVFYBDRKGQ-WZRZNKSUSA-N 0.000 claims description 15
- LJLLMEZGXRNUKF-YZEDFJHOSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(e,3r)-3-hydroxy-5-[3-(trifluoromethyl)phenyl]pent-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(C(F)(F)F)=C1 LJLLMEZGXRNUKF-YZEDFJHOSA-N 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- VTDDAIBJFNKLFT-IUGHAKTKSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(3r)-5-(3-fluorophenyl)-3-hydroxypentyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)CC1=CC=CC(F)=C1 VTDDAIBJFNKLFT-IUGHAKTKSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 230000001965 increasing effect Effects 0.000 claims description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- NYJQDOPEDYNIQA-IESHQQQVSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e)-3-fluoro-4-phenoxybut-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C(/[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)=C\C(F)COC1=CC=CC=C1 NYJQDOPEDYNIQA-IESHQQQVSA-N 0.000 claims description 12
- UNRXLLZEMIYCSS-CGNCDCDVSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e)-3,3-difluoro-5-phenylpent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C(/[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)=C\C(F)(F)CCC1=CC=CC=C1 UNRXLLZEMIYCSS-CGNCDCDVSA-N 0.000 claims description 11
- KLELHMGGSSXZLI-YZEDFJHOSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3r)-5-(3-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(F)=C1 KLELHMGGSSXZLI-YZEDFJHOSA-N 0.000 claims description 11
- STIUDYIBUCTXGS-WOWVNMMYSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3r)-5-(4-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=C(F)C=C1 STIUDYIBUCTXGS-WOWVNMMYSA-N 0.000 claims description 11
- XYSUXVVZEGYFJN-BQKFERFKSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3s)-5-(2-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC=C1F XYSUXVVZEGYFJN-BQKFERFKSA-N 0.000 claims description 11
- 208000030533 eye disease Diseases 0.000 claims description 11
- KLELHMGGSSXZLI-CNLKNKJVSA-N 4-[(3S,5aR,6R,7R,8aS)-6-[(E,3S)-5-(3-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(F)=C1 KLELHMGGSSXZLI-CNLKNKJVSA-N 0.000 claims description 10
- NYAXBGIICJMNHY-SNPARQQDSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]butyl]-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)OC1=CC=CC(C(F)(F)F)=C1 NYAXBGIICJMNHY-SNPARQQDSA-N 0.000 claims description 10
- XYSUXVVZEGYFJN-WZNJAVFASA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3r)-5-(2-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC=C1F XYSUXVVZEGYFJN-WZNJAVFASA-N 0.000 claims description 10
- SMCVTVKVNVIEKO-RFDDECLJSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(e)-3-hydroxy-5-(3-hydroxyphenyl)pent-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C(\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)=C/C(O)CCC1=CC=CC(O)=C1 SMCVTVKVNVIEKO-RFDDECLJSA-N 0.000 claims description 10
- ZIZFIKDTTFBTGC-LPSPAGPCSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(e,3r)-3-hydroxy-5-phenylpent-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC=C1 ZIZFIKDTTFBTGC-LPSPAGPCSA-N 0.000 claims description 10
- ARNOMXJMXSTRSZ-POHUPDAJSA-N 4-[(3s,5ar,6r,7r,8as)-6-(3,3-difluoro-5-phenylpentyl)-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC(F)(F)CCC1=CC=CC=C1 ARNOMXJMXSTRSZ-POHUPDAJSA-N 0.000 claims description 9
- SSFYYPKOXRTHPW-CNLKNKJVSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3s)-5-(3-chlorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=CC(Cl)=C1 SSFYYPKOXRTHPW-CNLKNKJVSA-N 0.000 claims description 9
- STIUDYIBUCTXGS-QZFHDSEVSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e,3s)-5-(4-fluorophenyl)-3-hydroxypent-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CC1=CC=C(F)C=C1 STIUDYIBUCTXGS-QZFHDSEVSA-N 0.000 claims description 9
- QTOYVFCYNIEQEE-RRJRHZJVSA-N 4-[(3s,5ar,6s,7r,8as)-7-hydroxy-6-[[(e)-3-phenylprop-2-enoxy]methyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC\C=C\C1=CC=CC=C1 QTOYVFCYNIEQEE-RRJRHZJVSA-N 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- RSLBOEORNFLHEM-ODFQLVLFSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(3s)-5-(4-fluorophenyl)-3-hydroxypentyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)CC1=CC=C(F)C=C1 RSLBOEORNFLHEM-ODFQLVLFSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- GJHJMMYZLSGZES-SBRKOPMVSA-N 4-[(3S,5aR,6R,7R,8aS)-6-[(E)-3-(1-benzofuran-2-yl)-3-hydroxyprop-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound O([C@H]1C[C@H]2O)C[C@@H](CCCC(O)=O)CC[C@@H]1[C@H]2/C=C/C(O)C1=CC2=CC=CC=C2O1 GJHJMMYZLSGZES-SBRKOPMVSA-N 0.000 claims description 7
- DQJCSJBXVXQNDF-IUGHAKTKSA-N 4-[(3s,5ar,6r,7r,8as)-7-hydroxy-6-[(3r)-3-hydroxy-5-[3-(trifluoromethyl)phenyl]pentyl]-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)CC1=CC=CC(C(F)(F)F)=C1 DQJCSJBXVXQNDF-IUGHAKTKSA-N 0.000 claims description 7
- GRIFSVHCRQHUCY-WSCWCYHSSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(3s)-5-(2-fluorophenyl)-3-hydroxypentyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@H](CC[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)O)CC1=CC=CC=C1F GRIFSVHCRQHUCY-WSCWCYHSSA-N 0.000 claims description 5
- KCJNQOVHBHRADJ-OHKBWBQRSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e)-4-(2,5-difluorophenoxy)but-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C(/[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)=C\CCOC1=CC(F)=CC=C1F KCJNQOVHBHRADJ-OHKBWBQRSA-N 0.000 claims description 5
- UMHRAANYZJWJNU-SPBRBWAMSA-N 4-[(3s,5ar,6r,7r,8as)-6-[(e)-4-(3-chlorophenoxy)but-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C(/[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)=C\CCOC1=CC=CC(Cl)=C1 UMHRAANYZJWJNU-SPBRBWAMSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 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 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- JLCFTLKYCVPISO-NBYDKTAJSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-(4-phenoxybutyl)-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)CCCOC1=CC=CC=C1 JLCFTLKYCVPISO-NBYDKTAJSA-N 0.000 claims description 4
- DGRXUNYGSJQMSA-NJNXWSLMSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(E)-3-hydroxy-5-(5-methylfuran-2-yl)pent-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound O1C(C)=CC=C1CCC(O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O DGRXUNYGSJQMSA-NJNXWSLMSA-N 0.000 claims description 4
- VFKOQTYRMGDHDC-BYZZZKFOSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(E)-3-hydroxydec-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound O1C[C@@H](CCCC(O)=O)CC[C@@H]2[C@@H](/C=C/C(O)CCCCCCC)[C@H](O)C[C@@H]21 VFKOQTYRMGDHDC-BYZZZKFOSA-N 0.000 claims description 4
- JBWVPQXSFRGWCV-CVSDKZCVSA-N 4-[(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(E,3S)-3-hydroxy-4-phenoxybut-1-enyl]-3,4,5,5a,6,7,8,8a-octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]2CC[C@H](CCCC(O)=O)CO[C@H]2C[C@H]1O)OC1=CC=CC=C1 JBWVPQXSFRGWCV-CVSDKZCVSA-N 0.000 claims description 4
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-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
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 229950008081 unoprostone isopropyl Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to general formula (I) (Wherein all symbols have the same meanings as described later), a salt thereof or a solvate thereof, or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention).
- Glaucoma is an eye disease characterized by temporary or permanent visual field loss and visual impairment that causes decreased visual acuity. This is because the aqueous humor accumulates due to the circulatory disturbance of the aqueous humor, and the intraocular pressure continuously increases, and thus the optic nerve is compressed.
- it is effective to lower the intraocular pressure, and in order to lower the intraocular pressure, for example, drug treatment (eye drops, internal medicine, drip treatment), laser treatment, and surgical treatment are performed.
- PGFs and PGIs are known as those that reduce intraocular pressure.
- Development of these derivatives as a therapeutic agent for glaucoma and ocular hypertension has been promoted, and there are actually commercially available drugs (for example, latanoprost).
- existing glaucoma treatment drugs alone may not have sufficient intraocular pressure lowering effects or sustained drug efficacy.
- seeking more intense intraocular pressure lowering effects frequent or high concentrations
- There are concerns about the occurrence of side effects because of the combination therapy of drugs or drugs with different mechanisms of action. Therefore, there is a demand for a drug that has a stronger and lasting action for lowering intraocular pressure and is highly safe.
- Examples of the PG derivative having a bicyclic mother skeleton include, for example, the general formula (a) (Where Is L a is — (CH 2 ) da —C (R 2a ) 2 — (where da is 0 to 5, R 2a is hydrogen, methyl or fluoro, the same or different, Q a is an oxygen atom or the like, R 1a is COOR 3a (where R 3a is hydrogen, alkyl of 1 to 12 carbon atoms, etc.), etc., and R 4a is , (Wherein R 5a and R 6a is hydrogen, a 1-4 alkyl or fluoro carbon atoms the same or different, Z a is an oxygen atom or the like, T a is 1 to 4 carbon atoms
- sa is 0-3, V a is a valence bond or —CH 2 , W a is — (CH 2 ) h
- Non-patent Documents 1 and 4 the agonist activity to IP receptors has been reported to cause hyperemia and aqueous humor protein increase, and there is a concern that irritation to eyes may be induced (Non-patent Documents 1 and 4). 2). Therefore, since the compound described in Patent Document 2 which is a PGI2 derivative has an agonist activity of the IP receptor, it may induce eye irritation and the like.
- the compound of the present invention is a compound having a low agonist activity for the IP receptor and EP1 receptor and a selective agonist activity for the FP receptor, and any prior art relates to such characteristics (selectivity). There is no description or suggestion.
- the inventors of the present invention have improved the selectivity of the PG receptor subtype, that is, have low agonist activity for the IP receptor and EP1 receptor, and are selective for the FP receptor. As a result of intensive investigations to find a compound having agonist activity, the present invention has been completed.
- A represents an oxygen atom or a sulfur atom;
- R 1 represents (1) COOH, (2) COOR 2 , (3) CH 2 OH, or (4) CONR 3 R 4 ,
- R 2 represents a hydroxyl group, ONO 2 or a C1-6 alkyl group which may be substituted with a C1-4 alkoxy group, and R 3 and R 4 each independently may be substituted with a hydrogen atom or ONO 2
- R 5 represents a halogen atom, a hydroxyl group, or a C1-4 alkoxy group
- R 8 represents a hydrogen atom or a halogen atom
- R 9 represents (In the group, an arrow represents a bonding position), and W 1 represents (1) a hydroxyl group,
- R 8 is a halogen atom
- R 9 is (In the group, all symbols have the same meanings as described in the above 1); or R 8 is a hydrogen atom, and R 9 is (Wherein all symbols have the same meanings as described in 1 above), the compound according to 1 above, a salt thereof, a solvate thereof, or a prodrug thereof, 3.
- Formula (I-1) (Wherein all symbols have the same meanings as described in the above 2), the compound according to the above 2, a salt thereof, a solvate thereof, or a prodrug thereof, 4).
- the compound according to the above 2 a salt, a solvate thereof, or a prodrug thereof, which is a compound selected from the group consisting of hydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and isomers thereof , 6).
- a pharmaceutical composition comprising the compound according to 2 above, a salt thereof, a solvate thereof, or a prodrug thereof; 7. 6.
- Eye disease is glaucoma, ocular hypertension, macular edema, macular degeneration, increased retina and optic nerve tension, myopia, hyperopia, astigmatism, dry eye, retinal detachment, cataract, increased intraocular pressure due to trauma or inflammation, increased intraocular pressure due to drugs Or the pharmaceutical composition according to 8 above, wherein the intraocular pressure is increased after surgery, 10.
- a method for preventing and / or treating an ophthalmic disease which comprises administering an effective amount of the compound according to 2 above, a salt thereof, a solvate thereof, or a prodrug thereof to a mammal; 11.
- the present invention relates to the use of the compound according to 2 above, a salt thereof, a solvate thereof, or a prodrug thereof for producing an agent for preventing and / or treating an eye disease.
- the compound of the present invention has a powerful and sustained intraocular pressure lowering action, and is useful as a therapeutic agent for glaucoma without eye side effects such as ocular irritation (hyperemia, corneal turbidity, etc.) and increased aqueous humor protein.
- the C1-6 alkyl group is linear or branched such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, etc.
- the C1-4 alkyl group means a linear or branched C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like.
- the C2-4 alkyl group in the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” means an ethyl, propyl, butyl group or the like.
- a C2-4 alkyl group in which any one carbon atom is replaced with an oxygen atom means —O—CH 3 , —CH 2 —OH, —O—C 2 H 5 , —CH 2 —.
- the C2-6 alkenyl group means ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-pro Penyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-ethyl-2-vinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2 -Dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1 -Methyl-2-butenyl, 2-methyl-1-butenyl, 1-i-propylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-
- the C1-4 alkoxy group means a linear or branched C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy and the like.
- the halogen atom means fluorine, chlorine, bromine or iodine.
- the C3-10 carbocyclic ring means a C3-10 monocyclic or bicyclic carbocyclic ring, a carbocyclic ring which may be partially or fully saturated, for example, cyclopropane, cyclobutane.
- the C3-7 carbocycle means a C3-7 monocyclic carbocycle, a carbocycle in which part or all of which may be saturated, such as cyclopropane, cyclobutane, cyclopentane. , Cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene and the like.
- the 3- to 10-membered heterocycle includes a 1- to 5-membered hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated.
- pyrrole imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole , Isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, aziridine, azet
- the sulfur atom in A includes, in addition to —S—, an oxidized sulfur atom, that is, —SO— or —SO 2 —.
- R 1 is preferably COOH or COOR 2 .
- R 2 represents a C1-6 alkyl group, and this group may be substituted with a hydroxyl group, ONO 2 or a C1-4 alkoxy group.
- R 2 is preferably methyl, ethyl, propyl, or isopropyl.
- R 5 is preferably a hydroxyl group or a halogen atom.
- Z is preferably — (CH 2 ) m —, — (CH 2 ) n —CH ⁇ CH—, — (CH 2 ) p —A—CH 2 —, or ring 1, and — (CH 2 ) M —, or — (CH 2 ) p —A—CH 2 — is more preferred, and — (CH 2 ) m — is more preferred.
- A an oxygen atom is preferable.
- R 8 is preferably a halogen atom.
- R 9 (Wherein all symbols have the same meaning as described above) is preferable.
- R 8 is a halogen atom, and R 9 is (Wherein all symbols have the same meaning as described above), or R 8 is a hydrogen atom, and R 9 is (Wherein all symbols have the same meaning as described above) is preferred.
- the “C1-6 alkyl group” represented by W 1 is preferably an ethyl group or a propyl group.
- the substituent of the “C1-6 alkyl group” is preferably a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, —O-ring2 or ring2.
- the “C2-6 alkenyl group” represented by W 2 is preferably a linear C3-6 alkenyl group, more preferably a pentenyl group or a hexenyl group, a 4-pentenyl group or a 5-hexenyl group. Is more preferable.
- a substituent of the “C2-6 alkenyl group” a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, —O-ring2 or ring2 is preferable, and a hydroxyl group, a halogen atom More preferably a C1-4 alkyl group or ring2.
- the “C2-4 alkyl group” of the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” represented by W 2 is preferably a propyl group or a butyl group.
- the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” represented by W 2 is —O—C 2 H 5 or — (CH 2 ) 2 —O. —CH 3 is preferred.
- the substituent of the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” includes a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group. , —O-ring2 or ring2 is preferable, and a hydroxyl group or ring2 is more preferable.
- the “C1-6 alkyl group” represented by W 3 is preferably a methyl group, an ethyl group, or a propyl group.
- a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, —O-ring2 or ring2 is preferable, and a hydroxyl group, —O -Ring2 or ring2 is more preferred.
- the “C2-6 alkenyl group” represented by W 3 is preferably a linear C3-6 alkenyl group, more preferably a propenyl group, and further preferably a 2-propenyl group.
- a substituent of the “C2-6 alkenyl group” a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, —O-ring2 or ring2 is preferable, and a hydroxyl group, a halogen atom More preferably a C1-4 alkyl group or ring2.
- the “C2-4 alkyl group” of the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” represented by W 3 is preferably a propyl group or a butyl group.
- the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” represented by W 3 is —O—C 2 H 5 , or — (CH 2 ) 2 —O. —CH 3 is preferred.
- the substituent of the “C2-4 alkyl group in which any one carbon atom is replaced by an oxygen atom” includes a hydroxyl group, an oxo group, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group. , —O-ring2 or ring2 is preferable, and a hydroxyl group or ring2 is more preferable.
- ring1 is preferably a benzene or thiazole ring.
- ring2 is preferably a C3 to 7-membered carbon ring, more preferably a benzene or cyclohexane ring, and even more preferably benzene.
- substituent of ring 2 a C1-4 alkyl group, a C1-4 alkoxy group, CF 3 , OCF 3 or a halogen atom is preferable, and a C1-4 alkyl group, CF 3 , OCF 3 or a halogen atom is more preferable. .
- m is preferably an integer of 2 to 4, and more preferably 3.
- n is preferably 1.
- the ⁇ chain means a side chain bonded to a 7-membered ring in each general formula, and the ⁇ chain means a side chain bonded to a 5-membered ring.
- the general formula (I-1) (Wherein all symbols have the same meaning as described above) is preferred.
- R 8 is a halogen atom
- R 9 is Or R 8 is a hydrogen atom and R 9 is A combination is preferred.
- the general formula (I-1-1) (Wherein all symbols have the same meaning as described above), a compound represented by the general formula (I-1-2) (Wherein all symbols have the same meaning as described above), a compound represented by the general formula (I-1-3) (Wherein all symbols have the same meanings as described above), a compound represented by the general formula (I-1-4) (Wherein all symbols have the same meanings as described above), a compound represented by the general formula (I-1-5) (Wherein all symbols have the same meanings as described above), or a compound represented by the general formula (I-2) (Wherein R 6 and R 7 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1-4 alkyl group or a C1-4 alkoxy group, and R 6 and R 7 together represent an oxo group) Also preferred is a compound represented by: Y represents —CH 2 —, —O— or —S—, and other symbols have the same meanings as described above.
- R 5 is preferably a halogen atom.
- R 5 is preferably a hydroxyl group or a halogen atom, more preferably a halogen atom.
- preferred compounds include (1) 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid, (2) 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-5-phenyl-1-penten-1-yl] octahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid, (3) 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (3-fluorophenyl) -3-hydroxy-1-penten-1-yl] -7 -Hydroxyocta
- alkyl groups include straight chain and branched chain.
- optically active compound in the present invention may include not only 100% pure compounds but also other optical isomers or diastereomers of less than 50%.
- optically active compound and diastereomer thereof according to the present invention include Example 108 (13): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (3R) -3.
- the compound represented by the general formula (I) is converted into a corresponding salt by a known method.
- the salt is preferably water-soluble. Suitable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine and the like.
- the compound represented by the general formula (I) and a salt thereof can be converted into a solvate.
- the solvate is preferably low toxic and water soluble.
- Suitable solvates include, for example, solvates with water and alcohol solvents (for example, ethanol).
- the prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in a living body.
- a prodrug of the compound represented by the general formula (I) when the compound represented by the general formula (I) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, Compounds in which the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); carboxyl group of the compound represented by the general formula (I) Esterified, amidated compounds (for example, the carboxyl group of the compound represented by the general formula (I) is ethyl esterified,
- the prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.
- the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to the compound represented by (I).
- the compound represented by the general formula (I) is an isotope (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.).
- a preferred prodrug of the compound represented by the general formula (I) is a compound represented by the general formula (I) in which a carboxyl group is methyl Esterification, ethyl esterification, propyl esterification, isopropyl esterification, butyl esterification, isobutyl esterification, sec-butyl esterification, tert-butyl esterification, pentyl esterification, isopentyl esterification, neopentyl esterification, cyclopentyl Esterification, hexyl esterification, cyclohexyl esterification, trifluoroethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalate Examples thereof include
- the compound of the present invention is 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 the Examples. It can manufacture by improving suitably etc. and using them in combination.
- R 101 represents a C1-6 alkyl group, and other symbols have the same meaning as described above.
- reaction 1 is known.
- a compound represented by general formula (II) and a compound represented by general formula (III) are combined with an organic solvent (for example, tetrahydrofuran (THF), dimethylformamide ( DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, dichloromethane, etc.) or in water or a mixture thereof, such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, And the like, in the presence of potassium tert-butoxide, potassium carbonate, tertiary amine + lithium chloride, etc.) at a temperature of ⁇ 20 to 70 ° C.
- organic solvent for example, tetrahydrofuran (THF), dimethylformamide ( DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, dichloromethane, etc.
- water or a mixture thereof such as sodium hydride, sodium
- reaction 2 is known, and the compound represented by general formula (IV) obtained in reaction 1 is dissolved in an organic solvent (eg, THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.).
- organic solvent eg, THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.
- the reaction is performed at ⁇ 20 to 50 ° C. using a reducing agent (for example, sodium borohydride, zinc borohydride, etc.) in the presence or absence of cerium chloride.
- a reducing agent for example, sodium borohydride, zinc borohydride, etc.
- an asymmetric reducing agent for example, chlorodiisopinocanphenylborane
- a combination of an asymmetric auxiliary agent and a reducing agent ((R) — 2-methyl-CBS-oxazaborolidine and borohydride / tetrahydrofuran complex or borane dimethylsulfide complex, (S)-( ⁇ )-binaphthol and lithium aluminum hydride, etc.)
- the deprotection reaction of the protecting group is known and can be carried out by the following method. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) silyl group deprotection reaction, (5) metal Deprotection reaction to be used, (6) Deprotection reaction using a metal complex, and the like.
- the deprotection reaction by alkali hydrolysis is carried out by using, for example, an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide) in an organic solvent (for example, methanol, tetrahydrofuran, dioxane, etc.), Performed at 0 to 40 ° C. using an alkaline earth metal hydroxide (eg, barium hydroxide, calcium hydroxide, etc.) or carbonate (eg, sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof, or a mixture thereof. It is.
- an alkali metal hydroxide for example, sodium hydroxide, potassium hydroxide, lithium hydroxide
- organic solvent for example, methanol, tetrahydrofuran, dioxane, etc.
- an alkaline earth metal hydroxide eg, barium hydroxide, calcium hydroxide, etc.
- carbonate eg, sodium carbonate, potassium carbonate, etc.
- the deprotection reaction under acid conditions is carried out by using, for example, an organic acid (eg, acetic acid, trifluoroacetic acid) in an organic solvent (eg, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.). , Methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide / acetic acid, etc.), the presence of 2,2,2-trifluoroethanol
- an organic acid eg, acetic acid, trifluoroacetic acid
- organic solvent eg, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.
- the deprotection reaction by hydrogenolysis is, for example, a solvent (eg, ether type (eg, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol type (eg, methanol, ethanol, etc.), benzene type (eg, Benzene, toluene, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), amides (eg, N, N-dimethylformamide, etc.), water, ethyl acetate, acetic acid or their 2
- a catalyst for example, palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.
- a catalyst for example, palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel,
- the deprotection reaction of the silyl group is carried out at 0 to 40 ° C. using tetrabutylammonium fluoride in an organic solvent miscible with water (for example, tetrahydrofuran, acetonitrile, etc.).
- an organic acid eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.
- an inorganic acid eg, hydrochloric acid, sulfuric acid, etc.
- a mixture thereof eg, hydrogen bromide / acetic acid, etc.
- the deprotection reaction using a metal is carried out in the presence of powdered zinc in an acidic solvent (for example, acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixed solution thereof with an organic solvent such as tetrahydrofuran), for example. If necessary, it is carried out at 0 to 40 ° C. while applying ultrasonic waves.
- an acidic solvent for example, acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixed solution thereof with an organic solvent such as tetrahydrofuran
- the deprotection reaction using a metal complex is performed by, for example, trapping reagent in an organic solvent (eg, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof.
- an organic solvent eg, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.
- Electrode Eg, tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.
- organic acids eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.
- organic acid salts eg, 2-ethylhexanoic acid, etc.
- Metal complexes for example, tetrakistriphenylphosphine palladium (0), bis (dichloride), in the presence or absence of phosphine reagents (for example, triphenylphosphine) in the presence of sodium, potassium 2-ethylhexanoate, etc.
- Triphenylphosphine Radium (II), palladium (II), with tris (triphenylphosphine) rhodium (I) etc.), carried out at 0 ⁇ 40 ° C..
- the deprotection reaction can be performed by a method described in, for example, T. W. Greene, Protective Groups, Organic, Synthesis, Wiley, New York, 1999.
- hydroxyl protecting groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl ( TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, p-phenylbenzoyl group, benzyl (Bn) group, p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, 2,2,2-trichloroethoxycarbonyl (Troc) group and the like.
- TMS trimethylsilyl
- TES triethylsilyl
- TDMS t-butyldimethylsilyl
- amino-protecting groups include benzyloxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group, trifluoroacetyl group , 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group and the like.
- the hydroxyl-protecting group is not particularly limited as long as it is a group that can be easily and selectively eliminated other than those described above.
- those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.
- the compound represented by the general formula (II) can be produced by the following reaction process formula 2.
- T 2 represents a hydroxyl-protecting group (eg, tert-butyldimethylsilyl (TBDMS) group)
- X represents a halogen atom or COOR 2-1
- R 2-1 has the same meaning as R 2 R 2 and R 2-1 may be the same or different, and the other symbols have the same meaning as described above.
- the compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to a protection reaction.
- a base eg, imidazole
- an organic solvent eg, DMF
- a silane compound eg, trimethylsilane chloride (TESCl), tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenyl chloride
- Silane eg, trimethylsilane chloride (TESCl), tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenyl chloride
- TDPSCl trimethylsilane chloride
- TBDPSCl tert-butyldimethylsilane chloride
- TBDPSCl tert-butyldiphenyl chloride
- the compound represented by the general formula (VIII) can be produced by subjecting the compound represented by the general formula (VII) to a reduction reaction.
- a reduction reaction is performed at ⁇ 78 to 80 ° C. in an organic solvent (eg, toluene, ethanol, tetrahydrofuran, hexane, etc.) using a reducing agent (eg, diisobutylaluminum hydride (DIBAL), lithium aluminum hydride, etc.).
- DIBAL diisobutylaluminum hydride
- the reaction 3 is known.
- an organic solvent for example, anhydrous toluene, dimethoxyethane, tetrahydrofuran, etc.
- a base for example, lithium hexamethyldisilazane (LHMDS), lithium diisopropylamide (LDA) , Butyllithium, potassium tert-butoxide, sodium hydride, etc.
- a Wittig reagent eg, methyltriphenylphosphonium bromide
- reaction 4 is known, for example, in an organic solvent (eg, tetrahydrofuran, DMF, DME, toluene, etc.), a base (eg, sodium hydride, potassium tert-butoxide, butyllithium, sodium hydroxide) Etc.) and an alkyl halide (for example, ethyl 2- (bromomethyl) acrylate, 2,3-dibromopropene, etc.) is used at a temperature of ⁇ 50 to 120 ° C.
- organic solvent eg, tetrahydrofuran, DMF, DME, toluene, etc.
- a base eg, sodium hydride, potassium tert-butoxide, butyllithium, sodium hydroxide
- an alkyl halide for example, ethyl 2- (bromomethyl) acrylate, 2,3-dibromopropene, etc.
- reaction 5 is known, and when X represents a halogen atom in the compound of general formula (X), for example, in an organic solvent (for example, toluene, THF, DMF, etc.), a palladium catalyst (for example, Bis (tri-tert-butylphosphine) palladium (Pd (P (t-Bu) 3 ) 2 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), bis (triphenylphosphine) palladium dichloride ( In the presence of PdCl 2 (PPh 3 ) 2 )), an organic zinc compound (for example, the following general formula (X-1) (Wherein X 1 represents a halogen atom, and other symbols have the same meanings as described above), etc.).
- an organic solvent for example, toluene, THF, DMF, etc.
- a palladium catalyst for example, Bis (tri-tert-butylpho
- the reaction 6 is known, for example, in an organic solvent (for example, toluene, dichloromethane, dichloroethane, etc.), a metathesis catalyst (for example, 2,6-diisopropylphenylimido neophylidene morbidenium (VI)) Bis (tert-butoxide), 2,6-diisopropylphenylimidoneophylidene morbidenium (VI) bis (hexafluoro tert-butoxide), etc.) is used at a temperature of 20 to 80 ° C.
- an organic solvent for example, toluene, dichloromethane, dichloroethane, etc.
- a metathesis catalyst for example, 2,6-diisopropylphenylimido neophylidene morbidenium (VI)
- tert-butoxide 2,6-diisopropylphenylimidoneophylidene morbidenium
- the compound represented by the general formula (XIII) can be produced by subjecting the compound represented by the general formula (XII) to a hydrolysis reaction.
- a hydrolysis reaction for example, in the presence of an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), a water-containing solvent (for example, an alcohol solvent (for example, methanol, ethanol, propanol, isopropyl alcohol, etc.) and water In a mixed solvent) at 0 to 80 ° C.
- an alkali metal hydroxide for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
- a water-containing solvent for example, an alcohol solvent (for example, methanol, ethanol, propanol, isopropyl alcohol, etc.) and water In a mixed solvent
- the compound represented by the general formula (XIV) can be produced by subjecting the compound represented by the general formula (XIII) to an esterification reaction.
- esterification reactions include: (1) a method using an alkyl halide, (2) a method using an acid halide, (3) a method using a mixed acid anhydride, (4) A method using a condensing agent is exemplified.
- alkyl halide For example, a method using an alkyl halide is specifically described.
- a carboxylic acid in an organic solvent for example, acetonitrile, acetone, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
- Alkyl halides in the presence of carbonates eg cesium carbonate, sodium carbonate, potassium carbonate etc.
- organic bases eg dimethylformamide, triethylamine, diisopropylethylamine etc.
- alkali metal hydrides sodium hydride etc.
- reaction 7 is known, and (1) an organic solvent (for example, palladium on carbon, platinum oxide, rhodium-alumina, Raney nickel, Wilkinson complex, ruthenium catalyst, iridium catalyst) is used.
- an organic solvent for example, palladium on carbon, platinum oxide, rhodium-alumina, Raney nickel, Wilkinson complex, ruthenium catalyst, iridium catalyst
- a reducing agent eg, sodium borohydride
- an organic solvent eg, methanol, ethanol, etc.
- optical resolution is performed by a conventional method (for example, a method using an optical resolution column), and the desired optical isomer is separated. And the compound represented by the general formula (XV) can be produced.
- the compound represented by the general formula (XVI) can be produced by subjecting the compound represented by the general formula (XV) to the above deprotection reaction.
- the compound represented by the general formula (II) can be produced by subjecting the compound represented by the general formula (XVI) to an oxidation reaction.
- an oxidation reaction for example, (1) a method using DMSO oxidation (for example, Swern oxidation), (2) Method using Dess-Martin Reagent, (3) Examples include a method using a TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) reagent.
- an activator eg, oxalyl chloride, acetic anhydride, pyridine-sulfur trioxide complex
- an organic solvent eg, chloroform, dichloromethane, ethyl acetate, etc.
- an activator eg, oxalyl chloride, acetic anhydride, pyridine-sulfur trioxide complex
- Etc. and an oxidizing agent (for example, dimethyl sulfoxide, etc.), and an alcohol compound is reacted, and a tertiary amine (for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo) [5.4.0] undec-7-ene etc.) at ⁇ 78 to 40 ° C.
- a tertiary amine for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo
- reaction process formula 2 As the compound having, a compound obtained by optical resolution by a conventional method (for example, a method using an optical resolution column) and fractionating a desired optical isomer may be used.
- the compound represented by the general formula (I-2) in the compound represented by the general formula (I-2), Is a compound in which the ⁇ chain represents the ⁇ configuration, R 1 represents COOR 2 , R 5 represents a hydroxyl group, and R 6 and R 7 each represent a fluoro group, ie, a compound represented by the general formula (I-2- b) (Wherein all symbols have the same meaning as described above), the compound represented by the general formula (IV) in the reaction process formula 1 is produced by the following reaction process formula 3 as a starting material. can do.
- reaction 8 is known.
- a compound represented by general formula (IV) in reaction scheme 1 is added to an additive (for example, dichloromethane, dichloroethane, chloroform, etc.) in an organic solvent (for example, dichloromethane, dichloroethane, chloroform, etc.).
- Fluorinating agent eg, diethylaminosulfur trifluoride, bis (2-methoxyethyl) aminosulfur trifluoride, etc.
- hydrogen fluoride-pyridine complex boron trifluoride-diethyl ether complex, ethanol, etc.
- the deprotection reaction of the protecting group is known and can be performed by the same method as the deprotection reaction of the protecting group described in the reaction process formula 1.
- reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.
- a solid-phase-supported reagent supported on a polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
- a polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
- the reaction product is obtained by a 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 scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
- a 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 scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
- the toxicity of the compound of the present invention is sufficiently low. For example, there is almost no eye irritation (hyperemia, corneal turbidity, etc.), aqueous humor protein increase, etc., and it can be safely used as a pharmaceutical product.
- the compound of the present invention Since the compound of the present invention has a selective FP agonist activity, based on its intraocular pressure lowering effect, the compound of the present invention has an eye disease such as glaucoma (acute closed angle glaucoma, chronic closed angle glaucoma, secondary closed angle glaucoma, primary Open-angle glaucoma, secondary open-angle glaucoma, congenital glaucoma, normal-tension glaucoma, excessive aqueous humor glaucoma, etc.), ocular hypertension, macular edema, macular degeneration, increased retinal and optic nerve tension, myopia, hyperopia, It is useful as a prophylactic and / or therapeutic agent for astigmatism, dry eye, retinal detachment, cataracts, increased intraocular pressure due to trauma or inflammation, increased intraocular pressure due to drugs such as steroids or hormones, and increased intraocular pressure after surgery.
- eye disease such as glaucoma (acute closed angle glau
- the compound of the present invention has FP agonist activity, labor induction agent, labor promotion agent, labor promotion agent, dysmenorrhea treatment agent, osteoporosis treatment agent, sunburn induction agent, gray hair prevention agent, hair growth promoter, eyelashes It is also useful as an elongating agent, Meniere's disease therapeutic agent, inner ear disease therapeutic agent, and the like.
- the compound of the present invention 1) complementation and / or enhancement of the prophylactic and / or therapeutic effect of the compound, It may be administered as a concomitant drug in combination with other drugs in order to 2) improve the kinetics / absorption of the compound, reduce the dose, and / or reduce the side effects of the compound.
- the concomitant drug of 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.
- simultaneous administration and administration by time difference are included.
- administration with a time difference may be such that the compound of the present invention is 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.
- Each administration method may be the same or different.
- the disease that exerts a preventive and / or therapeutic effect by the above concomitant drug is not particularly limited as long as it is a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention.
- Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention on glaucoma include, for example, sympathomimetic drugs ( ⁇ 2 agonists: for example, apraclonidine hydrochloride and the like, ⁇ 2 agonists: for example , Dipivefrin hydrochloride, etc.), parasympathomimetic drugs (eg, pilocarpine hydrochloride, carbachol, deme potassium, ecothiophosphate or distigmine bromide), sympathetic nerve inhibitors ( ⁇ 1 blockers: eg, bunazosin hydrochloride, etc., ⁇ blockers: eg, timolol maleate, hydrochloride befunolol, carteolol or betaxolol hydrochloride and the like,, alpha 1 beta-blockers: such as hydrochloric levobunolol, nipradilol, etc.), prostaglandin-
- the therapeutic agents for glaucoma to be combined with the compound of the present invention include not only those found so far but also those that will be found in the future.
- the compound of the present invention is usually administered systemically or locally in an oral or parenteral form.
- oral preparations include liquids for internal use (for example, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for internal use (for example, tablets (sublingual tablets, buccal cavity) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches.
- parenteral agents examples include liquids (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (eg, aqueous eye drops (aqueous eye drops) Liquid, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous ophthalmic solution (non-aqueous ophthalmic solution, non-aqueous suspension ophthalmic solution, etc.)), etc. Etc.), ear drops and the like.
- These preparations may be release control agents such as immediate-release preparations and sustained-release preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.
- Oral liquids for oral use are produced, for example, by dissolving, suspending or emulsifying active ingredients in diluents (eg, purified water, ethanol or a mixture thereof) generally used.
- this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
- the solid preparation for internal use as an oral preparation includes, for example, an active ingredient as an excipient (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (eg, hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). Magnesium oxide, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. According to the formulation. Moreover, you may coat
- an active ingredient as an excipient eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.
- a binder eg
- an ointment is produced by mixing or melting an active ingredient in a base.
- the ointment base is selected from known or commonly used ones.
- higher fatty acids or higher fatty acid esters for example, 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, whale wax, 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 eg,
- the parenteral injection includes solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use.
- An injection is used, for example, by dissolving, suspending or emulsifying an active ingredient in a solvent.
- the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
- this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like.
- a sterile solid preparation for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.
- Preferred dosage forms of the compound of the present invention include eye drops, eye ointments, tablets and the like, and more preferred are eye drops or eye ointments. These can be formulated using widely used techniques. For example, in the case of eye drops, isotonic agents, buffers, pH adjusters, solubilizers, thickeners, stabilizers, preservatives and the like can be appropriately added as additives. In addition, a stable eye drop can be obtained by adding a pH adjuster, a thickener, a dispersant and the like to suspend the drug.
- isotonic agent examples include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
- buffer examples include phosphoric acid, phosphate, citric acid, acetic acid, and ⁇ -aminocaproic acid.
- pH adjuster examples include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.
- solubilizer examples include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and the like.
- thickeners and dispersants include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
- stabilizers include edetic acid and sodium edetate. Can be mentioned.
- preservatives examples include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. It can also be used in combination.
- the ophthalmic solution containing the active ingredient of the present invention preferably has a pH of 4.0 to 8.5, and an osmotic pressure ratio of about 1.0.
- the dose of the active ingredient of the present invention can be appropriately selected depending on symptoms, age, dosage form, etc., but in the case of an oral preparation, it is preferably 1 to 1000 mg, more preferably 5 to 300 mg once to several times a day (for example, 1 to 3 times).
- an oral preparation it is preferably 1 to 1000 mg, more preferably 5 to 300 mg once to several times a day (for example, 1 to 3 times).
- eye drops one having a concentration of 0.000001 to 5% (w / v), more preferably 0.00001 to 0.05% (w / v), 1 to several drops at a time, 1 to several times a day (for example, 1 to 8 times).
- an eye ointment In the case of an eye ointment, it preferably has a concentration of 0.000001 to 5% (w / w), more preferably 0.00001 to 0.05% (w / w), 1 to several times a day (for example, 1 to 4 times). What is necessary is just to apply.
- the solvent in the parenthesis shown in the chromatographic separation site and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
- the NMR data is 1 H-NMR data unless otherwise specified.
- the parentheses shown in the NMR part indicate the solvent used for the measurement.
- the compound name used in this specification is generally a computer program for naming according to the rules of IUPAC, ACD / Name (registered trademark) of Advanced Chemistry Development, or according to the IUPAC nomenclature. It is named.
- Example 1 (3aR, 4S, 5R, 6aS) -4-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro -2H-cyclopenta [b] furan-2-one (3aR, 4S, 5R, 6aS) -4- (hydroxymethyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro-2H-cyclopenta [b] To a solution of furan-2-one (CAS No.
- DMF dimethylformamide
- imidazole 29.22 g
- tert-butyl under ice-cooling.
- Dimethylchlorosilane (30.87 g) was sequentially added and stirred at room temperature for 3.5 hours. After completion of the reaction, a small amount of ethanol was added, and the reaction solution was poured into ice water and extracted with ethyl acetate: hexane (2: 3).
- Example 2 (3aR, 4S, 5R, 6aS) -4-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro -2H-cyclopenta [b] furan-2-ol
- a solution of the compound prepared in Example 1 (76.2 g) in anhydrous toluene (390 mL) was cooled to -70 ° C, and 1 mol / L of diisobutylaluminum hydride was cooled.
- Example 3 (1S, 2R, 3S, 4R) -2-allyl-3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -4- (tetrahydro-2H-pyran-2 -Yloxy) cyclopentanol
- a suspension of methyltriphenylphosphonium bromide (326.6 g) in anhydrous toluene (300 mL) was added with 1.6 M tetrahydrofuran (hereinafter referred to as THF) of lithium hexamethyldisilazane under ice-cooling.
- THF tetrahydrofuran
- Example 4 ⁇ [(1S, 2R, 3S, 5R) -2-allyl-3-[(2-bromo-2-propen-1-yl) oxy] -5- (tetrahydro-2H-pyran-2- (Iloxy) cyclopentyl] methoxy ⁇ (dimethyl) (2-methyl-2-propanyl) silane
- 2,3-dibromopropene 8.4 mL, 81.0 mmol
- Sodium hydride (2.16 g, 54.1 mmol) was added and stirred for 5 minutes.
- Example 5 Ethyl 5-( ⁇ [(1S, 2R, 3S, 4R) -2-allyl-3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -4- (tetrahydro -2H-pyran-2-yloxy) cyclopentyl] oxy ⁇ methyl) -5-hexanoate
- the compound prepared in Example 4 (10.9 g, 22.2 mmol) was dissolved in toluene (100 mL).
- Ethoxy-4-oxobutyl zinc bromide 0.5 mol / L THF solution, 133 mL, 66.7 mmol
- Example 6 ethyl 4-[(5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2 -Yloxy) -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate Under argon atmosphere, the compound prepared in Example 5 (400 mg, 0.762 mmol) was dissolved in toluene. (76 mL).
- Example 7 4-[(5aR, 6S, 7R, 8aS) -6-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- the compound prepared in Example 6 (7.63 g, 15.4 mmol) was dissolved in ethanol (60 mL). Then, a 2.0 mol / L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 2 hours.
- Example 8 2-propanyl 4-[(5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran -2-yloxy) -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- the compound (15.4 mmol) prepared in Example 7 was DMF under argon atmosphere.
- potassium carbonate (5.31 g, 38.5 mmol) and isopropyl iodide (2.31 mL, 23.1 mmol) were added and stirred at 60 ° C.
- Example 9 2-propanyl 4-[(5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran -2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate Under argon atmosphere, a solution of the compound prepared in Example 8 (4.85 g, 9.45 mmol) in dichloromethane (62 mL) was sonicated. And deaerated and purged with argon.
- Example 10 (2): 2-propanyl 4-[(3S, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7-hydroxy Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- Example 10 (2): 2-propanyl 4-[(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2- Methyl-2-propanyl) silyl] oxy ⁇ methyl) -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- Compound prepared in Example 9 (3.02 g, 5.89 mmol) under argon atmosphere In dichloromethane (60 mL) was cooled to -20 ° C.
- Dimethylaluminum chloride solution (1.0 M hexane solution) was added, and the mixture was stirred for 3 hours and 40 minutes while warming to room temperature.
- the reaction solution was poured into an ice-cooled saturated aqueous sodium bicarbonate solution, Rochelle salt was added, and the mixture was stirred for 40 minutes.
- the aqueous layer was extracted twice with ethyl acetate, and the collected organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
- Example 11 2-propanyl 4-[(3S, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H -Pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- 3,4-dihydro-2H-pyran (403 ⁇ L, 4.42 mmol) and tosylic acid monohydrate (10 mg, 0.111 mmol) were added, and the mixture was stirred at room temperature for 15 minutes.
- Example 12 2-propanyl 4-[(3S, 5aR, 6S, 7R, 8aS) -6- (hydroxymethyl) -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] Oxepin-3-yl] butanoate Under an argon atmosphere, tetrabutylammonium fluoride (7 mL, 1.0 M THF solution) was added to a THF solution (3.6 mL) of the compound prepared in Example 11 (1.81 g, 3.53 mmol). And stirred at room temperature for 70 minutes.
- Tetrabutylammonium fluoride (3.5 mL, 1.0 mol / L THF solution) was added, and the mixture was further stirred at 45 ° C. for 100 minutes.
- the reaction solution was diluted with ethyl acetate (100 mL), washed once with saturated aqueous ammonium chloride solution and once with saturated brine, and dried over anhydrous sodium sulfate.
- Example 13 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-formyl-7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3 -Il] butanoate Under an argon atmosphere, a solution of the compound prepared in Example 12 (623 mg, 1.76 mmol) in ethyl acetate (4 mL) was added to dimethyl sulfoxide (hereinafter sometimes abbreviated as DMSO) (1.8 mL), diisopropyl. Ethylamine (1.8 mL, 10.56 mmol) was added and cooled to 0 ° C.
- DMSO dimethyl sulfoxide
- Example 14 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-oxo-4-phenoxy-1-buten-1-yl] -7- (tetrahydro -2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate Under argon atmosphere, a solution of the compound prepared in Example 13 (634 mg, 1.60 mmol) in THF (16 mL) in dimethyl- (3-Phenoxy-2-oxopropyl) -phosphonate (826 mg, 3.20 mmol) and potassium phosphate (679 mg, 3.20 mmol) were added and stirred at room temperature for one day.
- Example 15 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] -7- (Tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- (R) -2-Methyl-CBS-oxazaborolidine 65 ⁇ L, 1 mol / L toluene solution, 0.065 mmol
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 16 (2) to Example 16 (42) (3aR, 4S, 5R, 6aS) -4-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro-2H-cyclopenta [B] Using furan-2-one, using 4-ethoxy-4-oxobutylzinc bromide or the corresponding organozinc reagent, and using dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or Example 1 ⁇ Example 2 ⁇ Example 3 ⁇ Example 4 ⁇ Example 5 ⁇ Example 6 ⁇ Example 7 ⁇ Example 8 ⁇ Example 9 ⁇ Example 10 1) or Example 10 (2) ⁇ Example 11 ⁇ Example 12 ⁇ Example 13 ⁇ Example 14 ⁇ Example 15 ⁇ Example 16 To give Example Compound.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-5-phenyl-1-pentene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.41 (ethyl acetate);
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.48 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.88-1.19, 1.22, 1.35-1.96, 2.02-2.16, 2.23, 2.41-2.55, 2.56-2.69, 2.82-3.00, 3.62-3.79, 3.81-4.12, 4.42 -4.55, 4.89-5.08, 5.54-5.72, 6.77-6.84, 6.91-6.98, 7.20.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy) -1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.45 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.29, 1.35-1.97, 2.01-2.17, 2.23, 2.28-2.40, 2.42-2.54, 2.66-2.83, 2.83-2.97, 3.62-3.78, 3.78-4.12 , 4.40-4.56, 4.89-5.08, 5.54-5.73, 6.64-6.75, 6.78, 7.16.
- Example 16 ethyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoate
- Example 16 (6): ethyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoate
- TLC Rf 0.56 (ethyl acetate);
- Example 16 (8): ethyl 3- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoate
- TLC Rf 0.59 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.34-1.43, 1.47-1.95, 1.95-2.12, 2.15-2.33, 2.40-2.58, 2.66-3.19, 3.64-3.99, 4.02-4.14, 4.22, 4.30-4.42 , 4.43-4.54, 5.53-5.72, 6.81-7.00, 7.19-7.30, 7.32-7.42, 7.60-7.69, 7.84-7.92, 7.94-8.01.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.44 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.19, 1.22, 1.32-1.97, 2.01-2.17, 2.23, 2.40-2.56, 2.70-2.99, 2.99-3.24, 3.59-3.77, 3.80-4.11, 4.38 -4.56, 4.88-5.08, 5.52-5.70, 6.75-6.91, 7.18-7.25.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (4-methylphenoxy) -1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.49 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.18, 1.22, 1.37-1.83, 1.83-1.95, 2.01, 2.05-2.17, 2.23, 2.29, 2.40-2.56, 2.84-2.97, 3.66-3.79, 3.84 3.90-4.09, 4.50, 4.91-5.07, 5.57-5.73, 6.76-6.85, 7.03-7.12.
- Example 16 (11): 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-4- [4- (trifluoro Methyl) phenoxy] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- TLC Rf 0.47 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.19, 1.21, 1.36-1.96, 2.06-2.29, 2.41-2.68, 2.91, 3.66-3.79, 3.88-4.10, 4.48-4.60, 4.90-5.08, 5.57 -5.76, 6.97, 7.54.
- TLC Rf 0.53 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.85-1.19, 1.22, 1.34-1.96, 2.03-2.18, 2.18-2.29, 2.39-2.57, 2.71-2.84, 2.84-2.99, 3.63-3.80, 3.85-4.13 , 4.47-4.61, 4.88-5.09, 5.55-5.77, 6.84-7.15.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.55 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.19, 1.22, 1.34-1.97, 1.99-2.20, 2.23, 2.37-2.60, 2.91, 3.65-3.79, 3.81-4.12, 4.45-4.60, 4.91-5.10 , 5.56-5.75, 6.59-6.74, 7.11-7.32.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.55 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.18, 1.22, 1.36-1.98, 1.99-2.18, 2.23, 2.40-2.68, 2.84-2.97, 3.64-3.79, 3.79-3.89, 3.89-4.14, 4.44 -4.57, 4.89-5.11, 5.56-5.75, 6.80-6.91, 6.91-7.03.
- Example 16 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-4- [3- (trifluoro Methyl) phenoxy] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- TLC Rf 0.46 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.19, 1.19-1.25, 1.36-1.97, 2.00-2.19, 2.23, 2.41-2.56, 2.85-2.98, 3.67-3.80, 3.88-4.09, 4.48-4.60 , 4.91-5.08, 5.59-5.76, 7.09, 7.12-7.17, 7.21-7.25, 7.40.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methoxyphenoxy) -1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.43 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.18, 1.18-1.26, 1.35-1.97, 2.02-2.19, 2.23, 2.40-2.60, 2.83-2.98, 3.63-4.10, 4.45-4.58, 4.89-5.08 , 5.56-5.74, 6.43-6.58, 7.17.
- TLC Rf 0.44 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.18, 1.23, 1.35-1.96, 2.04-2.29, 2.40-2.55, 2.61, 2.84-2.97, 3.64-3.87, 3.89-4.09, 4.43-4.55, 4.91 -5.06, 5.56-5.73, 6.75-6.92.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (2-methylphenoxy) -1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.50 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.85-1.19, 1.19-1.26, 1.33-1.97, 1.98-2.18, 2.18-2.30, 2.38-2.59, 2.82-3.00, 3.62-3.81, 3.83-4.14, 4.46 -4.64, 4.88-5.09, 5.56-5.78, 6.77-6.84, 6.84-6.94, 7.05-7.21.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.48 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.18, 1.22, 1.35-1.95, 1.99-2.18, 2.23, 2.40-2.54, 2.62-2.74, 2.91, 3.65-3.80, 3.88-3.99, 3.99-4.11 , 4.49-4.65, 4.89-5.08, 5.57-5.76, 6.86-6.98, 7.15-7.24, 7.30-7.40.
- Example 16 (2): 2-propanyl 6- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ hexanoate
- TLC Rf 0.59 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.88-1.17, 1.18-1.37, 1.40-1.94, 1.98-2.19, 2.20-2.30, 2.36-2.56, 2.89, 3.66-4.10, 4.46-4.59, 4.91-5.07 , 5.57-5.75, 6.87-7.01, 7.24-7.33.
- Example 16 (21): 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.57 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.19, 1.17-1.25, 1.33-1.83, 1.82-1.98, 2.00-2.19, 2.23, 2.38-2.59, 2.82-2.97, 3.63-3.79, 3.80-4.16 , 4.40-4.61, 4.88-5.10, 5.52-5.75, 6.81, 6.97.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-5-fluorophenoxy) -3-hydroxy -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.56 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.17, 1.18-1.25, 1.34-1.83, 1.83-1.97, 2.04-2.18, 2.23, 2.40-2.55, 2.84-2.97, 3.64-3.79, 3.82-3.90 3.91-3.99, 3.99-4.13, 4.41-4.59, 4.90-5.09, 5.53-5.74, 6.48-6.59, 6.65-6.79.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,3-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.51 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.88-1.18, 1.18-1.26, 1.34-1.81, 1.82-1.99, 2.04-2.16, 2.18-2.28, 2.37-2.56, 2.73, 2.91, 3.63-3.80, 3.87 -4.15, 4.46-4.65, 4.86-5.07, 5.53-5.77, 6.67-6.85, 6.89-7.07.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.54 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.18, 1.18-1.25, 1.36-1.84, 1.82-1.97, 2.03-2.19, 2.23, 2.40-2.58, 2.83-2.99, 3.65-3.80, 3.81-3.90 3.90-4.12, 4.41-4.59, 4.87-5.11, 5.52-5.79, 6.32-6.54.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.54 (ethyl acetate); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.92-1.18, 1.21, 1.34-1.82, 1.82-1.96, 2.03-2.18, 2.23, 2.28, 2.41-2.54, 2.78, 2.84-2.98, 3.62-3.80, 3.86 -4.11, 4.47-4.61, 4.89-5.07, 5.54-5.76, 6.54-6.66, 6.66-6.76, 6.93-7.05.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (5-chloro-2-fluorophenoxy) -3-hydroxy -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.69 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.19, 1.22, 1.37-1.96, 2.03-2.29, 2.41-2.54, 2.68, 2.91, 3.65-3.80, 3.86-4.11, 4.48-4.60, 4.91-5.08 , 5.55-5.75, 6.86-6.94, 6.94-7.06.
- Example 16 (27): 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-4-fluorophenoxy) -3-hydroxy -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.58 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.19, 1.21, 1.37-1.97, 2.02-2.19, 2.23, 2.41-2.54, 2.91, 3.66-3.80, 3.80-3.89, 3.89-4.10, 4.45-4.56 , 4.99, 5.55-5.75, 6.73-6.81, 6.95, 7.00-7.10.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] -7-methoxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.88-1.19, 1.22, 1.36-1.81, 1.81-1.97, 2.15-2.29, 2.42, 2.46-2.59, 2.91, 3.25-3.47, 3.81-4.09, 4.46-4.59 , 4.89-5.10, 5.56-5.67, 5.69-5.82, 6.87-7.02, 7.23-7.35.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-2-fluorophenoxy) -3-hydroxy -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.37 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.84-1.18, 1.19-1.27, 1.34-1.97, 2.02-2.19, 2.23, 2.39-2.54, 2.66, 2.81-2.99, 3.61-3.82, 3.86-4.12, 4.45 -4.63, 4.88-5.09, 5.55-5.76, 6.82-6.91, 6.93-7.07.
- Example 16 (2propanyl ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ acetate
- TLC Rf 0.43 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.02-1.19, 1.22, 1.42-1.59, 1.63-1.96, 2.02-2.28, 2.41-2.55, 2.60, 2.92-3.04, 3.65-3.79, 3.82-3.92, 3.92 -4.12, 4.44-4.58, 4.89-5.08, 5.55-5.75, 6.80, 6.91, 6.95, 7.19.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,4-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.63 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.18, 1.18-1.25, 1.35-1.82, 1.82-1.94, 2.03-2.16, 2.23, 2.40-2.56, 2.84-2.95, 2.97, 3.70, 3.85-4.08 , 4.46-4.55, 4.92-5.06, 5.55-5.71, 6.73-6.98.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,4-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.62 (ethyl acetate); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.91-1.18, 1.22, 1.36-1.83, 1.83-1.96, 2.05-2.18, 2.23, 2.48, 2.53-2.59, 2.85-2.96, 3.65-3.78, 3.79-3.87 , 3.89-4.09, 4.44-4.55, 4.91-5.07, 5.56-5.73, 6.57-6.64, 6.73, 6.99-7.12.
- Example 16 2-propanyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.22, 1.34-1.98, 2.07-2.19, 2.21-2.33, 2.40, 2.77, 3.02, 3.40, 3.65-3.77, 3.78-4.03, 4.44-4.56, 4.92-5.08 , 5.57-5.71, 6.87-7.01, 7.24-7.34.
- Example 16 ethyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.25, 1.35-1.88, 2.08-2.23, 2.22-2.49, 2.67, 3.41, 3.64-4.06, 4.12, 4.46-4.59, 5.58-5.78, 6.85-7.06, 7.22 -7.37.
- Example 16 (35): ethyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.20, 1.25, 1.35-1.99, 2.03-2.19, 2.26, 2.41-2.54, 2.58, 2.91, 3.65-3.81, 3.83-4.08, 4.12, 4.46-4.61 , 5.58-5.75, 6.84-7.05, 7.22-7.37.
- Example 16 2-propanyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.47 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.23, 1.34-1.89, 2.07-2.22, 2.27, 2.34-2.46, 2.47-2.67, 3.41, 3.67-4.06, 4.43-4.60, 4.91-5.10, 5.54-5.77 , 6.78-6.84, 6.92, 6.93-6.99, 7.20.
- Example 16 (27) : 2-propanyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.47 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.23, 1.33-1.87, 1.86-1.96, 2.10-2.23, 2.23-2.50, 3.42, 3.68-3.90, 3.93-4.07, 4.44-4.63, 4.91-5.10, 5.56 -5.79, 6.77-6.85, 6.92, 6.93-7.00, 7.20.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-chlorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.65 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.66-2.01, 2.04-2.18, 2.23, 2.29-2.57, 2.91, 3.73, 3.85, 3.90-4.13, 4.45-4.59, 4.90-5.07, 5.53-5.78, 6.75 -6.84, 6.91, 6.92-6.98, 7.19.
- Example 16 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (2,5-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 16 (40) : 2-propanyl ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ acetate
- TLC Rf 0.59 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.02-1.18, 1.19-1.26, 2.10-2.39, 2.50, 2.76-2.89, 3.00, 3.67-3.80, 3.88-4.13, 4.50-4.61, 5.00, 5.58-5.75 , 6.62, 6.72, 7.03.
- Example 16 (21) : 2-propanyl 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1 -Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.55 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.15-1.34, 1.35-1.87, 2.11-2.25, 2.29, 2.42, 2.69, 3.43, 3.70-4.09, 4.51-4.62, 4.95-5.09, 5.58-5.76, 6.62 , 6.73, 7.03.
- Example 16 (22) : 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (cyclohexyloxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.33 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.35, 1.42-1.76, 1.85-1.93, 2.04-2.12, 2.22-2.27, 2.42-2.51, 2.67, 2.87-2.95, 3.26-3.32, 3.50-3.55 , 3.66-3.75, 3.93-4.07, 4.24-4.29, 4.96-5.05, 5.50-5.64.
- Example 17 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,3-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (2) to Example 17 (33) By subjecting the compounds produced in Example 16 (1) to Example 16 (22) and Example 16 (24) to Example 16 (33) to the same purpose operation as in Example 17 (1), Example compounds shown below were obtained.
- Example 17 (2): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-5-phenyl-1-penten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.87-1.23, 1.32-1.97, 2.00-2.13, 2.32, 2.40-2.54, 2.57-2.78, 2.91, 3.61-3.75, 3.85-4.20, 5.36-5.48, 5.52 -5.66, 7.11-7.33.
- Example 17 (4 ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.83-1.27, 1.35-1.97, 2.02-2.20, 2.33, 2.41-2.55, 2.84-2.99, 3.67-3.78, 3.80-4.11, 4.45-4.58, 5.54-5.74 , 6.76-6.84, 6.91-6.98, 7.20.
- Example 17 (4): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy) -1- Buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.80-1.21, 1.35-1.97, 2.00-2.19, 2.24-2.38, 2.40-2.55, 2.91, 3.65-3.78, 3.82-3.90, 3.90-4.08, 4.45-4.57 , 5.54-5.73, 6.65-6.75, 6.78, 7.16.
- Example 17 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.46-2.17, 2.40-2.56, 2.87-3.03, 3.33-3.45, 3.63-3.77, 3.83-4.23, 4.35-4.49, 5.58-5.76, 6.82-6.99, 7.16-7.37, 7.92.
- Example 17 (6): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid
- Example 17 3- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.49-2.20, 2.41-2.56, 2.86-3.03, 3.32-3.44, 3.63-3.78, 3.85-4.22, 4.37-4.49, 5.58-5.75, 6.84-6.98, 7.17-7.30, 7.33-7.48, 7.79-7.89.
- Example 17 (8): 3- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.48-1.72, 1.73-1.94, 1.95-2.13, 2.21-2.37, 2.43-2.59, 3.00-3.15, 3.66-4.00, 4.03-4.14, 4.25, 4.44-4.56 , 5.56-5.74, 6.82-6.99, 7.19-7.30, 7.39, 7.65, 7.94, 8.11.
- Example 17 (9): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-chlorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.93-1.26, 1.26-1.82, 1.82-2.07, 2.25, 2.36-2.50, 2.90-3.03, 3.59-3.71, 3.83-4.05, 4.35-4.45, 5.55- 5.70, 6.87-6.95, 7.19-7.28.
- Example 17 (10): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (4-methylphenoxy) -1- Buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD
- Example 17 (11): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-4- [4- (trifluoromethyl) phenoxy ] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.92-1.94, 1.94-2.08, 2.25, 2.36-2.50, 2.91-3.03, 3.59-3.73, 3.91-4.07, 4.40-4.49, 5.57-5.72, 7.01- 7.13, 7.49-7.61.
- Example 17 (13): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-fluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.80-1.22, 1.34-1.97, 2.05-2.18, 2.32, 2.40-2.56, 2.84-2.98, 3.66-3.78, 3.80-4.10, 4.46-4.57, 5.55-5.74 , 6.55-6.75, 7.14-7.28.
- Example 17 (14): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-fluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.83-1.21, 1.34-1.98, 2.05-2.18, 2.32, 2.39-2.57, 2.85-3.00, 3.66-3.79, 3.79-3.88, 3.89-4.09, 4.41-4.60 , 5.54-5.76, 6.79-6.91, 6.90-7.03.
- Example 17 (15): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-4- [3- (trifluoromethyl) phenoxy ] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- Example 17 (16): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methoxyphenoxy) -1- Buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.91-1.21, 1.27-1.83, 1.82-2.08, 2.25, 2.36-2.50, 2.90-3.03, 3.59-3.72, 3.75, 3.80-4.05, 4.34-4.45, 5.55-5.70, 6.44-6.55, 7.08-7.18.
- Example 17 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (4-methoxyphenoxy) -1- Buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD
- Example 17 (4 ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (2-methylphenoxy) -1- Buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.87-1.23, 1.24-1.93, 1.94-2.09, 2.15-2.32, 2.35-2.50, 2.89-3.03, 3.58-3.72, 3.85-4.07, 4.37-4.47, 5.56-5.71, 6.74-6.88, 7.03-7.15.
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.84-1.21, 1.22-1.93, 1.93-2.10, 2.25, 2.35-2.49, 2.96, 3.57-3.72, 3.89-4.06, 4.39-4.49, 5.57-5.71, 6.90, 7.05, 7.19-7.27, 7.33.
- Example 17 (20): 6- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ hexanoic acid
- 1 H-NMR 300 MHz, CD 3 OD
- Example 17 (21): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.90-1.22, 1.25-2.09, 2.25, 2.35-2.51, 2.97, 3.58-3.72, 3.83-4.08, 4.31-4.48, 5.50-5.73, 6.93, 6.98.
- Example 17 (22): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-5-fluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.90-1.22, 1.27-2.10, 2.26, 2.37-2.51, 2.97, 3.58-3.73, 3.85-4.06, 4.35-4.47, 5.54-5.72, 6.69, 6.75, 6.79-6.85.
- Example 17 (23): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (24): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.91-1.24, 1.24-2.11, 2.25, 2.35-2.51, 2.97, 3.57-3.75, 3.80-4.11, 4.29-4.50, 5.50-5.77, 6.38-6.68.
- Example 17 (25): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.89-1.23, 1.25-1.94, 1.95-2.10, 2.25, 2.35-2.51, 2.92-3.03, 3.58-3.73, 3.87-4.09, 4.35-4.50, 5.55- 5.75, 6.58-6.71, 6.84-6.97, 6.99-7.14.
- Example 17 (26): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (5-chloro-2-fluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (27): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-4-fluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.92-1.22, 1.30-1.47, 1.47-1.83, 1.82-2.07, 2.25, 2.36-2.49, 2.90-3.03, 3.59-3.72, 3.82-4.05, 4.35- 4.44, 5.54-5.70, 6.84-6.92, 7.04, 7.13.
- Example 17 (28): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] -7- Methoxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.22, 1.35-1.81, 1.81-1.97, 2.15-2.28, 2.32, 2.46-2.59, 2.92, 3.26-3.46, 3.82-4.09, 4.48-4.58, 5.55 -5.67, 5.69-5.82, 6.87-7.02, 7.24-7.34.
- Example 17 (29): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-2-fluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (30): ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ acetic acid
- 1 H-NMR 300 MHz, CD 3 OD
- Example 17 (41): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,4-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (42): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,4-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (43): 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (low polarity)
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.12-1.91, 2.07-2.91, 3.34-3.50, 3.65-4.06, 4.46-4.58, 5.56-5.73, 6.84-7.05, 7.22-7.35.
- Example 17 (44): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-1-octen-1-yl] octahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (3aR, 4S, 5R, 6aS) -4-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro- 2H-pyran-2-yloxy) hexahydro-2H-cyclopenta [b] furan-2-one and 4-ethoxy-4-oxobutylzinc bromide to dimethyl- (3-phenoxy-2-oxopropyl)- Example 1-> Example 2-> Example 3-> Example 4-> Example 5-> Example 6-> Example 7-> Example 8-> Real using the corresponding phosphonate instead of phosphonate Example 9-> Example 10-> Example
- Example 17 (45) : 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.36-1.86, 1.97-2.12, 2.29, 2.33-2.45, 3.45, 3.61-3.73, 3.77-3.85, 3.85-4.05, 4.34-4.47, 5.55-5.71, 6.83-6.89, 6.89-6.94, 6.94-6.97, 7.22.
- Example 17 (46) : 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (47) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.58 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.76-2.13, 2.25, 2.35-2.50, 2.90-3.03, 3.60-3.73, 3.82-3.92, 3.92-4.06, 4.35-4.49, 5.55-5.73, 6.83-6.89 , 6.89-6.94, 6.96, 7.22.
- Example 17 (48) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.90-1.71, 1.71-1.86, 1.84-2.11, 2.25, 2.34-2.52, 2.90-3.03, 3.56-3.75, 3.85-4.14, 4.37-4.56, 5.51- 5.78, 6.49-6.73, 6.82-7.00, 7.00-7.18.
- Example 17 (39) : ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.01-1.21, 1.33-1.62, 1.66-1.95, 1.95-2.18, 2.44, 2.94-3.12, 3.66, 3.94-4.08, 4.40-4.48, 5.57-5.72, 6.63, 6.92, 7.07.
- Example 17 (40) : 4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.38-1.86, 1.98-2.13, 2.29, 2.38, 3.46, 3.68, 3.76-3.87, 3.95-4.06, 4.40-4.49, 5.57-5.72, 6.63, 6.93, 7.08.
- Example 17 (41) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (cyclohexyloxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 (42) to Example 17 (45) (3aR, 4S, 5R, 6aS) -4-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro-2H-cyclopenta [B]
- furan-2-one using 4-ethoxy-4-oxobutylzinc bromide or the corresponding organozinc reagent, and using dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or
- a compound prepared by using the phosphonate corresponding to the above and using the method described in the section of Example 16 (2) to Example 16 (42) was subjected to the same operation as in Example 17 (1). By attaching, the following Example compounds were obtained.
- Example 17 (42) : 4-[(3S, 5aR, 6R, 7R, 8aS) -6- ⁇ (1E, 3R) -4- [2-fluoro-5- (trifluoromethyl) phenoxy] -3- Hydroxy-1-buten-1-yl ⁇ -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.97, 7.52-7.39, 7.31, 5.55, 5.48, 5.16, 4.60, 4.30, 4.04-4.00, 3.90-3.81, 3.48, 2.83, 2.27, 2.15, 1.89 -1.70, 1.66-1.18, 1.11-0.83.
- Example 17 (43) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,6-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.97, 7.12-7.07, 5.54, 5.47, 5.07, 4.60, 4.23, 3.97-3.82, 3.48, 2.83, 2.27, 2.15, 1.88-1.72, 1.65-1.20 , 1.07-0.85.
- Example 17 (44) : 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-4- [3- (trifluoromethoxy) phenoxy ] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.96, 7.39, 6.99-6.88, 5.55, 5.48, 5.11, 4.60, 4.28, 3.90-3.83, 3.50, 2.83, 2.27, 2.15, 1.90-1.73, 1.67 -1.20, 1.12-0.85.
- Example 17 (45) : 4-[(3S, 5aR, 6R, 7R, 8aS) -6- ⁇ (1E, 3R) -4- [2-fluoro-3- (trifluoromethyl) phenoxy] -3- Hydroxy-1-buten-1-yl ⁇ -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.96, 7.53, 7.33-7.23, 5.55, 5.47, 5.18, 4.61, 4.31, 4.03-3.95, 3.89-3.81, 3.50, 2.83, 2.27, 2.15, 1.90 -1.69, 1.65-1.17, 1.11-0.82.
- Example 18 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(3R) -3-hydroxy-4-phenoxybutyl] octahydro-2H-cyclopenta [B] Oxepin-3-yl ⁇ butanoate
- Example 16 (1) Under a hydrogen atmosphere, palladium-carbon (15 mg) was added to a 2-propanol solution (62 mL) of the compound (71 mg, 1.59 mmol) obtained in Example 16 (1), and the mixture was stirred at room temperature for 3 hours and 20 minutes.
- Example 18 (2) to Example 18 (4) Using the compound prepared in Example 16 (2), Example 16 (3) or Example 16 (25), dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or the corresponding phosphonic acid instead The following Example compound was obtained by subjecting the salt to the intended operation similar to Example 18 (1).
- Example 18 (2) 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6- [4- (3-chlorophenoxy) -3-hydroxybutyl] -7-hydroxyoctahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 18 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6- [4- (2,5-difluorophenoxy) -3-hydroxybutyl] -7-hydroxyoctahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.19, 1.19-1.25, 1.33-1.97, 2.13-2.73, 2.91, 3.66-3.80, 3.81-4.16, 4.90-5.10, 6.52-6.65, 6.65-6.76 6.93-7.09.
- Example 19 (1) to Example 19 (4) The following example compounds were obtained by subjecting the compounds produced in Example 18 (1) to Example 18 (4) to the same intended operations as in Example 17 (1).
- Example 19 (1): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(3R) -3-hydroxy-4-phenoxybutyl] octahydro-2H-cyclopenta [b] Oxepin-3-yl ⁇ butanoic acid TLC: Rf 0.39 (dichloromethane: methanol 9: 1); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.92-1.23, 1.36-1.98, 2.15-2.29, 2.33, 2.84-2.99, 3.67-3.78, 3.79-3.87, 3.88-4.07, 6.81-7.04, 7.15-7.41 .
- Example 19 (2): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(3R) -3-hydroxy-5-phenylpentyl] octahydro-2H-cyclopenta [b] Oxepin-3-yl ⁇ butanoic acid TLC: Rf 0.65 (ethyl acetate: methanol 10: 1); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.94-1.18, 1.22, 1.31-1.97, 2.12-2.30, 2.59-2.73, 2.73-2.85, 2.85-2.95, 3.53-3.76, 3.86-4.08, 4.85-5.08 , 7.05-7.37.
- Example 19 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6- [4- (3-chlorophenoxy) -3-hydroxybutyl] -7-hydroxyoctahydro-2H-cyclopenta [ b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 0.80-1.85, 1.85-2.06, 2.17-2.43, 2.91-3.04, 3.53-3.68, 3.82-4.04, 6.83-6.89, 6.89-6.94, 6.95, 7.22.
- Example 19 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6- [4- (2,5-difluorophenoxy) -3-hydroxybutyl] -7-hydroxyoctahydro-2H- Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 20 Ethyl 2-( ⁇ [(1R, 2S, 3R, 4S) -2-allyl-3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -4- (tetrahydro -H-pyran-2-yloxy) cyclopentyl] oxy ⁇ methyl) acrylate Under argon atmosphere, a solution of sodium hydride (631 mg) in anhydrous DMF (20 mL) under ice-cooling, the compound prepared in Example 3 (3.9 g). Anhydrous DMF (17 mL) solution was added and stirred at room temperature for 1 hour.
- Example 21 Ethyl (5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2-yloxy) -5,5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-carboxylate
- the compound prepared in Example 20 (200 mg, 0.190 mmol) in toluene (40 mL) under an argon atmosphere. Dissolved. A Schrock catalyst (48 mg, 0.062 mmol) was added and reacted at 60 ° C. for 18 hours.
- Example 22 (2): ethyl (3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran -2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-carboxylate Under argon atmosphere, the compound prepared in Example 21 (1.6 g) was added to 5% rhodium-alumina powder (160 mg) followed by ethanol (40 mL). ) And stirred at room temperature for 4 hours under a hydrogen atmosphere.
- the diastereomer (1.2 g) was dissolved in absolute ethanol (13 mL), a 20% ethanol solution of sodium ethoxide (895 mg) was added at room temperature under an argon atmosphere, and the mixture was stirred overnight at room temperature. After dilution with ethyl acetate, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was concentrated under reduced pressure.
- Example Compound 22 (1) having the following physical property values ( 757 mg) was obtained.
- Example 23 [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- (Iloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methanol
- Example 24 2-methyl-2-propanyl ⁇ [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- ( Tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methoxy ⁇ acetate 50 separately prepared in a solution of the compound prepared in Example 23 (300 mg) in benzene (1.8 mL) % Aqueous sodium hydroxide solution (0.6 mL) was added under ice cooling.
- Example 25 ⁇ [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2 -Yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methoxy ⁇ acetic acid
- methanol methanol
- 2N aqueous sodium hydroxide (1.75 mL)
- Example 26 2-propanyl ⁇ [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H- Pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methoxy ⁇ acetate
- the compound prepared in Example 25 was dissolved in DMF (2.8 mL) under an argon atmosphere, and potassium carbonate (2.8 mL) was dissolved at room temperature. 242 mg) and 2-iodopropane (0.105 mL) were sequentially added, and the mixture was stirred at 50 ° C. overnight.
- Example 27 2-propanil ⁇ [(3R, 5aR, 6S, 7R, 8aS) -6- (hydroxymethyl) -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin -3-yl] methoxy ⁇ acetate
- 1M THF solution 1. mL
- tetrabutylammonium fluoride was added to the compound prepared in Example 26 at room temperature, and the mixture was stirred for 6 hours.
- the reaction solution was diluted with ethyl acetate, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- the compound prepared in Example 27 (152 mg) was treated in the same manner as Example 13 ⁇
- Example 16 (1) using dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate To give the title compound (72 mg) having the following physical properties.
- Example 28 (1) to Example 28 (17) (3aR, 4S, 5R, 6aS) -4-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -5- (tetrahydro-2H-pyran-2-yloxy) hexahydro-2H-cyclopenta [B] Using furan-2-one, using ethyl 2- (bromomethyl) acrylate, using dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or the corresponding phosphonate instead Example 20-> Example 21 Example 22 (1) or Example 22 (2)-> Example 23-> Example 24-> Example 25-> Example 26-> Example 27-> For the same purpose operation as Example 28 By attaching, the following Example compounds were obtained.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.65 (ethyl acetate)
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.32, 1.40-1.60, 1.61-2.21, 2.40-2.56, 3.05-3.18, 3.25-3.41, 3.67-3.82, 3.82-3.92, 3.92-4.06, 4.15 -4.25, 4.45-4.58, 4.99-5.17, 5.56-5.76, 6.75-6.84, 6.87-6.99, 7.15-7.24.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2-fluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.49 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.09-1.35, 1.39-2.24, 2.40-2.57, 2.62-2.78, 3.10, 3.24-3.41, 3.64-3.80, 3.85-4.10, 4.14-4.26, 4.48-4.60 , 4.98-5.15, 5.55-5.77, 6.82-7.14.
- Example 28 (2) 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-fluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.45 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.07-1.34, 1.39-2.22, 2.37-2.58, 3.04-3.17, 3.24-3.40, 3.64-3.80, 3.83-3.91, 3.91-4.07, 4.11-4.28, 4.45 -4.59, 4.95-5.17, 5.54-5.77, 6.53-6.74, 7.10-7.32.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-fluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.42 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.34, 1.38-2.22, 2.39-2.57, 3.05-3.17, 3.25-3.40, 3.65-3.79, 3.80-3.88, 3.88-4.09, 4.10-4.26, 4.43 -4.58, 4.97-5.15, 5.54-5.74, 6.77-6.91, 6.90-7.04.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-chlorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.57 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.30, 1.40-1.58, 1.61-2.22, 2.40-2.56, 3.11, 3.25-3.41, 3.65-3.80, 3.80-3.90, 3.90-4.06, 4.13-4.25 , 4.44-4.59, 4.98-5.16, 5.55-5.75, 6.76-6.91, 7.16-7.30.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy)- 1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.60 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.09-1.31, 1.41-1.60, 1.61-2.22, 2.33, 2.41-2.57, 3.05-3.17, 3.25-3.41, 3.66-3.81, 3.81-3.91, 3.92-4.06 , 4.14-4.26, 4.45-4.58, 4.99-5.16, 5.57-5.74, 6.66-6.83, 7.16.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (4-methylphenoxy)- 1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.57 (ethyl acetate)
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.09-1.35, 1.40-1.59, 1.61-2.20, 2.29, 2.39-2.60, 3.03-3.18, 3.25-3.41, 3.65-3.79, 3.79-3.89, 3.89-4.07 , 4.13-4.26, 4.44-4.56, 4.98-5.16, 5.56-5.74, 6.74-6.86, 7.07.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2-chlorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.33 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.09-1.30, 1.40-1.57, 1.61-2.21, 2.40-2.56, 2.71, 3.04-3.18, 3.25-3.41, 3.65-3.81, 3.88-4.04, 4.08, 4.15 -4.24, 4.52-4.62, 5.00-5.16, 5.59-5.76, 6.88-6.98, 7.17-7.28, 7.33-7.41.
- Example 28 (9): 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (2-methylphenoxy)- 1-buten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.37 (ethyl acetate)
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.29, 1.41-1.57, 1.61-2.20, 2.24, 2.41-2.55, 3.11, 3.25-3.40, 3.66-3.81, 3.86-3.94, 3.94-4.05, 4.20 , 4.48-4.60, 5.00-5.17, 5.60-5.76, 6.82, 6.85-6.93, 7.10-7.20.
- Example 28 (10): 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-2-fluorophenoxy) -3-hydroxy- 1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.37 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.05-1.33, 1.38-2.25, 2.38-2.56, 2.65-2.74, 2.96-3.19, 3.24-3.41, 3.73, 3.87-4.10, 4.14-4.26, 4.46-4.61 , 4.98-5.15, 5.56-5.75, 6.83-6.92, 6.93-7.05.
- Example 28 (11): 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.51 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.32, 1.38-2.24, 2.32-2.43, 2.43-2.57, 3.05-3.19, 3.25-3.42, 3.65-3.82, 3.82-3.91, 3.92-4.06, 4.14 -4.27, 4.44-4.62, 4.99-5.18, 5.52-5.77, 6.82, 6.98.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.37, 1.37-2.24, 2.39-2.59, 3.04-3.18, 3.24-3.41, 3.65-3.80, 3.81-3.91, 3.91-4.05, 4.13-4.27, 4.43 -4.58, 4.99-5.16, 5.55-5.75, 6.48-6.59, 6.64-6.78.
- Example 28 (13): 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-difluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.07-1.32, 1.37-2.22, 2.39-2.58, 3.04-3.18, 3.24-3.41, 3.64-3.79, 3.81-3.90, 3.90-4.06, 4.12-4.27, 4.43 -4.58, 4.97-5.15, 5.55-5.74, 6.35-6.54.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,3-difluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.08-1.35, 1.36-2.32, 2.38-2.57, 2.63-2.84, 3.03-3.19, 3.22-3.44, 3.62-3.82, 3.87-4.10, 4.13-4.28, 4.46 -4.63, 4.98-5.20, 5.54-5.77, 6.66-6.87, 6.90-7.05.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1- Buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.07-1.32, 1.36-2.21, 2.27, 2.40-2.56, 2.77, 3.04-3.20, 3.23-3.41, 3.64-3.80, 3.84-4.08, 4.13-4.27, 4.48 -4.61, 4.98-5.16, 5.54-5.74, 6.53-6.65, 6.65-6.76, 6.94-7.08.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (5-chloro-2-fluorophenoxy) -3-hydroxy- 1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.52 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.10-1.30, 1.40-1.57, 1.61-2.21, 2.42-2.55, 2.60, 3.05-3.17, 3.25-3.40, 3.66-3.82, 3.87-4.08, 4.15-4.25 , 4.49-4.61, 4.99-5.16, 5.55-5.75, 6.85-6.93, 6.93-7.06.
- Example 28 2-propanyl ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chloro-4-fluorophenoxy) -3-hydroxy- 1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetate
- TLC Rf 0.40 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.11-1.30, 1.40-1.60, 1.62-2.21, 2.41-2.55, 3.05-3.17, 3.26-3.40, 3.66-3.79, 3.79-3.89, 3.89-4.06, 4.15 -4.25, 4.45-4.56, 4.99-5.15, 5.56-5.73, 6.73-6.80, 6.94, 7.00-7.09.
- Example 29 (1) to Example 29 (17) The compounds produced in Example 28 (1) to Example 28 (17) were each subjected to the same intended operation as in Example 29 to give the following example compounds.
- Example 29 (1): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.09-1.31, 1.40-2.26, 2.42-2.57, 3.03-3.17, 3.29-3.46, 3.68-3.81, 3.82-3.91, 3.93-4.09, 4.14-4.23, 4.46 -4.58, 5.57-5.75, 6.75-6.84, 6.87-6.99, 7.14-7.24.
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.07-1.24, 1.32-1.48, 1.49-1.63, 1.67-2.13, 2.35-2.51, 3.06-3.18, 3.20-3.42, 3.59-3.74, 3.90-4.08, 4.11-4.23, 4.38-4.49, 5.57-5.70, 6.83-6.95, 6.99-7.16.
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.09-1.24, 1.35-1.49, 1.49-1.61, 1.67-2.12, 2.37-2.50, 3.07-3.18, 3.21-3.40, 3.60-3.72, 3.83-4.05, 4.13-4.23, 4.34-4.47, 5.56-5.73, 6.56-6.83, 7.16-7.32.
- Example 29 (4): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-fluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.09-1.24, 1.34-1.49, 1.49-1.61, 1.68-2.11, 2.35-2.51, 3.08-3.19, 3.20-3.42, 3.60-3.73, 3.80-4.07, 4.12-4.24, 4.34-4.46, 5.56-5.71, 6.83-7.06.
- Example 29 ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (4-chlorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.06-1.28, 1.32-1.63, 1.64-2.12, 2.35-2.51, 3.06-3.19, 3.20-3.43, 3.57-3.74, 3.81-4.10, 4.10-4.24, 4.33-4.47, 5.52-5.73, 6.84-6.97, 7.16-7.29.
- Example 29 ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy) -1-butene -1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.07-1.26, 1.33-1.64, 1.66-2.13, 2.29, 2.37-2.51, 3.05-3.19, 3.20-3.44, 3.57-3.75, 3.82-4.08, 4.10- 4.24, 4.32-4.47, 5.54-5.72, 6.62-6.80, 7.04-7.17.
- Example 29 ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (4-methylphenoxy) -1-butene -1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.06-1.27, 1.31-1.64, 1.65-2.11, 2.25, 2.35-2.52, 3.04-3.20, 3.19-3.43, 3.58-3.74, 3.77-4.10, 4.10- 4.24, 4.31-4.46, 5.52-5.72, 6.79, 7.04.
- Example 29 ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2-chlorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.09-1.23, 1.32-1.46, 1.48-1.62, 1.68-2.11, 2.36-2.51, 3.11, 3.22-3.40, 3.60-3.73, 3.86-4.06, 4.12- 4.22, 4.40-4.50, 5.58-5.73, 6.90, 7.05, 7.23, 7.33.
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.05-1.62, 1.63-2.09, 2.35-2.52, 3.06-3.19, 3.19-3.42, 3.58-3.73, 3.93-4.06, 4.12-4.22, 4.37-4.52, 5.52-5.74, 6.89-7.18.
- Example 29 (11): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.06-1.62, 1.65-2.13, 2.37-2.52, 3.07-3.18, 3.20-3.45, 3.60-3.74, 3.82-4.07, 4.12-4.23, 4.33-4.47, 5.53-5.73, 6.93, 6.98.
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.07-1.33, 1.32-1.63, 1.63-2.13, 2.36-2.50, 3.06-3.18, 3.20-3.41, 3.60-3.73, 3.84-4.07, 4.12-4.23, 4.35-4.46, 5.53-5.72, 6.68, 6.75, 6.79-6.85.
- Example 29 (13): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.08-1.30, 1.32-1.63, 1.68-2.12, 2.36-2.51, 3.06-3.18, 3.21-3.41, 3.59-3.74, 3.82-4.06, 4.12-4.24, 4.35-4.48, 5.54-5.73, 6.39-6.64.
- Example 29 (14): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,3-difluorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- Example 29 (15): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- Example 29 (16): ( ⁇ (3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (5-chloro-2-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ methoxy) acetic acid
- 1 H-NMR 300 MHz, CD 3 OD
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.08-1.25, 1.34-1.63, 1.67-2.09, 2.37-2.51, 3.07-3.18, 3.20-3.42, 3.59-3.73, 3.82-4.07, 4.12-4.23, 4.35-4.44, 5.54-5.72, 6.87, 7.04, 7.12.
- Example 30 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-4-phenoxy-1-buten-1-yl] -7- (Tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- the compound prepared in Example 14 (280 mg, 0.53 mmol) was converted to (2-methoxyethyl) under argon It was dissolved in aminosulfur trifluoride (977 ⁇ L, 5.30 mmol) and stirred at room temperature for 4 days and 7 hours.
- Example 31 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-4-phenoxy-1-buten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 30 to the same intended operation as in Example 16 (1).
- Example 32 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-4-phenoxy-1-buten-1-yl] -7-hydroxyoctahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 31 to the same operation as in Example 17 (1).
- Example 32 (1) to Example 32 (5) Using the compound prepared in Example 13, using the corresponding phosphonate instead of dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate, Example 14 ⁇ Example 30 ⁇ Example 31 ⁇ The following example compounds were obtained by subjecting the same operation as in Example 32.
- Example 32 (1) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-4- (2-fluorophenoxy) -1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.52 (ethyl acetate);
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.98, 7.28-7.19, 7.13, 6.99, 6.06, 5.75, 4.79, 4.43, 3.90-3.84, 3.57, 2.84, 2.30, 2.15, 1.97, 1.80-1.64 , 1.61-1.21, 1.11-0.86.
- Example 32 (2) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-4- (3-fluorophenoxy) -1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.55 (ethyl acetate);
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.98, 7.33, 6.94-6.78, 6.05, 5.75, 4.81, 4.39, 3.91-3.85, 3.58, 2.85, 2.31, 2.16, 1.98, 1.81-1.67, 1.60 -1.22, 1.12-0.87.
- Example 32 (4 ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (3-chlorophenoxy) -3,3-difluoro-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.55 (ethyl acetate);
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.98, 7.32, 7.11, 7.04, 6.98, 6.05, 5.74, 4.80, 4.40, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.97, 1.81-1.64 , 1.59-1.21, 1.10-0.86.
- Example 32 4-[(3S, 5aR, 6R, 7R, 8aS) -6- ⁇ (1E) -3,3-difluoro-4- [3- (trifluoromethyl) phenoxy] -1- Buten-1-yl ⁇ -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- TLC Rf 0.68 (ethyl acetate);
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.98, 7.55, 7.35-7.32, 6.06, 5.76, 4.80, 4.48, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.98, 1.81-1.64, 1.59 -1.21, 1.10-0.86.
- Example 32 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (2,5-difluorophenoxy) -3,3-difluoro-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.65 (ethyl acetate);
- 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 11.98, 7.33-7.23, 6.82, 6.07, 5.74, 4.80, 4.48, 3.91-3.84, 3.58, 2.85, 2.31, 2.16, 1.97, 1.81-1.64, 1.60 -1.21, 1.10-0.86.
- Example 33 [(3S, 5aR, 6S, 7R, 8aS) -6- (hydroxymethyl) -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl ] Methyl acetate
- dichloromethane 5 mL
- pyridine 0.35 mL
- acetic anhydride 0.94 mL
- N-dimethylaminopyridine small amount
- the organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent was concentrated under reduced pressure.
- THF 0.5 mL
- a 1M THF solution 5 mL
- N-tetrabutylammonium fluoride was added under an argon atmosphere and ice cooling, followed by stirring for 5 hours.
- the reaction mixture was poured into an ice-cooled saturated aqueous ammonium chloride solution and extracted with ethyl acetate.
- the organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was concentrated under reduced pressure.
- Example 34 [(3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-oxo-4-phenoxy-1-buten-1-yl] -7- (tetrahydro-2H-pyran- 2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methyl acetate
- Example 33 By subjecting the compound produced in Example 33 (616 mg) to the same procedure as in Example 13 ⁇ Example 14, The title compound (568 mg) having the following physical data was obtained.
- Example 35 [(3R, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4-phenoxy-3- (tetrahydro-2H-pyran-2-yloxy) -1-butene-1- Yl] -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methanol
- the compound prepared in Example 34 was prepared in the same manner as in Example 15 ⁇ Example 11. By subjecting to the intended operation, the title compound (568 mg) having the following physical property values was obtained.
- TLC: Rf 0.26 (hexane: ethyl acetate 1: 1).
- Example 36 Ethyl 2-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4-phenoxy-3- (tetrahydro-2H-pyran-2-yloxy) -1-butene -1-yl] -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] -1,3-thiazol-4-carboxylate Examples under argon atmosphere To a solution of the compound synthesized in 35 (150 mg) in DMSO (0.5 mL) -ethyl acetate (1.0 mL) was added diisopropylethylamine (0.3 mL) under ice-cooling, followed by pyridine-sulfur trioxide (139 mg).
- Example 37 Ethyl 2- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ -1,3-thiazole-4-carboxylate
- p-toluenesulfonic acid monohydrate 2.0 mg
- Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
- the extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
- Example 38 2- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ -1,3-thiazole-4-carboxylic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 37 to the same operation as in Example 17 (1).
- Example 39 Ethyl ( ⁇ [(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4-phenoxy-3- (tetrahydro-2H-pyran-2-yloxy) -1-butene -1-yl] -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methyl ⁇ thio) acetate
- Anhydrous compound (90 mg) prepared in Example 35 Triethylamine (0.039 mL) and methanesulfonic acid chloride (0.020 mL) were successively added to the THF (1.7 mL) solution under ice cooling, and the mixture was stirred for 1 hour.
- Example 40 Ethyl [( ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ methyl) thio] acetate
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 39 to the same operation as in Example 37.
- Example 41 [( ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ methyl) thio] acetic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 40 to the same operation as in Example 17 (1).
- Example 42 (1) to Example 42 (2)
- Example 15 ⁇ Example 16 (1) By subjecting to the same operation as described in (1), the following compound was obtained.
- Example 42 (1): ethyl 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5 , 5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoate (low polarity)
- Example 42 (2): ethyl 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5 , 5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoate (high polarity)
- Example 43 (1) to Example 43 (5) Using the compound prepared in Example 4 and using 4-ethoxy-4-oxobutyl zinc bromide or the corresponding organozinc reagent instead, dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or instead Using the corresponding phosphonate, the same purpose as Example 5 ⁇ Example 6 ⁇ Example 12 ⁇ Example 13 ⁇ Example 14 ⁇ Example 15 ⁇ Example 16 (1) ⁇ Example 17 (1) The following example compounds were obtained by subjecting to the above procedure.
- Example 43 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5 5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid (low polarity)
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.58-1.74, 2.07-2.32, 2.40-2.55, 2.60-2.78, 3.66-3.80, 3.84-3.95, 3.95-4.04, 4.10-4.22, 4.38-4.56, 4.77-4.99, 5.62-5.79, 6.04, 6.85-6.99, 7.19-7.29, 7.39, 7.45-7.54, 7.83-7.94.
- Example 43 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5 5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ benzoic acid (high polarity)
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.58-1.74, 2.04-2.31, 2.40-2.55, 2.66, 3.66-3.81, 3.86-4.02, 4.15, 4.37-4.54, 4.73-5.00, 5.59-5.76, 6.01, 6.85-6.98, 7.19-7.30, 7.39, 7.45-7.53, 7.84-7.94.
- Example 43 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl]- 5,5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ propanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.61-1.79, 1.84-2.29, 2.36-2.60, 3.67-3.83, 3.86-4.16, 4.38, 4.48-4.67, 5.41-5.57, 5.57-5.87, 6.78-7.08 , 7.19-7.36.
- Example 43 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl]- 5,5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.62-1.79, 1.81-2.26, 2.26-2.64, 3.69-3.81, 3.82-3.91, 3.92-4.07, 4.39, 4.49-4.59, 5.42-5.53, 5.55-5.79 , 6.75-7.12, 7.19-7.41.
- Example 43 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-1-octen-1-yl] -5,5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.68-1.01, 1.06-2.93, 3.58-3.87, 3.88-4.24, 4.38, 5.25-5.81.
- Example 44 (1) to Example 44 (4) Example 5-> Example 6-> Example 7-> Example 8-> Implementation using the compound prepared in Example 4 and using 4-ethoxy-4-oxobutylzinc bromide or the corresponding organozinc reagent instead Example 12-> Example 13-> Example 14-> Example 15-> Example 16
- the following example compound was obtained by carrying out to the objective operation similar to Example 16 (1).
- Example 44 2-propanyl 5- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoate
- Example 44 2-propanyl 5- ⁇ (5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-butene-1 -Yl] -7-hydroxy-5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoate
- Example 44 2-propanyl 5- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy) -1 -Buten-1-yl] -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoate
- Example 44 2-propanyl 6- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ hexanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.18-1.46, 1.52-1.99, 2.00-2.30, 2.30-2.62, 2.77, 3.65-3.81, 3.81-4.08, 4.39, 4.46-4.59, 4.90-5.09, 5.42 , 5.55-5.75, 6.85-7.03, 7.22-7.35.
- Example 45 (1) to Example 45 (4) The compounds produced in Example 44 (1) to Example 44 (4) were subjected to the same intended operation as in Example 17 (1) to give the following Example compounds.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.31-1.48, 1.52-1.77, 1.77-1.98, 2.00-2.25, 2.34, 2.38-2.59, 3.67-3.81, 3.84-4.06, 4.38, 4.46-4.58, 5.43 , 5.57-5.73 6.85-7.02, 7.21-7.35.
- Example 45 (2): 5- ⁇ (5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (3-chlorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxy-5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoic acid
- Example 45 5- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4- (3-methylphenoxy) -1-butene- 1-yl] -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoic acid
- Example 45 6- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5 5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ hexanoic acid
- 1 H-NMR 300 MHz, CD 3 OD
- Example 46 Ethyl 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro-2H-cyclopenta [B] Oxepin-3-yl ⁇ butanoate (mixture of diastereomers)
- Example 9 Ethyl 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro-2H-cyclopenta
- Example 47 4- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro-2H-cyclopenta [ b] Oxepin-3-yl ⁇ butanoic acid (mixture of diastereomers)
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 46 to the same intended operation as in Example 17 (1).
- Example 48 (1) to Example 48 (2)
- Example 4 ⁇
- Example 5 ⁇
- Example 6 ⁇
- Example 7 ⁇
- Example 8 ⁇
- 9 ⁇
- Example 12 ⁇
- Example 13 ⁇
- Example 14 ⁇
- Example 15 ⁇
- Example 16 By subjecting to the same operation as in Example (1), the following Example compounds were obtained.
- Example 48 2-propanyl 3- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ propanoate (mixture of diastereomers)
- TLC Rf 0.47 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.23, 1.33-1.94, 2.01-2.60, 2.86-3.46, 3.66-4.09, 4.47-4.59, 4.92-5.07, 5.58-5.75, 6.86-7.02, 7.24-7.35 .
- Example 48 2-propanyl 5- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoate (mixture of diastereomers)
- Example 49 (1) to Example 49 (2) By subjecting the compounds produced in Example 48 (1) to Example 48 (2) to the same intended operations as in Example 17 (1), the following Example compounds were obtained.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.30-1.96, 2.06-2.55, 2.85-3.47, 3.57-4.10, 4.41-4.61, 5.55-5.74, 6.86-7.02, 7.22-7.37.
- Example 49 (2): 5- ⁇ (5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ pentanoic acid (mixture of diastereomers)
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.88-1.19, 1.20-1.52, 1.52-1.93, 2.05-2.19, 2.27-2.39, 2.40-2.54, 2.89, 3.64-3.77, 3.77-4.08, 4.44-4.57 , 5.55-5.72, 6.85-7.03, 7.21-7.36.
- Example 50 (1S, 2R, 3S, 4R) -3-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -2- (1-propen-1-yl) -4- (Tetrahydro-2H-pyran-2-yloxy) cyclopentanol
- carbonylchlorohydridotris (triphenylphosphine) ruthenium 9. mg
- the reaction mixture was stirred at 80 ° C. for 3.5 hours. Thereafter, the reaction mixture was concentrated in a small amount to obtain the title compound having the following physical property values.
- Example 51 2-methyl-2-propanyl ⁇ [(1S, 2R, 3S, 4R) -3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -2- (1- Propen-1-yl) -4- (tetrahydro-2H-pyran-2-yloxy) cyclopentyl] oxy ⁇ acetate
- the compound prepared in Example 50 (3.70 g) was dissolved in DMF (20 mL) under an argon atmosphere. After adding t-butyl bromoacetate (7.4 mL), sodium hydride (400 mg, 60% in oil) was added four times every 30 to 60 minutes (1600 mg in total).
- Example 52 allyl ⁇ [(1S, 2R, 3S, 4R) -3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -2- (1-propen-1-yl) -4- (Tetrahydro-2H-pyran-2-yloxy) cyclopentyl] oxy ⁇ acetate
- the compound prepared in Example 51 (3.37 g) was dissolved in THF (10 mL), 5N aqueous sodium hydroxide solution (5 mL), methanol ( 20 mL) was added and stirred at room temperature for 2 hours.
- Example 53 (1): methyl (2R) -2- ⁇ [(1S, 2R, 3S, 4R) -3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -2- (1-propen-1-yl) -4- (tetrahydro-2H-pyran-2-yloxy) cyclopentyl] oxy ⁇ -4-pentenoate
- Diisopropylamine 2.0 mL was dissolved in THF (16 mL) under an argon atmosphere and cooled to 0 ° C.
- Example Compound 53 (1) (1.26 g) having the following physical properties was obtained.
- Example compound 53 (2) (1.16 g) was obtained.
- Example 54 methyl (2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-carboxylate
- the compound (1.26 g) prepared in Example 53 (1) was dissolved in dichloromethane (30 mL). Then, a Schrock catalyst (0.44 g) was added, and the mixture was stirred at room temperature overnight.
- Example 55 [(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] methanol
- Lithium aluminum hydride (84 mg) is suspended in THF (2 mL) and cooled to 0 ° C. Then, a THF (3 mL) solution of the compound (0.95 g) produced in Example 54 was added dropwise, and the mixture was stirred at 0 ° C. for 15 minutes.
- Example 56 2-propanyl (2E) -3-[(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (Tetrahydro-2H-pyran-2-yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] acrylate
- the compound prepared in Example 55 (165 mg) Dissolved in DMSO (2 mL), Wittig reagent (carboisopropoxymethylene triphenylphosphorane, 218 mg), 1-hydroxy-1,2-benziodoxol-3 (1H) -one 1-oxide (IBX) 1-hydroxy-1,2-benziodoxol-3 (1H) -one 1-oxide, 168 mg) was added and stirred at 50 ° C.
- Example 57 2-propanyl 3-[(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H -Pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-2-yl] propanoate
- the compound prepared in Example 56 (174 mg) was dissolved in 2-propanol (2 mL), sodium bicarbonate (20 mg), 10% Palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 1 hr under a hydrogen atmosphere.
- Example 58 2-propanyl 3-[(2R, 5aR, 6S, 7R, 8aS) -6- (hydroxymethyl) -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b]
- Oxepin-2-yl] propanoate 1 mL of 1 mol / L tetrabutylammonium fluoride (THF solution) was added to the compound prepared in Example 57 (143 mg) and stirred overnight at room temperature.
- Example 59 2-propanyl 3- ⁇ (2R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-2-yl ⁇ propanoate
- the title compound having the following physical properties was obtained by subjecting the compound produced in Example 58 to the same operation as in Example 13 ⁇ Example 14 ⁇ Example 15 ⁇ Example 16 (1).
- Example 60 [(2S, 5aR, 6S, 7R, 8aS) -6-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] methanol
- Example 60 The title compound having the following physical property values was obtained by subjecting the compound produced in Example 60 to the same operation as in Example 56 ⁇ Example 57 ⁇ Example 58 ⁇ Example 59.
- Example 62 [(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] methyl methanesulfonate Compound (207 mg) prepared in Example 55 under dichloromethane (207 mg) under argon atmosphere 2 mL) and cooled to 0 ° C.
- Example 63 [(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [Dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- Yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] acetonitrile
- the compound prepared in Example 62 (273 mg) was dissolved in DMSO (1 mL) and cyanide. Sodium chloride (55 mg) was added and stirred at 80 ° C. overnight.
- Example 64 2-propanyl (2E) -3-[(2R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (Tetrahydro-2H-pyran-2-yloxy) -3,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-2-yl] acrylate
- the compound (195 mg) prepared in Example 63 was obtained. Dissolved in toluene (4 mL) and cooled to ⁇ 15 ° C.
- Example 65 2-propanyl 4- ⁇ (2R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-2-yl ⁇ butanoate
- the title compound having the following physical property values was obtained by subjecting the compound produced in Example 64 to the same operation as in Example 56 ⁇ Example 57 ⁇ Example 58 ⁇ Example 59.
- Example 66 2-propanyl 4- ⁇ (2S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-2-yl ⁇ butanoate
- Example 62 2-propanyl 4- ⁇ (2S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-2-yl ⁇ butanoate
- Example 67 (1) to Example 67 (4) The following example compounds were obtained by subjecting the compounds produced in Example 59, Example 61, Example 65 and Example 66 to the same operation as in Example 17 (1).
- Example 67 4- ⁇ (2S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-2-yl ⁇ butanoic acid
- Example 68 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (3-chlorophenoxy) -3-oxo-1-buten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- the compound (102 mg) produced in Example 17 (3) was dissolved in methylene chloride (2 mL) and acetone (1.5 mL), manganese dioxide (613 mg) was added, and the mixture was stirred at 50 ° C. for 4 hr.
- Manganese dioxide was removed with Celite (trade name) and washed with chloroform-acetone.
- Example 68 (1) : 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (2,5-difluorophenoxy) -3-oxo-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 17 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (2,5-difluorophenoxy) -3-oxo-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 69 (5aR, 6S, 7R, 8aS) -6-( ⁇ [(dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -3- [4-oxo-4- (2-propa Nyloxy) butyl] octahydro-2H-cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate
- methylene chloride 2.3 mL
- Triethylamine (0.246 mL), 4-phenylbenzoyl chloride (303 mg) and dimethylaminopyridine (2 mg) were added and stirred at room temperature for 6 hours, and triethylamine (0.123 mL) and 4-phenylbenzoyl chloride (151 mg) were added. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate.
- Example 70 (3S, 5aR, 6S, 7R, 8aS) -6- (hydroxymethyl) -3- [4-oxo-4- (2-propanyloxy) butyl] octahydro-2H-cyclopenta [b] oxepin -7-yl 4-biphenylcarboxylate
- THF 0.5 mL
- tetrabutylammonium fluoride 1 M THF (2.1 mL) for 2 hours. Stir. After completion of the reaction, the reaction was stopped with a saturated ammonium chloride aqueous solution diluted with ice and cooled with ice.
- Example 71 (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3- (tetrahydro-2H-pyran-2-yloxy)- 1-buten-1-yl] -3- [4-oxo-4- (2-propanyloxy) butyl] octahydro-2H-cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate prepared in Example 70
- the title compound having the following physical property values was obtained by subjecting the obtained compound to the same operation as in Example 13 ⁇ Example 14 ⁇ Example 15 ⁇ Example 11.
- TLC: Rf 0.58 (hexane: ethyl acetate 2: 1).
- Example 72 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3- (tetrahydro-2H-pyran -2-yloxy) -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Compound (950 mg) of 2-propanol (5 mL) prepared in Example 71 ) Lithium isopropoxide (2.0 M in THF, 2.3 mL) was added to the solution and the reaction mixture was stirred at 50 ° C. for 5 hours.
- Example 73 2-propanyl 4-[(3S, 5aR, 6R, 7S, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3- (tetrahydro-2H-pyran -2-yloxy) -1-buten-1-yl] -7- (formyloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- the compound prepared in Example 72 (29 mg) in THF (0.3
- triphenylphosphine 27 mg
- formic acid 4 ⁇ L
- a toluene solution of diethyl azodicarboxylate 47 ⁇ L, 2.2 mol / L
- Example 74 2-propanyl 4-[(3S, 5aR, 6R, 7S, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3- (tetrahydro-2H-pyran -2-yloxy) -1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- the compound prepared in Example 73 (10 mg) of 2-propanol (0.35
- potassium carbonate (3 mg) at 0 ° C., and the reaction mixture was stirred at 40 ° C. for 1 hour.
- Example 75 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7S, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate Using the compound prepared in Example 74, the same procedure as in Example 16 (1) was followed. Gave the title compound having the following physical data.
- Example 76 4- ⁇ (3S, 5aR, 6R, 7S, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- the compound prepared in Example 75 was used for the same purpose as in Example 17 (1).
- the title compound having the following physical property values was obtained.
- Example 77 (1R, 2R, 3S, 4R) -2-allyl-3-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -4- (tetrahydro-2H-pyran-2 -Iyloxy) cyclopentanol
- Example 78 2-propanyl 4-[(5aR, 6S, 7R, 8aR) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran -2-yloxy) -5,5a, 6,7,8,8a-hexahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- Example 4 Example using the compound prepared in Example 77 5 ⁇
- Example 7 ⁇ By subjecting to the same operation as in Example 8, the title compound having the following physical property values was obtained.
- TLC: Rf 0.39 (hexane: ethyl acetate 4: 1).
- Example 79 2-propanyl 4- ⁇ (5aR, 6R, 7R, 8aR) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl]- 5,5a, 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate Using the compound prepared in Example 78, Example 12 ⁇ Example 13 ⁇ Example 14 ⁇ Example 15 ⁇ Example 16 The title compound having the following physical data was obtained by subjecting it to the same operation as in Example (1).
- Example 80 4- ⁇ (5aR, 6R, 7R, 8aR) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] -5,5a , 6,7,8,8a-Hexahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- the compound prepared in Example 79 is used for the same purpose as in Example 17 (1).
- the title compound having the following physical property values was obtained.
- Example 81 2-propanyl 4- ⁇ (5aR, 6R, 7R, 8aR) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate Using the compound prepared in Example 78, Example 9 ⁇ Example 10 ⁇ Example 11 ⁇ Example 12 ⁇ Example 13 ⁇ Example 14 ⁇ Execution Example 15 ⁇ The title compound having the following physical data was obtained by subjecting it to the same operation as in Example 16 (1).
- Example 81 2-propanyl 4- ⁇ (5aR, 6R, 7R, 8aR) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate Alternatively, the title compound having the following physical property values was obtained by subjecting the corresponding phosphonate to the same operation as in Example 81.
- Example 82 to Example 82 (1) The following example compound was obtained by subjecting the compound produced in Example 81 or Example 81 (1) to the same intended operation as in Example 17 (1).
- Example 82 4- ⁇ (5aR, 6R, 7R, 8aR) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-buten-1-yl] octahydro-2H- Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 82 4- ⁇ (5aR, 6R, 7R, 8aR) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CD 3 OD): ⁇ 1.00-2.06, 2.22-2.33, 3.20-3.47, 3.74-3.86, 3.88-4.02, 4.45, 5.54-5.79, 6.57-6.68, 6.86-6.96, 7.01- 7.13.
- Example 83 4-[(3S, 5aR, 6R, 7R, 8aS) -6- (3,3-difluoro-4-phenoxybutyl) -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3- Iil] butanoic acid
- the title compound having the following physical properties was obtained by subjecting the compound produced in Example 30 to the same intended operation as in Example 18 ⁇ Example 19.
- Example 84 [(3S, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- (Iloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] methyl methanesulfonate
- methylene chloride 300 mL
- Triethylamine 27.36 mL
- mesyl mesyl under ice cooling.
- Acid chloride (7.98 mL) was added in order and stirred for 1 hour.
- Example 85 [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- (Iloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] acetonitrile
- sodium cyanide 8.18 g
- the reaction mixture was poured into ice water (750 mL) and extracted with ethyl acetate.
- Example 86 [(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (tetrahydro-2H-pyran-2- (Iloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] acetaldehyde
- a toluene (350 mL) solution of the compound prepared in Example 85 (29.4 g) was cooled to ⁇ 18 ° C., and DIBAL 1 M toluene The solution (103 mL) was added dropwise over 40 minutes.
- the reaction mixture was diluted with MTBE (300 mL), saturated aqueous sodium tartrate solution (50 mL) was added under ice-cooling, the mixture was stirred for a while, ice-cooled hydrochloric acid (1 N, 300 mL) was added, and the mixture was extracted with ethyl acetate. .
- the organic layer was washed with a saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was concentrated under reduced pressure to obtain the title compound (31.3 g) having the following physical property values.
- Example 87 2-propanyl (2E) -4-[(3R, 5aR, 6S, 7R, 8aS) -6-( ⁇ [dimethyl (2-methyl-2-propanyl) silyl] oxy ⁇ methyl) -7- (Tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] -2-butenoate
- methylene chloride 422 mL
- Isopropyl (triphenylphosphoranylidene) acetate 45.93 g
- Example 88 ethyl (2E) -4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1 -Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ -2-butenoate
- Example 12 ⁇
- Example 13 ⁇
- Example 15 Example using the compound prepared in Example 87 The title compound having the following physical properties was obtained by subjecting it to the same operation as in 16 (1).
- Example 89 (2E) -4- ⁇ (3R, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-4-phenoxy-1-butene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ -2-butenoic acid
- Example 90 4- ⁇ (3S, 5aR, 6R, 7S, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-Fluorooctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 72 the same as Example 30 ⁇
- Example 31 ⁇ Example 32 By subjecting to the intended operation, the title compound (4 mg) having the following physical property values was obtained.
- Example 91 ethyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- ethyl iodide 21 mg
- potassium carbonate (19 mg) were added and the reaction mixture was stirred at 50 ° C. for 30 min.
- the reaction mixture was poured into water and extracted with MTBE.
- the recovered raw material was retried with the above reagent (ethyl iodide 12 mg, potassium carbonate 6 mg) and stirred at 50 ° C. for 1 hour, and then the reaction mixture was poured into water and extracted with MTBE.
- Example 91 3-hydroxypropyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy- 1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate Using the compound prepared in Example 17 (25), 3- The title compound having the following physical data was obtained by conducting the same operation as in Example 91 using bromo-1-propanol.
- Example 92 (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -3 -(4-Hydroxybutyl) octahydro-2H-cyclopenta [b] oxepin-7-ol
- THF 1.4 mL
- lithium aluminum hydride (6 mg
- Example 93 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ -N-ethylbutanamide
- 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (7 mg) and an aqueous ethylamine solution (12 M, 19 ⁇ L) were added, and the reaction mixture was stirred at room temperature for 6 hours.
- Example 95 (3S, 5aR, 6S, 7R, 8aS) -6-[(E) -2-iodovinyl] -3- [4-oxo-4- (2-propanyloxy) butyl] octahydro-2H- Cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate
- chromium chloride 1.7 g
- Example 96 (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-hydroxy-5- (3-pyridinyl) -1-penten-1-yl] -3- [4-oxo -4- (2-propanyloxy) butyl] octahydro-2H-cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate
- Compound prepared in Example 95 (590 mg) and compound prepared in Example 94 (258 mg )
- THF (10 mL) was added chromium chloride (470 mg) and nickel chloride (2.5 mg), and the mixture was stirred overnight at room temperature.
- Example 97 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-5- (3-pyridinyl) -1-pentene-1 -Il] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- lithium isopropoxide 2.0 M in THF, 0.33
- Example 98 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-5- (3-pyridinyl) -1-penten-1-yl] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 100 5-[(3-phenoxypropyl) sulfonyl] -1-phenyl-1H-tetrazole
- dichloromethane 10 mL
- m-chloroperbenzoic acid 4.5 g
- a 5% aqueous sodium sulfite solution was added to the reaction solution, and the extract extracted with ethyl acetate was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated brine.
- the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
- Example 101 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4-phenoxy-1-buten-1-yl) -7- (tetrahydro-2H-pyran -2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate Under argon atmosphere, the compound prepared in Example 100 (165 mg) was dissolved in DME (2 mL) and cooled to ⁇ 78 ° C. Then 0.5M potassium hexamethyldisilazane / toluene solution (0.90 mL) was added. After stirring at ⁇ 78 ° C.
- Example 102 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -4-phenoxy-1-buten-1-yl] octahydro-2H-cyclopenta [B] Oxepin-3-yl ⁇ butanoate
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 101 to the same procedure as in Example 16 (1).
- Example 103 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -4-phenoxy-1-buten-1-yl] octahydro-2H-cyclopenta [b] Oxepin-3-yl ⁇ butanoic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 102 to the same intended operation as in Example 17 (1).
- Example 104 4- (nitrooxy) butylamine nitrate Fuming nitric acid (1.5 mL) was added dropwise to acetic acid (25 mL) cooled to an internal temperature of ⁇ 8 ° C. while maintaining the internal temperature at 0 ° C. or lower. After the mixture was stirred for 10 minutes, 4-amino-1-butanol (3.1 mL) was added dropwise while maintaining the internal temperature at 0 ° C. or lower. After stirring for 10 minutes, the temperature was raised to room temperature in a water bath. After stirring for 10 minutes, diethyl ether (100 mL) was added, and the mixture was concentrated under reduced pressure.
- Example 105 4-[(4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoyl) amino] butyl nitrate
- a DMF solution (1 mL) of the compound prepared in Example 104 (68 mg)
- the compound prepared in Example 17 (25) (50 mg)
- 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 87 mg
- triethylamine 95 ⁇ L
- Example 106 (1) to Example 106 (17) Using the compound prepared in Example 7, using isopropyl iodide or methyl iodide instead, dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate or the corresponding phosphonate instead ( S) -2-methyl-CBS-oxazaborolidine or using (R) -2-methyl-CBS-oxazaborolidine instead, Example 8 ⁇ Example 9 ⁇ Example 10 (1) ⁇ Example 11-> Example 12-> Example 13-> Example 14-> Example 15-> Example 16 The following example compound was obtained by carrying out to the operation similar to Example 16 (1).
- Example 106 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-4-phenoxy-1-butene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.22, 1.40-1.95, 2.12, 2.23, 2.45, 2.60, 2.91, 3.72, 3.86, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.90 , 6.96, 7.28.
- TLC Rf 0.53 (ethyl acetate);
- Example 106 (3): methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (3-fluorophenyl) -3-hydroxy-1-pentene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.37-1.95, 2.05, 2.28, 2.45, 2.61-2.80, 2.90, 3.66, 3.69, 3.90-4.18, 5.46, 5.61, 6.81-7.00, 7.22 .
- Example 106 (4): methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (3-fluorophenyl) -3-hydroxy-1-pentene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.58, 6.81-7.00, 7.22 .
- Example 106 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (4-fluorophenyl) -3-hydroxy-1-pentene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.46, 5.61, 6.91-7.00, 7.10 -7.18.
- Example 106 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (4-fluorophenyl) -3-hydroxy-1-pentene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.58-2.78, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.60, 6.91-7.00, 7.10 -7.18.
- TLC Rf 0.57 (ethyl acetate);
- Example 106 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (2-fluorophenyl) -3-hydroxy-1-pentene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- TLC Rf 0.42 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.92-1.19, 1.38-1.92, 2.04-2.12, 2.25-2.30, 2.42-2.51, 2.64-2.80, 2.87-2.95, 3.66-3.74, 3.92-4.14, 5.43 -5.51, 5.58-5.65, 6.97-7.08, 7.14-7.24.
- Example 106 (9): methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (3-chlorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.46, 5.61, 7.05, 7.11-7.22 .
- Example 106 (10): methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (3-chlorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.58-2.78, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.60, 7.05, 7.11-7.22 .
- Example 106 (11): methyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-5- [3- (trifluoromethyl) Phenyl] -1-penten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- TLC Rf 0.54 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.92-1.18, 1.39-1.89, 2.05-2.13, 2.26-2.31, 2.42-2.51, 2.69-2.95, 3.66-3.72, 3.90-4.12, 5.44-5.52, 5.59 -5.66, 7.37-7.45.
- Example 106 (12): methyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3S) -3-hydroxy-5- [3- (trifluoromethyl) Phenyl] -1-penten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- TLC Rf 0.41 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.93-1.20, 1.43-1.96, 2.05-2.13, 2.25-2.30, 2.43-2.51, 2.68-2.95, 3.66-3.74, 3.90-4.10, 5.42-5.50, 5.58 -5.65, 7.38-7.45.
- Example 106 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3S) -3-hydroxy-4- [3- (trifluoro Methyl) phenoxy] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.36, 2.49, 2.91, 3.72, 3.80-4.10, 4.55, 4.99, 5.60-5.78, 7.08, 7.14 , 7.22, 7.39.
- Example 106 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (2-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.40-2.53, 2.91, 3.72, 3.80-4.10, 4.55, 4.99, 5.58-5.75, 6.88-7.12 .
- Example 106 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.45, 2.91, 3.72, 3.85, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.60-6.72 , 7.21.
- Example 106 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (4-fluorophenoxy) -3-hydroxy-1-butene -1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.45, 2.49, 2.91, 3.72, 3.82, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.80 -6.88, 6.97.
- TLC Rf 0.37 (ethyl acetate);
- Example 107 (1) to Example 107 (17) The compounds prepared in Example 106 (1) to Example 106 (17) were subjected to the same intended operation as in Example 17 (1) to give the following Example compounds.
- Example 107 (1): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-4-phenoxy-1-buten-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid TLC: Rf 0.17 (ethyl acetate: hexane 6: 1); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.40-1.98, 2.16, 2.33, 2.46, 2.92, 3.74, 3.86, 3.90-4.08, 4.55, 5.58-5.75, 6.90, 6.93, 7.28.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.89-1.22, 1.39-1.93, 2.08, 2.32, 2.47, 2.63-2.81, 2.92, 3.70, 3.96, 4.05, 4.14, 5.48, 5.63, 7.17-7.22, 7.28 -7.32.
- Example 107 (4 ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (3-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (3-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (4-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (4-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (2-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.92-1.20, 1.39-1.92, 2.04-2.13, 2.30-2.35, 2.41-2.50, 2.64-2.82, 2.87-2.95, 3.65-3.73, 3.92-4.08, 5.43 -5.52, 5.59-5.66, 6.97-7.07, 7.13-7.23.
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (2-fluorophenyl) -3-hydroxy-1-pentene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.92-1.20, 1.40-1.92, 2.04-2.12, 2.25-2.30, 2.42-2.51, 2.63-2.80, 2.87-2.95, 3.66-3.74, 3.92-4.14, 5.42 -5.50, 5.57-5.64, 6.97-7.07, 7.13-7.24.
- Example 107 (9): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -5- (3-chlorophenyl) -3-hydroxy-1-penten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.90-1.20, 1.38-1.95, 2.08, 2.33, 2.46, 2.60-2.80, 2.91, 3.69, 3.92-4.18, 5.47, 5.62, 7.07, 7.11-7.22.
- Example 107 (10): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5- (3-chlorophenyl) -3-hydroxy-1-penten-1-yl ] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.20, 1.38-1.98, 2.06, 2.32, 2.47, 2.58-2.78, 2.91, 3.68, 3.92-4.18, 5.43, 5.58, 7.07, 7.11-7.22.
- Example 107 (11): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3R) -3-hydroxy-5- [3- (trifluoromethyl) phenyl ] -1-penten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.92-1.21, 1.39-1.92, 2.04-2.14, 2.30-2.35, 2.42-2.51, 2.69-2.95, 3.66-3.74, 3.92-4.12, 5.44-5.52, 5.59 -5.66, 7.37-7.44.
- Example 107 (4[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3S) -3-hydroxy-5- [3- (trifluoromethyl) phenyl ] -1-penten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.20, 1.39-1.91, 2.04-2.13, 2.30-2.35, 2.43-2.51, 2.67-2.85, 2.87-2.95, 3.66-3.74, 3.92-4.12, 5.41 -5.49, 5.57-5.64, 7.37-7.44.
- Example 107 (13): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (1E, 3S) -3-hydroxy-4- [3- (trifluoromethyl) phenoxy ] -1-buten-1-yl ⁇ octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.40-1.98, 2.16, 2.33, 2.46, 2.92, 3.75, 3.88-4.10, 4.55, 5.60-5.78, 7.08, 7.14, 7.22, 7.39.
- Example 107 (14): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (2-fluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.40-1.98, 2.16, 2.32, 2.46, 2.91, 3.72, 3.88-4.10, 4.54, 5.60-5.78, 6.88-7.10.
- Example 107 (4 ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (3-fluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.40-1.98, 2.11, 2.33, 2.46, 2.92, 3.72, 3.85, 3.90-4.10, 4.52, 5.58-5.78, 6.58-6.70, 7.20.
- Example 107 (16): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -4- (4-fluorophenoxy) -3-hydroxy-1-butene-1- Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.20, 1.40-1.98, 2.12, 2.33, 2.46, 2.92, 3.72, 3.82, 3.90-4.10, 4.52, 5.58-5.78, 6.80-6.88, 6.97.
- Example 107 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -5-cyclohexyl-3-hydroxy-1-penten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.85-1.30, 1.38-1.77, 1.86-1.93, 2.02-2.11, 2.30-2.35, 2.42-2.51, 2.87-2.95, 3.65-3.73, 3.91-4.06, 5.38 -5.46, 5.52-5.59.
- Example 108 (1) to Example 108 (13) By subjecting the compound produced in Example 107 (1) to Example 107 (12) or Example 17 (15) to the same operation as in Example 18 (1), the following example compounds were obtained. Obtained.
- Example 108 (2): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(3S) -3-hydroxy-5-phenylpentyl] octahydro-2H-cyclopenta [b] Oxepin-3-yl ⁇ butanoic acid TLC: Rf 0.40 (ethyl acetate: acetic acid 100: 1); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.98-1.22, 1.30-1.94, 2.24, 2.34, 2.63-2.85, 2.93, 3.64, 3.72, 3.95, 4.03, 7.17-7.22, 7.28-7.32.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.35-1.95, 2.21, 2.31, 2.68, 2.77, 2.90, 3.62, 3.70, 3.92, 4.00, 6.82-7.00, 7.24.
- Example 108 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3R) -5- (3-fluorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.35-1.95, 2.21, 2.31, 2.68, 2.77, 2.91, 3.62, 3.70, 3.92, 4.00, 6.82-7.00, 7.24.
- Example 108 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3S) -5- (4-fluorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.30-1.95, 2.21, 2.32, 2.68, 2.77, 2.91, 3.62, 3.70, 3.92, 4.00, 6.90-7.00, 7.10-7.18.
- Example 108 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3R) -5- (4-fluorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.30-1.95, 2.21, 2.32, 2.68, 2.77, 2.91, 3.61, 3.70, 3.93, 4.00, 6.90-7.00, 7.10-7.18.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.96-1.20, 1.37-1.92, 2.18-2.26, 2.30-2.35, 2.66-2.85, 2.87-2.95, 3.57-3.62, 3.67-3.73, 3.90-4.04, 6.97 -7.07, 7.13-7.21.
- Example 108 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3R) -5- (2-fluorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.97-1.20, 1.25-1.92, 2.16-2.25, 2.30-2.35, 2.66-2.86, 2.87-2.95, 3.57-3.65, 3.68-3.73, 3.90-4.04, 6.97 -7.07, 7.13-7.21.
- Example 108 (9): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3S) -5- (3-chlorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.32-1.95, 2.22, 2.33, 2.67, 2.78, 2.91, 3.61, 3.69, 3.93, 4.00, 7.07, 7.11-7.22.
- Example 108 (10): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3R) -5- (3-chlorophenyl) -3-hydroxypentyl] -7-hydroxyoctahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.32-1.95, 2.22, 2.33, 2.67, 2.78, 2.91, 3.61, 3.70, 3.93, 4.00, 7.07, 7.11-7.22.
- Example 108 (11): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (3S) -3-hydroxy-5- [3- (trifluoromethyl) phenyl] pentyl ⁇ Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.16, 1.37-1.92, 2.20-2.33, 2.66-2.76, 2.81-2.94, 3.58-3.73, 3.89-4.03, 7.35-7.44.
- Example 108 (4[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (3R) -3-hydroxy-5- [3- (trifluoromethyl) phenyl] pentyl ⁇ Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.97-1.20, 1.32-1.92, 2.17-2.25, 2.30-2.35, 2.67-2.77, 2.81-2.95, 3.58-3.73, 3.90-4.03, 7.36-7.44.
- Example 108 (13): 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- ⁇ (3R) -3-hydroxy-4- [3- (trifluoromethyl) phenoxy] butyl ⁇ Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 1.00-1.20, 1.45-1.95, 2.25, 2.34, 2.93, 3.76, 3.86-4.08, 7.09, 7.15, 7.24, 7.41.
- Example 109 2-propanyl 4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6-( ⁇ [(2E) -3-phenyl-2-propen-1-yl] oxy ⁇ methyl ) Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- cinnamyl bromide 220 mg
- DMF 1.5 mL
- reaction mixture was diluted with MTBE, washed with saturated aqueous ammonium chloride solution, water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
- Example 110 4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6-( ⁇ [(2E) -3-phenyl-2-propen-1-yl] oxy ⁇ methyl) octahydro- 2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 109 to the same intended operation as in Example 17 (1).
- TLC: Rf 0.53 (dichloromethane: methanol 9: 1).
- Example 111 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -7- (tetrahydro-2H-pyran-2-yloxy) -6-vinyloctahydro-2H-cyclopenta [b] oxepin- 3-yl] butanoate methyltriphenylphosphonium bromide (2.60 g) was suspended in THF (10 mL) and cooled to 0 ° C. Sodium hexamethyldisilazane (7.0 mL, 1 mol / L THF solution) was added and stirred at the same temperature for 30 minutes.
- Example 112 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6- (2-hydroxyethyl) -7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [ b] oxepin-3-yl] butanoate
- 2-methyl borane tetrahydrofuran complex (0.44 mL) cooled to ⁇ 30 ° C. or lower was added 2-methyl-2-butene (110 ⁇ L), and the mixture was stirred at 0 ° C. for 2.5 hours.
- a THF solution (1 mL) of the compound prepared in Example 111 (170 mg) was added, and the mixture was stirred at room temperature overnight.
- Example 113 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- [2- (2-oxo-2-phenylethoxy) ethyl] octahydro-2H-cyclopenta [b Oxepin-3-yl ⁇ butanoate
- 2-diazoacetophenone 14 mg
- toluene 0.5 mL
- Saturated multistory water was added to stop the reaction, and the reaction solution was extracted with MTBE.
- Example 114 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- [2- (2-phenylethoxy) ethyl] octahydro-2H-cyclopenta [b] oxepin-3 -Il ⁇ butanoate
- ethyl acetate ethyl acetate
- palladium carbon 1.0 mg
- Example 115 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- [2- (2-phenylethoxy) ethyl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ Butanoic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 114 to the same intended operation as in Example 17 (1).
- Example 116 Methyl 4-[(3S, 5aR, 6S, 7R, 8aS) -6-ethynyl-7- (tetrahydro-2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl ] Butanoate To a methanol solution (2.3 mL) of the compound (180 mg) prepared in Example 13, potassium carbonate (94 mg) and Bestmann Reagent (dimethyl-1-diazo-2-oxopropyl phosphonate, 105 mg) And stirred at room temperature for 6 and a half hours.
- Example 117 Methyl 4-[(3S, 5aR, 6S, 7R, 8aS) -6- (3-hydroxy-5-phenyl-1-pent-1-yl) -7- (tetrahydro-2H-pyran-2 -Iloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- a solution of the compound prepared in Example 116 (52 mg) in THF (0.5 mL) was cooled to -78 ° C, and an n-butyllithium hexane solution ( 1.67M, 0.7 mL) was added and stirred for 30 minutes.
- Example 118 Methyl 4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6- (3-hydroxy-5-phenyl-1-pent-1-yl) octahydro-2H-cyclopenta [b ] Oxepin-3-yl] butanoate
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 117 to the same intended operation as in Example 16 (1).
- Example 119 4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6- (3-hydroxy-5-phenyl-1-pent-1-yl) octahydro-2H-cyclopenta [b] Oxepin-3-yl] butanoic acid (4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6-((3R) -3-hydroxy-5-phenyl-1-pent-1-yl ) Octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid and 4-[(3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6-((3S) -3-hydroxy-5- A mixture of phenyl-1-pentyn-1-yl) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid) The title compound having the following physical data was
- Example 120 2-propanyl 4-[(3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-hydroxy-4-phenoxy-1-buten-1-yl] -7- (tetrahydro -2H-pyran-2-yloxy) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- a solution of the compound prepared in Example 14 (260 mg) in methanol (2.5 mL) was stirred under ice-cooling with cerium chloride.
- Heptahydrate (220 mg) and sodium borohydride (22 mg) were sequentially added, and the mixture was stirred for 20 minutes. Water was added and extracted with ethyl acetate.
- Example 121 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-fluoro-4-phenoxy-1-buten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 121 (2) 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(2E)- 1-Fluoro-4-phenoxy-2-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- a solution of the compound prepared in Example 120 (280 mg) in dichloromethane ( 2.5 mL) was added diethylsulfur trifluoride (98 ⁇ L) with stirring at ⁇ 78 degrees.
- Example 122 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3-fluoro-4-phenoxy-1-buten-1-yl] -7-hydroxyoctahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -3-fluoro-4-phenoxy-1-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3S)- 3-fluoro-4-phenoxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl
- Example 123 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(2E) -1-fluoro-4-phenoxy-2-buten-1-yl] -7-hydroxyoctahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1R, 2E) -1-fluoro-4-phenoxy-2-butene- 1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1S, 2E)- 1-fluoro-4-phenoxy-2-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl
- Example 124 (1) to Example 124 (5) By using the compound produced in Example 13 and using the corresponding sulfone instead of the compound produced in Example 100, the same procedure as in Example 101 ⁇ Example 16 (1) was applied, and the following procedure was performed. Example compounds were obtained.
- Example 124 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (3-chlorophenoxy) -1-buten-1-yl]- 7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.95-1.16, 1.24, 1.40-1.80, 1.91, 2.06, 2.25, 2.44-2.56, 2.92, 3.69, 3.93-4.08, 5.01, 5.37, 5.60, 6.78, 6.89 -6.94, 7.20.
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.16, 1.24, 1.42-1.83, 1.90, 2.06, 2.25, 2.48, 2.57, 2.92, 3.69, 3.93-4.10, 5.01, 5.38, 5.61, 6.86-7.11 .
- Example 124 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (3-fluorophenoxy) -1-buten-1-yl]- 7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.16, 1.24, 1.42-1.80, 1.90, 2.06, 2.25, 2.43-2.56, 2.92, 3.69, 3.93-4.08, 5.01, 5.37, 5.60, 6.58-6.69 , 7.22.
- Example 7 using methyl iodide instead of isopropyl iodide, and corresponding sulfone instead of the compound prepared in Example 100 are used for the same operation as in Example 8 ⁇
- Example 101 ⁇ Example 16 (1) The title compound having the following physical property values was obtained.
- Example 125 (1) to Example 125 (5) The following example compounds were obtained by subjecting the compounds produced in Examples 124 (1) to (5) to the same intended operations as in Example 17 (1).
- TLC Rf 0.49 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.21, 1.37-1.79, 1.90, 2.06, 2.33, 2.43-2.60, 2.92, 3.68, 3.93-4.08, 5.37, 5.60, 6.78, 6.88-6.94, 7.19 .
- TLC Rf 0.51 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.23, 1.38-1.79, 1.90, 2.06, 2.33, 2.43-2.60, 2.92, 3.68, 3.93-4.09, 5.38, 5.60, 6.86-7.11.
- Example 125 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (3-fluorophenoxy) -1-buten-1-yl] -7-hydroxy Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.49 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.24, 1.39-1.79, 1.90, 2.06, 2.34, 2.43-2.56, 2.92, 3.68, 3.93-4.08, 5.37, 5.60, 6.58-6.69, 7.22.
- Example 125 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (2,5-difluorophenoxy) -1-buten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.46 (ethyl acetate);
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.94-1.23, 1.38-1.79, 1.90, 2.06, 2.34, 2.43-2.60, 2.92, 3.69, 3.93-4.08, 5.38, 5.60, 6.58, 6.69, 7.01.
- Example 125 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -4-hydroxy-6-phenyl-1-hexen-1-yl] octahydro -2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 4R) -4-hydroxy-6- Phenyl-1-hexen-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[( 1E, 4S) -4-hydroxy-6-phenyl-1-hexen-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇
- Example 126 4-[(3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6- (4-phenoxybutyl) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoic acid
- Example 103 The title compound having the following physical properties was obtained by subjecting the compound produced in (1) to the same intended operation as in Example 18 (1).
- Example 127 (3S, 5aR, 6S, 7R, 8aS) -6-formyl-3- [4-oxo-4- (2-propanyloxy) butyl] octahydro-2H-cyclopenta [b] oxepin-7- Il 4-biphenylcarboxylate
- Example 128 (3S, 5aR, 6S, 7R, 8aS) -6-[(E) -2-iodovinyl] -3- [4-oxo-4- (2-propanyloxy) butyl] octahydro-2H- Cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate
- chromium chloride 1.7 g
- iodoform was added to a solution of (1.4 g) in THF (7 mL) was added and stirred as such for 4 hours.
- Example 129 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(E) -2-iodovinyl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Methanol (70 mL) and potassium carbonate (2.2 g) were added to a THF (30 mL) solution of the compound (9.0 g) prepared in Example 128, and the mixture was stirred overnight at room temperature.
- the reaction mixture was filtered through Celite (trade name) and concentrated. MTBE and water were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
- Example 130 Methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-acetoxy-6-[(E) -2-iodovinyl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Acetic anhydride (2.3 mL) was added to a solution of the compound prepared in Example 129 (5.0 g) in pyridine (25 mL), and the reaction mixture was stirred at room temperature overnight. Water was added to stop the reaction, and the reaction mixture was poured into ice-cooled 1N hydrochloric acid.
- Example 131 Methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-acetoxy-6-[(1E) -3-hydroxy-8-methyl-1,7-nonadien-1-yl] octahydro -H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- chromium chloride 440 mg
- Nickel chloride 2.0 mg
- Example 132 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-8-methyl-1,7-nonadien-1-yl ] Octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy- 8-methyl-1,7-nonadien-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy- 6-[(1E, 3S) -3-hydroxy-8-methyl-1,7-nonadien-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-
- Example 132 (2) to Example 132 (10) By using the compound produced in Example 130 and subjecting to the same purpose as in Example 131 ⁇ Example 132 (1) using the corresponding aldehyde instead of 6-methylhept-5-enal, Example compound was obtained.
- Example 132 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -4- (benzyloxy) -3-hydroxy-1-buten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (benzyloxy) -3-Hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS)- Of 6-[(1E, 3S) -4- (benzyloxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cycl
- Example 132 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-1,7-octadien-1-yl] octahydro-2H -Cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3-hydroxy-1,7- Octadien-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-1,7-octadien-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ but
- Example 132 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-5- (5-methyl-2-furyl) -1 -Penten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R ) -3-Hydroxy-5- (5-methyl-2-furyl) -1-penten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR , 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-5- (5-methyl-2-furyl) -1-penten-1-yl]
- Example 132 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-4,8-dimethyl-1,7-nonadiene-1 -Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R, 4R)- 3-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid, 4- ⁇ (3S, 5aR, 6R, 7R, 8aS ) -7-hydroxy-6-[(1E, 3R, 4S) -3-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl] o
- Example 132 (9): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3- (1-benzofuran-2-yl) -3-hydroxy-1-propene-1 -Yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -3 -(1-Benzofuran-2-yl) -3-hydroxy-1-propen-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S , 5aR, 6R, 7R, 8aS) -6-[(1E, 3S) -3- (1-benzofuran-2-yl) -3-hydroxy-1-propen-1-yl]
- Example 132 (10): 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E) -3-hydroxy-5- (3-hydroxyphenyl) -1-pentene- 1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid (4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -7-hydroxy-6-[(1E, 3R) -3 -Hydroxy-5- (3-hydroxyphenyl) -1-penten-1-yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid and 4- ⁇ (3S, 5aR, 6R, 7R, 8aS ) -7-hydroxy-6-[(1E, 3S) -3-hydroxy-5- (3-hydroxyphenyl) -1-penten-1-yl] octahydro
- Example 133 (3S, 5aR, 6S, 7R, 8aS) -3- [4-oxo-4- (2-propanyloxy) butyl] -6-[(tetrahydro-2H-pyran-2-yloxy) methyl ] Octahydro-2H-cyclopenta [b] oxepin-7-yl 4-biphenylcarboxylate 3,4-Dihydro-2H-pyran in a dichloromethane solution (30 mL) of the compound prepared in Example 70 (2.9 g) with stirring at room temperature. (803 ⁇ L) and pyridinium paratoluenesulfonate (150 mg) were added, and the mixture was stirred at room temperature for 5 hours.
- Example 134 2-propanyl 4- ⁇ (3S, 5aR, 6S, 7R, 8aS) -7-hydroxy-6-[(tetrahydro-2H-pyran-2-yloxy) methyl] octahydro-2H-cyclopenta [b]
- Oxepin-3-yl ⁇ butanoate Lithium isopropoxide (2.0 M tetrahydrofuran solution, 5.9 mL) was added to an isopropanol solution (30 mL) of the compound prepared in Example 133 (3.84 g), and the mixture was stirred at 45 degrees for 1.5 hours. Ice-cooled, 1N hydrochloric acid (12 mL) and water were added, and the mixture was extracted with ethyl acetate.
- Example 135 2-propanyl 4- ⁇ (3S, 5aR, 6S, 8aS) -7-oxo-6-[(tetrahydro-2H-pyran-2-yloxy) methyl] octahydro-2H-cyclopenta [b] oxepin 3-Il ⁇ butanoate
- dimethyl sulfoxide (9 mL) and diisopropylethylamine (5.8 mL) were added with stirring under ice cooling, and a sulfur trioxide / pyridine complex ( 2.67 g) was added in small portions. Stir at 0 degrees for 1 hour.
- Example 136 2-propanyl 4-[(3S, 5aR, 6S, 8aS) -7,7-difluoro-6- (hydroxymethyl) octahydro-2H-cyclopenta [b] oxepin-3-yl] butanoate
- Example 135 To a dichloroethane solution (8 mL) of the compound (1.3 g) prepared in 1 above, morpholylsulfur trifluoride (1.2 mL) was added and stirred at 45 degrees for 50 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
- Example 137 2-propanyl 4- ⁇ (3S, 5aR, 6S, 8aS) -7,7-difluoro-6-[(E) -2-iodovinyl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ Butanoate
- a dichloromethane solution 3.5 mL
- desmartin periodinane 372 mg
- a saturated aqueous sodium thiosulfate solution and saturated multistory water were added, and the mixture was extracted with ethyl acetate.
- Example 138 (1) and Example 138 (2) Using the compound produced in Example 137 and using the corresponding aldehyde in place of 6-methylhept-5-enal, the same procedure as in Example 131 was performed to obtain the following Example compound. It was.
- Example 138 (1): 2-propanyl 4- ⁇ (3S, 5aR, 6R, 8aS) -7,7-difluoro-6-[(1E) -3-hydroxy-1-octen-1-yl] octahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate TLC: Rf 0.28 (ethyl acetate: hexane 1: 4); 1 H-NMR (300 MHz, CDCl 3 ): ⁇ 0.80-0.96, 0.98-2.22, 2.23, 2.42-2.70, 2.93, 4.00-4.18, 4.99, 5.52, 5.64.
- Example 138 (2): 2-propanyl 4- ⁇ (3S, 5aR, 6R, 8aS) -7,7-difluoro-6-[(1E) -3-hydroxy-5-phenyl-1-pentene-1- Yl] octahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.98-1.20, 1.22, 1.40-2.20, 2.24, 2.45-2.80, 2.94, 4.02-4.20, 4.99, 5.42-5.62, 5.67, 7.15-7.32.
- Example 139 (1) and Example 139 (2) The following example compounds were obtained by subjecting the compound produced in Example 138 (1) or Example 138 (2) to the same intended operation as in Example 17 (1).
- Example 140 (1) to Example 140 (4) Using the compound prepared in Example 127 and using the corresponding phosphonate instead of dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate, the same purpose as Example 14 ⁇ Example 30 ⁇ Example 129 The following example compounds were obtained by subjecting to the above procedure.
- Example 140 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-5-phenyl-1-penten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- 1 H-NMR 300 MHz, CDCl 3 ): ⁇ 0.93-1.20, 1.40-1.92, 2.10-2.30, 2.41-2.50, 2.76-2.81, 2.87-2.95, 3.66, 3.70-3.79, 3.92-4.05, 5.60-5.72 , 5.85-5.93, 7.16-7.22, 7.25-7.31.
- Example 140 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -5-cyclopentyl-3,3-difluoro-1-penten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 140 methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -5-cyclohexyl-3,3-difluoro-1-penten-1-yl] -7 -Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 140 (4): methyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) 3,3-difluoro-1-octen-1-yl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoate
- Example 141 (1) to Example 141 (4) By subjecting the compounds produced in Example 140 (1) to Example 140 (4) to the same operation as in Example 17 (1), the following Example compounds were obtained.
- Example 141 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-5-phenyl-1-penten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- TLC Rf 0.29 (ethyl acetate);
- Example 141 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -5-cyclopentyl-3,3-difluoro-1-penten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 141 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -5-cyclohexyl-3,3-difluoro-1-penten-1-yl] -7- Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 141 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-1-octen-1-yl] -7-hydroxyoctahydro- 2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 141 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E) -3,3-difluoro-8-methyl-1,7-nonadien-1-yl]- 7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid
- Example 14 Using the compound prepared in Example 127 and using the corresponding phosphonate instead of dimethyl- (3-phenoxy-2-oxopropyl) -phosphonate, Example 14 ⁇
- Example 30 Example 17 (1)
- the title compound having the following physical property values was obtained by subjecting it to the same purpose operation.
- Example 142 4-[(3S, 5aR, 6R, 7R, 8aS) -6- (3,3-difluoro-5-phenylpentyl) -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3- Iil] butanoic acid
- the title compound having the following physical data was obtained by subjecting the compound produced in Example 141 (1) to the same intended operation as in Example 18 (1).
- DMSO dimethyl sulfoxide
- ⁇ Cell culture> Various mouse prostanoid receptor forced expression cells were inactivated (56 ° C., 30 minutes), 9.8 vol% dialyzed FBS (dialysed-FBS) (Invitrogen) and penicillin-streptomycin-glutamine (penicillin-streptomycin-glutamine) ⁇ -MEM medium (Sigma) containing GIBCO-BRL) (for FP-CHO and EP1-CHO culture) or inactivated (56 ° C., 30 minutes) 9.8 vol% dialysed-FBS (Invitrogen) and Using a nucleic acid-containing ⁇ -MEM (Sigma) (for IP-CHO culture) containing penicillin-streptomycin-glutamine (Invitrogen), left at 37 ° C. in the presence of 5% CO 2. Cultured. Subculture was performed by the following method.
- the medium was removed and washed twice with phosphate buffered saline without Ca 2+ and Mg 2+ .
- An appropriate amount of trypsin-EDTA (Invtrogen) was added and incubated at 37 ° C. for about 3 minutes. After detachment of the cells, a 10-fold volume of trypsin-EDTA medium was added to stop the enzyme reaction.
- the cells were collected in a centrifuge tube and centrifuged at 120 g for 3 minutes at room temperature, and then the supernatant was removed. Cells were suspended in an appropriate amount of medium and seeded in culture flasks.
- the plate was washed twice with Hank's balanced salt solution (Nissui Pharmaceutical Co., Ltd., 9.8 g of this product was dissolved in 1 L of distilled water). 120 ⁇ L of a buffer solution for measurement was added to each well, and the plate was allowed to stand for 30 minutes in a CO 2 incubator for stabilization and used for the experiment.
- Hank's balanced salt solution Nasui Pharmaceutical Co., Ltd.
- a 96-well UV plate was set in a fluorescence spectrophotometer (FDSS-3000, Hamamatsu Photonics), and the intracellular calcium concentration was measured. 30 ⁇ L of a measurement buffer solution containing agonists of various concentrations was added and allowed to react. The intracellular calcium concentration was measured by alternately irradiating cells with excitation light of 340 nm and 380 nm, measuring the fluorescence intensity of 500 nm, and determining the fluorescence intensity ratio of two-wavelength excitation.
- FDSS-3000 fluorescence spectrophotometer
- IP agonist activity measurement For IP-CHO, the medium was removed on the day of measurement, and the medium was washed once with phosphate buffered saline containing 2 mmol / L EDTA but not containing Ca 2+ and Mg 2+ . Add appropriate amounts of 2 mmol / L EDTA-containing Ca 2+ and Mg 2+ -free phosphate buffered saline, incubate at 37 ° C. for about 10 minutes, peel off the cells, collect the cells in a centrifuge tube, collect 500 g, 3 After centrifugation at room temperature for minutes, the supernatant was removed.
- phosphate buffered saline containing 2 mmol / L EDTA but not containing Ca 2+ and Mg 2+ .
- Add appropriate amounts of 2 mmol / L EDTA-containing Ca 2+ and Mg 2+ -free phosphate buffered saline incubate at 37 ° C. for about 10 minutes, peel off the
- buffer solution for measurement 1 MEM medium (Invitrogen) containing 0.1 w / v% bovine serum albumin (Sigma) and 2 ⁇ mol / L diclofenac (Sigma)
- 500 g for 3 minutes at room temperature After centrifuging with, the supernatant was removed.
- Buffer solution 2 for measurement (MEM medium (Invitrogen) containing 0.1 w / v% bovine serum albumin (Sigma), 2 ⁇ mol / L diclofenac (Sigma) and 1 mmol / L 3-isobutyl-1-methylxanthine) 25 ⁇ L each was dispensed in a 96-well 1/2 area plate so that the number of cells was 5.0 ⁇ 10 4 cells per well. 25 ⁇ L of measurement buffer solution 2 containing agonists of various concentrations was added and reacted at room temperature for 30 minutes. The cAMP concentration was measured using a cAMP HTRF HiRange kit (CIS bio International).
- EC 50 values were calculated as indicators of agonist activity of the compounds of the present invention against mouse FP, mouse EP1 and mouse IP receptor.
- the compound described in Example 108 (13), the compound described in Example 110, the compound described in Example 115, the compound described in Example 119, the compound described in Example 122, the compound described in Example 123, and Example 132 The compound described in (3), the compound described in Example 132 (7), the compound described in Example 139 (2), the compound described in Example 141 (1), the compound described in Example 141 (5), and the comparative compound have the following structures: Table 1 shows the results of the compound of Example 12 described in the formula (hereinafter sometimes abbreviated as Comparative Compound A) described in Patent Document 2.
- Comparative Compound A not only has agonist activity for the FP receptor, but also has agonist activity for the EP1 receptor and the IP receptor. It has been found that the agonist activity against the body and IP receptor is low, and it has selective agonist activity against the FP receptor.
- an ophthalmic surface anesthetic (Benoxyl ophthalmic solution 0.4%, Santen Pharmaceutical Co., Ltd.) was instilled and locally anesthetized, and the intraocular pressure of each test compound before and after instillation 2, 4, 6, 8, 24 hours later was measured. It was measured.
- the intraocular pressure was measured using a pneumatic flat tonometer (Model 30 Classic, Leichhardt).
- the intraocular pressure decrease rate (%) was calculated by the following formula.
- aqueous humor in the anterior chamber at 0, 1, 2, 4, 6 and 8 hours after instillation was collected, and the protein concentration in the aqueous humor was measured.
- Comparative Compound B the above methyl ester form of the compound of Example 12 described in Patent Document 2 (that is, the compound of Example 10 described in Patent Document 2) (hereinafter sometimes abbreviated as Comparative Compound B) is used. It was.
- the general state of the eye was observed at 0, 1, 2, 4, 6 and 8 hours after instillation, and macroscopic findings of the cornea, iris and conjunctiva were observed according to the known criteria of the Draize method.
- the total score ( A 1 ⁇ B 1 ⁇ 5 + A 2 ⁇ 5 + (A 3 + B 3 + C 3 ) ⁇ 2) of the obtained items was evaluated as a Draize score.
- For classification criteria of Draize score refer to “Medical Device Examination No. 36, Pharmaceuticals and Medical Devices Agency, March 19, 2003 for reference materials related to basic concepts of biological safety testing” Created.
- Draize score 0 or more and 5 or less, non-irritant, greater than 5, 15 or less, mild stimulant, greater than 15 or less, 30 or less, stimulus greater than 30 or less than 60, moderately stimulated, greater than 60 or less than 80 Were medium to strong irritants, and those greater than 80 and 110 or less were strong irritants.
- a dose up to the solubility limit (150 to 1000 ⁇ g / mL) was administered, and the action of each active substance was evaluated.
- Comparative compound B was classified as a mild irritant from the maximum Draize score based on its agonist activity at the IP receptor, and also increased the protein concentration in the aqueous humor, thus inducing side effects on the eye.
- the compounds of Example 16 (35), Example 16 (3) and Example 16 (25), which are the compounds of the present invention are all non-irritant in the Draize score, and the protein concentration in the aqueous humor is measured. It was found that there was no effect to raise.
- the compound of the present invention has low agonist activity for EP1 receptor and IP receptor and has selective agonist activity for FP receptor. It was suggested that eye irritation based on body agonist activity and eye irritation such as hyperemia based on IP receptor agonist activity and side effects on the eye such as increased aqueous humor protein can be avoided.
- the intraocular pressure of both eyes was measured using a pneumatic applanation tonometer (Model 30 Classic, Leichart) (5 to 8 cases in each group).
- the difference in intraocular pressure between the control eye and the eye administered with the test substance is calculated as the intraocular pressure decrease rate using the following formula, and the maximum intraocular pressure decrease rate during measurement and the intraocular pressure decrease rate after 24 hours are calculated.
- the test substance the compound of Comparative Compound B, Example 16 (3), Example 16 (25) and Example 16 (35) was used, and the administration dose was 10 ⁇ g / mL.
- Formulation Example 1 Eye Drops An eye drop of the following formulation was prepared using a widely used method. Glycerin (2.5 g) and polysorbate 80 (500 mg) were added to sterilized purified water, and then the compound of Example 16 (35) (1 mg) was added and dissolved. Thereafter, it was filled in a predetermined container to obtain an eye drop. In the same manner as above, an ophthalmic solution containing 0.1 mg and 0.5 mg of the compound of Example 140 (1) in 100 mL can be prepared. Moreover, it can replace with the compound of Example 140 (1), and another this invention compound can be used.
- Formulation Example 2 Eye Ointment An eye ointment having the following formulation was prepared using a widely used method. Liquid paraffin and white petrolatum were heat sterilized in advance. The compound (1 mg) of Example 140 (1) was thoroughly triturated with liquid paraffin (10 g), and white petrolatum was added to make a total amount of 100 g, which was sufficiently kneaded to obtain an eye ointment.
- the compound of the present invention has a strong and continuous action for lowering intraocular pressure, and further has no eye side effects such as eye irritation (hyperemia, corneal turbidity, etc.) and elevation of aqueous humor protein, and thus excellent prevention of glaucoma and the like. And / or useful as a therapeutic agent.
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Abstract
Description
二環式の母骨格を有するPG誘導体としては、例えば、一般式(a)
1. 一般式(I)
2. R8がハロゲン原子であり、R9が
3. 一般式(I-1)
4. (1)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(12)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(13)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]-1-ブテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(14)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(2-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(15)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(3-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(16)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(4-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(17)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-シクロヘキシル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(18)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-4-フェノキシブチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(19)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-5-フェニルペンチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(20)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(21)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(22)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(23)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(24)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(25)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(26)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(27)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(28)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(29)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(30)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]ブチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(31)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(32)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-クロロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(33)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(34)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(35)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-ジフルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(36)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(37)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-(4-フェノキシブチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(38)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(39)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(40)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(41)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(42)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(43)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-5-フェニル-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(44)4-[(3S,5aR,6R,7R,8aS)-6-(3,3-ジフルオロ-5-フェニルペンチル)-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(45)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(46)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロヘキシル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(47)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-1-オクテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、およびその異性体からなる群から選択される化合物である前記1記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ、
5. (1)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-({[(2E)-3-フェニル-2-プロペン-1-イル]オキシ}メチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[2-(2-フェニルエトキシ)エチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-(3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(12)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-8-メチル-1,7-ノナジエン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、およびその異性体からなる群から選択される化合物である前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ、
6. 前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグを含有してなる医薬組成物、
7. 前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグが、FPアゴニストである前記6記載の医薬組成物、
8. 眼疾患の予防および/または治療剤である前記6記載の医薬組成物、
9. 眼疾患が、緑内障、高眼圧症、黄斑浮腫、黄斑変性、網膜および視神経張力上昇、近視、遠視、乱視、ドライアイ、網膜剥離、白内障、外傷または炎症による眼圧上昇、薬剤による眼圧上昇、または術後の眼圧上昇である前記8記載の医薬組成物、
10. 前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグの有効量を哺乳動物に投与することを特徴とする、眼疾患の予防および/または治療方法、
11. 眼疾患の予防および/または治療のための前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ、
12. 眼疾患の予防および/または治療剤を製造するための前記2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグの使用等に関する。
本発明において、C1~6アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、tert-ペンチル、ネオペンチル、ヘキシル等の直鎖状または分岐鎖状のC1~6アルキル基を意味する。
本発明において、C1~4アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec-ブチル、tert-ブチル等の直鎖状または分岐鎖状のC1~4アルキル基を意味する。
本発明において、任意の1個の炭素原子が酸素原子で置き換えられたC2~4アルキル基とは、-O-CH3、-CH2-OH、-O-C2H5、-CH2-O-CH3、-(CH2)2-OH、-O-(CH2)2-CH3、-CH2-O-C2H5、-(CH2)2-O-CH3、-(CH2)3-OHを意味する。
本発明において、C3~10の炭素環とは、C3~10の単環または二環式炭素環、その一部または全部が飽和されていてもよい炭素環を意味し、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、パーヒドロインダン、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等が挙げられる。
(1)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(12)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(13)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]-1-ブテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(14)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(2-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(15)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(3-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(16)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(4-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(17)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-シクロヘキシル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(18)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-4-フェノキシブチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(19)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-5-フェニルペンチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(20)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(21)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(22)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(23)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(24)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(25)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(26)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(27)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(28)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(29)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(30)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]ブチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(31)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(32)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-クロロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(33)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(34)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(35)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-ジフルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(36)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(37)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-(4-フェノキシブチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(38)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(39)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(40)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(41)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(42)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(43)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-5-フェニル-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(44)4-[(3S,5aR,6R,7R,8aS)-6-(3,3-ジフルオロ-5-フェニルペンチル)-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(45)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(46)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロヘキシル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(47)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-1-オクテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(48)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(49)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(50)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,4R)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(51)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,4S)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(52)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(53)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(54)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(55)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(56)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(57)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(58)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(59)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(60)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、または
(61)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、その塩、その溶媒和物、またはそれらのプロドラッグが挙げられる。
(1)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-({[(2E)-3-フェニル-2-プロペン-1-イル]オキシ}メチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[2-(2-フェニルエトキシ)エチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-(3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(12)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-8-メチル-1,7-ノナジエン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(13)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-((3R)-3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(14)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-((3S)-3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(15)4-{(3S,5aR,6R,7R,8aS)-6-[(1R,2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(16)4-{(3S,5aR,6R,7R,8aS)-6-[(1S,2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(17)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(18)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(19)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(20)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(21)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(22)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(23)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(24)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(25)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,4R)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(26)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,4S)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(27)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,4R)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(28)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,4S)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(29)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3R)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(30)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3S)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(31)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3R)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、または
(32)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3S)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、その塩、その溶媒和物、またはそれらのプロドラッグも好ましい。
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、アルキル基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体、Z体、シス体、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。また、本発明においては、互変異性体による異性体をもすべて包含する。
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。
(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、テトラヒドロフラン、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。
(1)ハロゲン化アルキルを用いる方法、
(2)酸ハライドを用いる方法、
(3)混合酸無水物を用いる方法、
(4)縮合剤を用いる方法
等が挙げられる。
(2)還元剤(例えば、水素化ホウ素ナトリウム等)を用いて、有機溶媒中(例えば、メタノール、エタノール等)、添加剤として塩化セリウム等の存在下あるいは非存在下で、-40~80℃で反応させることによって行われる。
(1)DMSO酸化(例えばスワン酸化(Swern oxidation))を用いる方法、
(2)デス-マーチン試薬(Dess-Martin Reagent)を用いる方法,
(3)TEMPO(2,2,6,6-tetramethylpiperidine 1-oxyl)試薬を用いる方法
等が挙げられる。
本発明化合物の毒性は十分に低いものであり、例えば、眼刺激性(充血、角膜混濁等)、房水タンパク質上昇等がほとんどなく、医薬品として安全に使用することができる。
本発明化合物は、選択的なFPアゴニスト活性を有するため、その眼圧下降作用に基づき、眼疾患、例えば、緑内障(急性閉塞隅角緑内障、慢性閉塞隅角緑内障、続発性閉塞隅角緑内障、原発性開放隅角緑内障、続発性開放隅角緑内障、先天性緑内障、正常眼圧緑内障、房水産生過多緑内障等)、高眼圧症、黄斑浮腫、黄斑変性、網膜および視神経張力上昇、近視、遠視、乱視、ドライアイ、網膜剥離、白内障、外傷または炎症等による眼圧上昇、ステロイドまたはホルモン剤等の薬物による眼圧上昇、術後の眼圧上昇等の予防および/または治療剤として有用である。
1)その化合物の予防および/または治療効果の補完および/または増強、
2)その化合物の動態・吸収改善、投与量の低減、および/または
3)その化合物の副作用の軽減のために他の薬物と組み合わせて、併用薬として投与してもよい。
(3aR,4S,5R,6aS)-4-(ヒドロキシメチル)-5-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサヒドロ-2H-シクロペンタ[b]フラン-2-オン(CAS番号69222-61-3)(50g)のジメチルホルムアミド(以下、DMFと略記することがある。)(100mL)溶液に、氷冷下イミダゾール(29.22g)、tert-ブチルジメチルクロロシラン(30.87g)を順次加え、室温にて3.5時間撹拌した。反応終了後少量のエタノールを加えた後、氷水中に反応液を注ぎ、酢酸エチル:ヘキサン(2:3)にて抽出した。1N塩酸、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水にて洗浄し、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(76.2g)を得た。
TLC:Rf 0.42 (ヘキサン:酢酸エチル=3:1)。
アルゴン雰囲気下、実施例1で製造した化合物(76.2g)の無水トルエン(390mL)溶液を-70℃に冷却し、水素化ジイソブチルアルミニウムの1mol/Lトルエン溶液(212.4mL)を約1時間かけて滴下後、そのまま30分撹拌した。反応終了後、tert-ブチルメチルエーテル(以下、MTBEと略記することがある。)(400mL)にて希釈し、飽和硫酸ナトリウム水溶液を加えた。析出した白色沈殿をセライト(商品名)でろ過後、溶媒を減圧濃縮し、以下の物性値を有する標題化合物(80.7g)を得た。
TLC:Rf 0.30 (ヘキサン:酢酸エチル=3:1)。
アルゴン雰囲気下、臭化メチルトリフェニルホスホニウム(326.6g)の無水トルエン(300mL)懸濁液に、氷冷下にてリチウムヘキサメチルジシラザンの1.6Mテトラヒドロフラン(以下、THFと略記することがある。)溶液(500mL)を滴下後、室温にて1時間撹拌した。再度-70℃まで冷却し、実施例2で製造した化合物(85.2g)の無水トルエン(400mL)溶液を約1.5時間かけて滴下した後、室温にて2時間撹拌した。反応終了後、塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を水、飽和食塩水にて洗浄、硫酸ナトリウムにて乾燥後、溶媒を減圧濃縮した。得られた残渣を山善社製カラム装置(Hiflash-SI、Size 5L×4、ヘキサン:酢酸エチル=100:0→85:15→75:25)にて精製し、以下の物性値を有する標題化合物 (41.87g)を得た。
TLC:Rf 0.57(ヘキサン:酢酸エチル=3:1)。
アルゴン雰囲気下、2,3-ジブロモプロペン(8.4mL、81.0mmol)をフラスコに入れ、氷水を用いて内温5℃に冷却した。水素化ナトリウム(2.16g、54.1mmol)を投入し5分間撹拌した。実施例3で製造した化合物(10g、27mmol)を50分間かけて滴下し、室温で2時間撹拌した。反応液を飽和塩化アンモニウム水溶液に注意深く注ぎ、MTBEで抽出し、飽和塩化アンモニウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し濃縮した。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→80:20)で精製し、以下の物性値を有する標題化合物(10.9g)を得た。
TLC:Rf 0.72 (ヘキサン:酢酸エチル=9:1)。
アルゴン雰囲気下、実施例4で製造した化合物(10.9g、22.2mmol)をトルエン(100mL)に溶解し、4-エトキシ-4-オキソブチルジンクブロマイド(0.5mol/LのTHF溶液、133mL、66.7mmol)を室温で加えた。ビス(トリ-tert-ブチルホスフィン)パラジウム(567mg、1.11mmol)を加えて80℃で2時間撹拌した。室温まで冷却し飽和塩化アンモニウム水溶液を加え、濃縮した。得られた残渣をMTBEで溶解しセライト(商品名)を用いてろ過した。ろ液を塩化アンモニウム水溶液、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マグネシウムで乾燥し濃縮した。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→50:50)で精製し、以下の物性値を有する標題化合物(9.73g)を得た。
TLC:Rf 0.65 (ヘキサン:酢酸エチル=9:1)。
アルゴン雰囲気下、実施例5で製造した化合物(400mg、0.762mmol)をトルエン(76mL)に溶解した。シュロック触媒(Schrock’s catalyst:2,6-ジイソプロピルフェニルイミドネオフィリデンモルビデニウム(VI)ビス(ヘキサフルオロtert-ブトキシド))(785mg、0.925mmol)を加えて85℃で18時間反応させた。放冷後、濃縮し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→50:50)で精製し、以下の物性値を有する標題化合物(4.8mg)を得た。
TLC:Rf 0.47 (ヘキサン:酢酸エチル=4:1)。
実施例6で製造した化合物(7.63g、15.4mmol)をエタノール(60mL)に溶解し、2.0mol/Lの水酸化ナトリウム水溶液(20mL)を加えて室温で2時間撹拌した。濃縮し酢酸エチルと2mol/L塩酸を加えて抽出した。飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し濃縮した。得られた標題化合物は精製することなく次の反応に用いた。
TLC:Rf 0.48 (クロロホルム:メタノール=9:1)。
アルゴン雰囲気下、実施例7で製造した化合物(15.4mmol)をDMFに溶解し炭酸カリウム(5.31g、38.5mmol)、ヨウ化イソプロピル(2.31mL、23.1mmol)を加えて60℃で3時間撹拌した。冷却後、MTBEと水を加えて抽出し、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥し、濃縮した。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→50:50)で精製し、以下の物性値を有する標題化合物(7.25g)を得た。
TLC:Rf 0.90 (酢酸エチル)。
アルゴン雰囲気下、実施例8で製造した化合物(4.85g、9.45mmol)のジクロロメタン溶液(62mL)を、超音波を用いて脱気、アルゴン置換した。クラブツリー触媒(Crabtree’s catalyst:(トリシクロヘキシルホスフィン)(1,5-シクロオクタジエン)(ピリジン)イリジウム(I) ヘキサフルオロホスファート)(760mg、0.945mmol)を加え、水素雰囲気下で室温において3時間50分撹拌した。溶液を減圧濃縮し、山善社製カラム装置(Hiflash-SI、Size 2L、ヘキサン→酢酸エチル:ヘキサン=3:7)で精製し、以下の物性値を有する標題化合物(3.05g)を得た。
TLC:Rf 0.72(ヘキサン:酢酸エチル=1:2)。
実施例10(2):2-プロパニル 4-[(3R,5aR,6S,7R,8aS)-6-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタノアート
アルゴン雰囲気下、実施例9で製造した化合物(3.02g、5.89mmol)のジクロロメタン溶液(60mL)を-20℃に冷却した。ジメチルアルミニウムクロライド溶液(1.0Mのヘキサン溶液)を加え、室温に昇温しながら3時間40分撹拌した。反応溶液を氷冷した飽和炭酸水素ナトリウム水溶液に注ぎ込み、ロッシェル塩を加え40分撹拌した。水層を酢酸エチルで2回抽出し、集めた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、山善社製カラム装置 (Hiflash-SI、Size 5L、トルエン:アセトン=10:1)で1回、(Hiflash-SI、Size 2L+YAMAZEN ULTRA PACK SI-C、Size 37×300、トルエン:アセトン=10:1)で2回精製し、以下の物性値を有する実施例10(1)の化合物(1.60g)および実施例10(2)の化合物(810mg)を得た。
TLC:Rf 0.30(トルエン:アセトン=9:1)(実施例10(1)の化合物);
TLC:Rf 0.31(トルエン:アセトン=9:1)(実施例10(2)の化合物)。
アルゴン雰囲気下、実施例10(1)で製造した化合物(1.58g、3.69mmol)のトルエン溶液(1.85mL)に、3,4-ジヒドロ-2H-ピラン(403μL、4.42mmol)、トシル酸一水和物(10mg、0.111mmol)を加え、室温で15分撹拌した。トシル酸一水和物(10mg、0.111mmol)を加え45分撹拌し、トリエチルアミン(100μL)を加え、反応溶液を減圧濃縮した。山善社製カラム装置(Hiflash-SI、Size 2L、ヘキサン→酢酸エチル:ヘキサン=3:7)で精製し、以下の物性値を有する標題化合物(1.82g)を得た。
TLC:Rf 0.46 (ヘキサン:酢酸エチル=1:1)。
アルゴン雰囲気下、実施例11で製造した化合物(1.81g、3.53mmol)のTHF溶液(3.6mL)に、テトラブチルアンモニウムフルオライド(7mL、1.0MのTHF溶液)を加え、室温で70分撹拌した。テトラブチルアンモニウムフルオライド(3.5mL、1.0mol/LのTHF溶液)を加え、45℃でさらに100分撹拌した。反応溶液を酢酸エチル(100mL)で希釈し、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、無水硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、山善社製カラム装置(Hiflash-SI、Size L、酢酸エチル:ヘキサン=2:8→酢酸エチル:ヘキサン=8:2)で精製し、以下の物性値を有する標題化合物(1.21g)を得た。
TLC:Rf 0.40(ヘキサン:酢酸エチル=1:2)。
アルゴン雰囲気下、実施例12で製造した化合物(623mg、1.76mmol)の酢酸エチル溶液(4mL)に、ジメチルスルホキシド(以下、DMSOと略記することがある。)(1.8mL)、ジイソプロピルエチルアミン(1.8mL、10.56mmol)を加え、0℃に冷却した。ピリジン-三酸化硫黄コンプレックス(840mg、5.28mmol)を加え、0℃で40分撹拌した。反応溶液を酢酸エチルで希釈し、氷冷した塩酸水溶液(0.5N)に注ぎ込んだ。水層を酢酸エチルで1回抽出し、集めた有機層を飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で一回洗浄し、無水硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、以下の物性値を有する標題化合物の粗生成物(634mg)を得た。
TLC:Rf 0.73 (ヘキサン:酢酸エチル=2:1)。
アルゴン雰囲気下、実施例13で製造した化合物(634mg、1.60mmol)のTHF溶液(16mL)にジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナート(826mg、3.20mmol)、リン酸カリウム(679mg、3.20mmol)を加え室温で一日撹拌した。反応溶液を飽和塩化アンモニウム水溶液に加え、水層を酢酸エチルで2回抽出した。集めた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、山善社製カラム装置(Hiflash-SI、Size L、ヘキサン→酢酸エチル:ヘキサン=4:6)で精製し、以下の物性値を有する標題化合物(426mg)を得た。
TLC:Rf 0.55 (ヘキサン:酢酸エチル=1:1)。
実施例14で製造した化合物(137mg、0.259mmol)のTHF溶液(16mL)に、(R)-2-メチル-CBS-オキサザボロリジン(65μL、1mol/Lのトルエン溶液、0.065mmol)を加えた。ボランジメチルスルフィド錯体(155μL、1mol/Lのトルエン溶液、0.155mmol)を滴下した。室温で45分撹拌した後、溶液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液に注ぎこんだ。水層を酢酸エチルで2回抽出し、集めた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。得られた溶液を減圧濃縮し、以下の物性値を有する標題化合物の粗生成物(151mg)を得た。
TLC:Rf 0.32 (ヘキサン:酢酸エチル=2:1)。
1H-NMR (300 MHz, CDCl3):δ 0.90-1.19, 1.22, 1.36-1.83, 1.84-1.96, 2.03-2.18, 2.23, 2.41-2.53, 2.57, 2.84-2.97, 3.64-3.80, 3.83-3.91, 3.92-4.09, 4.44-4.59, 4.88-5.09, 5.53-5.77, 6.83-7.04, 7.14-7.35。
(3aR,4S,5R,6aS)-4-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-5-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサヒドロ-2H-シクロペンタ[b]フラン-2-オンを用い、4-エトキシ-4-オキソブチルジンクブロマイドまたはその代わりに相当する有機亜鉛試薬を用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例1→実施例2→実施例3→実施例4→実施例5→実施例6→実施例7→実施例8→実施例9→実施例10(1)または実施例10(2)→実施例11→実施例12→実施例13→実施例14→実施例15→実施例16(1)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。
TLC:Rf 0.41 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.19, 1.22, 1.34-1.98, 2.00-2.14, 2.23, 2.39-2.54, 2.59-2.80, 2.84-2.97, 3.59-3.78, 3.88-4.23, 4.90-5.09, 5.37-5.51, 5.53-5.65, 7.10-7.24, 7.23-7.38。
1H-NMR (300 MHz, CDCl3):δ 0.88-1.19, 1.22, 1.35-1.96, 2.02-2.16, 2.23, 2.41-2.55, 2.56-2.69, 2.82-3.00, 3.62-3.79, 3.81-4.12, 4.42-4.55, 4.89-5.08, 5.54-5.72, 6.77-6.84, 6.91-6.98, 7.20。
TLC:Rf 0.45 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.29, 1.35-1.97, 2.01-2.17, 2.23, 2.28-2.40, 2.42-2.54, 2.66-2.83, 2.83-2.97, 3.62-3.78, 3.78-4.12, 4.40-4.56, 4.89-5.08, 5.54-5.73, 6.64-6.75, 6.78, 7.16。
TLC:Rf 0.19 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 1.32-1.43, 1.50-1.81, 1.80-2.11, 2.11-2.28, 2.41-2.60, 2.99, 3.28, 3.71-3.85, 3.84-3.94, 4.01, 4.05-4.18, 4.35, 4.48-4.62, 5.60-5.80, 6.85-7.03, 7.16-7.36, 7.90-8.02。
TLC:Rf 0.22 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 1.33-1.43, 1.46-1.96, 1.96-2.10, 2.11-2.43, 2.43-2.58, 2.58-2.78, 2.93-3.13, 3.66-4.18, 4.25, 4.30-4.42, 4.49, 5.54-5.77, 6.83-7.02, 7.17-7.33, 7.41-7.50, 7.92-8.01。
TLC:Rf 0.56 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.39, 1.53-2.32, 2.43-2.66, 2.91-3.11, 3.30, 3.69-3.84, 3.85-3.95, 3.97-4.05, 4.05-4.18, 4.37, 4.48-4.60, 5.60-5.79, 6.84-7.04, 7.19-7.43, 7.80-7.93。
TLC:Rf 0.59 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.34-1.43, 1.47-1.95, 1.95-2.12, 2.15-2.33, 2.40-2.58, 2.66-3.19, 3.64-3.99, 4.02-4.14, 4.22, 4.30-4.42, 4.43-4.54, 5.53-5.72, 6.81-7.00, 7.19-7.30, 7.32-7.42, 7.60-7.69, 7.84-7.92, 7.94-8.01。
TLC:Rf 0.44 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.19, 1.22, 1.32-1.97, 2.01-2.17, 2.23, 2.40-2.56, 2.70-2.99, 2.99-3.24, 3.59-3.77, 3.80-4.11, 4.38-4.56, 4.88-5.08, 5.52-5.70, 6.75-6.91, 7.18-7.25。
TLC:Rf 0.49 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.18, 1.22, 1.37-1.83, 1.83-1.95, 2.01, 2.05-2.17, 2.23, 2.29, 2.40-2.56, 2.84-2.97, 3.66-3.79, 3.84, 3.90-4.09, 4.50, 4.91-5.07, 5.57-5.73, 6.76-6.85, 7.03-7.12。
TLC:Rf 0.47 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.19, 1.21, 1.36-1.96, 2.06-2.29, 2.41-2.68, 2.91, 3.66-3.79, 3.88-4.10, 4.48-4.60, 4.90-5.08, 5.57-5.76, 6.97, 7.54。
TLC:Rf 0.53 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.85-1.19, 1.22, 1.34-1.96, 2.03-2.18, 2.18-2.29, 2.39-2.57, 2.71-2.84, 2.84-2.99, 3.63-3.80, 3.85-4.13, 4.47-4.61, 4.88-5.09, 5.55-5.77, 6.84-7.15。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.19, 1.22, 1.34-1.97, 1.99-2.20, 2.23, 2.37-2.60, 2.91, 3.65-3.79, 3.81-4.12, 4.45-4.60, 4.91-5.10, 5.56-5.75, 6.59-6.74, 7.11-7.32。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.18, 1.22, 1.36-1.98, 1.99-2.18, 2.23, 2.40-2.68, 2.84-2.97, 3.64-3.79, 3.79-3.89, 3.89-4.14, 4.44-4.57, 4.89-5.11, 5.56-5.75, 6.80-6.91, 6.91-7.03。
TLC:Rf 0.46 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.19, 1.19-1.25, 1.36-1.97, 2.00-2.19, 2.23, 2.41-2.56, 2.85-2.98, 3.67-3.80, 3.88-4.09, 4.48-4.60, 4.91-5.08, 5.59-5.76, 7.09, 7.12-7.17, 7.21-7.25, 7.40。
TLC:Rf 0.43(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.18, 1.18-1.26, 1.35-1.97, 2.02-2.19, 2.23, 2.40-2.60, 2.83-2.98, 3.63-4.10, 4.45-4.58, 4.89-5.08, 5.56-5.74, 6.43-6.58, 7.17。
TLC:Rf 0.44 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.18, 1.23, 1.35-1.96, 2.04-2.29, 2.40-2.55, 2.61, 2.84-2.97, 3.64-3.87, 3.89-4.09, 4.43-4.55, 4.91-5.06, 5.56-5.73, 6.75-6.92。
TLC:Rf 0.50 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.85-1.19, 1.19-1.26, 1.33-1.97, 1.98-2.18, 2.18-2.30, 2.38-2.59, 2.82-3.00, 3.62-3.81, 3.83-4.14, 4.46-4.64, 4.88-5.09, 5.56-5.78, 6.77-6.84, 6.84-6.94, 7.05-7.21。
TLC:Rf 0.48 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.18, 1.22, 1.35-1.95, 1.99-2.18, 2.23, 2.40-2.54, 2.62-2.74, 2.91, 3.65-3.80, 3.88-3.99, 3.99-4.11, 4.49-4.65, 4.89-5.08, 5.57-5.76, 6.86-6.98, 7.15-7.24, 7.30-7.40。
TLC:Rf 0.59 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.88-1.17, 1.18-1.37, 1.40-1.94, 1.98-2.19, 2.20-2.30, 2.36-2.56, 2.89, 3.66-4.10, 4.46-4.59, 4.91-5.07, 5.57-5.75, 6.87-7.01, 7.24-7.33。
TLC:Rf 0.57 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.19, 1.17-1.25, 1.33-1.83, 1.82-1.98, 2.00-2.19, 2.23, 2.38-2.59, 2.82-2.97, 3.63-3.79, 3.80-4.16, 4.40-4.61, 4.88-5.10, 5.52-5.75, 6.81, 6.97。
TLC:Rf 0.56 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.17, 1.18-1.25, 1.34-1.83, 1.83-1.97, 2.04-2.18, 2.23, 2.40-2.55, 2.84-2.97, 3.64-3.79, 3.82-3.90, 3.91-3.99, 3.99-4.13, 4.41-4.59, 4.90-5.09, 5.53-5.74, 6.48-6.59, 6.65-6.79。
TLC:Rf 0.51 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.88-1.18, 1.18-1.26, 1.34-1.81, 1.82-1.99, 2.04-2.16, 2.18-2.28, 2.37-2.56, 2.73, 2.91, 3.63-3.80, 3.87-4.15, 4.46-4.65, 4.86-5.07, 5.53-5.77, 6.67-6.85, 6.89-7.07。
TLC:Rf 0.54 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.18, 1.18-1.25, 1.36-1.84, 1.82-1.97, 2.03-2.19, 2.23, 2.40-2.58, 2.83-2.99, 3.65-3.80, 3.81-3.90, 3.90-4.12, 4.41-4.59, 4.87-5.11, 5.52-5.79, 6.32-6.54。
1H-NMR (300 MHz, CDCl3):δ 0.92-1.18, 1.21, 1.34-1.82, 1.82-1.96, 2.03-2.18, 2.23, 2.28, 2.41-2.54, 2.78, 2.84-2.98, 3.62-3.80, 3.86-4.11, 4.47-4.61, 4.89-5.07, 5.54-5.76, 6.54-6.66, 6.66-6.76, 6.93-7.05。
TLC:Rf 0.69 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.19, 1.22, 1.37-1.96, 2.03-2.29, 2.41-2.54, 2.68, 2.91, 3.65-3.80, 3.86-4.11, 4.48-4.60, 4.91-5.08, 5.55-5.75, 6.86-6.94, 6.94-7.06。
TLC:Rf 0.58 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.19, 1.21, 1.37-1.97, 2.02-2.19, 2.23, 2.41-2.54, 2.91, 3.66-3.80, 3.80-3.89, 3.89-4.10, 4.45-4.56, 4.99, 5.55-5.75, 6.73-6.81, 6.95, 7.00-7.10。
TLC:Rf 0.72 (ヘキサン:酢酸エチル=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.88-1.19, 1.22, 1.36-1.81, 1.81-1.97, 2.15-2.29, 2.42, 2.46-2.59, 2.91, 3.25-3.47, 3.81-4.09, 4.46-4.59, 4.89-5.10, 5.56-5.67, 5.69-5.82, 6.87-7.02, 7.23-7.35。
TLC:Rf 0.37 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.84-1.18, 1.19-1.27, 1.34-1.97, 2.02-2.19, 2.23, 2.39-2.54, 2.66, 2.81-2.99, 3.61-3.82, 3.86-4.12, 4.45-4.63, 4.88-5.09, 5.55-5.76, 6.82-6.91, 6.93-7.07。
TLC:Rf 0.43 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.02-1.19, 1.22, 1.42-1.59, 1.63-1.96, 2.02-2.28, 2.41-2.55, 2.60, 2.92-3.04, 3.65-3.79, 3.82-3.92, 3.92-4.12, 4.44-4.58, 4.89-5.08, 5.55-5.75, 6.80, 6.91, 6.95, 7.19。
TLC:Rf 0.63 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.18, 1.18-1.25, 1.35-1.82, 1.82-1.94, 2.03-2.16, 2.23, 2.40-2.56, 2.84-2.95, 2.97, 3.70, 3.85-4.08, 4.46-4.55, 4.92-5.06, 5.55-5.71, 6.73-6.98。
TLC:Rf 0.62 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.18, 1.22, 1.36-1.83, 1.83-1.96, 2.05-2.18, 2.23, 2.48, 2.53-2.59, 2.85-2.96, 3.65-3.78, 3.79-3.87, 3.89-4.09, 4.44-4.55, 4.91-5.07, 5.56-5.73, 6.57-6.64, 6.73, 6.99-7.12。
TLC:Rf 0.28 (ジクロロメタン:メタノール=20:1);
1H-NMR (300 MHz, CDCl3):δ 1.22, 1.34-1.98, 2.07-2.19, 2.21-2.33, 2.40, 2.77, 3.02, 3.40, 3.65-3.77, 3.78-4.03, 4.44-4.56, 4.92-5.08, 5.57-5.71, 6.87-7.01, 7.24-7.34。
実施例16(34):エチル 4-{(3R,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタノアート
TLC:Rf 0.25 (ジクロロメタン:メタノール=20:1);
1H-NMR (300 MHz, CDCl3):δ 1.25, 1.35-1.88, 2.08-2.23, 2.22-2.49, 2.67, 3.41, 3.64-4.06, 4.12, 4.46-4.59, 5.58-5.78, 6.85-7.06, 7.22-7.37。
1H-NMR (300 MHz, CDCl3):δ 0.89-1.20, 1.25, 1.35-1.99, 2.03-2.19, 2.26, 2.41-2.54, 2.58, 2.91, 3.65-3.81, 3.83-4.08, 4.12, 4.46-4.61, 5.58-5.75, 6.84-7.05, 7.22-7.37。
TLC:Rf 0.47 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.23, 1.34-1.89, 2.07-2.22, 2.27, 2.34-2.46, 2.47-2.67, 3.41, 3.67-4.06, 4.43-4.60, 4.91-5.10, 5.54-5.77, 6.78-6.84, 6.92, 6.93-6.99, 7.20。
TLC:Rf 0.47 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.23, 1.33-1.87, 1.86-1.96, 2.10-2.23, 2.23-2.50, 3.42, 3.68-3.90, 3.93-4.07, 4.44-4.63, 4.91-5.10, 5.56-5.79, 6.77-6.85, 6.92, 6.93-7.00, 7.20。
TLC:Rf 0.65 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.66-2.01, 2.04-2.18, 2.23, 2.29-2.57, 2.91, 3.73, 3.85, 3.90-4.13, 4.45-4.59, 4.90-5.07, 5.53-5.78, 6.75-6.84, 6.91, 6.92-6.98, 7.19。
TLC:Rf 0.39 (イソプロピルアルコール:ヘキサン=1:5);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.18, 1.18-1.26, 1.36-1.83, 1.83-1.97, 2.05-2.19, 2.23, 2.39-2.56, 2.91, 3.63-3.81, 3.82-4.11, 4.48-4.64, 4.88-5.08, 5.54-5.77, 6.53-6.65, 6.66-6.79, 6.93-7.09。
TLC:Rf 0.59 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.02-1.18, 1.19-1.26, 2.10-2.39, 2.50, 2.76-2.89, 3.00, 3.67-3.80, 3.88-4.13, 4.50-4.61, 5.00, 5.58-5.75, 6.62, 6.72, 7.03。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.15-1.34, 1.35-1.87, 2.11-2.25, 2.29, 2.42, 2.69, 3.43, 3.70-4.09, 4.51-4.62,4.95-5.09, 5.58-5.76, 6.62, 6.73, 7.03。
TLC:Rf 0.33 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.35, 1.42-1.76, 1.85-1.93, 2.04-2.12, 2.22-2.27, 2.42-2.51, 2.67, 2.87-2.95, 3.26-3.32, 3.50-3.55, 3.66-3.75, 3.93-4.07, 4.24-4.29, 4.96-5.05, 5.50-5.64。
TLC:Rf 0.56 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.78-1.24, 1.24-2.08, 2.25, 2.36-2.49, 2.91-3.02, 3.59-3.73, 3.86-4.07, 4.38-4.49, 5.54-5.71, 6.75-6.86, 6.86-6.94, 6.98-7.10。
実施例16(1)~実施例16(22)および実施例16(24)~実施例16(33)で製造した化合物を、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
TLC:Rf 0.38 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.23, 1.32-1.97, 2.00-2.13, 2.32, 2.40-2.54, 2.57-2.78, 2.91, 3.61-3.75, 3.85-4.20, 5.36-5.48, 5.52-5.66, 7.11-7.33。
1H-NMR (300 MHz, CDCl3):δ 0.83-1.27, 1.35-1.97, 2.02-2.20, 2.33, 2.41-2.55, 2.84-2.99, 3.67-3.78, 3.80-4.11, 4.45-4.58, 5.54-5.74, 6.76-6.84, 6.91-6.98, 7.20。
TLC:Rf 0.46 (ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.80-1.21, 1.35-1.97, 2.00-2.19, 2.24-2.38, 2.40-2.55, 2.91, 3.65-3.78, 3.82-3.90, 3.90-4.08, 4.45-4.57, 5.54-5.73, 6.65-6.75, 6.78, 7.16。
TLC:Rf 0.36 (クロロホルム:メタノール=9:1);
1H-NMR (300 MHz, CD3OD):δ 1.46-2.17, 2.40-2.56, 2.87-3.03, 3.33-3.45, 3.63-3.77, 3.83-4.23, 4.35-4.49, 5.58-5.76, 6.82-6.99, 7.16-7.37, 7.92。
TLC:Rf 0.34 (クロロホルム:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.47-1.96, 1.95-2.12, 2.16-2.36, 2.44-2.61, 2.97-3.15, 3.67-4.18, 4.28, 4.45-4.61, 5.56-5.75, 6.85-7.02, 7.22-7.34, 7.46-7.54, 7.99-8.07。
TLC:Rf 0.45 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.49-2.20, 2.41-2.56, 2.86-3.03, 3.32-3.44, 3.63-3.78, 3.85-4.22, 4.37-4.49, 5.58-5.75, 6.84-6.98, 7.17-7.30, 7.33-7.48, 7.79-7.89。
TLC:Rf 0.45 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.48-1.72, 1.73-1.94, 1.95-2.13, 2.21-2.37, 2.43-2.59, 3.00-3.15, 3.66-4.00, 4.03-4.14, 4.25, 4.44-4.56, 5.56-5.74, 6.82-6.99, 7.19-7.30, 7.39, 7.65, 7.94, 8.11。
TLC:Rf 0.40 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.93-1.26, 1.26-1.82, 1.82-2.07, 2.25, 2.36-2.50, 2.90-3.03, 3.59-3.71, 3.83-4.05, 4.35-4.45, 5.55-5.70, 6.87-6.95, 7.19-7.28。
TLC:Rf 0.40 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.90-2.08, 2.18-2.33, 2.34-2.51, 2.97, 3.58-3.73, 3.79-4.07, 4.31-4.47, 5.54-5.71, 6.73-6.86, 7.04。
TLC:Rf 0.40 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.92-1.94, 1.94-2.08, 2.25, 2.36-2.50, 2.91-3.03, 3.59-3.73, 3.91-4.07, 4.40-4.49, 5.57-5.72, 7.01-7.13, 7.49-7.61。
TLC:Rf 0.39 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CD3OD):δ 0.78-2.10, 2.25, 2.35-2.49, 2.89-3.02, 3.58-3.74, 3.90-4.06, 4.34-4.51, 5.53-5.72, 6.83-6.96, 7.01-7.15。
TLC:Rf 0.37 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 0.80-1.22, 1.34-1.97, 2.05-2.18, 2.32, 2.40-2.56, 2.84-2.98, 3.66-3.78, 3.80-4.10, 4.46-4.57, 5.55-5.74, 6.55-6.75, 7.14-7.28。
TLC:Rf 0.40 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 0.83-1.21, 1.34-1.98, 2.05-2.18, 2.32, 2.39-2.57, 2.85-3.00, 3.66-3.79, 3.79-3.88, 3.89-4.09, 4.41-4.60, 5.54-5.76, 6.79-6.91, 6.90-7.03。
TLC:Rf 0.37 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.92-2.09, 2.25, 2.37-2.50, 2.88-3.04, 3.57-3.74, 3.89-4.07, 4.37-4.49, 5.54-5.74, 7.13-7.27, 7.38-7.51。
TLC:Rf 0.37 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.91-1.21, 1.27-1.83, 1.82-2.08, 2.25, 2.36-2.50, 2.90-3.03, 3.59-3.72, 3.75, 3.80-4.05, 4.34-4.45, 5.55-5.70, 6.44-6.55, 7.08-7.18。
TLC:Rf 0.39 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.93-1.24, 1.30-1.47, 1.47-1.82, 1.82-2.09, 2.25, 2.36-2.50, 2.90-3.03, 3.59-3.71, 3.73, 3.78-3.92, 3.93-4.05, 4.32-4.42, 5.54-5.70, 6.74-6.92。
TLC:Rf 0.61 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.87-1.23, 1.24-1.93, 1.94-2.09, 2.15-2.32, 2.35-2.50, 2.89-3.03, 3.58-3.72, 3.85-4.07, 4.37-4.47, 5.56-5.71, 6.74-6.88, 7.03-7.15。
TLC:Rf 0.50 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.84-1.21, 1.22-1.93, 1.93-2.10, 2.25, 2.35-2.49, 2.96, 3.57-3.72, 3.89-4.06, 4.39-4.49, 5.57-5.71, 6.90, 7.05, 7.19-7.27, 7.33。
TLC:Rf 0.24 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.90-1.20, 1.22-1.47, 1.46-1.67, 1.66-1.93, 1.93-2.08, 2.21-2.32, 2.36-2.49, 2.95, 3.59-3.72, 3.83-4.07, 4.35-4.47, 5.55-5.71, 6.86-6.95, 7.19-7.30。
TLC:Rf 0.62 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.90-1.22, 1.25-2.09, 2.25, 2.35-2.51, 2.97, 3.58-3.72, 3.83-4.08, 4.31-4.48, 5.50-5.73, 6.93, 6.98。
TLC:Rf 0.62 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.90-1.22, 1.27-2.10, 2.26, 2.37-2.51, 2.97, 3.58-3.73, 3.85-4.06, 4.35-4.47, 5.54-5.72, 6.69, 6.75, 6.79-6.85。
1H-NMR (300 MHz, CDCl3):δ 0.90-1.30, 1.37-1.81, 1.82-1.96, 2.04-2.19, 2.32, 2.41-2.54, 2.85-2.98, 3.65-3.79, 3.84-4.10, 4.47-4.58, 5.57-5.74, 6.86-7.03, 7.23-7.35。
TLC:Rf 0.59 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.91-1.24, 1.24-2.11, 2.25, 2.35-2.51, 2.97, 3.57-3.75, 3.80-4.11, 4.29-4.50, 5.50-5.77, 6.38-6.68。
1H-NMR (300 MHz, CD3OD):δ 0.89-1.23, 1.25-1.94, 1.95-2.10, 2.25, 2.35-2.51, 2.92-3.03, 3.58-3.73, 3.87-4.09, 4.35-4.50, 5.55-5.75, 6.58-6.71, 6.84-6.97, 6.99-7.14。
TLC:Rf 0.59 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.92-1.20, 1.29-1.46, 1.46-2.08, 2.25, 2.36-2.49, 2.91-3.02, 3.59-3.71, 3.92-4.05, 4.38-4.47, 5.55-5.71, 6.88-6.94, 7.07, 7.13。
TLC:Rf 0.58 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.92-1.22, 1.30-1.47, 1.47-1.83, 1.82-2.07, 2.25, 2.36-2.49, 2.90-3.03, 3.59-3.72, 3.82-4.05, 4.35-4.44, 5.54-5.70, 6.84-6.92, 7.04, 7.13。
TLC:Rf 0.43 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.22, 1.35-1.81, 1.81-1.97, 2.15-2.28, 2.32, 2.46-2.59, 2.92, 3.26-3.46, 3.82-4.09, 4.48-4.58, 5.55-5.67, 5.69-5.82, 6.87-7.02, 7.24-7.34。
TLC:Rf 0.26 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 0.89-1.23, 1.25-2.06, 2.25, 2.31-2.51, 2.87-3.03, 3.57-3.75, 3.87-4.09, 4.35-4.50, 5.52-5.73, 6.89-7.15。
TLC:Rf 0.26 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.04-1.20, 1.35-1.63, 1.65-2.19, 2.37-2.50, 2.97-3.09, 3.25-3.38, 3.59-3.72, 3.85-4.07, 4.35-4.46, 5.55-5.70, 6.86, 6.89-6.97, 7.22。
TLC:Rf 0.22 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.87-1.26, 1.26-1.82, 1.81-1.94, 1.94-2.07, 2.25, 2.43, 2.97, 3.65, 3.91-4.06, 4.36-4.47, 5.54-5.71, 6.79-6.89, 6.95, 7.09。
TLC:Rf 0.22 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 0.93-1.24, 1.27-1.83, 1.82-1.94, 1.94-2.07, 2.25, 2.43, 2.97, 3.65, 3.81-4.06, 4.35-4.44, 5.54-5.71, 6.67-6.76, 6.86, 7.13。
TLC:Rf 0.40 (クロロホルム:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 1.12-1.91, 2.07-2.91, 3.34-3.50, 3.65-4.06, 4.46-4.58, 5.56-5.73, 6.84-7.05, 7.22-7.35。
(3aR,4S,5R,6aS)-4-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-5-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサヒドロ-2H-シクロペンタ[b]フラン-2-オンを用い、4-エトキシ-4-オキソブチルジンクブロマイドを用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートの代わりに相当するホスホン酸塩を用いて、実施例1→実施例2→実施例3→実施例4→実施例5→実施例6→実施例7→実施例8→実施例9→実施例10→実施例11→実施例12→実施例13→実施例14→実施例15→実施例16(1)→実施例17(1)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 0.53 (酢酸エチル:メタノール=8:1);
1H-NMR (300 MHz, CD3OD):δ 0.77-1.21, 1.22-1.82, 1.82-2.05, 2.25, 2.35-2.48, 2.91-3.02, 3.56-3.69, 3.88-4.07, 5.34-5.56。
実施例16(36)~実施例16(42)で製造した化合物を用いて、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
TLC:Rf 0.64 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.36-1.86, 1.97-2.12, 2.29, 2.33-2.45, 3.45, 3.61-3.73, 3.77-3.85, 3.85-4.05, 4.34-4.47, 5.55-5.71, 6.83-6.89, 6.89-6.94, 6.94-6.97, 7.22。
TLC:Rf 0.63 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CDCl3):δ 1.37-1.88, 1.94-2.13, 2.29, 2.33-2.46, 3.45, 3.60-3.74, 3.76-3.93, 3.94-4.06, 4.36-4.47, 5.57-5.72, 6.84-6.89, 6.89-6.94, 6.96, 7.22。
TLC:Rf 0.58 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.76-2.13, 2.25, 2.35-2.50, 2.90-3.03, 3.60-3.73, 3.82-3.92, 3.92-4.06, 4.35-4.49, 5.55-5.73, 6.83-6.89, 6.89-6.94, 6.96, 7.22。
TLC:Rf 0.44 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CD3OD):δ 0.90-1.71, 1.71-1.86, 1.84-2.11, 2.25, 2.34-2.52, 2.90-3.03, 3.56-3.75, 3.85-4.14, 4.37-4.56, 5.51-5.78, 6.49-6.73, 6.82-7.00, 7.00-7.18。
TLC:Rf 0.50 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.01-1.21, 1.33-1.62, 1.66-1.95, 1.95-2.18, 2.44, 2.94-3.12, 3.66, 3.94-4.08, 4.40-4.48, 5.57-5.72, 6.63, 6.92,7.07。
TLC:Rf 0.49 (ジクロロメタン:メタノール=7:1);
1H-NMR (300 MHz, CD3OD):δ 1.38-1.86, 1.98-2.13, 2.29, 2.38, 3.46, 3.68, 3.76-3.87, 3.95-4.06, 4.40-4.49,5.57-5.72, 6.63, 6.93, 7.08。
TLC:Rf 0.81 (ジクロロメタン:メタノール=4:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.90, 2.05-2.15, 2.32-2.37, 2.43-2.52, 2.89-2.97, 3.27-3.33, 3.51-3.55, 3.66-3.75, 3.93-4.08, 4.25-4.31, 5.50-5.64。
(3aR,4S,5R,6aS)-4-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-5-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサヒドロ-2H-シクロペンタ[b]フラン-2-オンを用い、4-エトキシ-4-オキソブチルジンクブロマイドまたはその代わりに相当する有機亜鉛試薬を用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例16(2)~実施例16(42)の項に記載の方法を用いて製造した化合物を、実施例17(1)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。
TLC:Rf 0.38 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, DMSO-d6):δ 11.97, 7.52-7.39, 7.31, 5.55, 5.48, 5.16, 4.60, 4.30, 4.04-4.00, 3.90-3.81, 3.48, 2.83, 2.27, 2.15, 1.89-1.70, 1.66-1.18, 1.11-0.83。
TLC:Rf 0.36 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, DMSO-d6):δ 11.97, 7.12-7.07, 5.54, 5.47, 5.07, 4.60, 4.23, 3.97-3.82, 3.48, 2.83, 2.27, 2.15, 1.88-1.72, 1.65-1.20, 1.07-0.85。
TLC:Rf 0.36 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, DMSO-d6):δ 11.96, 7.39, 6.99-6.88, 5.55, 5.48, 5.11, 4.60, 4.28, 3.90-3.83, 3.50, 2.83, 2.27, 2.15, 1.90-1.73, 1.67-1.20, 1.12-0.85。
TLC:Rf 0.32 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, DMSO-d6):δ 11.96, 7.53, 7.33-7.23, 5.55, 5.47, 5.18, 4.61, 4.31, 4.03-3.95, 3.89-3.81, 3.50, 2.83, 2.27, 2.15, 1.90-1.69, 1.65-1.17, 1.11-0.82。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.19, 1.22, 1.35-1.99, 2.15-2.29, 2.33-2.59, 2.81-3.01, 3.58-4.18, 4.81-5.16, 6.78-7.11, 7.15-7.46。
実施例16(2)、実施例16(3)または実施例16(25)で製造した化合物を用いて、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例18(1)と同様の目的の操作に付すことにより、下記の実施例化合物を得た。
実施例18(2):2-プロパニル 4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3R)-3-ヒドロキシ-5-フェニルペンチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタノアート
TLC:Rf 0.82 (酢酸エチル:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.18, 1.22, 1.31-1.97, 2.12-2.30, 2.59-2.73, 2.73-2.85, 2.85-2.95, 3.53-3.76, 3.86-4.08, 4.85-5.08, 7.05-7.37。
TLC:Rf 0.58 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CDCl3):δ 0.70-1.99, 2.16-2.29, 2.30-2.64, 2.92, 3.66-3.78, 3.78-3.87, 3.90-4.10, 4.89-5.09, 6.80, 6.91, 6.95, 7.20。
TLC:Rf 0.42 (イソプロピルアルコール:ヘキサン=1:5);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.19, 1.19-1.25, 1.33-1.97, 2.13-2.73, 2.91, 3.66-3.80, 3.81-4.16, 4.90-5.10, 6.52-6.65, 6.65-6.76,6.93-7.09。
実施例18(1)~実施例18(4)で製造した化合物を用いて、実施例17(1)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。
実施例19(1):4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3R)-3-ヒドロキシ-4-フェノキシブチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
1H-NMR (300 MHz, CDCl3):δ 0.92-1.23, 1.36-1.98, 2.15-2.29, 2.33, 2.84-2.99, 3.67-3.78, 3.79-3.87, 3.88-4.07, 6.81-7.04, 7.15-7.41。
TLC:Rf 0.65 (酢酸エチル:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.18, 1.22, 1.31-1.97, 2.12-2.30, 2.59-2.73, 2.73-2.85, 2.85-2.95, 3.53-3.76, 3.86-4.08, 4.85-5.08, 7.05-7.37。
TLC:Rf 0.58 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 0.80-1.85, 1.85-2.06, 2.17-2.43, 2.91-3.04, 3.53-3.68, 3.82-4.04, 6.83-6.89, 6.89-6.94, 6.95, 7.22。
TLC:Rf 0.41 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CD3OD):δ 0.93-1.24, 1.37-1.84, 1.84-2.01, 2.16-2.38, 2.90-3.04, 3.50-3.70, 3.83-4.08, 6.53-6.71, 6.82-7.00, 6.99-7.15。
アルゴン雰囲気下、水素化ナトリウム(631mg)の無水DMF(20mL)溶液に氷冷下、実施例3で製造した化合物(3.9g)の無水DMF(17mL)溶液を加えて室温にて1時間撹拌した。続けて2-(ブロモメチル)アクリル酸エチル(2.91mL)を加え、室温にて3時間撹拌した。飽和塩化アンモニウム水溶液を加え、ヘキサン:酢酸エチル(2:1)にて抽出した。有機層を水、飽和食塩水にて洗浄、硫酸ナトリウムにて乾燥後、溶媒を減圧濃縮した。得られた残渣を山善社製カラム装置(Hiflash-SI、Size 3L、ヘキサン:酢酸エチル=100:0→93:7→86:14)にて精製し、以下の物性値を有する標題化合物(4.32g)を得た。
TLC:Rf 0.53 (ヘキサン:酢酸エチル=5:1)。
アルゴン雰囲気下、実施例20で製造した化合物(200mg、0.190mmol)をトルエン(40mL)に溶解した。シュロック触媒(48mg、0.062mmol)を加えて60℃で18時間反応させた。放冷後,濃縮し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=95:10→50:50)で精製し以下の物性値を有する標題化合物(3.2mg)を得た。TLC:Rf 0.53 (ヘキサン:酢酸エチル=4:1)。
実施例22(1):エチル (3S,5aR,6S,7R,8aS)-6-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-7-(テトラヒドロ-2H-ピラン-2-イルオキシ)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-カルボキシラート
アルゴン雰囲気下、実施例21で製造した化合物(1.6g)に5%ロジウム-アルミナ粉末(160mg)、続けてエタノール(40mL)を加え、水素雰囲気下、室温にて4時間撹拌した。反応液をセライト(商品名)にてろ過後、減圧濃縮し、得られた残渣を山善社製カラム装置(Hiflash-SI、Size 3L、ヘキサン:酢酸エチル=95:5→8:2)にて精製し、以下の物性値を有する実施例22(1)の化合物(270mg)とそのジアステレオマー体(実施例22(2))(1.2g)を得た。
TLC:Rf 0.58(ヘキサン:酢酸エチル=4:1)(実施例22(1)の化合物);
TLC:Rf 0.44(ヘキサン:酢酸エチル=5:1)(実施例22(2)の化合物)。
アルゴン雰囲気下、水素化リチウムアルミニウム(87mg)のTHF(4mL)溶液に氷冷下、実施例22(1)で製造した化合物(945mg)のTHF(6.4mL)溶液を加え、室温にて20分撹拌した。MTBEにて希釈後、飽和硫酸ナトリウム水溶液を加え、セライト(商品名)にてろ過し、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(884mg)を得た。
TLC:Rf 0.16 (ヘキサン:酢酸エチル=2:1)。
実施例23で製造した化合物(300mg)のベンゼン(1.8mL)溶液に、別途調製した50%水酸化ナトリウム水溶液(0.6mL)を氷冷下にて加えた。続いて硫酸水素テトラブチルアンモニウム塩(61mg)、ブロモ酢酸tert-ブチル(282mg)を加え、室温にて一晩撹拌した。MTBEにて希釈後、水を加えMTBEにて抽出した。水、飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥、溶媒を減圧濃縮した。得られた残渣を山善社製カラム装置(SMB Silica Column、10μm、Size 60、ヘキサン:酢酸エチル=95:5→90:10→80:20→50:50)にて精製し、以下の物性値を有する標題化合物(371mg)を得た。
TLC:Rf 0.54 (ヘキサン:酢酸エチル=4:1)。
実施例24で製造した化合物(371mg)のメタノール(5.25mL)溶液に、室温にて2N水酸化ナトリウム水溶液(1.75mL)を加え50℃で3.5時間撹拌した。メタノールを減圧濃縮にて留去した後、MTBEにて希釈、氷冷した2N塩酸にて酸性にし、酢酸エチルにて抽出した。水、飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥、溶媒を減圧濃縮し、以下の物性値を有する標題化合物(371mg)を得た。得られた標題化合物は、精製することなく次の反応に用いた。
TLC:Rf 0.24 (酢酸エチル)。
アルゴン雰囲気下、実施例25で製造した化合物をDMF(2.8mL)に溶解させ、室温にて炭酸カリウム(242mg)、2-ヨードプロパン(0.105mL)を順次加え50℃にて一晩撹拌した。反応溶液を酢酸エチルにて希釈し、水を加え酢酸エチルにて抽出した。水、飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥、溶媒を減圧濃縮し、以下の物性値を有する標題化合物(371mg)を得た。得られた標題化合物は、精製することなく次の反応に用いた。
TLC:Rf 0.81 (ヘキサン:酢酸エチル=1:1)。
アルゴン雰囲気下、実施例26で製造した化合物に、室温にてテトラブチルアンモニウムフルオライドの1MTHF溶液(1.4mL)を加え、6時間撹拌した。反応溶液を酢酸エチルにて希釈し、飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。水、飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥、溶媒を減圧濃縮した。得られた残渣を山善社製カラム装置(Hiflash-SI、Size M、ヘキサン:酢酸エチル=90:10→50:50→20:80)にて精製し、以下の物性値を有する標題化合物(240mg)を得た。
TLC:Rf 0.21(ヘキサン:酢酸エチル=1:1)。
TLC:Rf 0.33 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.31, 1.40-1.57, 1.58-2.19, 2.19-2.29, 2.41-2.55, 2.61-2.73, 3.24-3.41, 3.63-3.81, 3.83-4.07, 4.14-4.25, 4.42-4.60, 4.98-5.16, 5.58-5.73, 6.86-7.03, 7.23-7.34。
(3aR,4S,5R,6aS)-4-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-5-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサヒドロ-2H-シクロペンタ[b]フラン-2-オンを用い、2-(ブロモメチル)アクリル酸エチルを用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例20→実施例21実施例22(1)または実施例22(2)→実施例23→実施例24→実施例25→実施例26→実施例27→実施例28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。
TLC:Rf 0.65 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.32, 1.40-1.60, 1.61-2.21, 2.40-2.56, 3.05-3.18, 3.25-3.41, 3.67-3.82, 3.82-3.92, 3.92-4.06, 4.15-4.25, 4.45-4.58, 4.99-5.17, 5.56-5.76, 6.75-6.84, 6.87-6.99, 7.15-7.24。
TLC:Rf 0.49 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.35, 1.39-2.24, 2.40-2.57, 2.62-2.78, 3.10, 3.24-3.41, 3.64-3.80, 3.85-4.10, 4.14-4.26, 4.48-4.60, 4.98-5.15, 5.55-5.77, 6.82-7.14。
TLC:Rf 0.45 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.07-1.34, 1.39-2.22, 2.37-2.58, 3.04-3.17, 3.24-3.40, 3.64-3.80, 3.83-3.91, 3.91-4.07, 4.11-4.28, 4.45-4.59, 4.95-5.17, 5.54-5.77, 6.53-6.74, 7.10-7.32。
TLC:Rf 0.42 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.34, 1.38-2.22, 2.39-2.57, 3.05-3.17, 3.25-3.40, 3.65-3.79, 3.80-3.88, 3.88-4.09, 4.10-4.26, 4.43-4.58, 4.97-5.15, 5.54-5.74, 6.77-6.91, 6.90-7.04。
TLC:Rf 0.57 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.30, 1.40-1.58, 1.61-2.22, 2.40-2.56, 3.11, 3.25-3.41, 3.65-3.80, 3.80-3.90, 3.90-4.06, 4.13-4.25, 4.44-4.59, 4.98-5.16, 5.55-5.75, 6.76-6.91, 7.16-7.30。
TLC:Rf 0.60 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.31, 1.41-1.60, 1.61-2.22, 2.33, 2.41-2.57, 3.05-3.17, 3.25-3.41, 3.66-3.81, 3.81-3.91, 3.92-4.06, 4.14-4.26, 4.45-4.58, 4.99-5.16, 5.57-5.74, 6.66-6.83, 7.16。
TLC:Rf 0.57 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.35, 1.40-1.59, 1.61-2.20, 2.29, 2.39-2.60, 3.03-3.18, 3.25-3.41, 3.65-3.79, 3.79-3.89, 3.89-4.07, 4.13-4.26, 4.44-4.56, 4.98-5.16, 5.56-5.74, 6.74-6.86, 7.07。
TLC:Rf 0.33 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.30, 1.40-1.57, 1.61-2.21, 2.40-2.56, 2.71, 3.04-3.18, 3.25-3.41, 3.65-3.81, 3.88-4.04, 4.08, 4.15-4.24, 4.52-4.62, 5.00-5.16, 5.59-5.76, 6.88-6.98, 7.17-7.28, 7.33-7.41。
TLC:Rf 0.37 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.29, 1.41-1.57, 1.61-2.20, 2.24, 2.41-2.55, 3.11, 3.25-3.40, 3.66-3.81, 3.86-3.94, 3.94-4.05, 4.20, 4.48-4.60, 5.00-5.17, 5.60-5.76, 6.82, 6.85-6.93, 7.10-7.20。
TLC:Rf 0.37 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.05-1.33, 1.38-2.25, 2.38-2.56, 2.65-2.74, 2.96-3.19, 3.24-3.41, 3.73, 3.87-4.10, 4.14-4.26, 4.46-4.61, 4.98-5.15, 5.56-5.75, 6.83-6.92, 6.93-7.05。
TLC:Rf 0.51 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.32, 1.38-2.24, 2.32-2.43, 2.43-2.57, 3.05-3.19, 3.25-3.42, 3.65-3.82, 3.82-3.91, 3.92-4.06, 4.14-4.27, 4.44-4.62, 4.99-5.18, 5.52-5.77, 6.82, 6.98。
TLC:Rf 0.73 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.37, 1.37-2.24, 2.39-2.59, 3.04-3.18, 3.24-3.41, 3.65-3.80, 3.81-3.91, 3.91-4.05, 4.13-4.27, 4.43-4.58, 4.99-5.16, 5.55-5.75, 6.48-6.59, 6.64-6.78。
TLC:Rf 0.79 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.07-1.32, 1.37-2.22, 2.39-2.58, 3.04-3.18, 3.24-3.41, 3.64-3.79, 3.81-3.90, 3.90-4.06, 4.12-4.27, 4.43-4.58, 4.97-5.15, 5.55-5.74, 6.35-6.54。
TLC:Rf 0.77 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.08-1.35, 1.36-2.32, 2.38-2.57, 2.63-2.84, 3.03-3.19, 3.22-3.44, 3.62-3.82, 3.87-4.10, 4.13-4.28, 4.46-4.63, 4.98-5.20, 5.54-5.77, 6.66-6.87, 6.90-7.05。
TLC:Rf 0.77 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.07-1.32, 1.36-2.21, 2.27, 2.40-2.56, 2.77, 3.04-3.20, 3.23-3.41, 3.64-3.80, 3.84-4.08, 4.13-4.27, 4.48-4.61, 4.98-5.16, 5.54-5.74, 6.53-6.65, 6.65-6.76, 6.94-7.08。
TLC:Rf 0.52 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.10-1.30, 1.40-1.57, 1.61-2.21, 2.42-2.55, 2.60, 3.05-3.17, 3.25-3.40, 3.66-3.82, 3.87-4.08, 4.15-4.25, 4.49-4.61, 4.99-5.16, 5.55-5.75, 6.85-6.93, 6.93-7.06。
TLC:Rf 0.40 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.11-1.30, 1.40-1.60, 1.62-2.21, 2.41-2.55, 3.05-3.17, 3.26-3.40, 3.66-3.79, 3.79-3.89, 3.89-4.06, 4.15-4.25, 4.45-4.56, 4.99-5.15, 5.56-5.73, 6.73-6.80, 6.94, 7.00-7.09。
TLC:Rf 0.13 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.08-1.23, 1.39-1.57, 1.59-1.95, 1.95-2.20, 2.42-2.55, 3.03-3.16, 3.27-3.42, 3.66-3.78, 3.84-4.03, 4.05, 4.15-4.25, 4.46-4.57, 5.56-5.74, 6.86-7.02, 7.23-7.33。
実施例28(1)~実施例28(17)で製造した化合物を、それぞれ、実施例29と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
TLC:Rf 0.21 (クロロホルム:メタノール:酢酸=20:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.31, 1.40-2.26, 2.42-2.57, 3.03-3.17, 3.29-3.46, 3.68-3.81, 3.82-3.91, 3.93-4.09, 4.14-4.23, 4.46-4.58, 5.57-5.75, 6.75-6.84, 6.87-6.99, 7.14-7.24。
TLC:Rf 0.23 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.07-1.24, 1.32-1.48, 1.49-1.63, 1.67-2.13, 2.35-2.51, 3.06-3.18, 3.20-3.42, 3.59-3.74, 3.90-4.08, 4.11-4.23, 4.38-4.49, 5.57-5.70, 6.83-6.95, 6.99-7.16。
TLC:Rf 0.26 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.09-1.24, 1.35-1.49, 1.49-1.61, 1.67-2.12, 2.37-2.50, 3.07-3.18, 3.21-3.40, 3.60-3.72, 3.83-4.05, 4.13-4.23, 4.34-4.47, 5.56-5.73, 6.56-6.83, 7.16-7.32。
TLC:Rf 0.24 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.09-1.24, 1.34-1.49, 1.49-1.61, 1.68-2.11, 2.35-2.51, 3.08-3.19, 3.20-3.42, 3.60-3.73, 3.80-4.07, 4.12-4.24, 4.34-4.46, 5.56-5.71, 6.83-7.06。
TLC:Rf 0.42 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.06-1.28, 1.32-1.63, 1.64-2.12, 2.35-2.51, 3.06-3.19, 3.20-3.43, 3.57-3.74, 3.81-4.10, 4.10-4.24, 4.33-4.47, 5.52-5.73, 6.84-6.97, 7.16-7.29。
TLC:Rf 0.43 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.07-1.26, 1.33-1.64, 1.66-2.13, 2.29, 2.37-2.51, 3.05-3.19, 3.20-3.44, 3.57-3.75, 3.82-4.08, 4.10-4.24, 4.32-4.47, 5.54-5.72, 6.62-6.80, 7.04-7.17。
TLC:Rf 0.45 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.06-1.27, 1.31-1.64, 1.65-2.11, 2.25, 2.35-2.52, 3.04-3.20, 3.19-3.43, 3.58-3.74, 3.77-4.10, 4.10-4.24, 4.31-4.46, 5.52-5.72, 6.79, 7.04。
TLC:Rf 0.18 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.09-1.23, 1.32-1.46, 1.48-1.62, 1.68-2.11, 2.36-2.51, 3.11, 3.22-3.40, 3.60-3.73, 3.86-4.06, 4.12-4.22, 4.40-4.50, 5.58-5.73, 6.90, 7.05, 7.23, 7.33。
TLC:Rf 0.18 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.08-1.22, 1.34-1.49, 1.55, 1.68-2.10, 2.20, 2.43, 3.07-3.17, 3.25-3.39, 3.66, 3.86-4.07, 4.17, 4.38-4.47, 5.57-5.73, 6.76-6.89, 7.04-7.14。
TLC:Rf 0.29 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.05-1.62, 1.63-2.09, 2.35-2.52, 3.06-3.19, 3.19-3.42, 3.58-3.73, 3.93-4.06, 4.12-4.22, 4.37-4.52, 5.52-5.74, 6.89-7.18。
TLC:Rf 0.24 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 1.06-1.62, 1.65-2.13, 2.37-2.52, 3.07-3.18, 3.20-3.45, 3.60-3.74, 3.82-4.07, 4.12-4.23, 4.33-4.47, 5.53-5.73, 6.93, 6.98。
TLC:Rf 0.46 (ジクロロメタン:メタノール:酢酸=3:1:0.2);
1H-NMR (300 MHz, CD3OD):δ 1.07-1.33, 1.32-1.63, 1.63-2.13, 2.36-2.50, 3.06-3.18, 3.20-3.41, 3.60-3.73, 3.84-4.07, 4.12-4.23, 4.35-4.46, 5.53-5.72, 6.68, 6.75, 6.79-6.85。
TLC:Rf 0.47 (ジクロロメタン:メタノール:酢酸=3:1:0.2);
1H-NMR (300 MHz, CD3OD):δ 1.08-1.30, 1.32-1.63, 1.68-2.12, 2.36-2.51, 3.06-3.18, 3.21-3.41, 3.59-3.74, 3.82-4.06, 4.12-4.24, 4.35-4.48, 5.54-5.73, 6.39-6.64。
TLC:Rf 0.48 (ジクロロメタン:メタノール:酢酸=3:1:0.2);
1H-NMR (300 MHz, CD3OD):δ 1.08-1.28, 1.33-1.61, 1.65-2.12, 2.36-2.52, 3.12, 3.20-3.42, 3.58-3.73, 3.90-4.07, 4.11-4.22, 4.38-4.49, 5.53-5.73, 6.75-6.86, 6.86-6.95, 6.97-7.11。
TLC:Rf 0.48 (ジクロロメタン:メタノール:酢酸=3:1:0.2);
1H-NMR (300 MHz, CD3OD):δ 1.06-1.24, 1.32-1.65, 1.66-2.13, 2.35-2.52, 3.05-3.18, 3.22-3.42, 3.58-3.73, 3.88-4.07, 4.11-4.24, 4.37-4.51, 5.53-5.74, 6.54-6.69, 6.84-6.96, 6.99-7.14。
TLC:Rf 0.12 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.07-1.24, 1.33-1.49, 1.49-1.62, 1.67-2.10, 2.36-2.51, 3.07-3.19, 3.19-3.42, 3.60-3.72, 3.93-4.07, 4.11-4.23, 4.38-4.48, 5.55-5.72, 6.90, 7.07, 7.13。
TLC:Rf 0.11 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.08-1.25, 1.34-1.63, 1.67-2.09, 2.37-2.51, 3.07-3.18, 3.20-3.42, 3.59-3.73, 3.82-4.07, 4.12-4.23, 4.35-4.44, 5.54-5.72, 6.87, 7.04, 7.12。
アルゴン雰囲気下、実施例14で製造した化合物(280mg、0.53mmol)を(2-メトキシエチル)アミノサルファートリフルオライド(977μL、5.30mmol)に溶かし、室温で4日と7時間撹拌した。反応溶液を氷冷した飽和炭酸水素ナトリウム水溶液にゆっくり注ぎ込み、水層を酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。山善社製カラム装置(Hiflash-SI、size M、ヘキサン→酢酸エチル:ヘキサン=3:7)で精製し、以下の物性値を有する標題化合物(171mg)を得た。
TLC:Rf 0.54 (ヘキサン:酢酸エチル=3:7)。
TLC:Rf 0.42 (酢酸エチル:ヘキサン=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.87-1.19, 1.18-1.26, 1.35-1.96, 2.11-2.30, 2.35-2.56, 2.84-2.97, 3.67-3.84, 3.90-4.11, 4.19, 4.89-5.08, 5.68-5.87, 5.95-6.11, 6.85-6.95, 6.95-7.05, 7.21-7.35。
TLC:Rf 0.34 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.23, 1.36-1.96, 2.12-2.27, 2.33, 2.40-2.53, 2.84-2.98, 3.71-3.83, 3.90-4.10, 4.19, 5.69-5.88, 5.95-6.10, 6.86-6.94, 6.95-7.05, 7.21-7.35。
実施例13で製造した化合物を用いて、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートの代わりに相当するホスホン酸塩を用いて、実施例14→実施例30→実施例31→実施例32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。
TLC:Rf 0.52 (酢酸エチル);
1H-NMR(300 MHz, DMSO-d6):δ 11.98, 7.28-7.19, 7.13, 6.99, 6.06, 5.75, 4.79, 4.43, 3.90-3.84, 3.57, 2.84, 2.30, 2.15, 1.97, 1.80-1.64, 1.61-1.21, 1.11-0.86。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, DMSO-d6):δ 11.98, 7.33, 6.94-6.78, 6.05, 5.75, 4.81, 4.39, 3.91-3.85, 3.58, 2.85, 2.31, 2.16, 1.98, 1.81-1.67, 1.60-1.22, 1.12-0.87。
TLC:Rf 0.55 (酢酸エチル);
1H-NMR (300 MHz, DMSO-d6):δ 11.98, 7.32, 7.11, 7.04, 6.98, 6.05, 5.74, 4.80, 4.40, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.97, 1.81-1.64, 1.59-1.21, 1.10-0.86。
TLC:Rf 0.68 (酢酸エチル);
1H-NMR (300 MHz, DMSO-d6):δ 11.98, 7.55, 7.35-7.32, 6.06, 5.76, 4.80, 4.48, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.98, 1.81-1.64, 1.59-1.21, 1.10-0.86。
TLC:Rf 0.65 (酢酸エチル);
1H-NMR (300 MHz, DMSO-d6):δ 11.98, 7.33-7.23, 6.82, 6.07, 5.74, 4.80, 4.48, 3.91-3.84, 3.58, 2.85, 2.31, 2.16, 1.97, 1.81-1.64, 1.60-1.21, 1.10-0.86。
実施例23で製造した化合物(884mg)のジクロロメタン(5mL)溶液に、室温にてピリジン(0.335mL)、無水酢酸(0.294mL)、N-ジメチルアミノピリジン(少量)を順次加え、3時間撹拌した。酢酸エチルにて希釈、水を加えて酢酸エチルにて抽出した。有機層を1N塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水にて順次洗浄後、硫酸ナトリウムにて乾燥し、溶媒を減圧濃縮した。得られた残渣にTHF(0.5mL)を加え、アルゴン雰囲気下かつ氷冷下にてN-テトラブチルアンモニウムフルオライドの1M THF溶液(5mL)を加え、5時間撹拌した。氷冷した飽和塩化アンモニウム水溶液中に反応液を注ぎ、酢酸エチルにて抽出した。有機層を水、飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥後、溶媒を減圧濃縮した。得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size L、ヘキサン:酢酸エチル=8:2→1:1→0:1)にて精製し、以下の物性値を有する標題化合物(616mg)を得た。
TLC:Rf 0.19 (ヘキサン:酢酸エチル=1:1)。
実施例33で製造した化合物(616mg)を、実施例13→実施例14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(568mg)を得た。
TLC:Rf 0.53 (ヘキサン:酢酸エチル=1:1)。
実施例34で製造した化合物を、実施例15→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(568mg)を得た。
TLC:Rf 0.26 (ヘキサン:酢酸エチル=1:1)。
アルゴン雰囲気下、実施例35で合成した化合物(150mg)のDMSO(0.5mL)-酢酸エチル(1.0mL)溶液に、氷冷下にてジイソプロピルエチルアミン(0.3mL)を加え、続けてピリジン-サルファートリオキシド(139mg)を加え、約30分撹拌した。酢酸エチルにて希釈後、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。飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で有機層を洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をトルエン(1.5mL)に溶解させ、氷冷下トリエチルアミン(0.061mL)、L-システインエチルエステル塩酸塩(81mg)を順次加え、室温にて一晩撹拌した。酢酸エチルにて希釈後、水を加え、酢酸エチルにて抽出した。クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水にて順次洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をトルエン(5.8mL)に溶解させ、二酸化マンガン(756mg)を加えて60℃にて一晩撹拌した。セライト(商品名)にてろ過、酢酸エチルにて洗浄を複数回行い、ろ液を減圧濃縮した。得られた残渣を山善社製分取クロマトグラフ(SMB Silica Column、10μm、Size 20、ヘキサン:酢酸エチル=9:1→75:25→6:4→3:7)にて精製し、以下の物性値を有する標題化合物(65mg)を得た。
TLC:Rf 0.42, 0.38(ヘキサン:酢酸エチル=3:2)。
TLC:Rf 0.65 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.39, 1.59-1.97, 2.04, 2.10-2.35, 2.45-2.60, 3.39-3.56, 3.69-3.83, 3.89, 3.97-4.05, 4.10, 4.31-4.47, 4.49-4.60, 5.61-5.76, 6.86-7.01, 7.24-7.34, 8.04。
TLC:Rf 0.19 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.56-2.01, 2.10-2.39, 2.47-2.61, 3.35-3.55, 3.78, 3.85-3.94, 3.97-4.06, 4.11, 4.38, ,4.51-4.60, 5.63-5.77, 6.87-7.02, 7.23-7.35, 8.15。
実施例35で製造した化合物(90mg)の無水THF(1.7mL)溶液に、氷冷下でトリエチルアミン(0.039mL)、メタンスルホン酸クロライド(0.020mL)を続けて加え、1時間撹拌した。酢酸エチルで希釈し水を加えて抽出した。飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄し、硫酸ナトリウムにて乾燥した。溶媒を減圧濃縮し残渣(109mg)を得た。得られた残渣を無水THF(1.7mL)溶液に溶解し、チオグリコール酸エチル(0.029mL)を加えた。続けて60%水素化ナトリウム(11mg)を室温で加え、50℃で一晩撹拌した。酢酸エチルで希釈し水を加えて抽出した。飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄し、硫酸ナトリウムにて乾燥した。溶媒を減圧濃縮し、得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size S、ヘキサン:酢酸エチル=75:25→0:100)にて精製し、以下の物性値を有する標題化合物(61mg)を得た。
TLC:Rf 0.81 (ヘキサン:酢酸エチル=1:2)。
TLC:Rf 0.16 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 1.00-1.18, 1.24-1.33, 1.38-1.56, 1.56-1.85, 1.84-2.19, 2.25, 2.39-2.55, 2.68, 2.98, 3.13-3.22, 3.64-3.79, 3.83-3.92, 3.92-4.03, 4.09-4.26, 4.45-4.58, 5.57-5.72, 6.85-7.02, 7.22-7.34。
TLC:Rf 0.35 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.01-1.17, 1.38-1.55, 1.60-1.86, 1.86-2.20, 2.41-2.55, 2.93-3.05, 3.22, 3.67-3.79, 3.84-3.93, 3.93-4.04, 4.14-4.24, 4.48-4.57, 5.59-5.74, 6.87-7.03, 7.24-7.34。
実施例4で製造した化合物を用い、4-エトキシ-4-オキソブチルジンクブロマイドの代わりに相当する有機亜鉛試薬を用いて、実施例5→実施例6→実施例12→実施例13→実施例14→実施例15→実施例16(1)と同様の目的の操作に付すことにより、以下の化合物を得た。
1H-NMR (300 MHz, CDCl3):δ 1.35-1.44, 1.71-1.86, 2.04, 2.11-2.32, 2.43-2.64, 2.64-2.86, 3.73-3.94, 4.02, 4.07-4.21, 4.31-4.50, 4.50-4.61, 4.81-4.95, 5.61-5.81, 5.96-6.10, 6.86-7.03, 7.21-7.46, 7.84-7.98。
TLC:Rf 0.33 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 1.40, 1.72-1.86, 2.08-2.32, 2.44-2.58, 2.61, 2.75, 3.74-3.86, 3.85-3.96, 3.98-4.07, 4.15, 4.33-4.51, 4.55, 4.83-4.95, 5.62-5.80, 5.97-6.08, 6.88-7.03, 7.23-7.46, 7.88-7.96。
実施例4で製造した化合物を用い、4-エトキシ-4-オキソブチルジンクブロマイドまたはその代わりに相当する有機亜鉛試薬を用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例5→実施例6→実施例12→実施例13→実施例14→実施例15→実施例16(1)→実施例17(1)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。
実施例43(1):3-{(5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]-5,5a,6,7,8,8a-ヘキサヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}安息香酸(低極性体)
1H-NMR (300 MHz, CD3OD):δ 1.58-1.74, 2.07-2.32, 2.40-2.55, 2.60-2.78, 3.66-3.80, 3.84-3.95, 3.95-4.04, 4.10-4.22, 4.38-4.56, 4.77-4.99, 5.62-5.79, 6.04, 6.85-6.99, 7.19-7.29, 7.39, 7.45-7.54, 7.83-7.94。
TLC:Rf 0.20 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.58-1.74, 2.04-2.31, 2.40-2.55, 2.66, 3.66-3.81, 3.86-4.02, 4.15, 4.37-4.54, 4.73-5.00, 5.59-5.76, 6.01, 6.85-6.98, 7.19-7.30, 7.39, 7.45-7.53, 7.84-7.94。
TLC:Rf 0.56 (ジクロロメタン:メタノール=5:1);
1H-NMR (300 MHz, CDCl3):δ 1.61-1.79, 1.84-2.29, 2.36-2.60, 3.67-3.83, 3.86-4.16, 4.38, 4.48-4.67, 5.41-5.57, 5.57-5.87, 6.78-7.08, 7.19-7.36。
TLC:Rf 0.38 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.62-1.79, 1.81-2.26, 2.26-2.64, 3.69-3.81, 3.82-3.91, 3.92-4.07, 4.39, 4.49-4.59, 5.42-5.53, 5.55-5.79, 6.75-7.12, 7.19-7.41。
TLC:Rf 0.33 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.68-1.01, 1.06-2.93, 3.58-3.87, 3.88-4.24, 4.38, 5.25-5.81。
実施例4で製造した化合物を用い、4-エトキシ-4-オキソブチルジンクブロマイドまたはその代わりに相当する有機亜鉛試薬を用いて、実施例5→実施例6→実施例7→実施例8→実施例12→実施例13→実施例14→実施例15→実施例16(1)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。
1H-NMR (300 MHz, CDCl3):δ 1.22, 1.31-1.44, 1.51-1.78, 1.77-1.98, 2.01-2.31, 2.37-2.61, 3.49, 3.68-3.82, 3.83-3.93, 3.93-4.06, 4.39, 4.47-4.59, 4.92-5.06, 5.37-5.49, 5.57-5.75, 6.86-7.02, 7.22-7.35。
TLC:Rf 0.26 (ヘキサン:酢酸エチル=2:3);
1H-NMR (300 MHz, CDCl3):δ 1.22, 1.31-1.46, 1.52-1.65, 1.65-1.77, 1.77-1.97, 2.01-2.32, 2.37-2.65, 3.68-3.82, 3.82-3.92, 3.92-4.05, 4.39, 4.51, 4.91-5.08, 5.39-5.50, 5.57-5.75, 6.77-6.84, 6.89-6.99, 7.20。
TLC:Rf 0.29 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 1.20-1.25, 1.31-1.45, 1.51-1.65, 1.65-1.77, 1.77-1.98, 2.00-2.21, 2.21-2.30, 2.30-2.36, 2.38-2.61, 3.68-3.80, 3.81-3.91, 3.91-4.06, 4.32-4.45, 4.51, 4.92-5.07, 5.38-5.49, 5.57-5.74, 6.66-6.83, 7.16。
TLC:Rf 0.15 (ヘキサン:酢酸エチル=1:1);
1H-NMR (300 MHz, CDCl3):δ 1.18-1.46, 1.52-1.99, 2.00-2.30, 2.30-2.62, 2.77, 3.65-3.81, 3.81-4.08, 4.39, 4.46-4.59, 4.90-5.09, 5.42, 5.55-5.75, 6.85-7.03, 7.22-7.35。
実施例44(1)~実施例44(4)で製造した化合物を、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
実施例45(1):5-{(5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]-5,5a,6,7,8,8a-ヘキサヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ペンタン酸
1H-NMR (300 MHz, CDCl3):δ 1.31-1.48, 1.52-1.77, 1.77-1.98, 2.00-2.25, 2.34, 2.38-2.59, 3.67-3.81, 3.84-4.06, 4.38, 4.46-4.58, 5.43, 5.57-5.73 6.85-7.02, 7.21-7.35。
TLC:Rf 0.36 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.22-1.49, 1.53-1.76, 1.78-1.98, 1.98-2.28, 2.34, 2.38-2.57, 3.67-3.80, 3.84-3.93, 3.93-4.05, 4.32-4.44, 4.45-4.55, 5.44, 5.56-5.73, 6.77-6.84, 6.89-6.98, 7.20。
TLC:Rf 0.43 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.32-1.47, 1.49-1.65, 1.79-1.94, 2.01-2.13, 2.21-2.34, 2.34-2.54, 3.62-3.75, 3.83-4.08, 4.32-4.45, 5.44, 5.54-5.72, 6.66-6.78, 7.06-7.17。
TLC:Rf 0.57 (クロロホルム:メタノール:酢酸=10:1:0.1);
1H-NMR (300 MHz, CD3OD):δ 1.22-1.46, 1.50-1.67, 1.77-1.94, 1.98-2.13, 2.27, 2.36-2.55, 3.60-3.76, 3.85-4.08, 4.31-4.47, 5.38-5.48, 5.56-5.72, 6.86-6.97, 7.20-7.30。
実施例6で製造した化合物を用いて、実施例9→実施例12→実施例13→実施例14→実施例15→実施例16(1)と同様の目的の操作に付すことにより、下記の物性値を有する標題化合物を得た。
TLC:Rf 0.33 (ジクロロメタン:メタノール=20:1);
1H-NMR (300 MHz, CDCl3):δ 1.21-1.34, 1.37-1.89, 2.09-2.53, 2.57-2.67, 3.41, 3.66-4.06, 4.07-4.23, 4.45-4.56, 5.57-5.73, 6.87-7.05, 7.20-7.36。
実施例46で製造した化合物を用いて、実施例17(1)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 0.36 (ジクロロメタン:メタノール=10:1);
1H-NMR (300 MHz, CDCl3):δ 1.09-1.88, 2.08-2.23, 2.26-2.59, 2.85-3.55, 3.60-4.17, 4.45-4.60, 5.52-5.84, 6.84-7.03, 7.13-7.43。
実施例3で製造した化合物を用いて、2,3-ジブロモプロペンの代わりに相当するアルキルハライドを用いて、実施例4→実施例5→実施例6→実施例7→実施例8→実施例9→実施例12→実施例13→実施例14→実施例15→実施例16(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
実施例48(1):2-プロパニル 3-{(5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}プロパノアート(ジアステレオマー混合物)
TLC:Rf 0.47 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.23, 1.33-1.94, 2.01-2.60, 2.86-3.46, 3.66-4.09, 4.47-4.59, 4.92-5.07, 5.58-5.75, 6.86-7.02, 7.24-7.35。
TLC:Rf 0.19 (ヘキサン:酢酸エチル=1:2);
1H-NMR (300 MHz, CDCl3):δ 0.87-2.03, 2.03-2.33, 2.33-2.57, 2.89, 3.65-4.10, 4.46-4.59, 4.91-5.07, 5.57-5.74, 6.86-7.02, 7.19-7.34。
実施例48(1)~実施例48(2)で製造した化合物を、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
実施例49(1):3-{(5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}プロパン酸(ジアステレオマー混合物)
TLC:Rf 0.51 (クロロホルム:メタノール:水=10:1:0.1);
1H-NMR (300 MHz, CDCl3):δ 1.30-1.96, 2.06-2.55, 2.85-3.47, 3.57-4.10, 4.41-4.61, 5.55-5.74, 6.86-7.02, 7.22-7.37。
TLC:Rf 0.53 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.88-1.19, 1.20-1.52, 1.52-1.93, 2.05-2.19, 2.27-2.39, 2.40-2.54, 2.89, 3.64-3.77, 3.77-4.08, 4.44-4.57, 5.55-5.72, 6.85-7.03, 7.21-7.36。
アルゴン雰囲気下、実施例3で製造した化合物(74.1mg)のトルエン溶液(1mL)に、カルボニルクロロヒドリドトリス(トリフェニルホスフィン)ルテニウム(9.5mg)を加え、反応混合物を80℃で3時間半撹拌した。その後反応混合物を少量とって濃縮し、下記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=75:25)。
アルゴン雰囲気下、実施例50で製造した化合物(3.70g)をDMF(20mL)に溶解した。ブロモ酢酸t-ブチル(7.4mL)を加えた後、水素化ナトリウム(400mg、60% in oil)を30分から60分毎に4回(合計1600mg)加えた。室温で一晩撹拌した後、反応混合物に水を加え、酢酸エチルで抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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→75:25)で精製し、以下の物性値を有する標題化合物(3.5g)を得た。
TLC:Rf 0.50 (ヘキサン:酢酸エチル=80:20)。
実施例51で製造した化合物(3.37g)をTHF(10mL)に溶解し、5N水酸化ナトリウム水溶液(5mL)、メタノール(20mL)を加え、室温で2時間撹拌した。反応混合物に2N塩酸を加え、酢酸エチルで抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮して、カルボン酸(3.02g)を得た。カルボン酸(3.02g)をDMF(15mL)に溶解し、炭酸カリウム(1.60g)、アリルブロマイド(1.0mL)を加え、室温で一晩撹拌した。反応混合物に水を加え、ヘキサン/酢酸エチル(1/1)で抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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=97:3→80:20)で精製し、以下の物性値を有する標題化合物(2.93g)を得た。
TLC:Rf 0.50 (ヘキサン:酢酸エチル=80:20)。
実施例53(2):メチル (2S)-2-{[(1S,2R,3S,4R)-3-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-2-(1-プロペン-1-イル)-4-(テトラヒドロ-2H-ピラン-2-イルオキシ)シクロペンチル]オキシ}-4-ペンテノアート
アルゴン雰囲気下、ジイソプロピルアミン(2.0mL)をTHF(16mL)に溶解し、0℃に冷却した。1.66M n-ブチルリチウムヘキサン溶液(8.0mL)を滴下した後、同温度で30分撹拌した。-78℃に冷却し、トリメチルクロロシラン(2.0mL)を滴下した後、実施例52で製造した化合物(3.28g)のTHF(7mL)溶液を滴下した。-78℃で30分撹拌した後、室温まで昇温し、1時間撹拌した。反応混合液に水を加えて1時間撹拌した後、1N塩酸を加え、酢酸エチルで抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣を酢酸エチル(40mL)に溶解し、メタノール(4mL)、2.0M トリメチルシリルジアゾメタンヘキサン溶液(7mL)を加え、室温で1時間撹拌した。反応混合物を減圧下濃縮した後、残渣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=97:3→80:20)で精製し、以下の物性値を有する実施例化合物53(1)(1.26g)および実施例化合物53(2)(1.16g)を得た。
TLC:Rf 0.42 (ヘキサン:酢酸エチル=86:14)(実施例53(1)の化合物);
TLC:Rf 0.36 (ヘキサン:酢酸エチル=86:14)(実施例53(2)の化合物)。
実施例53(1)で製造した化合物(1.26g)をジクロロメタン(30mL)に溶解し、シュロック触媒(0.44g)を加え、室温で一晩撹拌した。反応混合物を減圧下濃縮した後、残渣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→75:25)で精製し、以下の物性値を有する標題化合物(0.95g)を得た。
TLC:Rf 0.48 (ヘキサン:酢酸エチル=75:25)。
水素化リチウムアルミニウム(84mg)をTHF(2mL)に懸濁し、0℃に冷却した後、実施例54で製造した化合物(0.95g)のTHF(3mL)溶液を滴下し、0℃で15分撹拌した。反応混合液に水を加えた後、酢酸エチル、1N塩酸を加えて抽出した抽出液を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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=60:40→40:60)で精製し、以下の物性値を有する標題化合物(793mg)を得た。
TLC:Rf 0.43 (ヘキサン:酢酸エチル=50:50)。
実施例55で製造した化合物(165mg)をDMSO(2mL)に溶解し、ウィティッヒ(Wittig)試薬(カルボイソプロポキシメチレントリフェニルホスホラン、218mg)、1-ヒドロキシ-1,2-ベンズヨードキソール-3(1H)-オン 1-オキサイド(IBX;1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide、168mg)を加え、50℃で5時間撹拌した。反応混合物に酢酸エチルと水を加え、不溶物をろ過した。ろ液を酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液、食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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=97:3→80:20)で精製し、以下の物性値を有する標題化合物(174mg)を得た。
TLC:Rf 0.50 (ヘキサン:酢酸エチル=80:20)。
実施例56で製造した化合物(174mg)を2-プロパノール(2mL)に溶解し、炭酸水素ナトリウム(20mg)、10%パラジウム-炭素(20mg)を加え,水素雰囲気下、室温で1時間撹拌した。反応混合物をセライト(商品名)でろ過したろ液を、減圧下濃縮し、残渣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=97:3→80:20)で精製し、以下の物性値を有する標題化合物(150mg)を得た。
TLC:Rf 0.50 (ヘキサン:酢酸エチル=80:20)。
実施例57で製造した化合物(143mg)に1mol/Lのテトラブチルアンモニウムフルオライド(THF溶液)を1mL加え、室温で一晩撹拌した。反応混合物を減圧下濃縮した後、残渣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=60:40→20:80)で精製し、以下の物性値を有する標題化合物(98mg)を得た。
TLC:Rf 0.32 (ヘキサン:酢酸エチル=50:50)。
TLC:Rf 0.32 (ヘキサン:酢酸エチル=1:3);
1H-NMR (300 MHz, CDCl3):δ 7.27-7.31, 6.89-6.99, 5.59-5.72, 4.93-5.05, 4.49-4.55, 4.21, 3.99, 3.88, 3.69-3.83, 2.55, 2.19-2.44, 1.45-1.88, 1.23。
実施例53(2)で製造した化合物を用いて、実施例54→実施例55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 0.58 (ヘキサン:酢酸エチル=50:50)。
実施例61:2-プロパニル 3-{(2S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-2-イル}プロパノアート
TLC:Rf 0.34 (ヘキサン:酢酸エチル=1:3);
1H-NMR (300 MHz, CDCl3):δ 7.27-7.32, 6.90-7.00, 5.59-5.72, 4.94-5.06, 4.49-4.55, 3.93-4.01, 3.88, 3.69-3.79, 3.17-3.25, 2.52, 2.27-2.46, 2.06-2.19, 1.65-1.84, 1.26-1.49, 1.23。
アルゴン雰囲気下、実施例55で製造した化合物(207mg)をジクロロメタン(2mL)に溶解し、0℃に冷却した。トリエチルアミン(0.14mL)、メタンスルホニルクロライド(0.040mL)を加え、0℃で15分撹拌した。反応混合物に水を加え、酢酸エチルで抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮して、以下の物性値を有する標題化合物(273mg)を得た。
TLC:Rf 0.40 (ヘキサン:酢酸エチル=67:33)。
実施例63:[(2R,5aR,6S,7R,8aS)-6-({[ジメチル(2-メチル-2-プロパニル)シリル]オキシ}メチル)-7-(テトラヒドロ-2H-ピラン-2-イルオキシ)-3,5a,6,7,8,8a-ヘキサヒドロ-2H-シクロペンタ[b]オキセピン-2-イル]アセトニトリル
実施例62で製造した化合物(273mg)をDMSO(1mL)に溶解し、シアン化ナトリウム(55mg)を加え、80℃で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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→70:30)で精製して、以下の物性値を有する標題化合物(205mg)を得た。
TLC:Rf 0.55 (ヘキサン:酢酸エチル=75:25)。
実施例63で製造した化合物(195mg)をトルエン(4mL)に溶解し、-15℃に冷却した。1M 水素化ジイソブチルアルミニウムのトルエン溶液(0.8mL)を加え、同温度で1時間30分撹拌した。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抽出液を1N塩酸、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をジクロロメタン(2mL)に溶解し、ホスホラン(250mg)を加え、室温で一晩撹拌した。反応混合物を減圧下濃縮した後、残渣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→75:25)で精製して、以下の物性値を有する標題化合物(39mg)を得た。
TLC:Rf 0.46 (ヘキサン:酢酸エチル=80:20)。
TLC:Rf 0.36 (ヘキサン:酢酸エチル=1:3);
1H-NMR (300 MHz, CDCl3):δ 7.26-7.31, 6.89-6.99, 5.60-5.72, 4.93-5.06, 4.50-4.55, 4.17-4.24, 3.99, 3.88, 3.70-3.82, 2.56-2.61, 2.21-2.34, 1.51-1.78, 1.26-1.37, 1.23。
TLC:Rf 0.42 (ヘキサン:酢酸エチル=1:3);
1H-NMR (300 MHz, CDCl3):δ 7.26-7.31, 6.89-6.99, 5.58-5.72, 4.93-5.05, 4.48-4.55, 3.97-4.03, 3.87, 3.69-3.77, 3.13-3.22, 2.52-2.59, 2.38-2.47, 2.23-2.29, 2.11-2.19, 1.28-1.84, 1.22。
実施例59、実施例61、実施例65および実施例66で製造した化合物を用いて、実施例17(1)と同様の目的の操作に付すことにより、以下に示す実施例化合物を得た。
実施例67(1):3-{(2R,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-2-イル}プロパン酸
1H-NMR (300 MHz, CDCl3):δ 7.24-7.30, 6.89-6.98, 5.54-5.70, 4.48, 4.19, 3.95, 3.69-3.85, 2.19-2.54, 1.47-1.93。
TLC:Rf 0.39 (クロロホルム:メタノール=5:1);
1H-NMR (300 MHz, CDCl3):δ 7.24-7.30, 6.88-6.98, 5.56-5.67, 4.45-4.52, 3.86-4.02, 3.67-3.76, 3.20-3.29, 2.33-2.52, 2.09-2.18, 1.63-1.86, 1.22-1.48。
TLC:Rf 0.37 (クロロホルム:メタノール=5:1);
1H-NMR (300 MHz, CD3OD):δ 7.21-7.26, 6.87-6.93, 5.56-5.69, 4.38-4.44, 4.21-4.29, 3.84-4.00, 3.65-3.77, 2.27-2.36, 2.07-2.17, 1.50-1.84, 1.28-1.40。
TLC:Rf 0.42 (クロロホルム:メタノール=5:1);
1H-NMR (300 MHz, CDCl3):δ 7.25-7.30, 6.88-6.98, 5.56-5.69, 4.46-4.53, 3.86-4.02, 3.67-3.75, 3.14-3.23, 2.40-2.49, 2.35, 2.09-2.18, 1.24-1.84。
TLC:Rf 0.24 (クロロホルム:メタノール=19:1);
1H-NMR (300 MHz, CD3OD):δ 0.96-1.22, 1.36-1.51, 1.51-1.72, 1.84-2.00, 2.15-2.31, 2.43-2.55, 2.99, 3.81, 3.96-4.10, 4.93, 6.37, 6.81-7.00, 7.19-7.29。
実施例17(25)で製造した化合物を用いて、実施例68と同様の目的の操作に付すことにより下記の実施例化合物を得た。
TLC:Rf 0.42 (ジクロロメタン:メタノール=10:1);
1H-NMR(CD3OD):δ 0.96-1.25, 1.36-1.75, 1.84-2.03, 2.15-2.33, 2.50, 2.99, 3.81, 3.96-4.11, 5.00, 6.37, 6.67, 6.79,6.91,7.11。
実施例10で製造した化合物(500mg)の塩化メチレン(2.3mL)溶液に、氷冷かつアルゴン雰囲気下にてトリエチルアミン(0.246mL)、4-フェニルベンゾイルクロリド(303mg)、ジメチルアミノピリジン(2mg)を加え室温にて6時間撹拌した。さらに、トリエチルアミン(0.123mL)、4-フェニルベンゾイルクロリド(151mg)を追加し、室温にて終夜撹拌した。反応終了後、酢酸エチルにて希釈、水を加え、酢酸エチルにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水、飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥後、溶媒を減圧留去し、析出した結晶をMTBEにて除去後、ろ液を減圧濃縮した。得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size L、ヘキサン:酢酸エチル=100:0→9:1→4:1→3:2)にて精製し、以下の物性値を有する標題化合物(641mg)を得た。
TLC:Rf 0.64(ヘキサン:酢酸エチル=3:1)。
実施例69で製造した化合物(640mg)のTHF(0.5mL)溶液に、室温にてテトラブチルアンモニウムフルオリドの1M THF溶液(2.1mL)を加えて、2時間撹拌した。反応終了後、酢酸エチルにて希釈、氷冷した飽和塩化アンモニウム水溶液にて反応を停止した。酢酸エチルにて抽出、有機層を水、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥後、溶媒を減圧濃縮した。得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size L、ヘキサン:酢酸エチル=85:15→7:3→1:1→3:7)にて精製し、以下の物性値を有する標題化合物(214mg)を得た。
TLC:Rf 0.30(ヘキサン:酢酸エチル=2:1)。
実施例70で製造した化合物を用いて、実施例13→実施例14→実施例15→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 0.58 (ヘキサン:酢酸エチル=2:1)。
実施例71で製造した化合物(950mg)の2-プロパノール(5mL)溶液に、リチウムイソプロポキシド(2.0M THF溶液、2.3mL)を加え、反応混合物を50℃で5時間撹拌した。反応混合物を0℃に冷却し、同じく0℃に冷却した水-酢酸エチル混合液に注ぎ、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。得られた残渣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→酢酸エチルのみ)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(530mg)を得た。
TLC:Rf 0.26 (ヘキサン:酢酸エチル=1:1)。
実施例72で製造した化合物(29mg)のTHF(0.3mL)溶液に、-15℃でトリフェニルホスフィン(27mg)、ギ酸(4μL)およびアゾジカルボン酸ジエチルのトルエン溶液(47μL、2.2mol/L)を加え、反応混合物を0℃で1.5時間撹拌した。さらに0℃でトリフェニルホスフィン(27mg)、ギ酸(4μL)およびアゾジカルボン酸ジエチルのトルエン溶液(47μL、2.2mol/L)を加え、反応混合物を室温で2時間撹拌した。反応混合物に飽和重層水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣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=8:2→5:5)に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(10mg)を得た。
TLC:Rf 0.32(ヘキサン:酢酸エチル=2:3)。
実施例73で製造した化合物(10mg)の2-プロパノール(0.35mL)溶液に、0℃で炭酸カリウム(3mg)を加え、反応混合物を40℃で1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。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(8mg)を得た。
TLC:Rf 0.39(ヘキサン:酢酸エチル=1:1)。
実施例74で製造した化合物を用いて、実施例16(1)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 0.47(ヘキサン:酢酸エチル=1:4);
1H-NMR (300 MHz, CDCl3):δ 7.00,6.71,6.60,5.90,5.63,4.99,4.56,4.28,4.18,4.08-3.88,2.97,2.78,2.15-2.00,1.95-0.95。
実施例75で製造した化合物を用いて、実施例17(1)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 0.28 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 7.08-6.90, 6.78-6.52, 5.90, 5.63, 4.57, 4.29,4.22-3.85, 2.97, 2.40-2.20, 2.13, 1.98-1.80, 1.80-1.50, 1.45-0.95。
実施例3で製造した化合物を用いて、実施例73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 0.59 (ヘキサン:酢酸エチル=2:1)。+
実施例77で製造した化合物を用いて、実施例4→実施例5→実施例6→実施例7→実施例8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 0.39 (ヘキサン:酢酸エチル=4:1)。
実施例78で製造した化合物を用いて、実施例12→実施例13→実施例14→実施例15→実施例16(1)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 0.52 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.19-1.33, 1.43-1.58, 1.65-1.79, 1.86-2.16, 2.16-2.34, 2.59, 3.77, 3.92, 3.97-4.19, 4.51-4.62, 5.01, 5.58-5.82,6.89-7.04, 7.25-7.36。
実施例79で製造した化合物を用いて、実施例17(1)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 0.64 (ジクロロメタン:メタノール=7:1);
1H-NMR (300 MHz, CD3OD):δ 1.25-1.49, 1.57-1.76, 1.87-2.12, 2.18-2.34, 3.77, 3.89-4.19, 4.44, 5.57-5.77, 6.84-7.01, 7.21-7.33。
実施例78で製造した化合物を用いて、実施例9→実施例10→実施例11→実施例12→実施例13→実施例14→実施例15→実施例16(1)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 0.46 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.97-2.14, 2.18-2.34, 2.53-2.63, 3.23, 3.44, 3.71-4.18, 4.49-4.61, 4.93-5.09, 5.58-5.82, 6.88-7.04, 7.24-7.36。
実施例78で製造した化合物を用いて、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用いて、実施例81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 0.52 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 1.00-1.91, 1.91-2.13, 2.22-2.33, 2.59-2.68, 3.23, 3.44, 3.73-4.19, 4.52-4.63, 4.95-5.07,5.56-5.83, 6.57-6.68, 6.68-6.78, 6.97-7.10。
実施例81または実施例81(1)で製造した化合物を用いて、実施例17(1)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。
TLC:Rf 0.53 (ジクロロメタン:メタノール=7:1);
1H-NMR (300 MHz, CD3OD):δ 0.99-2.04, 2.21-2.33, 3.20-3.46, 3.73-4.03, 4.43, 5.56-5.77, 6.86-5.77, 6.86-6.95, 7.20-7.30。
TLC:Rf 0.47 (ジクロロメタン:メタノール=7:1);
1H-NMR (300 MHz, CD3OD):δ 1.00-2.06, 2.22-2.33, 3.20-3.47, 3.74-3.86, 3.88-4.02, 4.45, 5.54-5.79, 6.57-6.68, 6.86-6.96,7.01-7.13。
実施例30で製造した化合物を用いて、実施例18→実施例19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 0.51 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 7.35-7.29, 7.02, 6.95-6.91, 4.13, 4.04, 3.97, 3.74, 2.93, 2.34, 2.28-2.03, 1.95-1.51, 1.22-1.00。
実施例23で製造した化合物(40.7g)の塩化メチレン(300mL)溶液に、氷冷下トリエチルアミン(27.36mL)、メシル酸クロリド(7.98mL)を順に加え1時間撹拌した。氷水(300mL)中に反応液を注ぎ、酢酸エチルにて抽出した。水(100mL)、飽和食塩水(100mL)にて洗浄した後、無水硫酸ナトリウムにて乾燥した。溶媒を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(50.2g)を得た。
TLC:Rf 0.71, 0.63(塩化メチレン:酢酸エチル=2:1)。
実施例84で製造した化合物(50.2g)のDMSO(250mL)溶液に、室温にてシアン化ナトリウム(8.18g)を加えて70℃にて終夜撹拌した。氷水(750mL)中に反応液を注ぎ酢酸エチルにて抽出した。有機層を水(200mL)、飽和食塩水(200mL)にて洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧濃縮し、得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size 5Lx2、ヘキサン:酢酸エチル=90:10→2:1→1:1)にて精製し、以下の物性値を有する標題化合物(36.4g)を得た。
TLC:Rf 0.42(ヘキサン:酢酸エチル=2:1)。
アルゴン雰囲気下、実施例85で製造した化合物(29.4g)のトルエン(350mL)溶液を-18℃に冷却し、DIBALの1Mトルエン溶液(103mL)を40分かけて滴下した。反応液をMTBE(300mL)にて希釈し、氷冷下にて飽和酒石酸ナトリウム水溶液(50mL)を加えてしばらく撹拌した後、氷冷した塩酸(1N、300mL)を加え、酢酸エチルにて抽出した。有機層を飽和塩化アンモニウム水溶液、水、飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。溶媒を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(31.3g)を得た。
TLC:Rf 0.45(ヘキサン:酢酸エチル=3:1)。
実施例86で製造した化合物(38.0g)の塩化メチレン(422mL)溶液に、室温にてイソプロピル(トリフェニルホスホラニリデン)アセテート(45.93g)を加えて室温にて終夜撹拌した。反応終了後、溶液を減圧濃縮した後、ジエチルエーテル-ヘキサン(1:1、200mL)を加えた。グラスフィルターにて析出物を除去、ろ液を減圧濃縮した。得られた残渣を山善社製分取クロマトグラフ(Hiflash-SI、Size 5Lx2、ヘキサン:酢酸エチル=100:0→4:1→7:3)にて精製し、以下の物性値を有する標題化合物(36.0g)を得た。
TLC:Rf 0.56, 0.49(ヘキサン:酢酸エチル=4:1)。
実施例87で製造した化合物を用いて、実施例12→実施例13→実施例14→実施例15→実施例16(1)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 0.46 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.12, 1.25-1.33, 1.41-1.54, 1.63-2.18, 2.45-2.54, 2.69, 2.92-2.30, 3.69-3.78, 3.87-4.23, 4.52-4.55, 5.61-5.74, 5.77-5.83, 6.84-7.01, 7.24-7.33。
実施例88で製造した化合物を用いて、実施例17(1)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 0.31 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 1.00-1.51, 1.68-2.14, 2.45-2.54, 2.93-3.00, 3.69-3.77, 3.87-4.07, 4.52-4.54, 5.65-5.67, 5.79-5.84, 6.91-7.04, 7.27-7.32。
実施例72で製造した化合物(100mg)を用いて、実施例30→実施例31→実施例32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(4mg)を得た。
1H-NMR (300 MHz, CDCl3):δ 0.85-2.62, 2.96-3.04, 3.92-4.09, 4.24-4.31, 4.55-4.61, 4.84-4.86, 5.02-5.04, 5.60-5.67, 5.85-5.93, 6.58-6.66, 6.70-6.76, 6.99-7.08。
実施例17(25)で製造した化合物(50mg)のDMF(0.3mL)溶液に、ヨウ化エチル(21mg)および炭酸カリウム(19mg)を加え、反応混合物を50℃で30分間撹拌した。反応混合物を水に注ぎ、MTBEで抽出した。一方で水層を1N塩酸で酸性にし(pH=4)、酢酸エチルで抽出、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、減圧濃縮することで,未反応原料(15mg)を回収した。回収した原料に対し、上記試薬により再度反応を試み(ヨウ化エチル12mg、炭酸カリウム6mg)、50℃で1時間撹拌した後、反応混合物を水に注ぎ、MTBE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、得られた残渣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→0:100)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(21mg)を得た。
TLC:Rf 0.53 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.30, 1.40-1.95, 2.09-2.31, 2.45-2.54, 2.71-2.73, 2.89-2.97, 3.70-3.79, 3.90-4.17, 4.53-4.60, 5.59-5.74, 6.58-6.66, 6.69-6.76, 6.99-7.08。
実施例17(25)で製造した化合物を用いて、ヨウ化エチルの代わりに3-ブロモ-1-プロパノールを用いて、実施例91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 0.38 (ジクロロメタン:アセトン=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.20, 1.40-1.94, 2.08-2.17, 2.28-2.33, 2.45-2.54, 2.89-2.96, 3.67-3.80, 3.91-4.07, 4.22-4.26, 4.52-4.58, 5.59-5.74, 6.58-6.66, 6.69-6.75, 6.99-7.07。
実施例91で製造した化合物(25mg)のTHF(1.4mL)溶液に、0℃にて水素化アルミニウムリチウム(6mg)を加え、反応混合物をそのまま1時間撹拌した。反応混合物に飽和硫酸ナトリウム水溶液を加え、混合物をセライト(商品名)ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル→ジクロロメタン:メタノール=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(22mg)を得た。
TLC:Rf 0.24 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.95, 2.01-2.18, 2.45-2.54, 2.62-2.64, 2.89-2.97, 3.62-3.80, 3.90-4.09, 4.54-4.61, 5.60-5.75, 6.58-6.66, 6.69-6.76, 6.99-7.08。
実施例17(25)で製造した化合物(10mg)のTHF(0.2mL)溶液に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(7mg)、及びエチルアミン水溶液(12M、19μL)を加え,反応混合物を室温で6時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出、有機層を1N塩酸、飽和重曹水、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,残渣を得た。得られた残渣を、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=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(10mg)を得た。
TLC:Rf 0.44 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CD3OD):δ 0.85-1.20, 1.30-1.92, 1.97-2.06, 2.11-2.16, 2.39-2.48, 2.92-3.01, 3.14-3.23, 3.62-3.71, 3.96-4.03, 4.41-4.47, 5.58-5.71, 6.59-6.67, 6.88-6.95, 7.03-7.12, 7.94。
3-(3-ピリジル)プロパノール(1.5g)の酢酸エチル(30mL)溶液にジメチルスルホキシド(15mL)、トリエチルアミン(9mL)を加え、0℃にて撹拌しながら、ピリジンサルファートリオキシドコンプレックス(5.2g)を加えてそのまま2時間撹拌した。反応混合物を減圧濃縮し、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=30:70→0:100)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(1.1g)を得た。
TLC:Rf 0.23 (ヘキサン:酢酸エチル=1:2)。
実施例70で製造した化合物(0.85g)のTHF(10mL)溶液に、塩化クロム(1.7g)を加え0℃にて撹拌しながら、ヨードホルム(1.4g)のTHF(7mL)溶液を加え、そのまま4時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出、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。得られた残渣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→75:25)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。
TLC:Rf 0.47 (ヘキサン:酢酸エチル=3:1)。
実地例95で製造した化合物(590mg)および実施例94で製造した化合物(258mg)のTHF(10mL)溶液に、塩化クロム(470mg)、塩化ニッケル(2.5mg)を加え室温にて終夜撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。水層、有機層ともにそれぞれ飽和重曹水を加えて撹拌し、両者を合わせてセライト(商品名)ろ過したのち再度分液し、得られた有機層を硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残渣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=30:70→0:100)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(210mg)を得た。
TLC:Rf 0.38 (酢酸エチル)。
実地例96で製造した化合物(210mg)の2-プロパノール(0.4mL)溶液に、リチウムイソプロポキシド(2.0M THF溶液、0.33mL)を加え、反応混合物を50℃で4時間撹拌した。反応混合物を0℃に冷却し、同じく0℃に冷却した水-酢酸エチル混合液に注ぎ、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。得られた残渣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=100:0→90:10)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(108mg)を得た。
TLC:Rf 0.53 (ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.93-1.29, 1.39-1.93, 2.04-2.14, 2.22-2.27, 2.42-2.52, 2.63-2.82, 2.88-2.96, 3.65-3.75, 3.92-4.14, 4.94-5.06, 5.42-5.67, 7.20-7.24, 7.52-7.54, 8.44-8.46。
実施例97で製造した化合物を用いて、実施例17(1)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 0.64 (ジクロロメタン:メタノール=4:1);
1H-NMR(300 MHz, CD3OD):δ 0.97-2.04, 2.24-2.29, 2.37-2.47, 2.70-2.77, 2.94-3.02, 3.58-3.68, 3.96-4.05, 5.42-5.60, 7.33-7.38, 7.71-7.74, 8.33-8.40。
3-フェノキシプロピルブロミド(1.53g)をアセトン(9mL)に溶解し、1-フェニル-5-メルカプト-1H-テトラゾール(1.27g)、炭酸カリウム(985mg)を加え、室温で3時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した抽出液を水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮し、以下の物性値を有する標題化合物(2.23g)を得た。
TLC:Rf 0.62 (ヘキサン:酢酸エチル=67:33)。
実施例99で製造した化合物(2.23g)をジクロロメタン(10mL)に溶解し、m-クロロ過安息香酸(4.5g)を加え、室温で一晩攪拌した。反応溶液に5%亜硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した抽出液を飽和重曹水、水、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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=85:15→65:35)で精製して、以下の物性値を有する標題化合物(1.78g)を得た。
TLC:Rf 0.59 (ヘキサン:酢酸エチル=67:33)。
アルゴン雰囲気下、実施例100で製造した化合物(165mg)を、DME(2mL)に溶解し、-78℃に冷却した後、0.5Mカリウムヘキサメチルジシラザン/トルエン溶液(0.90mL)を加えた。-78℃で20分攪拌した後、実施例13で製造した化合物のDME(1.5mL)溶液を滴加し、同温度で10分攪拌した。反応溶液を0℃に昇温した後、水を加え、酢酸エチルで抽出した抽出液を水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣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→65:35)で精製して、以下の物性値を有する標題化合物(177mg)を得た。
TLC:Rf 0.58 (ヘキサン:酢酸エチル=67:33)。
実施例101で製造した化合物を用いて、実施例16(1)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 0.52 (ヘキサン:酢酸エチル=33:67);
1H-NMR (300 MHz, CDCl3):δ 7.32-7.25, 6.97-6.88, 5.62, 5.37, 5.01, 4.08-3.93, 3.68, 2.92, 2.57-2.43, 2.25, 2.06, 1.91, 1.82-1.40, 1.24, 1.18-0.93。
実施例102で製造した化合物を用いて、実施例17(1)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 0.69 (酢酸エチル:メタノール=9:1);
1H-NMR (300 MHz, DMSO-d6):δ 11.98, 7.27, 6.93-6.88, 5.51-5.32, 4.61, 3.99-3.93, 3.90-3.81, 3.47, 2.84, 2.42, 2.26, 2.15, 1.87-1.74, 1.65-1.20, 1.10-0.86。
内温-8℃に冷却した酢酸(25mL)に、内温0℃以下を維持しながら、発煙硝酸(1.5mL)を滴加した。混合液を10分撹拌した後、内温0℃以下を維持しながら、4-アミノ-1-ブタノール(3.1mL)を滴加した。10分撹拌した後に、水浴にて室温に昇温した。10分撹拌した後に、ジエチルエーテル(100mL)を加え、減圧濃縮した。得られた濃縮物にジエチルエーテル(100mL)を加え、撹拌した後、上清を除去した。得られた残渣を、減圧濃縮し、以下の物性値を有する標題化合物(6.31g)を得た。
1H-NMR (300 MHz, DMSO-d6):δ 1.44-1,82, 2.68-2.93, 4.53, 7.20-8.15。
実施例104で製造した化合物(68mg)のDMF溶液(1mL)に、実施例17(25)で製造した化合物(50mg)と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(87mg)とトリエチルアミン(95μL)を室温で順次加えた。終夜撹拌した後に、溶液を酢酸エチルで希釈し、1N塩酸水溶液で2回、水で1回、飽和食塩水で1回洗浄した。無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた粗精製物を、カラム装置(Hi-Flash M、酢酸エチル→酢酸エチル:メタノール=7:3)で精製した。さらにプレパラティブTLC(トルエン:アセトン=1:1)およびプレパラティブTLC(酢酸エチル:メタノール=5:1)で精製し、以下の物性値を有する標題化合物(7.5mg)を得た。
TLC:Rf 0.72 (酢酸エチル:メタノール=7:1);
1H-NMR (300 MHz, CDCl3):δ 0.83-1.54, 1.54-1.97, 1.97-2.43, 2.49, 2.71-3.01, 3.30, 3.74, 3.89-4.10, 4.48,4.52-4.60,5.42-5.55, 5.58-5.75, 6.62,6.72, 7.03。
実施例7で製造した化合物を用い、ヨウ化イソプロピルまたはその代わりにヨウ化メチルを用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートまたはその代わりに相当するホスホン酸塩を用い、(S)-2-メチル-CBS-オキサザボロリジンまたはその代わりに(R)-2-メチル-CBS-オキサザボロリジンを用いて、実施例8→実施例9→実施例10(1)→実施例11→実施例12→実施例13→実施例14→実施例15→実施例16(1)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。
TLC:Rf 0.21(酢酸エチル:ヘキサン=2:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.40-1.95, 2.12, 2.23, 2.45, 2.60, 2.91, 3.72, 3.86, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.90, 6.96, 7.28。
TLC:Rf 0.53(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.21, 1.40-1.93, 2.09, 2.29, 2.47, 2.64-2.81, 2.92, 3.67, 3.70, 3.96, 4.05, 4.14, 5.48, 5.63, 7.17-7.22, 7.28-7.32。
TLC:Rf 0.46(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.37-1.95, 2.05, 2.28, 2.45, 2.61-2.80, 2.90, 3.66, 3.69, 3.90-4.18, 5.46, 5.61, 6.81-7.00, 7.22。
TLC:Rf 0.31(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.58, 6.81-7.00, 7.22。
TLC:Rf 0.46(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.46, 5.61, 6.91-7.00, 7.10-7.18。
TLC:Rf 0.30(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.58-2.78, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.60, 6.91-7.00, 7.10-7.18。
TLC:Rf 0.57(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.17, 1.39-1.92, 2.03-2.12, 2.26-2.30, 2.41-2.50, 2.65-2.81, 2.87-2.95, 3.66-3.71, 3.92-4.15, 5.44-5.52, 5.59-5.66, 6.97-7.07, 7.14-7.24。
TLC:Rf 0.42(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.19, 1.38-1.92, 2.04-2.12, 2.25-2.30, 2.42-2.51, 2.64-2.80, 2.87-2.95, 3.66-3.74, 3.92-4.14, 5.43-5.51, 5.58-5.65, 6.97-7.08, 7.14-7.24。
TLC:Rf 0.46(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.60-2.80, 2.90, 3.66, 3.69, 3.90-4.15, 5.46, 5.61, 7.05, 7.11-7.22。
TLC:Rf 0.32(酢酸エチル:ヘキサン=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.20, 1.39-1.95, 2.07, 2.28, 2.46, 2.58-2.78, 2.90, 3.66, 3.69, 3.90-4.15, 5.44, 5.60, 7.05, 7.11-7.22。
TLC:Rf 0.54(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.18, 1.39-1.89, 2.05-2.13, 2.26-2.31, 2.42-2.51, 2.69-2.95, 3.66-3.72, 3.90-4.12, 5.44-5.52, 5.59-5.66, 7.37-7.45。
TLC:Rf 0.41 (酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.93-1.20, 1.43-1.96, 2.05-2.13, 2.25-2.30, 2.43-2.51, 2.68-2.95, 3.66-3.74, 3.90-4.10, 5.42-5.50, 5.58-5.65, 7.38-7.45。
TLC:Rf 0.25(酢酸エチル:ヘキサン=2:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.36, 2.49, 2.91, 3.72, 3.80-4.10, 4.55, 4.99, 5.60-5.78, 7.08, 7.14, 7.22, 7.39。
TLC:Rf 0.25(酢酸エチル:ヘキサン=2:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.40-2.53, 2.91, 3.72, 3.80-4.10, 4.55, 4.99, 5.58-5.75, 6.88-7.12。
TLC:Rf 0.25(酢酸エチル:ヘキサン=2:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.45, 2.91, 3.72, 3.85, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.60-6.72, 7.21。
TLC:Rf 0.25(酢酸エチル:ヘキサン=2:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.40-1.95, 2.16, 2.24, 2.45, 2.49, 2.91, 3.72, 3.82, 3.90-4.10, 4.55, 4.99, 5.58-5.75, 6.80-6.88, 6.97。
TLC:Rf 0.37(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.85-1.30, 1.38-1.78, 1.86-1.93, 2.02-2.14, 2.26-2.31, 2.42-2.51, 2.87-2.95, 3.66-3.73, 3.90-4.07, 5.38-5.46, 5.53-5.60。
実施例106(1)~実施例106(17)で製造した化合物を、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
実施例107(1):4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
TLC:Rf 0.17(酢酸エチル:ヘキサン=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.98, 2.16, 2.33, 2.46, 2.92, 3.74, 3.86, 3.90-4.08, 4.55, 5.58-5.75, 6.90, 6.93, 7.28。
TLC:Rf 0.44(酢酸エチル:酢酸=100:1);
1H-NMR (300 MHz, CDCl3):δ 0.89-1.22, 1.39-1.93, 2.08, 2.32, 2.47, 2.63-2.81, 2.92, 3.70, 3.96, 4.05, 4.14, 5.48, 5.63, 7.17-7.22, 7.28-7.32。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.95, 2.16, 2.32, 2.48, 2.61-2.80, 2.91, 3.71, 3.95, 4.00-4.17, 5.47, 5.62, 6.83-7.00, 7.21。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.38-1.95, 2.16, 2.32, 2.48, 2.60-2.80, 2.91, 3.71, 3.95, 4.00-4.17, 5.43, 5.58, 6.83-7.00, 7.21。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.95, 2.16, 2.32, 2.48, 2.60-2.80, 2.91, 3.71, 3.95, 4.00-4.17, 5.46, 5.62, 6.90-7.00, 7.10-7.20。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.38-1.95, 2.16, 2.32, 2.48, 2.60-2.80, 2.91, 3.71, 3.95, 4.00-4.17, 5.42, 5.58, 6.90-7.00, 7.10-7.20。
TLC:Rf 0.23(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.20, 1.39-1.92, 2.04-2.13, 2.30-2.35, 2.41-2.50, 2.64-2.82, 2.87-2.95, 3.65-3.73, 3.92-4.08, 5.43-5.52, 5.59-5.66, 6.97-7.07, 7.13-7.23。
TLC:Rf 0.25(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.20, 1.40-1.92, 2.04-2.12, 2.25-2.30, 2.42-2.51, 2.63-2.80, 2.87-2.95, 3.66-3.74, 3.92-4.14, 5.42-5.50, 5.57-5.64, 6.97-7.07, 7.13-7.24。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.20, 1.38-1.95, 2.08, 2.33, 2.46, 2.60-2.80, 2.91, 3.69, 3.92-4.18, 5.47, 5.62, 7.07, 7.11-7.22。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.20, 1.38-1.98, 2.06, 2.32, 2.47, 2.58-2.78, 2.91, 3.68, 3.92-4.18, 5.43, 5.58, 7.07, 7.11-7.22。
TLC:Rf 0.39(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.21, 1.39-1.92, 2.04-2.14, 2.30-2.35, 2.42-2.51, 2.69-2.95, 3.66-3.74, 3.92-4.12, 5.44-5.52, 5.59-5.66, 7.37-7.44。
TLC:Rf 0.21(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.20, 1.39-1.91, 2.04-2.13, 2.30-2.35, 2.43-2.51, 2.67-2.85, 2.87-2.95, 3.66-3.74, 3.92-4.12, 5.41-5.49, 5.57-5.64, 7.37-7.44。
TLC:Rf 0.48(ジクロロメタン:メタノール:水=60:10:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.98, 2.16, 2.33, 2.46, 2.92, 3.75, 3.88-4.10, 4.55, 5.60-5.78, 7.08, 7.14, 7.22, 7.39。
TLC:Rf 0.48(ジクロロメタン:メタノール:水=60:10:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.98, 2.16, 2.32, 2.46, 2.91, 3.72, 3.88-4.10, 4.54, 5.60-5.78, 6.88-7.10。
TLC:Rf 0.48(ジクロロメタン:メタノール:水=60:10:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.98, 2.11, 2.33, 2.46, 2.92, 3.72, 3.85, 3.90-4.10, 4.52, 5.58-5.78, 6.58-6.70, 7.20。
TLC:Rf 0.48(ジクロロメタン:メタノール:水=60:10:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.40-1.98, 2.12, 2.33, 2.46, 2.92, 3.72, 3.82, 3.90-4.10, 4.52, 5.58-5.78, 6.80-6.88, 6.97。
TLC:Rf 0.34(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.85-1.30, 1.38-1.77, 1.86-1.93, 2.02-2.11, 2.30-2.35, 2.42-2.51, 2.87-2.95, 3.65-3.73, 3.91-4.06, 5.38-5.46, 5.52-5.59。
実施例107(1)~実施例107(12)または実施例17(15)で製造した化合物を、実施例18(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
TLC:Rf 0.44(酢酸エチル:酢酸=100:1);
1H-NMR (300 MHz, CDCl3):δ 1.00-1.22, 1.45-1.94, 2.22-2.37, 2.94, 3.75, 3.85, 3.94-4.07, 6.90-7.00, 7.30-7.32。
TLC:Rf 0.40(酢酸エチル:酢酸=100:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.22, 1.30-1.94, 2.24, 2.34, 2.63-2.85, 2.93, 3.64, 3.72, 3.95, 4.03, 7.17-7.22, 7.28-7.32。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.35-1.95, 2.21, 2.31, 2.68, 2.77, 2.90, 3.62, 3.70, 3.92, 4.00, 6.82-7.00, 7.24。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.35-1.95, 2.21, 2.31, 2.68, 2.77, 2.91, 3.62, 3.70, 3.92, 4.00, 6.82-7.00, 7.24。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.30-1.95, 2.21, 2.32, 2.68, 2.77, 2.91, 3.62, 3.70, 3.92, 4.00, 6.90-7.00, 7.10-7.18。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.30-1.95, 2.21, 2.32, 2.68, 2.77, 2.91, 3.61, 3.70, 3.93, 4.00, 6.90-7.00, 7.10-7.18。
TLC:Rf 0.45(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.96-1.20, 1.37-1.92, 2.18-2.26, 2.30-2.35, 2.66-2.85, 2.87-2.95, 3.57-3.62, 3.67-3.73, 3.90-4.04, 6.97-7.07, 7.13-7.21。
TLC:Rf 0.32(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.97-1.20, 1.25-1.92, 2.16-2.25, 2.30-2.35, 2.66-2.86, 2.87-2.95, 3.57-3.65, 3.68-3.73, 3.90-4.04, 6.97-7.07, 7.13-7.21。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.32-1.95, 2.22, 2.33, 2.67, 2.78, 2.91, 3.61, 3.69, 3.93, 4.00, 7.07, 7.11-7.22。
TLC:Rf 0.42(ジクロロメタン:メタノール=6:1);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.32-1.95, 2.22, 2.33, 2.67, 2.78, 2.91, 3.61, 3.70, 3.93, 4.00, 7.07, 7.11-7.22。
TLC:Rf 0.43(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.16, 1.37-1.92, 2.20-2.33, 2.66-2.76, 2.81-2.94, 3.58-3.73, 3.89-4.03, 7.35-7.44。
TLC:Rf 0.41(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.97-1.20, 1.32-1.92, 2.17-2.25, 2.30-2.35, 2.67-2.77, 2.81-2.95, 3.58-3.73, 3.90-4.03, 7.36-7.44。
1H-NMR (300 MHz, CDCl3):δ 1.00-1.20, 1.45-1.95, 2.25, 2.34, 2.93, 3.76, 3.86-4.08, 7.09, 7.15, 7.24, 7.41。
実施例12で製造した化合物(150mg)およびシンナミルブロミド(220mg)のDMF(1.5mL)溶液に、0℃にて水素化ナトリウム(17mg)を加え、室温で終夜撹拌した。反応混合物を、MTBEで希釈し、飽和塩化アンモニウム水溶液、水、飽和食塩水で洗浄した後、硫酸マグネシウムにて乾燥し、ろ過、減圧濃縮した。残渣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=97:3→34:66)で精製し、以下の物性値を有する標題化合物(39mg)を得た。
TLC:Rf 0.42(ヘキサン:酢酸エチル=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.91-1.16, 1.21-1.29, 1.51-1.76, 1.82-1.91, 2.20-2.25, 2.32-2.41, 2.86-2.94, 3.36-3.42, 3.61-3.66, 3.82-3.90, 3.92-4.02, 4.13-4.16, 4.94-5.03, 6.20-6.30, 6.55-6.60, 7.21-7.39。
TLC:Rf 0.53(ジクロロメタン:メタノール=9:1)。
1H-NMR (300 MHz, CDCl3):δ 0.92-1.17, 1.51-1.76, 1.82-1.92, 2.26-2.42, 2.87-2.94, 3.36-3.42, 3.61-3.65, 3.82-4.04, 4.09-4.18, 6.20-6.30, 6.55-6.60, 7.21-7.39。
メチルトリフェニルホスホニウムブロミド(2.60g)をTHF(10mL)に懸濁し、0℃に冷却した。ナトリウムヘキサメチルジシラザン(7.0mL、1mol/LのTHF溶液)を加え、同温度で30分攪拌した。実施例13で製造した化合物(1.0g)のTHF(1mL)溶液を滴加し、同温度で1時間攪拌した。反応溶液を0℃に冷却した1N塩酸に注ぎ、酢酸エチルで抽出した抽出液を水、飽和重曹水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製して、以下の物性値を有する標題化合物(967mg)を得た。
TLC:Rf 0.67(ヘキサン:酢酸エチル=2:1)。
-30℃以下に冷却したボランテトラヒドロフラン錯体(0.44mL)に、2-メチル-2-ブテン(110μL)を加え0℃にて2時間半撹拌した。実施例111で製造した化合物(170mg)のTHF溶液(1mL)を加え、室温で終夜撹拌した。再び0℃に冷却し、5N水酸化ナトリウム水溶液(260μL)及び30%過酸化水素水(260μL)を加えて1時間撹拌した。反応混合物を、MTBEにて希釈し、飽和塩化アンモニウム水溶液、亜硫酸ナトリウム水溶液、水、飽和食塩水で洗浄した後、硫酸マグネシウムにて乾燥し、ろ過、減圧濃縮した。残渣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=97:3→35:65)で精製し、以下の物性値を有する標題化合物(58mg)を得た。
TLC:Rf 0.61(ヘキサン:酢酸エチル=1:3)。
実施例112で製造した化合物(29mg)及び2-ジアゾアセトフェノン(14mg)のトルエン(0.5mL)溶液に、室温下インジウムトリフラート(4mg)を加え5時間撹拌した。飽和重層水を加えて反応を停止し、反応液をMTBEで抽出した。有機層を水、飽和食塩水で洗浄した後、硫酸マグネシウムにて乾燥し、ろ過、減圧濃縮した。残渣をメタノール(1mL)に溶解させ、トシル酸水和物を加え室温下撹拌した。反応混合物を濃縮して残渣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→35:65)で精製し、以下の物性値を有する標題化合物(3mg)を得た。
TLC:Rf 0.27(ヘキサン:酢酸エチル=1:1)。
実施例113で製造した化合物(2.5mg)の酢酸エチル(0.25mL)溶液に、5%パラジウム炭素(1.0mg)を加え、水素雰囲気下室温で3日間撹拌した。反応混合物をセライト(商品名)ろ過した後、減圧濃縮し、残渣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)で精製し、以下の物性値を有する標題化合物(1mg)を得た。
TLC:Rf 0.48(ヘキサン:酢酸エチル=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.86-1.28, 1.40-1.72, 1.87-1.91, 2.20-2.26, 2.36-2.44, 2.87-2.94, 3.48-3.70, 3.90-4.03, 4.37, 4.95-5.03, 7.18-7.32。
TLC:Rf 0.44(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.83-1.72, 1.88-1.95, 2.30-2.45, 2.87-2.94, 3.48-3.70, 3.90-4.03, 4.40, 7.18-7.28。
実施例13で製造した化合物(180mg)のメタノール溶液(2.3mL)に、炭酸カリウム(94mg)及びベストマン試薬(Bestmann Reagent:ジメチル-1-ジアゾ-2-オキソプロピルホスフォネート、105mg)を加え、室温にて6時間半撹拌した。更に炭酸カリウム(47mg)及びベストマン試薬(53mg)を追加し室温にて終夜撹拌した。反応混合物を0℃に冷却し、酢酸エチルで希釈した後、水を加え分液した。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、ろ過,減圧濃縮し、残渣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=97:3→65:35)で精製し、以下の物性値を有する標題化合物(47mg)を得た。
TLC:Rf 0.50(ヘキサン:酢酸エチル=2:1)。
実施例116で製造した化合物(52mg)のTHF溶液(0.5mL)を-78℃に冷却し、n-ブチルリチウムヘキサン溶液(1.67M、0.7mL)を加え30分撹拌した。3-フェニルプロピオンアルデヒド(28mg)を加え、そのまま終夜撹拌し室温まで自然昇温させた。反応混合物をMTBEにて希釈し、飽和塩化アンモニウム水溶液を加え分液し、飽和食塩水で洗浄後、硫酸マグネシウムにて乾燥、ろ過、減圧濃縮した。残渣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→50:50)で精製し、以下の物性値を有する標題化合物(5mg)を得た。
TLC:Rf 0.68(ヘキサン:酢酸エチル=1:2)。
実施例117で製造した化合物を用いて、実施例16(1)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 (300 MHz, CDCl3):δ 0.83-1.37, 1.51-1.76, 1.88-2.09, 2.25-2.31, 2.37-2.46, 2.75-2.80, 2.86-2.94, 3.66, 3.90-4.06, 4.37, 7.17-7.31。
(4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-((3R)-3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸と4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-((3S)-3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸の混合物)
TLC:Rf 0.28(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.83-0.90, 0.98-1.28, 1.42-1.75, 1.90-2.06, 2.31-2.46, 2.75-2.80, 2.87-2.94, 3.89-4.08, 4.35-4.40, 7.16-7.31。
実施例14で製造した化合物(260mg)のメタノール溶液(2.5mL)に氷冷撹拌下、塩化セリウム・7水和物(220mg)、水素化ホウ素ナトリウム(22mg)を順次加え、20分撹拌した。水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→50:50)で精製し、以下の物性値を有する標題化合物(280 mg)を得た。
TLC:Rf 0.33(酢酸エチル:ヘキサン=1:2)。
実施例121(2):2-プロパニル 4-{(3S,5aR,6R,7R,8aS)-6-[(2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタノアート
実施例120で製造した化合物(280mg)のジクロロメタン溶液(2.5mL)に-78度撹拌下、ジエチルスルファートリフルオライド(98μL)を加えた。4時間かけてゆっくり0度まで昇温した。飽和重層水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=15:85→30:70)で精製し、位置異性体混合物(241mg)を得た。
TLC:Rf 0.50(酢酸エチル:ヘキサン=1:2)。
実施例121(1)の化合物
TLC:Rf 0.20(酢酸エチル:ヘキサン=1:2);
1H-NMR (300 MHz, CDCl3):δ 0.90-1.20, 1.22, 1.40-2.00, 2.23, 2.53, 2.92, 3.45, 3.60-4.20, 4.60, 4.99, 5.02-5.32, 5.60-5.90, 6.89, 6.94, 7.27。
実施例121(2)の化合物
TLC:Rf 0.22(酢酸エチル:ヘキサン=1:2);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.20, 1.22, 1.45-2.20, 2.32, 2.92, 3.92-4.10, 4.55-4.61, 4.75-5.15, 5.80-6.08, 6.89, 6.94, 7.27。
(4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.21(酢酸エチル:ヘキサン=3:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.28, 1.40-1.98, 2.16, 2.33, 2.46, 2.92, 3.75, 3.92-4.20, 5.12-5.35, 5.63-5.82, 6.90, 6.93, 7.28。
(4-{(3S,5aR,6R,7R,8aS)-6-[(1R,2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-6-[(1S,2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.21(酢酸エチル:ヘキサン=3:1);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.28, 1.45-2.20, 2.32, 2.92, 3.60-3.82, 3.92-4.20, 4.50-4.62, 4.75-5.15, 5.80-6.08, 6.89, 6.94, 7.27)。
実施例13で製造した化合物を用い、実施例100で製造した化合物の代わりに相当するスルホンを用いて、実施例101→実施例16(1)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。
TLC:Rf 0.44(ヘキサン:酢酸エチル=50:50);
1H-NMR (300 MHz, CDCl3):δ 0.95-1.16, 1.24, 1.40-1.80, 1.91, 2.06, 2.25, 2.44-2.56, 2.92, 3.69, 3.93-4.08, 5.01, 5.37, 5.60, 6.78, 6.89-6.94, 7.20。
TLC:Rf 0.40(ヘキサン:酢酸エチル=50:50);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.16, 1.24, 1.42-1.83, 1.90, 2.06, 2.25, 2.48, 2.57, 2.92, 3.69, 3.93-4.10, 5.01, 5.38, 5.61, 6.86-7.11。
TLC:Rf 0.42(ヘキサン:酢酸エチル=50:50);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.16, 1.24, 1.42-1.80, 1.90, 2.06, 2.25, 2.43-2.56, 2.92, 3.69, 3.93-4.08, 5.01, 5.37, 5.60, 6.58-6.69, 7.22。
TLC:Rf 0.44(ヘキサン:酢酸エチル=50:50);
1H-NMR (300 MHz, CDCl3):δ 0.93-1.16, 1.24, 1.38-1.82, 1.90, 2.06, 2.25, 2.43-2.60, 2.92, 3.69, 3.92-4.08, 5.01, 5.38, 5.60, 6.58, 6.69, 7.01。
実施例7で製造した化合物を用い、ヨウ化イソプロピルの代わりにヨウ化メチルを用い、実施例100で製造した化合物の代わりに相当するスルホンを用いて、実施例8→実施例9→実施例10→実施例11→実施例12→実施例13→実施例101→実施例16(1)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 0.24(ヘキサン:酢酸エチル=1:3);
1H-NMR(CDCl3):δ 0.91-1.19, 1.36-1.50, 1.52-1.91, 2.00-2.19, 2.25-2.33, 2.41-2.50, 2.62-2.94, 3.58-3.70, 3.89-4.04, 5.25-5.35, 5.44-5.59, 7.15-7.30。
実施例124(1)~(5)で製造した化合物を用いて、実施例17(1)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。
実施例125(1):4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-クロロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
TLC:Rf 0.49(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.21, 1.37-1.79, 1.90, 2.06, 2.33, 2.43-2.60, 2.92, 3.68, 3.93-4.08, 5.37, 5.60, 6.78, 6.88-6.94, 7.19。
TLC:Rf 0.51(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.23, 1.38-1.79, 1.90, 2.06, 2.33, 2.43-2.60, 2.92, 3.68, 3.93-4.09, 5.38, 5.60, 6.86-7.11。
TLC:Rf 0.49(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.24, 1.39-1.79, 1.90, 2.06, 2.34, 2.43-2.56, 2.92, 3.68, 3.93-4.08, 5.37, 5.60, 6.58-6.69, 7.22。
TLC:Rf 0.46(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.94-1.23, 1.38-1.79, 1.90, 2.06, 2.34, 2.43-2.60, 2.92, 3.69, 3.93-4.08, 5.38, 5.60, 6.58, 6.69, 7.01。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,4R)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,4S)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.36(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.92-1.20, 1.37-1.50, 1.54-1.90, 2.00-2.19, 2.24-2.35, 2.42-2.50, 2.62-2.95, 3.60-3.70, 3.90-4.05, 5.27-5.36, 5.45-5.58, 7.15-7.31。
実施例103で製造した化合物を用いて、実施例18(1)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 0.57(酢酸エチル:酢酸=100:1);
1H-NMR (300 MHz, CDCl3):δ 1.00-1.24, 1.30-1.93, 2.20, 2.34, 2.93, 3.74, 3.97, 4.04, 6.88-6.97, 7.25-7.31。
実施例70で製造した化合物を用いて、実施例13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 0.47(ヘキサン:酢酸エチル=2:1)。
実施例127で製造した化合物(0.85g)のTHF(10mL)溶液に、塩化クロム(1.7g)を加え0℃にて撹拌しながら、ヨードホルム(1.4g)のTHF(7mL)溶液を加え、そのまま4時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出、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。残渣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→75:25)で精製し、以下の物性値を有する標題化合物(600mg)を得た。
TLC:Rf 0.47(ヘキサン:酢酸エチル=3:1)。
実施例128で製造した化合物(9.0g)のTHF(30mL)溶液に、メタノール(70mL)及び炭酸カリウム(2.2g)を加え、室温下終夜撹拌した。反応混合物をセライト(商品名)ろ過し濃縮した。MTBEおよび水を加えて分液し、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。残渣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→45:55)で精製し、以下の物性値を有する標題化合物(5.0g)を得た。
TLC:Rf 0.53(ヘキサン:酢酸エチル=1:1)。
実施例129で製造した化合物(5.0g)のピリジン(25mL)溶液に、無水酢酸(2.3mL)を加え、反応混合物を室温下終夜撹拌した。水を加えて反応を停止し、反応混合物を氷冷した1N塩酸に注いだ。酢酸エチルで抽出し、有機層を1N塩酸、飽和重層水、水、飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、ろ過、減圧濃縮した。残渣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→70:30)で精製し、以下の物性値を有する標題化合物(5.2g)を得た。
TLC:Rf 0.53(ヘキサン:酢酸エチル=3:1)。
実施例130で製造した化合物(400mg)および6-メチルヘプト-5-エナール(220 mg)のジメチルスルホキシド(4mL)溶液に、塩化クロム(440mg)、塩化ニッケル(2.0mg)を加え室温にて3時間半撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出し有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、ろ過、減圧濃縮した。残渣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=97:3→55:45)で精製し、以下の物性値を有する標題化合物(380mg)を得た。
TLC:Rf 0.50(ヘキサン:酢酸エチル=1:1)。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
実施例131で製造した化合物(110mg)のメタノール溶液(3mL)に2N水酸化ナトリウム水溶液(1mL)を加え、反応混合物を室温で5時間撹拌した。水を加え、2N塩酸で中和した後、酢酸エチルで抽出し、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、ろ過、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(95mg)を得た。
TLC:Rf 0.36(ジクロロメタン:メタノール=9:1);
1H-NMR (300 MHz, CDCl3):δ 0.93-1.20, 1.31-1.80, 1.85-2.11, 2.29-2.34, 2.41-2.51, 2.87-2.95, 3.61-3.72, 3.90-4.10, 5.07-5.12, 5.35-5.62。
実施例130で製造した化合物を用いて、6-メチルヘプト-5-エナールの代わりに相当するアルデヒドを用いて、実施例131→実施例132(1)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。
実施例132(2):4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.59(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.46(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO-d6):δ 0.85, 0.88-1.09, 1.20-1.53, 1.57-1.66, 1.77-1.84, 2.15, 2.26, 2.84, 3.46, 3.82-3.88, 4.47, 4.54, 5.28-5.39。
(4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.46(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.40(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.85-1.10, 1.25-1.32, 1.35-1.52, 1.55-1.65, 1.75-1.85, 2.15, 2.26, 2.84, 3.47, 3.83-3.89, 4.11, 4.48-4.50, 4.58, 4.81, 5.39-5.51, 7.13-7.35。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.52(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.44(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.88-1.09, 1.24-1.52, 1.57-1.66, 1.77-1.83, 1.98-2.02, 2.15, 2.26, 2.84, 3.46, 3.83-3.89, 4.51, 4.56, 4.92-5.01, 5.30-5.39, 5.78。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.56(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.49(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.89-1.09, 1.25-1.53, 1.58-1.66, 1.77-1.85, 2.15, 2.19, 2.27, 2.50-2.60, 2.84, 3.47, 3.84-3.91, 4.57, 4.67, 5.34-5.42, 5.88-5.91。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.48(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.38(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.89-1.09, 1.23-1.54, 1.56-1.66, 1.76-1.85, 1.96-2.04, 2.15, 2.26, 2.84, 3.46, 3.83-3.89, 4.55, 5.28-5.41。
(4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.48(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.38(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.89-1.09, 1.20-1.72, 1.77-1.84, 2.15, 2.26, 2.84, 3.46, 3.81-3.88, 4.47, 4.54, 5.29-5.40。
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,4R)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R,4S)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,4R)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、および4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S,4S)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.54(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.41(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.78-0.81, 0.89-1.09, 1.25-1.53, 1.56, 1.57-1.62, 1.64, 1.77-2.00, 2.15, 2.26, 2.84, 3.46, 3.71-3.79, 3.83-3.89, 4.42-4.53, 5.07, 5.32-5.36。
(4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
低極性体
TLC:Rf 0.48(酢酸エチル:酢酸=100:1)。
高極性体
TLC:Rf 0.39(酢酸エチル:酢酸=100:1)。
1H-NMR (500 MHz, DMSO- d6):δ 0.89-1.08, 1.26-1.53, 1.59-1.70, 1.75-1.83, 1.92, 2.15, 2.27, 2.85, 3.52, 3.85-3.90, 4.65, 5.17, 5.62-5.74, 6.67, 7.20, 7.25, 7.52, 7.59
(4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.65(ジクロロメタン:メタノール=4:1);
1H-NMR (300 MHz, CDCl3):δ 0.88-2.02, 2.23-2.27, 2.37-2.46, 2.57-2.62, 2.93-3.01, 3.58-3.67, 3.98-4.02, 5.41-5.58, 6.55-6.66, 7.01-7.07。
実施例70で製造した化合物(2.9g)のジクロロメタン溶液(30mL)に室温撹拌下、3,4-ジヒドロ-2H-ピラン(803μL)、パラトルエンスルホン酸ピリジニウム(150mg)を加え、室温で5時間撹拌した。飽和重層水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95→25:75)で精製し、以下の物性値を有する標題化合物(3.84g)を得た。
TLC:Rf 0.44(酢酸エチル:ヘキサン=1:4)。
実施例133で製造した化合物(3.84g)のイソプロパノール溶液(30mL)にリチウムイソプロポキシド(2.0Mテトラヒドロフラン溶液、5.9mL)を加え45度で1.5時間撹拌した。氷冷し、1N塩酸(12mL)と水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=35:65→70:30)で精製し、以下の物性値を有する標題化合物(2.23g)を得た。
TLC:Rf 0.34(酢酸エチル:ヘキサン=1:2)。
実施例134で製造した化合物(2.23g)のジクロロメタン溶液(18mL)に氷冷撹拌下、ジメチルスルホキシド(9mL)、ジイソプロピルエチルアミン(5.8mL)を加え、三酸化硫黄・ピリジン錯体(2.67g)を少しずつ加えた。0度で1時間撹拌した。水を加え、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=15:85→35:65)で精製し、以下の物性値を有する標題化合物(2.21g)を得た。
TLC:Rf 0.71(酢酸エチル:ヘキサン=1:1)。
実施例135で製造した化合物(1.3g)のジクロロエタン溶液(8mL)にモルホリルスルファートリフルオリド(1.2mL)を加え45度で50時間撹拌した。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、無水硫酸マグネシウムで乾燥し、濃縮した。残渣のメタノール溶液(6mL)にパラトルエンスルホン酸ピリジニウム(30mg)を加え、室温で8時間撹拌した。飽和重層水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→45:55)で精製し、以下の物性値を有する標題化合物(329mg)を得た。
TLC:Rf 0.30(酢酸エチル:ヘキサン=1:2)。
実施例136で製造した化合物(245mg)のジクロロメタン溶液(3.5mL)に氷冷撹拌下、デスマーチンペリオジナン(372mg)を加え1時間撹拌した。飽和チオ硫酸ナトリウム水溶液と飽和重層水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣のテトラヒドロフラン溶液(7mL)溶液に氷冷撹拌下、無水塩化クロム(720mg)、ヨードホルム(577mg)を順次加え、室温で1.5時間撹拌した。水を加え、酢酸エチルにて抽出した。有機層を水で2回、飽和食塩水で1回順次洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95)で精製し、以下の物性値を有する標題化合物(206mg)を得た。
TLC:Rf 0.50(酢酸エチル:ヘキサン=1:4)。
実施例137で製造した化合物を用いて、6-メチルヘプト-5-エナールの代わりに相当するアルデヒドを用いて、実施例131と同様の目的の操作に付すことにより、以下に示す実施例化合物を得た。
実施例138(1):2-プロパニル 4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタノアート
TLC:Rf 0.28(酢酸エチル:ヘキサン=1:4);
1H-NMR (300 MHz, CDCl3):δ 0.80-0.96, 0.98-2.22, 2.23, 2.42-2.70, 2.93, 4.00-4.18, 4.99, 5.52, 5.64。
TLC:Rf 0.28(酢酸エチル:ヘキサン=1:4);
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.22, 1.40-2.20, 2.24, 2.45-2.80, 2.94, 4.02-4.20, 4.99, 5.42-5.62, 5.67, 7.15-7.32。
実施例138(1)または実施例138(2)で製造した化合物を用いて、実施例17(1)と同様の目的の操作に付すことにより、以下に示す実施例化合物を得た。
実施例139(1):4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
(4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3R)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3S)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
TLC:Rf 0.27(酢酸エチル:ヘキサン=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.80-0.96, 0.98-2.22, 2.33, 2.42-2.70, 2.95, 4.02-4.18, 5.53, 5.64。
(4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3R)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸と4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E,3S)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸の混合物)
1H-NMR (300 MHz, CDCl3):δ 0.98-1.20, 1.41, 1.55-2.24, 2.33, 2.44-2.80, 2.94, 4.02-4.18, 5.53, 5.67, 7.18-7.32。
実施例127で製造した化合物を用い、ジメチル-(3-フェノキシ-2-オキソプロピル)-ホスホナートの代わりに相当するホスホン酸塩を用い、実施例14→実施例30→実施例129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。
TLC:Rf 0.39(ヘキサン:酢酸エチル=1:1);
1H-NMR (300 MHz, CDCl3):δ 0.93-1.20, 1.40-1.92, 2.10-2.30, 2.41-2.50, 2.76-2.81, 2.87-2.95, 3.66, 3.70-3.79, 3.92-4.05, 5.60-5.72, 5.85-5.93, 7.16-7.22, 7.25-7.31。
TLC:Rf 0.44 (ヘキサン:酢酸エチル=1:1);
1H-NMR(CDCl3):δ0.94-1.18, 1.41-1.98, 2.11-2.31, 2.42-2.51, 2.88-2.95, 3.66, 3.72-3.81, 3.94-4.06, 5.57-5.69, 5.81-5.89。
TLC:Rf 0.45 (ヘキサン:酢酸エチル=1:1);
1H-NMR(CDCl3):δ0.82-1.36, 1.41-1.97, 2.11-2.20, 2.26-2.31, 2.42-2.51, 2.88-2.95, 3.66, 3.71-3.81, 3.94-4.06, 5.56-5.69, 5.81-5.89。
TLC:Rf 0.46 (ヘキサン:酢酸エチル=1:1);
1H-NMR(CDCl3):0.87-0.92, 0.94-1.16, 1.25-1.96, 2.11-2.20, 2.26-2.31, 2.42-2.51, 2.88-2.95, 3.66, 3.72-3.81, 3.94-4.07, 5.57-5.69, 5.81-5.89。
実施例140(1)~実施例140(4)で製造した化合物を、実施例17(1)と同様の目的の操作に付すことにより、下記に示す実施例化合物を得た。
1H-NMR (300 MHz, CDCl3):δ 0.94-1.28, 1.40-1.93, 2.11-2.35, 2.42-2.51, 2.76-2.82, 2.88-2.96, 3.72-3.80, 3.93-4.08, 5.60-5.73, 5.86-5.94, 7.17-7.23, 7.26-7.32。
TLC:Rf 0.50 (ジクロロメタン:メタノール=9:1);
1H-NMR(CDCl3):0.95-1.20, 1.40-1.97, 2.11-2.20, 2.30-2.35, 2.42-2.51, 2.88-2.96, 3.72-3.80, 3.94-4.07, 5.56-5.68, 5.80-5.88。
TLC:Rf 0.45 (ジクロロメタン:メタノール=9:1);
1H-NMR(CDCl3):0.82-1.36, 1.40-1.96, 2.11-2.20, 2.30-2.35, 2.42-2.51, 2.88-2.96, 3.72-3.80, 3.93-4.07, 5.56-5.68, 5.80-5.88。
TLC:Rf 0.45 (ジクロロメタン:メタノール=9:1);
1H-NMR(CDCl3):0.87-0.92, 0.95-1.19, 1.25-1.95, 2.11-2.20, 2.30-2.35, 2.42-2.51, 2.88-2.96, 3.72-3.80, 3.94-4.07, 5.56-5.69, 5.80-5.88。
実施例141(5):4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-8-メチル-1,7-ノナジエン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸
TLC:Rf 0.34 (ジクロロメタン:メタノール=9:1);
1H-NMR(CDCl3):0.95-1.38, 1.40-2.04, 2.11-2.20, 2.30-2.35, 2.42-2.51, 2.88-2.96, 3.72-3.80, 3.93-4.07, 5.05-5.09, 5.56-5.68, 5.80-5.88。
実施例141(1)で製造した化合物を用いて、実施例18(1)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 0.25(酢酸エチル);
1H-NMR (300 MHz, CDCl3):δ 0.91-0.96, 0.98-1.28, 1.49-2.25, 2.30-2.35, 2.77-2.83, 2.87-2.95, 3.66-3.71, 3.91-4.05, 7.17-7.31。
(1)インビトロ(in vitro)試験
(1-1)各種マウスプロスタノイド受容体に対するアゴニスト活性の測定
各種マウスプロスタノイド受容体をそれぞれ強制発現させたCHO細胞(それぞれFP-CHO、EP1-CHOおよびIP-CHO)を用いて、FPおよびEP1については細胞内カルシウム濃度、IPについては細胞内サイクリックAMP(以下、cAMPと略記する。)産生量を指標に、各種プロスタノイド受容体に対する被験化合物のアゴニスト活性を検討した。
被験化合物は、ジメチルスルホキシド(DMSO)にて溶解し、10mmol/L溶液を調製した。調製した10mmol/L溶液は、使用時に10mmol/L溶液を解凍し、DMSOを用いて段階希釈を行い、測定用緩衝溶液もしくは測定用緩衝溶液2にて希釈して実験に供した。
各種マウスプロスタノイド受容体強制発現細胞は、非働化(56℃、30分)した9.8vol% 透析FBS(dialysed-FBS)(Invitrogen社)およびペニシリン-ストレプトマイシン-グルタミン(penicillin-streptomycin-glutamine)(GIBCO-BRL社)を含むα-MEM培地(Sigma社)(FP-CHOおよびEP1-CHO培養用)、もしくは非働化(56℃、30分)した9.8vol% dialysed-FBS(Invitrogen社)およびペニシリン-ストレプトマイシン-グルタミン(penicillin-streptomycin-glutamine)(Invitrogen社)を含む核酸含有α-MEM(Sigma社)(IP-CHO培養用)を用いて、5%CO2存在下、37℃で静置培養した。継代培養は以下の方法で行なった。
FP-CHOおよびEP1-CHOは、継代培養と同様の方法にて細胞を剥離および懸濁し、測定の2日前に、96穴UVプレートに、1ウェルあたり1.0×104個の細胞数となるよう播種し、5%CO2存在下、37℃で静置培養した。測定日に、96穴UVプレートの各ウェルから培地を除去した後、各ウェルをCa2+およびMg2+を含まないリン酸緩衝生理食塩水で1回洗浄した。各ウェルに5μmol/L fura 2-AM(DOJINDO社)、2.5mmol/L プロベネシド(Sigma社)、20μmol/L インドメタシン(Sigma社)および10mmol/L HEPES(Invitrogen社)を含む培地を100μL加え、CO2インキュベーター内で約60分間インキュベーションした。インキュベーション終了後、培地を除去し、測定用緩衝溶液(0.1もしくは1w/v% ウシ血清アルブミン、2μmol/L インドメタシン、2.5mmol/L プロベネシドおよび10mmol/L HEPES-NaOH(pH7.4)を含有したハンクス液(Hank’s balanced salt solution)(日水製薬社、本品9.8gを蒸留水1Lで溶解))にて2回洗浄した。各ウェルに測定用緩衝溶液を120μL添加し、CO2インキュベーター内で30分静置し安定化させ、実験に供した。
IP-CHOは、測定日に、培地を除去し、2mmol/L EDTAを含有するCa2+およびMg2+を含まないリン酸緩衝生理食塩水で1回洗浄した。適量の2mmol/L EDTAを含有するCa2+およびMg2+を含まないリン酸緩衝生理食塩水を加え、37℃で約10分間インキュベーションし、細胞を剥離後、遠心管に細胞を回収し500g、3分間室温で遠心分離した後、上清を除去した。適量の測定用緩衝溶液1(0.1w/v% ウシ血清アルブミン(Sigma社)および2μmol/L ジクロフェナク(Sigma社)を含有したMEM培地(Invitrogen社))にて懸濁し、500g、3分間室温で遠心分離した後、上清を除去した。測定用緩衝溶液2(0.1w/v% ウシ血清アルブミン(Sigma社)、2μmol/L ジクロフェナク(Sigma社)および1mmol/L 3-イソブチル-1-メチルキサンチンを含有したMEM培地(Invitrogen社))にて懸濁し、96穴1/2エリアプレートに1ウェル当たり5.0×104個の細胞数となるように25μLずつ分注した。種々の濃度のアゴニストを含む測定用緩衝溶液2を25μL添加し、室温で30分間反応させた。cAMP濃度の測定は、cAMP HTRF HiRangeキット(CIS bio International社)を用いて行った。キット説明書のTwo step protocolに従い、ライシス緩衝液(Lysis Buffer)にて希釈したcAMP-D2およびクリプターゼ(Cryptase)を25μLずつ添加し、1時間室温にてインキュベーションした。1時間のインキュベーション後に、Analyst GT(Molecular Device社)を用いて340nmにて励起した時の620nmおよび660nmにおける時間分解蛍光を測定し、その比(TRF ratio)を求めることで、検量線よりcAMP濃度を算出した。
以上の方法から得られた測定値を用いて、本発明化合物のマウスFP、マウスEP1およびマウスIP受容体に対するアゴニスト活性の指標としてEC50値を算出した。
例えば、実施例108(13)記載の化合物、実施例110記載の化合物、実施例115記載の化合物、実施例119記載の化合物、実施例122記載の化合物、実施例123記載の化合物、実施例132(3)記載の化合物、実施例132(7)記載の化合物、実施例139(2)、実施例141(1)記載の化合物、実施例141(5)記載の化合物および比較化合物として下記の構造式で示される特許文献2記載の実施例12の化合物(以下、比較化合物Aと略記することがある。)の結果を表1に示す。
インビボ(in vivo)試験においては、当業者には容易に理解できることではあるが、いずれの被験化合物についても、活性本体であるカルボン酸は角膜透過性が悪いことから、メチルエステル体、エチルエステル体、イソプロピルエステル体等のエステル体に変換した化合物を点眼投与することによって、活性本体の薬理作用を評価した。なお、本願化合物群において、エステル体は、下記で薬理作用を確認する実験動物(ウサギ、イヌ等)において、点眼投与した後、房水中におけるカルボン酸の薬物濃度を測定することによって、当該エステル体が速やかに相当するカルボン酸に変換されることを確認した。
予め十分に馴化を行った雄性イヌ(TOYO Beagle)に、基剤(クエン酸緩衝液pH6.5、0.5%ポリソルベート80、1%プロピレングリコール、0.01%塩化ベンザルコニウム含)で0.01%(w/v)または0.001%(w/v)に調製した各被験化合物(実施例16(35)、実施例16(3)および実施例16(25)の化合物)を、それぞれ片眼に30μL点眼した。対眼は無処置とした。陽性対照化合物として、公知化合物であるラタノプロストを用いた。
雄性ウサギ(NewZealandWhite、2.0~3.0kg)に、基剤(クエン酸緩衝液pH6.5、0.5%ポリソルベート80、1%プロピレングリコール、0.01%塩化ベンザルコニウム含)で0.1%(w/v)に調製した実施例16(35)、実施例16(3)および実施例16(25)の化合物を、それぞれ片眼に30μL点眼した。その後、点眼0、1、2、4、6および8時間後の前房中の眼房水を採取し、房水中のタンパク質濃度を測定した。比較化合物として、上記した特許文献2記載の実施例12の化合物のメチルエステル体(すなわち、特許文献2記載の実施例10の化合物)(以下、比較化合物Bと略記することがある。)を用いた。
覚醒下の雄性サル(カニクイザル)の左眼に、被験物質を上記と同様の基剤を用いて調製した溶液と、右眼には対照として基剤のみの溶液をそれぞれ30μL点眼投与した。投与後の眼圧を経時的に投与開始から24時間後まで測定した。眼圧測定の際には、カニクイザルをモンキーチェアーに保定後、眼科用表面麻酔剤(ベノキシール点眼液0.4%、参天製薬株式会社)を点眼投与して麻酔した。開瞼器(株式会社はんだや)を装着後、空圧圧平式眼圧計(モデル30クラシック、ライカート社)を用いて、両眼の眼圧を測定した(各群5~8例)。対照眼と被験物質を投与した眼との眼圧値の差を、以下の式を用いて眼圧下降率として算出し、測定中の最大眼圧下降率と24時間後の眼圧下降率を用いて、眼圧下降作用の持続性を評価した。被験物質としては、比較化合物B、実施例16(3)、実施例16(25)および実施例16(35)の化合物を用い、投与用量はいずれも10μg/mLとした。
本発明に用いられる代表的な製剤例を以下に示す。
製剤例1:点眼剤
以下の処方の点眼剤を汎用される方法を用いて調製した。
滅菌精製水にグリセリン(2.5g)およびポリソルベート80(500mg)を加えた後、実施例16(35)の化合物(1mg)を加え溶解し、滅菌精製水で全量100mLとし、メンブランフィルターで滅菌濾過した後、所定の容器に充填し、点眼液を得た。
上記と同様にして、実施例140(1)の化合物を100mL中に0.1mgおよび0.5mg含有する点眼剤等を調製することができる。また、実施例140(1)の化合物に代えて、他の本発明化合物を用いることができる。
以下の処方の眼軟膏を汎用される方法を用いて調製した。
流動パラフィンと白色ワセリンをあらかじめ加熱滅菌した。実施例140(1)の化合物(1mg)を流動パラフィン(10g)と十分研和後、白色ワセリンを加えて全量100gとし、十分練り合わせ、眼軟膏を得た。
Claims (12)
- 一般式(I)
- (1)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3S)-3-ヒドロキシ-4-フェノキシ-1-ブテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,3R)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(4-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(2-フルオロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-(3-クロロフェニル)-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(12)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]-1-ペンテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(13)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(1E,3S)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]-1-ブテン-1-イル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(14)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(2-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(15)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(3-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(16)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-4-(4-フルオロフェノキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(17)4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3S)-5-シクロヘキシル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(18)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-4-フェノキシブチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(19)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(3S)-3-ヒドロキシ-5-フェニルペンチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(20)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(21)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(22)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(23)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(4-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(24)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(25)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(2-フルオロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(26)4-{(3S,5aR,6R,7R,8aS)-6-[(3S)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(27)4-{(3S,5aR,6R,7R,8aS)-6-[(3R)-5-(3-クロロフェニル)-3-ヒドロキシペンチル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(28)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3S)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(29)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-5-[3-(トリフルオロメチル)フェニル]ペンチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(30)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-{(3R)-3-ヒドロキシ-4-[3-(トリフルオロメチル)フェノキシ]ブチル}オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(31)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-フルオロ-4-フェノキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(32)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-クロロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(33)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(34)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(3-フルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(35)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-ジフルオロフェノキシ)-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(36)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-4-ヒドロキシ-6-フェニル-1-ヘキセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(37)4-[(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-(4-フェノキシブチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(38)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1-デセン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(39)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(5-メチル-2-フリル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(40)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3-ヒドロキシ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(41)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3-(1-ベンゾフラン-2-イル)-3-ヒドロキシ-1-プロペン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(42)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-5-(3-ヒドロキシフェニル)-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(43)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-5-フェニル-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(44)4-[(3S,5aR,6R,7R,8aS)-6-(3,3-ジフルオロ-5-フェニルペンチル)-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(45)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロペンチル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(46)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-5-シクロヘキシル-3,3-ジフルオロ-1-ペンテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(47)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-1-オクテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、およびその異性体からなる群から選択される化合物である請求項1記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ。 - (1)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-({[(2E)-3-フェニル-2-プロペン-1-イル]オキシ}メチル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(2)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[2-(2-フェニルエトキシ)エチル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(3)4-[(3S,5aR,6S,7R,8aS)-7-ヒドロキシ-6-(3-ヒドロキシ-5-フェニル-1-ペンチン-1-イル)オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル]ブタン酸、
(4)4-{(3S,5aR,6R,7R,8aS)-6-[(2E)-1-フルオロ-4-フェノキシ-2-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(5)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-8-メチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(6)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(ベンジルオキシ)-3-ヒドロキシ-1-ブテン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(7)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-1,7-オクタジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(8)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E,6Z)-3-ヒドロキシ-1,6-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(9)4-{(3S,5aR,6R,7R,8aS)-7-ヒドロキシ-6-[(1E)-3-ヒドロキシ-4,8-ジメチル-1,7-ノナジエン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(10)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-1-オクテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(11)4-{(3S,5aR,6R,8aS)-7,7-ジフルオロ-6-[(1E)-3-ヒドロキシ-5-フェニル-1-ペンテン-1-イル]オクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、
(12)4-{(3S,5aR,6R,7R,8aS)-6-[(1E)-3,3-ジフルオロ-8-メチル-1,7-ノナジエン-1-イル]-7-ヒドロキシオクタヒドロ-2H-シクロペンタ[b]オキセピン-3-イル}ブタン酸、およびその異性体からなる群から選択される化合物である請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ。 - 請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグを含有してなる医薬組成物。
- 請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグが、FPアゴニストである請求項6記載の医薬組成物。
- 眼疾患の予防および/または治療剤である請求項6記載の医薬組成物。
- 眼疾患が、緑内障、高眼圧症、黄斑浮腫、黄斑変性、網膜および視神経張力上昇、近視、遠視、乱視、ドライアイ、網膜剥離、白内障、外傷または炎症による眼圧上昇、薬剤による眼圧上昇、または術後の眼圧上昇である請求項8記載の医薬組成物。
- 請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグの有効量を哺乳動物に投与することを特徴とする、眼疾患の予防および/または治療方法。
- 眼疾患の予防および/または治療のための請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグ。
- 眼疾患の予防および/または治療剤を製造するための請求項2記載の化合物、その塩、その溶媒和物、またはそれらのプロドラッグの使用。
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8614340B2 (en) | 2009-07-28 | 2013-12-24 | Ono Pharmaceuticals Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
WO2018003945A1 (ja) * | 2016-06-30 | 2018-01-04 | 小野薬品工業株式会社 | 二環式化合物の製造方法 |
WO2019124488A1 (ja) * | 2017-12-21 | 2019-06-27 | 参天製薬株式会社 | セペタプロストとRhoキナーゼ阻害剤との組み合わせ医薬 |
WO2019124489A1 (ja) * | 2017-12-21 | 2019-06-27 | 参天製薬株式会社 | セペタプロストとep2アゴニストとの組み合わせ医薬 |
CN112745316A (zh) * | 2016-04-01 | 2021-05-04 | 里科瑞尔姆Ip控股有限责任公司 | 雌激素受体调节剂 |
WO2021145356A1 (ja) * | 2020-01-15 | 2021-07-22 | 参天製薬株式会社 | 近視の治療、近視の予防および/または近視の進行抑制のための医薬組成物 |
WO2023204297A1 (ja) * | 2022-04-22 | 2023-10-26 | 参天製薬株式会社 | セペタプロストを含有する眼科用組成物 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021051149A1 (en) * | 2019-09-19 | 2021-03-25 | Polyactiva Pty Ltd | Biodegradable drug-polymer conjugate |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5037780A (ja) | 1973-08-11 | 1975-04-08 | ||
JPS5295644A (en) | 1976-02-04 | 1977-08-11 | Upjohn Co | Composition and method |
JPS53132573A (en) * | 1977-04-19 | 1978-11-18 | Upjohn Co | Product and method |
US4490548A (en) | 1977-04-19 | 1984-12-25 | The Upjohn Company | Enlarged-hetero-ring prostacyclin analogs |
JPS6468367A (en) * | 1987-09-08 | 1989-03-14 | Ono Pharmaceutical Co | Novel bicyclic ethers or lactones |
WO2011013651A1 (ja) * | 2009-07-28 | 2011-02-03 | 小野薬品工業株式会社 | 二環式化合物およびその医薬用途 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI71138C (fi) | 1976-12-31 | 1986-11-24 | Erba Farmitalia | Foerfarande foer framstaellning av terapeutiskt aktiva bisykliska prostaglandiner |
US4490537A (en) | 1977-04-19 | 1984-12-25 | The Upjohn Company | Enlarged-hetero-ring prostacyclin analogs |
JPS5573678A (en) | 1978-11-29 | 1980-06-03 | Ono Pharmaceut Co Ltd | Simultated compound of thio-prostaglandin i1, its preparation and drug composition containing it as active ingredient |
DE2947526A1 (de) | 1978-11-29 | 1980-06-12 | Ono Pharmaceutical Co | Prostacyclin-analoge |
DE60010913T2 (de) | 1999-10-15 | 2005-06-09 | Sucampo Ag | Bizyklische Verbindungen, Zusammenstellung und Verfahren zu ihrer Stabilisierung |
US7906552B2 (en) | 2004-08-10 | 2011-03-15 | Allergan, Inc. | Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
JP2009541340A (ja) | 2006-06-20 | 2009-11-26 | アラーガン インコーポレイテッド | 治療用化合物 |
ES2581852T3 (es) | 2011-01-27 | 2016-09-07 | Ono Pharmaceutical Co., Ltd. | Compuesto bicíclico y uso del mismo para fines médicos |
-
2012
- 2012-01-26 JP JP2012554851A patent/JP5835236B2/ja active Active
- 2012-01-26 EP EP12738803.1A patent/EP2669279B1/en active Active
- 2012-01-26 WO PCT/JP2012/051721 patent/WO2012102357A1/ja active Application Filing
- 2012-01-26 US US13/982,001 patent/US9029574B2/en active Active
- 2012-01-30 TW TW101102847A patent/TW201309664A/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5037780A (ja) | 1973-08-11 | 1975-04-08 | ||
JPS5295644A (en) | 1976-02-04 | 1977-08-11 | Upjohn Co | Composition and method |
JPS53132573A (en) * | 1977-04-19 | 1978-11-18 | Upjohn Co | Product and method |
US4490548A (en) | 1977-04-19 | 1984-12-25 | The Upjohn Company | Enlarged-hetero-ring prostacyclin analogs |
JPS6468367A (en) * | 1987-09-08 | 1989-03-14 | Ono Pharmaceutical Co | Novel bicyclic ethers or lactones |
WO2011013651A1 (ja) * | 2009-07-28 | 2011-02-03 | 小野薬品工業株式会社 | 二環式化合物およびその医薬用途 |
Non-Patent Citations (8)
Title |
---|
"Administrative Notice Medical Device Examination", 19 March 2003, PHARMACEUTICAL AND MEDICAL DEVICES AGENCY, article "Regarding Reference Material concerning Basic Idea of Biological Safety Test" |
"Molecular Design", vol. 7, 1990, HIROKAWA-SHOTEN LTD., article "Development of Medicaments", pages: 163 - 198 |
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 23, 1982, pages 383 - 392 |
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 28, 1987, pages 470 - 476 |
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS INC |
See also references of EP2669279A4 * |
T. W. GREENE: "Protective Groups in Organic Synthesis", 1999, WILEY |
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 279, no. 1, 1996, pages 137 - 142 |
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US8962868B2 (en) | 2009-07-28 | 2015-02-24 | Ono Pharmaceutical Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
US9388157B2 (en) | 2009-07-28 | 2016-07-12 | Ono Pharmaceuticals Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
US11617733B2 (en) | 2009-07-28 | 2023-04-04 | Ono Pharmaceutical Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
US9889114B2 (en) | 2009-07-28 | 2018-02-13 | Ono Pharmaceutical Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
US10201520B2 (en) | 2009-07-28 | 2019-02-12 | Ono Pharmaceutical Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
US8614340B2 (en) | 2009-07-28 | 2013-12-24 | Ono Pharmaceuticals Co., Ltd. | Bicyclic compound and use thereof for medical purposes |
CN112745316A (zh) * | 2016-04-01 | 2021-05-04 | 里科瑞尔姆Ip控股有限责任公司 | 雌激素受体调节剂 |
US10899729B2 (en) | 2016-06-30 | 2021-01-26 | Ono Pharmaceutical Co.. Ltd. | Method for producing bicyclic compound |
JPWO2018003945A1 (ja) * | 2016-06-30 | 2019-04-18 | 小野薬品工業株式会社 | 二環式化合物の製造方法 |
WO2018003945A1 (ja) * | 2016-06-30 | 2018-01-04 | 小野薬品工業株式会社 | 二環式化合物の製造方法 |
WO2019124489A1 (ja) * | 2017-12-21 | 2019-06-27 | 参天製薬株式会社 | セペタプロストとep2アゴニストとの組み合わせ医薬 |
JPWO2019124488A1 (ja) * | 2017-12-21 | 2020-12-17 | 参天製薬株式会社 | セペタプロストとRhoキナーゼ阻害剤との組み合わせ医薬 |
WO2019124488A1 (ja) * | 2017-12-21 | 2019-06-27 | 参天製薬株式会社 | セペタプロストとRhoキナーゼ阻害剤との組み合わせ医薬 |
US11446273B2 (en) | 2017-12-21 | 2022-09-20 | Santen Pharmaceutical Co., Ltd. | Medicament comprising combination of sepetaprost and Rho-associated coiled-coil containing protein kinase inhibitor |
WO2021145356A1 (ja) * | 2020-01-15 | 2021-07-22 | 参天製薬株式会社 | 近視の治療、近視の予防および/または近視の進行抑制のための医薬組成物 |
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